Clinical trial NCT04493684
Conditions: HIV Infections
Keywords: Acquired Immunodeficiency Syndrome First-time-in-human Pharmacokinetics Safety Tolerability
Sponsor: ViiV Healthcare
Start date: 2020-07-31; Completion date: 2021-08-30
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-controlled, single- and repeat-dose escalation study including a weekly oral dose (MAD) cohort and a relative bioavailability (RBA) and food effect (FE) cohort to investigate the safety, tolerability and PK of VH3739937 in healthy participants. This is a three part study. Part 1 and Part 2 is designed to gain information on the safety, tolerability, and pharmacokinetic (PK) properties of GSK3739937 when administered as powder-in-a-bottle (PiB). Part 3 will evaluate the RBA of the GSK3739937 PiB and GSK3739937 Tablet and the safety, tolerability and PK parameters of the tablet formulation when administered under fasting and fed conditions.

Detailed description:

Arms: arm 1: Part 1 cohort 1 may contain up to 4 escalating doses (Period 1- 10 milligram \[mg\], Period 2- 80 mg, and Period 3- 320 mg, Period 4- 800 mg) of GSK3739937. arm 2: In this cohort, participants will be randomized to receive placebo. arm 3: Part 1 cohort 2 may contain up to 3 escalating doses ( Period 1- 30 mg, Period 2- 160 mg, and Period 3- 640 mg) of GSK3739937. arm 4: In this cohort, participants will be randomized to receive placebo. arm 5: Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 25 mg GSK3739937 for 14 days. arm 6: Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days. arm 7: Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 50 mg GSK3739937 for 14 days. arm 8: Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days. arm 9: Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 100 mg GSK3739937 for 18 days. arm 10: Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 18 days. arm 11: Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 7 participants will be randomized to receive three 500 mg doses of GSK3739937 administered at once weekly intervals over two weeks. arm 12: Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 3 participants will be randomized to receive three doses of placebo administered at once weekly intervals over two weeks. arm 13: Participants will receive Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 1; Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 2; and Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 3. arm 14: Participants will receive Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 1; Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 2; and Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 3. arm 15: Participants will receive Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 1; Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 2; and Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 3.
Interventions: intervention 1: GSK3739937 (PIB) intervention 2: Placebo intervention 3: GSK3739937 (Tablet)
Intervention descriptions: intervention 1: GSK3739937 will be administered as oral suspension. intervention 2: Placebo will be given orally during each dosing day. intervention 3: GSK3739937 Tablet will be administered via oral route.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 2 
 
 
Study ID: 212548 
Official Title of Study: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-
Controlled, Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability 
and Pharmacokinetics of GSK3739937 in Healthy Participants 
IND Number: 147773 
EudraCT Number: 2020-002834-34 
Date of document: 16-March-2021 
 


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TITLE PAGE 
Protocol Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3739937 in Healthy Participants 
Protocol Number: 212548/ Amendment 02 
Compound 
Number: 
GSK3739937/VH3739937 
Study Phase: Phase 1  
Short Title: GSK3739937 First-Time-In-Human Study 
US IND Sponsor Name and Legal Registered Address:  
ViiV Healthcare Company 
Five Moore Drive 
P.O. 13398 
Research Triangle Park, NC 27709-3398, USA  
Telephone: + 1 919 438 2100 
 
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as Sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the Vice President, Global Research and Medical Strategy 
This study is sponsored by ViiV Healthcare. Parexel with GlaxoSmithKline is supporting 
ViiV Healthcare in the conduct of this study. 
Medical Monitor Name and Contact Information: Refer to the Study Reference 
Manual 
Regulatory Agency Identifying Number(s):  
IND Number: 147773 
EudraCT Number: 2020-002834-34 
 
Approval Date: 16-MAR-2021 
 
Copyright 2021 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY 
Protocol Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3739937 in Healthy Participants 
Protocol Number: 212548/ Amendment 02 
Compound Number  GSK3739937/VH3739937  
 
 
 
 
Max Lataillade, DO, MPH  
Vice President, Head of Global Research Strategy 
ViiV Healthcare 
 
 
Date 
The signed page is a separate document. 
 
 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment [02] 
16-MAR-2021 
TMF-11892450 
Amendment [01] 
11-JUN-2020 
2019N400726_01 
Original Protocol  
20-APR-2020  
2019N400726_00  
 
Amendment [02]; 16-MAR-2021 
Overall Rationale for the Amendment:  
Updates made following acquisition of clinical pharmacology data in Part 1, the Single 
Ascending Dose (SAD) 10 mg, 30 mg, 80 mg, 160 mg, 320 mg and 640mg treatment 
periods and Multiple Ascending Dose (MAD) Cohort 3; 25 mg to: 
• extend the period of post dosing assessment to include outpatient visits in the 
study;  
• include a higher dose SAD treatment period (800 mg); 
• revise the duration of dosing in MAD Cohort 5 (100 mg); and  
• inclusion of an additional MAD Cohort 6 (500 mg) to evaluate weekly oral 
dosing. 
Part 3 of the study was included to evaluate the relative bioavailability (RBA) of 
VH3739937 when administered as GSK3739937 powder-in-a-bottle (PiB) or as 
GSK3739937 100 mg Tablet under fasted and fed (moderate fat) conditions.   
 
 
 
 
 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Updates supporting conduct 
of additional 800 mg SAD 
treatment period, reduced 
dosing duration of MAD 
Cohort 5, weekly MAD 
Cohort 6 and Relative 
Bioavailability (RBA) and 
Food Effect (FE) cohort. 
Updated text regarding use 
of GSK3739937 (also 
known as VH3739937). 
Revisions and updates based on 
observed longer PK half-life and 
observed safety data through to 
640 mg SAD dose period and 
MAD Cohort 3. Sponsor decision 
to use GSK3739937 (also known 
as VH3739937) where indicated 
to further clarify Sponsor asset. 
1.2 Schedule of Activities 
(SOA) 
All SOA updated to include 
additional outpatient visits 
and assessments. SAD 
SOA revised to include 
additional treatment period. 
Update to support MAD 
Cohort 5 SOA reduced 
dosing duration. Addition of 
SOA for weekly MAD cohort 
and RBA and FE cohort 
Revisions and updates to SOA 
were based on emerging PK data 
indicating longer PK half-life than 
anticipated and following review 
of emerging safety data and to 
support operational efficiencies 
2.1 Study Rationale 
Updates supporting conduct 
of additional 800 mg SAD 
treatment period, reduced 
dosing duration of MAD 
Cohort 5, weekly MAD 
cohort and Relative 
Bioavailability (RBA) and 
Food Effect (FE) cohort. 
Revisions and update based on 
observed longer PK half-life and 
following review of emerging 
safety data 
2.2.1 Background Key Safety 
and PK data with Prior 
Maturation Inhibitors 
(GSK3532795 and 
GSK3640254) 
Inclusion of text to support 
conduct of additional 800 
mg SAD treatment period, 
reduced dosing duration of 
MAD Cohort 5, and weekly 
MAD cohort. 
To support updated study design 
based on emerging PK data 
indicating longer PK half-life than 
anticipated, a population model 
was conducted as an alternate 
analysis approach to 
characterize the 
pharmacokinetics and the 
simulation was implemented to 
predict higher single dose and 
multiple dose cohort PK profile 
based on the model 


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Section # and Name 
Description of Change 
Brief Rationale 
2.3 Benefit/Risk Assessment 
Updates to risk assessment 
summarizing current safety 
data in study and to align 
with conduct of the updated 
study design. Clarification 
on gastric toxicity (effects 
on parietal cells and chief 
cells) and skin and 
subcutaneous tissue 
disorders (maculopapular 
rash)  
To provide further clarification of 
risks based on current 
information  
3.0 Objectives 
Updates to objectives and 
endpoints in alignment with 
conduct of the updated 
study design. 
Based on emerging PK data 
indicating longer half-life, 
updates were made to objectives 
and endpoints to support 
updated study design 
4.1 Study Design 
Updates supporting conduct 
of additional 800 mg SAD 
treatment period, reduced 
dosing duration of MAD 
Cohort 5, weekly MAD 
Cohort 6 and Relative 
Bioavailability (RBA) and 
Food Effect (FE) cohort. 
Based on emerging PK data 
indicating longer half-life and 
following review of emerging 
safety data and to facilitate 
operational efficiencies 
4.2 Scientific Rationale for 
Study design 
Updates supporting conduct 
of additional 800 mg SAD 
treatment period, reduced 
dosing duration of MAD 
Cohort 5, weekly MAD 
Cohort 6 and Relative 
Bioavailability (RBA) and 
Food Effect (FE) cohort. 
Updates including summary 
of current safety data in 
study. 
Revisions and updates were 
based on emerging PK data 
indicating longer PK half-life than 
anticipated and following review 
of emerging safety data and to 
support operational efficiencies 
4.3.1 Predicted Human 
Pharmacokinetics 
Updates summarizing 
predicted PK parameters 
are included.   
To support updated study design 
based on emerging PK data 
indicating longer PK half-life than 
anticipated  
4.3.2 Predicted Human 
Effective Dose 
Updates summarizing 
predicted PK parameters 
To support updated study design 
based on emerging PK data 
indicating longer PK half-life than 


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Section # and Name 
Description of Change 
Brief Rationale 
are included.  
anticipated 
4.3.3. Part 1 (SAD) Starting 
Dose and Dose Escalation 
Revised text to align with 
the additional 800 mg dose 
SAD period based on 
emerging PK data 
To support the updated study 
design based on emerging PK 
data indicating longer PK half-life 
than anticipated. Revision 
supported following review of 
emerging safety data. 
4.3.4. Part 2 (MAD) Starting 
Dose and Dose Escalation 
Revised text to align with 
the proposed daily MAD 
Cohort 5 and weekly MAD 
Cohort 6 based on 
emerging PK data 
To support the updated study 
design based on emerging PK 
data indicating longer PK half-life 
than anticipated 
4.3.5 Part 3 RBA Dose 
Selection 
New section added 
To support updated study design 
based on emerging PK data 
indicating longer PK half-life than 
anticipated and following review 
of emerging safety data and to 
facilitate operational efficiencies 
4.3.6. Dose Escalation 
Committee 
Revised text for dose 
escalation decision based 
on updated day of 
assessments in Part 1 and 
Part 2 
Updated based on emerging PK 
data indicating longer PK half- 
life than anticipated 
4.3.7. Anticipated Exposure 
and Safety Cover for a 
Range of Potential Doses 
Updated table based upon 
predicted PK data outlining 
predicted safety and 
comparison to efficacy 
target and preclinical 
exposure. 
To support the updated study 
design based on predicted PK 
data and based on observation of 
longer PK half-life than 
anticipated 
5.1 Inclusion Criteria 
Revised text to further 
clarify participants 
requirement for SARs-CoV-
2 test frequency. 
To mitigate risk to study conduct 
during the COVID-19 pandemic 
5.3.1 Meals and Dietary 
Restrictions 
Updated text with 
instructions on water intake, 
requirements and updated 
instructions on time period 
for dosing post food intake  
for relative bioavailability 
and food effect cohort, and 
To facilitate conduct of the 
updated study design and outline 
requirements for Part 3 RBA and 
FE 


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Section # and Name 
Description of Change 
Brief Rationale 
updated day for bile test 
assessment. 
6. Study Intervention 
Updated text regarding use 
of GSK3739937 (also 
known as VH3739937) 
To further clarify the active 
investigation interventions used 
in study 212548 are 
GSK3733937 Powder in bottle 
(PiB) and GSK3733937 Tablet, 
100 mg (can also be referred to 
as VH3733973 PiB and VH 
3739937 Tablet, 100 mg) 
6.1 Study Intervention(s) 
Administered 
Revision to details of Study 
Interventions to include 
tablet for Part 3 of the study 
Update with tablet study 
intervention 
6.3 Method of Treatment 
Assignment 
Revised text indicating 
RAMOS NG will not be 
used for SAD 800 mg 
period, weekly MAD cohort 
and RBA FE.  Inclusion of  
randomization details for 
SAD 800 mg, weekly MAD 
Cohort 6 and RBA FE.  
To support operational 
efficiencies of the updated study 
design 
6.4 Measure to Minimize 
Bias: Randomization and 
Blinding 
Updates describing 
randomization and blinding 
for Part 1 additional 800 mg 
SAD treatment period, and 
Part 2 weekly MAD cohort. 
To further clarify randomization 
and blinding for the updated 
study design and to support 
operational efficiencies 
6.6 Concomitant Therapy 
Update to permitted 
medications 
To permit vaccination with an 
approved vaccine for SARS-
CoV-2 prior to or during study 
participation 
7.1.4. PK Stopping Criteria 
for SAD and MAD 
Updated text describing 
MAD PK stopping criteria 
for Part 2 
Updated based on emerging PK 
data indicating longer PK half-life 
than anticipated 
7.2 Participant 
Discontinuation /Withdrawal 
from the Study   
Addition of text clarifying 
data to be collected at time 
of study discontinuation 
To provide further clarification in 
study conduct 


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Section # and Name 
Description of Change 
Brief Rationale 
8.1.3 Screening for COVID-
19 Infection  
Added text to clarify SARS-
COV-2 testing upon 
admission to the unit, 
approximately one week 
prior to re-admission to unit, 
weekly while in the unit and 
at discharge.  
To mitigate risk to study conduct 
during the COVID-19 pandemic 
8.1.4. Electrocardiograms 
Updated text to specify pre-
dose and post-dose 
timepoint for 12-Lead ECG 
assessment in the study  
To further assist in clarity for 
study conduct 
8.4 Pharmacokinetics 
Updated to include PK and 
metabolite sampling 
requirements for additional 
outpatient visits and 
assessments throughout the 
study in alignment with the 
updated SOA. Addition of 
text to expand use of Part 3 
samples collected for 
VH3739937 plasma 
concentration.  
Updated in alignment with the 
updated SOA. To support any 
additional analysis of samples 
collected for VH3739937 plasma 
concentration in Part 3 
9.2.1 Sample Size 
Assumptions 
New section added  
Addition of text and 90% 
Confidence Intervals table to 
support Part 3 in the updated 
study design 
9.2.2. Sample Size 
Sensitivity 
Addition of text and table to 
support sample size 
sensitivity for Part 3.   
To support Part 3 in the updated 
study design 
9.4.3 Pharmacokinetic 
Analyses 
Updated text to include 
individual plasma PK 
parameters for each 
participant and dosing 
group for Part 2 repeated 
once weekly dosing 
To support updated study design 
based on emerging PK data 
indicating longer PK half-life than 
anticipated 


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Section # and Name 
Description of Change 
Brief Rationale 
9.4.4 Statistical Analysis of 
Pharmacokinetic Data 
Revised text to include 
accumulation evaluation for 
updated Cohort 5 and 
Cohort 6; Added text to 
describe assessment of 
RBA and FE.  
To support updated study design 
and study objectives/endpoints 
9.5 Interim Analyses 
Updates to Bayesian model 
Operating Characteristic 
related to 800 mg SAD 
period, Part 2 MAD once 
daily dosing and weekly 
dosing 
To support updated study design 
and study objectives/endpoints 
 
10.1.8 Data Quality 
Assurance 
Inclusion of text to clarify 
detailed information about 
study data collection and 
management process 
including systems used can 
be found in the study Data 
Management Plan 
To further support sponsor or 
designee is responsible for data 
management of this study 
including quality checking of the 
data 
10. 2 Appendix 2 Clinical 
Laboratory Tests 
Addition of serum creatine 
phosphokinase to clinical 
laboratory tests 
To further support routine clinical 
laboratory safety assessment 
10.7 Appendix 7 Permissible 
Procedures during COVID-19 
Pandemic  
Added text to clarify 
requirement for SARS-
COV-2 testing upon 
admission to the unit, 
approximately one week 
prior to re-admission to unit, 
weekly while in the unit and 
at discharge. Additional 
testing may be performed if 
deemed necessary.  
To mitigate risk to study conduct 
during the COVID-19 pandemic 
10.8 Appendix Abbreviations 
and Trademarks 
Revised to include the 
abbreviations included in 
revisions in this protocol 
amendment 
Inclusion of all abbreviations 
cited 
10.9 Appendix 9 Protocol 
Amendment History  
Updated with Overall 
Rationale for Protocol 
Amendment 1 and 
Summary of Changes table 
For reference of overall rationale 
for protocol amendment 1 and 
summary of changes 


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Section # and Name 
Description of Change 
Brief Rationale 
11. References 
Updated with Investigator’s 
Brochure Supplement 
Version 02 
For reference of Investigator’s 
Brochure Supplement Version 02 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 14 
1.1. 
Synopsis ..................................................................................................... 14 
1.2. 
Schedule of Activities (SoA) ........................................................................ 23 
2. 
INTRODUCTION .................................................................................................... 49 
2.1. 
Study Rationale .......................................................................................... 49 
2.2. 
Background ................................................................................................ 49 
2.2.1. 
Background Key Safety and PK data with Prior Maturation 
Inhibitors (GSK3532795 and GSK3640254) ................................ 50 
2.3. 
Benefit/Risk Assessment ............................................................................ 52 
2.3.1. 
Risk Assessment ......................................................................... 54 
2.3.2. 
Benefit Assessment ..................................................................... 59 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 59 
2.3.4. 
Acute Monitoring in FTIH Studies ................................................ 59 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 59 
4. 
STUDY DESIGN .................................................................................................... 61 
4.1. 
Overall Design ............................................................................................ 61 
4.2. 
Scientific Rationale for Study Design .......................................................... 67 
4.3. 
Justification for Dose .................................................................................. 68 
4.3.1. 
Predicted Human Pharmacokinetics ............................................ 68 
4.3.2. 
Predicted Human Effective Dose ................................................. 69 
4.3.3. 
Part 1 (SAD) Starting Dose and Dose Escalation ......................... 69 
4.3.4. 
Part 2 (MAD) Starting Dose and Dose Escalation ........................ 70 
4.3.5. 
Part 3 RBA Dose Selection .......................................................... 71 
4.3.6. 
Dose Escalation Committee (DEC) .............................................. 71 
4.3.7. 
Anticipated Exposure and Safety Cover for a Range of 
Potential Doses............................................................................ 71 
4.4. 
End of Study Definition ............................................................................... 73 
5. 
STUDY POPULATION ........................................................................................... 74 
5.1. 
Inclusion Criteria ......................................................................................... 74 
5.2. 
Exclusion Criteria ........................................................................................ 75 
5.3. 
Lifestyle Considerations .............................................................................. 78 
5.3.1. 
Meals and Dietary Restrictions .................................................... 78 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 79 
5.3.3. 
Activity ......................................................................................... 79 
5.4. 
Screen Failures........................................................................................... 79 
6. 
STUDY INTERVENTION ........................................................................................ 80 
6.1. 
Study Intervention(s) Administered ............................................................. 80 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 81 
6.3. 
Method of Treatment Assignment ............................................................... 82 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................... 82 
6.5. 
Study Intervention Compliance ................................................................... 84 
6.6. 
Concomitant Therapy.................................................................................. 84 


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6.7. 
Dose Modification ....................................................................................... 85 
6.8. 
Intervention after the End of the Study ........................................................ 85 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 85 
7.1. 
Discontinuation of Study Intervention .......................................................... 85 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 86 
7.1.1.1. 
Study Intervention Restart or Rechallenge after 
liver stopping criteria met ............................................ 87 
7.1.2. 
QTc Stopping Criteria .................................................................. 87 
7.1.3. 
Temporary Discontinuation .......................................................... 88 
7.1.4. 
PK Stopping Criteria for SAD and MAD ....................................... 88 
7.1.5. 
Clinical Criteria for Stopping the Study ......................................... 88 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 89 
7.3. 
Lost to Follow Up ........................................................................................ 90 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 90 
8.1. 
Safety Assessments ................................................................................... 91 
8.1.1. 
Physical Examinations ................................................................. 91 
8.1.2. 
Vital Signs .................................................................................... 91 
8.1.3. 
Screening for COVID-19 Infection ................................................ 91 
8.1.4. 
Electrocardiograms ...................................................................... 92 
8.1.4.1. 
Cardiodynamic assessment (ECGs extracted 
from Holter recordings) ............................................... 93 
8.1.5. 
Clinical Safety Laboratory Assessments ...................................... 94 
8.1.6. 
Suicidal Ideation and Behaviour Risk Monitoring ......................... 95 
8.2. 
Adverse Events and Serious Adverse Events ............................................. 95 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 96 
8.2.2. 
Method of Detecting AEs and SAEs ............................................. 96 
8.2.3. 
Follow-up of AEs and SAEs ......................................................... 96 
8.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 97 
8.2.5. 
Pregnancy ................................................................................... 97 
8.3. 
Treatment of Overdose ............................................................................... 97 
8.4. 
Pharmacokinetics ....................................................................................... 98 
8.5. 
Pharmacodynamics .................................................................................. 100 
8.6. 
Genetics ................................................................................................... 100 
8.7. 
Biomarkers ............................................................................................... 100 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 100 
9.1. 
Statistical Hypotheses............................................................................... 100 
9.2. 
Sample Size Determination ...................................................................... 100 
9.2.1 
Sample Size Assumptions ......................................................... 100 
9.2.2 
Sample Size Sensitivity .............................................................. 101 
9.3. 
Populations for Analyses .......................................................................... 102 
9.4. 
Statistical Analyses ................................................................................... 102 
9.4.1. 
Safety Analyses ......................................................................... 102 
9.4.2. 
Other Analyses .......................................................................... 103 
9.4.3. 
Pharmacokinetic Analyses ......................................................... 103 
9.4.4. 
Statistical Analysis of Pharmacokinetic Data .............................. 103 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........................... 104 
9.5. 
Interim Analyses ....................................................................................... 104 


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9.6. 
Final Analyses .......................................................................................... 106 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 108 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 108 
10.1.1. 
Regulatory and Ethical Considerations ...................................... 108 
10.1.2. 
Financial Disclosure ................................................................... 108 
10.1.3. 
Informed Consent Process ........................................................ 109 
10.1.4. 
Data Protection .......................................................................... 109 
10.1.5. 
Committees Structure ................................................................ 109 
10.1.6. 
Publication Policy ....................................................................... 109 
10.1.7. 
Dissemination of Clinical Study Data ......................................... 110 
10.1.8. 
Data Quality Assurance ............................................................. 110 
10.1.9. 
Source Documents .................................................................... 111 
10.1.10. Study and Site Closure .............................................................. 112 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 113 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 115 
10.3.1. 
Definition of AE .......................................................................... 115 
10.3.2. 
Definition of SAE ........................................................................ 116 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................. 117 
10.3.4. 
Reporting of SAE to ViiV/GSK ................................................... 119 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 120 
10.4.1. 
Definitions: ................................................................................. 120 
10.4.2. 
Highly Effective Methods of Contraception ................................. 121 
10.4.3. 
Collection of Pregnancy Information: ......................................... 122 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 123 
10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events Corrected Version 
2.1, July 2017 ........................................................................................... 125 
10.7. 
Appendix 7: Permissible Procedures During COVID-19 Pandemic ........... 126 
10.8. 
Appendix 8: Abbreviations and Trademarks .............................................. 128 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 134 
11. REFERENCES ..................................................................................................... 138 
 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3739937 in Healthy Participants 
Short Title:  GSK3739937 First-Time-In-Human Study 
Rationale: The inhibition of maturation and release of human immunodeficiency virus-1 
(HIV-1) is a novel target for drug development, distinct from viral protease, reverse 
transcriptase and integrase. There are no maturation inhibitors (MI) approved for the 
treatment of HIV infection. GSK3739937 (also known as VH3739937) is a MI that 
displays in vitro evidence of low nanomolar potency against multiple HIV-1 Gag 
polymorphisms and a broad spectrum covering multiple HIV-1 subtypes, supporting 
compound development. This study is designed in three parts; i) to gain information on 
the safety, tolerability, and pharmacokinetic properties of VH3739937 when administered 
as powder-in-a-bottle (PiB); ii) the relative bioavailability (RBA) of the GSK3739937 
PiB and GSK3739937 Tablet and; iii) to evaluate the safety, tolerability and 
pharmacokinetic (PK) parameters of the tablet formulation when administered under 
fasting and fed conditions. This study will enable further clinical development of 
VH3739937, including a Phase IIA Proof of Concept (PoC) study in HIV-infected 
patients and a First-Time-in-Human (FTiH) study of the long acting formulation of 
VH3739937. 
 
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
• To investigate the safety and 
tolerability of VH3739937 following 
single, repeated daily, and weekly 
oral administration in healthy 
participants (Part 1 & 2)  
• To assess the safety and tolerability 
of VH3739937 following single oral 
administration in healthy 
participants under fasted or fed 
(moderate calorie and fat) conditions 
(Part 3) 
• To evaluate the relative 
bioavailability (RBA) of 
GSK3739937 powder-in-bottle 
(PiB) versus GSK3739937Tablet 
and the effect of food on the PK of 
VH3739937 safety parameters:  
• Adverse events (AEs); post baseline 
values and changes over time of 
clinical laboratory evaluations 
(haematology, clinical chemistry, 
urinalysis), vital signs, and 
electrocardiogram (ECG) 
parameters from pre-dose values 
(Parts 1, 2 and 3) 
 
Derived PK parameters for VH3739937: 
• Part 3 (single dose):  AUC (0-24), 
AUC(0-inf), Cmax  


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Objective 
Endpoint 
GSK3739937 Tablets and 
GSK3739937 PiB (Part 3) 
 
Secondary 
• To describe the pharmacokinetic 
(PK) profile of VH3739937 
following single (Part 1 & 3), 
repeated daily and weekly (Part 2) 
oral administration in healthy 
participants 
 
Derived PK parameters for VH3739937: 
• Part 1 (single dose): AUC(0-24), 
AUC(0-t) , AUC(0-inf) , Cmax, C24, tmax, 
tlag, t1/2, Clast, tlast, CL/F 
• Part 2 (repeated once daily [QD] 
dose), as data permits: 
o Day 1:  AUC (0-24), Cmax, C24,         
tmax, tlag 
o Day 14 (Cohort 3 and 4): AUC(0-
t), Cmax, Ct, tmax, t1/2, and CL/F 
o Day 18 (Cohort 5): AUC(0-t), 
Cmax, Ct, tmax, t1/2, and CL/F 
• Part 2 (repeated once weekly [QW] 
dose) 
o Day 1 (Cohort 6): AUC (0-168), 
Cmax, C168, tmax, tlag 
o Day 15 (Cohort 6): AUC(0-t), 
Cmax, Ct, tmax, t1/2, and CL/F 
 
• Part 3 (single dose): C24, tmax, tlag, 
t1/2, Clast, tlast, CL/F 
 
• To examine dose proportionality 
following single and repeated doses 
of VH3739937 (Part 1 & 2) 
Derived PK parameters for VH3739937: 
• Part 1 (single dose): AUC(0-inf), Cmax.  
• Part 2 (repeated dose): AUC(0-), 
Cmax, C 
• To predict the accumulation from 
single dose data (Part 1) and assess 
accumulation of VH3739937 after 
repeat doses (Part 2 at steady state) 
Accumulation indices for PK 
parameters for VH3739937:  
• Part 2 (repeated dose)  
Observed accumulation ratios: 
RAUC(0-) , R(Cmax), R (C)  
• To assess time to steady-state of 
VH3739937 (Part 2) 
Derived PK parameters for VH3739937: 
• Part 2 (repeated dose):  


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Objective 
Endpoint 
o Cohorts 3 and 4: Pre-dose 
concentrations on Day 2-14  
o Cohort 5: Pre-dose 
concentrations on Day 2-18 
AUC(0-24) = Area under the plasma concentration time curve from zero (pre-dose) to 24; AUC(0-t) = Area 
under the plasma concentration time curve from zero (pre-dose) to t; AUC(0-inf) = Area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time; AUC(0-) = Area under 
the curve (Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing 
interval at steady state); Cmax = Maximum observed concentration; tmax = Time of occurrence of Cmax; t1/2 = 
Apparent terminal phase half-life; tlag = lag time; C24 = Drug concentration at 24 hours post-dose;  Clast = 
last observable concentration; tlast = time of last observable concentration; C (or Ctrough) = trough serum 
concentration; CL/F= Apparent oral clearance; ECG= Electrocardiogram; PiB = powder-in-bottle; RAUC(0-
) = Accumulation ratio of area under the concentration-time curve over the dosing interval; R(Cmax) = 
Ratio of maximum observed concentration; R (C) = Ratio of concentration over the dosing interval; RBA 
= Relative Bioavailability 
 
Overall Design and Schematic: 
This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-
controlled, single- and repeat-dose escalation study including a weekly oral dose (MAD) 
cohort and a relative bioavailability (RBA) and food effect (FE) cohort to investigate the 
safety, tolerability and PK of VH3739937 in healthy participants.    
 
In Part 1, the proposed dosing schedule is designed to investigate single ascending dose 
(SAD) of oral VH3739937 initially in Cohorts 1 and 2.  Then, at a suitable cross-over 
point (described below), Part 2 will involve 4 cohorts of multiple ascending dosing of 
oral VH3739937 when administered:  
• once daily for 14 days (Cohorts 3 and 4);  
• once daily for 18 days (Cohort 5); and  
• three oral doses administered at weekly intervals over two weeks (Cohort 6) 
(Figure 1).  
 
In Part 3, the RBA and FE (Cohort 7) will include a randomized, open-label, single dose, 
3-period crossover design to compare the RBA of single doses of the GSK3739937 PiB 
with GSK3739937 Tablet, and to assess the effect of food (fasted or fed (under moderate 
calorie and fat conditions)) upon the safety, tolerability and PK of the GSK3739937 
Tablet  (Figure 2).  All doses will be administered immediately following a standardized 
meal for each dosing period that contains approximately 600 calories with approximately 
30% of calories from fat (unless otherwise indicated in Part 3 dosing in fasted condition).  
 
A summary of the overall study design, including doses, sample size, and order, is 
presented in Figure 1 and Figure 2 below.  
 
 
 
 
 


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Figure 1 
Phase 1 Study in Healthy Participants using planned doses of 
VH3739937 Part 1 and Part 2 
 
 
 
 
A=Active; P=Placebo 
QD = once daily; QW = once weekly 
*= Period 4 may include participants from both Cohorts 1 and 2 
Highlighted cohorts and treatment periods denote completed  
 
Figure 2 
Phase 1 Study in Healthy Participants using planned doses of 
VH3739937 Part 3 
 
 
 
Note: The doses shown in Figure 1 above are intended to demonstrate general concepts 
relating to factors of escalation. The modelling and simulation implemented using the 
data currently available following oral administration of a suspension formulation in the 
fed state indicated the predicted efficacious dose for the daily dose is 25 mg and the 
weekly dose is 500 mg.  Due to the observed half-life of ~90 h, the anticipated 
accumulation ratio following repeated daily and weekly doses is ~ 6-fold and 1.3-fold, 
respectively. Dosing will be conducted in accordance with PK stopping criteria. 
 
In Part 1, dose escalation will be determined by the Dose Escalation Committee (ViiV 
Healthcare (VH)/GlaxoSmithKline (GSK) study team and the Principal Investigator (PI)) 


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and guided by safety data and PK stopping criteria. Post-dose safety and PK data through 
Day 16 from a minimum of 4 participants receiving VH3739937 are required for dose 
escalation in Part 1. The suitable crossover point from Part 1 to Part 2 referenced in the 
above text was determined once the single dose safety and preliminary PK data for the 
anticipated minimally effective dose was evaluated in Part 1 single ascending dose (SAD) 
and the maximum exposure for the MAD dose was covered by the SAD certain dose 
level.  In Part 2, Cohorts 3 and 4, dose escalation will be determined by the VH/GSK 
study team and the PI and guided by the safety and PK data (minimally up to Day 29, 15 
days following the Day 14 dose) from the previous dosing Cohort(s).  Dose escalation 
from Cohort 5 will be similarly guided by safety and PK data minimally up to Day 33, 15 
days following the Day 18 dose.  
 
Based on human PK predicted from preclinical species, assuming an average 
bioavailability of ~14% and dose proportionality as well as predicted moderate between-
participant PK variability, the highest dose to be assessed in Part 1 was anticipated to be 
~640 mg QD. However, as indicated by data evaluated for Part 1 Treatment Periods 
through 640 mg, VH3739937 exposures are lower than predicted, therefore an additional 
higher dose SAD treatment period will be evaluated. This higher dose will be conducted 
in accordance with PK stopping criteria. 
Disclosure Statement:  This is a double-blind (sponsor unblinded) three-part study that 
includes two placebo-controlled single ascending dose cohorts (Part 1), four placebo-
controlled multiple ascending dose cohorts (Part 2) and an open label RBA and FE cohort 
(Part 3).    
Number of Participants: 
Overall, approximately 76 participants will be randomly assigned to study intervention. 
In Part 1, approximately 18 participants will be randomized with approximately 9 
participants within each of Cohort 1 and Cohort 2. Part 1 will include an additional higher 
dose treatment period (800 mg) evaluated in approximately 9 participants, as supported 
by emerging data.  In Part 2, approximately 40 participants will be randomized with 
approximately 10 participants within each of Cohorts 3 to 6. In Part 3, approximately 18 
participants will be treated to ensure that approximately 12 evaluable participants 
complete Cohort 7.  
Participants will not be replaced if the reason for discontinuation from the study is due to 
a safety concern e.g. when a participant meets stopping criteria. 
If participants prematurely discontinue the study for non-safety reasons in the SAD, they 
may be replaced at the discretion of the Sponsor in consultation with the investigator. The 
replacement participants will be assigned to the same treatment sequence, starting where 
the prior participant prematurely discontinued. Previously administered doses will not be 
repeated by replacement participants if dose escalation criteria are met.  
If participants prematurely discontinue the study for non-safety reasons in the MAD, they 
may be replaced at the discretion of the Sponsor in consultation with the investigator. The 
replacement participants will be assigned to the same treatment in the same Cohort where 
the prior participant prematurely discontinued.  


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If participants prematurely discontinue Part 3, additional participants may be randomized 
after consultation with the sponsor to ensure that 12 evaluable participants complete the 
study.  
Assignment of replacement numbers will be detailed in the Study Reference Manual 
(SRM). 
 
Intervention Groups and Duration: 
Part 1 (SAD): 
 
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts each of approximately 9 healthy participants. Each of these two cohorts 
may contain a minimum of 3 escalating doses of VH3739937 through to 640 mg.  An 
additional 800 mg dose will be evaluated as this was indicated following review of safety 
and PK data from participants dosed up to 640mg. The interlocking design and the 
randomization sequence will allow the 9 participants in each cohort to potentially receive 
one of the lower and one of the higher doses of VH3739937.  Participants in Cohort 1 and 
Cohort 2 will follow the same randomization strategy with alternating ascending doses).  
In each escalating dose period, 6 participants will be randomized to receive VH3739937 
and 3 participants will be randomized to receive placebo (PBO).  Each participant will 
receive PBO at least once. When the 800 mg dose is evaluated, 6 participants from both 
Cohorts 1 and 2 may be randomized to receive VH3739937 and 3 participants will be 
randomized to receive placebo, independent of which prior doses they received. 
 
Dose escalation in Part 1 will be determined by the DEC (VH/GSK study team and the 
PI) based on the double-blind (sponsor-unblinded) safety data and the PK data from the 
current and previous dosing period(s) according to the dose escalation charter. Dose 
escalation will generally not exceed approximately 3-fold between doses up to 
approximately the predicted minimally effective dose and will not exceed 2-fold 
thereafter. However, if after the first SAD dose, the exposures are significantly different 
from the predicted level, the second dose or the sample collection schedule will be re-
estimated and a different fold increase may be used. Post-dose safety and PK data 
through Day 16 from a minimum of 4 participants receiving VH3739937 are required for 
dose escalation in Part 1.  
 
For Part 1 SAD, 24-hour continuous Holter/ ECG recordings will be collected on the day 
before dosing (Day -1), and Day 1 for extraction of ECGs paired with PK sampling. 
 
Participants in Part 1 will have a screening visit within 28 days prior to the first dose and 
a follow-up visit approximately 28 days after the last dose.  Flexibility of visit scheduling 
may be required if a pandemic situation applies (see Appendix 7).  Otherwise, study 
assessments will be performed as indicated in the Schedule of Activities (SoA).  Study 
participants will be confined to the clinic from Day −2 until discharge.  Additional 
outpatient visits will be required on Days 9, 12 and 16.  Duration of study participation in 
Part 1 may be a minimum of approximately 27 weeks for SAD treatment periods 1 to 3.  
However, in Part 1, study duration will be extended up to approximately 31 weeks to 
evaluate a higher dose (800 mg) for participants included in this dose period.  Participants 


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who have completed Part 1 may be able to re-enroll to complete 800 mg treatment period. 
To ensure safety, participants will need to go through re-eligibility assessments.  
 
Part 2 (MAD): 
 
Part 2 (MAD) consists of approximately 4 ascending repeat-dose cohorts (Cohorts 3 to 
6), each with 10 participants who will receive a once-daily dose of VH3739937 or 
PBO for 14 days (Cohorts 3 [25 mg] and 4 [50 mg]), or for 18 days (Cohort 5 [100 mg]), 
or three oral doses administered at weekly intervals over two weeks (Cohort 6 [500 mg]).  
The duration of dosing in Cohort 5 is to support up to 18-day dosing as an oral lead for 
the future SAD and MAD studies of the long acting formulation of VH3739937. This 
duration is to potentially allow the identification of any early drug hypersensitivity 
reactions (HSR) which may occur before the administration of the long acting 
formulation. In each escalating dose cohort, 7 participants will be randomized to receive 
VH3739937 and 3 participants will be randomized to receive placebo (PBO).  Dose 
escalation in Part 2 will be determined by the VH/GSK study team and the PI based on 
the double-blind (sponsor-unblinded) safety and PK data (minimally up to 15 days 
following the last dose) from the previous dosing Cohort(s). Specifically, safety and PK 
data through Day 29 in Cohorts 3 and 4, and through Day 33 in Cohort 5 from a 
minimum of 5 participants receiving active drug will be required for dose escalation.  
Part 2 of the study was initiated once the single dose safety and preliminary PK data was 
evaluated in the SAD and the maximum exposure for the first MAD dose in Cohort 3 was 
covered by the SAD certain dose level.  The potential minimally effective daily dose for 
VH3739937 with the suspension formulation was determined by the modeling and 
simulation utilising data for all doses in Part 1, as 25 mg, and is anticipated to be that 
which is predicted to provide a steady state C ≥ 0.258 g/mL in 95% of participants.. 
More detailed information may be found in the IB Supplement [GlaxoSmithKline 
Document Number 2021 RPS_CLIN_004025].   
Dose escalation in the MAD will not exceed 2-fold between cohorts 3 to 5 and will be 
driven by safety and PK stopping criteria (see Section 7.1.4).  The 500 mg dose included 
in the MAD Cohort 6 was determined following modelling and simulation of PK data 
acquired in the SAD treatment periods through to 640 mg and MAD Cohort 3.  In 
addition, a dose will not be assessed in the MAD until the anticipated steady-state 
exposure (Cmax and AUC(0-) on Day 14 for Cohorts 3 and 4, on Day 18 for Cohort 5 
and at Day 14 following the third QW dose in Cohort 6) for that dose have been 
evaluated and shown not to have met safety stopping criteria in the SAD portion of the 
study (Part 1).  
 
For Part 2 MAD Cohorts 3, 4 and 5, 24-hour continuous Holter/ECG recordings will be 
collected, on the day before the first dose (Day -1), Day 1, and Day 14 for extraction of 
ECGs paired with PK sampling.  In addition, 12-Lead ECGs will be collected for Part 2 
at timepoints indicated in the SoA. 


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Participants in Part 2 will have a screening visit within 28 days prior to first dose and a 
follow-up visit approximately 28 days after the last dose.  Flexibility of visit scheduling 
may be required if a pandemic situation applies (see Appendix 7).  Otherwise, study 
assessments will be performed as indicated in SoA. Study participants will be confined to 
the clinic from Day −2 until discharge with requirement to complete all scheduled 
outpatient visits. Maximum duration of study participation from admission into the unit 
until completion of follow visit will be approximately 5 weeks. 
Part 3 (RBA): 
Part 3 is a randomized, open-label, single-dose, 3-period crossover optional Cohort 7 to 
compare the RBA of the GSK3739937 PiB with GSK3739937 Tablet and to assess the 
effect of food on the safety, tolerability and PK of GSK3739937 Tablet in healthy 
participants. In Part 3, approximately 18 participants will be treated to ensure that 12 
evaluable participants complete Cohort 7.  If participants prematurely discontinue Part 3, 
additional participants may be randomized after consultation with the sponsor to ensure 
that 12 evaluable participants complete the study.   
Part 3 will consist of a screening period and 3 sequential treatment periods with a single 
dose of study intervention per treatment period.  
Prior to dosing on Day 1 of Period 1, participants will be randomly assigned to 1 of 3 
treatment sequences (ABC, BAC or CAB).  Participants will receive each of the 
following treatments administered as 1 treatment per period: 
• Treatment A: GSK3739937 PiB,100 mg (administered as oral suspension) 
administered under moderate fat conditions (reference) 
• Treatment B: GSK3739937 Tablet, 100 mg (single dose given as a 100 mg 
tablet(s)) administered under moderate fat conditions (test) 
• Treatment C: GSK3739937 Tablet, 100 mg (single dose given as 100 mg 
tablet(s)) 
administered under fasted conditions (reference). 
 
To ensure adequate washout, there will be at least 24 days between each dose of study 
intervention, with an allowance window of 4 hours (i.e., 24 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic.  
 
For treatments administered in the fed state, participants will fast overnight for at least 
9.5 hours prior to dosing and will receive a moderate fat meal (Treatments A and B) 25 
minutes prior to dosing.  Dose administration will occur within 5 minutes of completion 
of meal consumption.  Participants will not receive any further food until 4 hours after 
dosing. Treatment C will be administered in the fasted state. For treatments administered 
in the fasted state, participants will fast overnight for at least 9.5 hours prior to dosing and 
until 4 hours after dosing. 
Pharmacokinetic blood samples for the analysis of VH3739937 will be collected prior to 
dosing (0 hour) on Day 1 and up to 360 hours post-dose in Periods 1, 2 and 3.  Additional 
outpatient visits up to approximately Day 16 post each Treatment A, B and C will be 
required for collecting necessary PK and safety assessments.  Safety and tolerability will 


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be assessed by monitoring and recording of adverse events, clinical laboratory test 
results, vital sign measurements, 12-lead electrocardiogram results, and physical 
examination findings. 
In Part 3, assessments will be performed as indicated in the SoA. Participants will be 
confined to the clinic from Day −2 until discharge on Day 6 of each treatment period. 
Participants are required to complete all outpatient visits during study conduct. Re-
admission to the unit will occur on Day -2 for Treatment Periods 2 and 3. A washout 
period of 24 days is required during treatment periods 1 and 2 prior to dosing in 
subsequent treatment periods. The duration of Part 3, including Screening, is 
approximately 16 weeks. 
 
Dose Escalation Committee: Yes (Part 1 and Part 2 only) 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2. 
Schedule of Activities (SoA) 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the SoA, are essential and required for study 
conduct. This section lists the procedures and parameters of each planned study 
assessment. The exact timing of each assessment is listed in the SoA.  
 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.  
 
No more than 500 mL of blood will be collected over each 56-day period during the 
duration of the study, including any extra assessments that may be required. 
When electrocardiogram (ECG) extractions coincide with safety ECGs, vital signs 
assessment and blood draws, procedures will be carried out in said order.  
PI will use initial screening data for all participants who are enrolled, randomized and 
dosed.  All safety parameters will be reviewed by PI and VH/GSK study team members 
prior to the Dose Escalation Committee (DEC) making the decision to escalate dosing of 
participants at a higher dose. 
Note: 
• The Institutional Review Board/ Independent Ethics Committee (IRB/IEC) 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 competent authorities and the ethics 
committee before implementation. 
• The timing and number of planned study assessments, including safety, 
pharmacokinetic (PK), or other assessments 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 
plasma concentrations) to ensure appropriate monitoring.  
• The duration and schedule of dosing in SAD and MAD cohorts and the doses to be 
administered may be altered during the course of the study, based on newly available 
data (e.g. to achieve Cmax and / or AUC levels required to optimize data acquisition 
including the generation of data closer to the time of peak plasma concentrations), to 
inform clinical development while ensuring study conduct in line with the PK and 
Safety Stopping Criteria.   
 
• Any changes in the timing or addition of time points for any planned study 
assessments, or changes in the duration and schedule of dosing and the doses to be 
administered in the SAD and MAD cohorts, as the result of emerging PK 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. 
 


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Table 1 
Screening and Follow-Up Assessments (Part 1, Part 2, and Part 3)1 
Procedure 
Screening (up to 28 
days before Day 1) 
Follow-Up2 
(approx. 28 days 
post last dose) 
Notes 
Outpatient Visit 
X 
X 
 
Informed Consent 
X 
 
 
Inclusion/Exclusion Criteria 
and Demography 
X 
 
 
Medical/medication/ 
drug/alcohol history 
X 
 
 
Full Physical Examination 
X 
X 
A Full Physical Exam will include 
at a minimum, assessments of 
the Skin, Cardiovascular, 
Respiratory, Gastrointestinal and 
Neurological systems 
SARS CoV-2 Testing2 
X 
  
An approved molecular test 
(PCR) will be used. For further 
detail see Appendix 7 and 
Section 8.1.3 
Columbia Suicide Severity 
Rating Scale (CSSRS)2 
X 
 
 
Height, Weight, Body Mass 
Index (BMI) 
X 
 
 
Vital signs 
X 
X 
 
12 Lead ECG 
X 
X 
Triplicate ECGs will be used to 
determine participant eligibility at 
screening 
Pregnancy Test 
X 
X 
Follow up test may be obtained 
up to 37 days post last dose  
Urine drug/alcohol/cotinine 
screen 
X 
 
Performed at the standard 
practice of the site 
Hepatitis B surface antigen 
(HbsAg), Hepatitis C (HCV), 
Human immunodeficiency 
virus (HIV) tests3 
X 
 
If test otherwise performed within 
3 months prior to first dose of 
study intervention, testing at 
screening is not required 
Haematology/Chemistry/Urine 
tests 
X 
X 
Laboratory procedures may be 
repeated and additional tests may 
be performed, if needed, at the 
discretion of the investigator. 
Serious Adverse Event (SAE) 
Review 
X 
X 
All SAEs will be collected from 
screening visit until the follow up 
visit 
AE Review 
 
X 
All AEs will be collected from start 
of intervention until follow up visit 
Concomitant Medication 
Review 
X 
X 
 
1 In a pandemic situation see Appendix 7 
2For early discontinuation that occurs prior to discharge from unit, SARS-CoV-2 testing, CSSRS, and final follow up 
assessments will be performed. For early discontinuation that occurs post discharge from unit, only final follow up 
assessments will be performed. 
 3 HIV Ab/Ag 4th generation test (point of care test or laboratory immunoassay) 
 


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Table 2 
Part 1 Single ascending dose (SAD) Study Intervention (Periods 1 through 4) – In Unit Duration 
Procedure 
Day -2 
Day -1 
Day 1 (Hours) 
Day 2 
(24 h) 
Day 3 
(48 h) 
Day 4 
(72 h) 
Day 5 
(96 h) 
Day 6   
 (120 h) 
Notes  
Hours (h) 
relate to PK 
sampling post 
last dose 
Pre-
dose 
0  
1 
2 
3  
4 
5 
6  
7 
8  
9  
10 
12 
16 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
In a pandemic 
situation see 
Appendix 7  
Discharge from Unit 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
In a pandemic 
situation see 
Appendix 7 
Brief Physical Exam 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
X 
Brief physical 
examinations 
may be made 
full and 
laboratory 
procedures 
may be 
repeated if 
needed at the 
discretion of 
the principal 
investigator 
(PI).  
Weight, BMI 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
CSSRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
X  
  
 
X 
X 
  
X 
X  
X  
  
  
 
  
X 
 
X 
X 
X 
X 
X 
Vital signs to 
be performed 
pre-dose. 
Temperature 
will be 
monitored 


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Procedure 
Day -2 
Day -1 
Day 1 (Hours) 
Day 2 
(24 h) 
Day 3 
(48 h) 
Day 4 
(72 h) 
Day 5 
(96 h) 
Day 6   
 (120 h) 
Notes  
Hours (h) 
relate to PK 
sampling post 
last dose 
Pre-
dose 
0  
1 
2 
3  
4 
5 
6  
7 
8  
9  
10 
12 
16 
every day 
during study 
participation. 
For further 
detail, see    
Section 8.1.2 
12-lead safety ECGs 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
ECG 
timepoints 
may be 
reduced in 
subsequent 
dosing 
groups. For 
further detail, 
see Section 
8.1.4. 
Continuous ECG (full 
time matched baseline 
on Day-1) 
 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
For further 
detail, see 
Section 8.1.4. 
Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Female 
participants 
only. See 
Appendix 2 
Testing for SARS CoV-2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
An approved 
molecular test 
(PCR) will be 
used. An 
additional 
SARS-CoV-2 
test will be 
performed 
approximately 


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Procedure 
Day -2 
Day -1 
Day 1 (Hours) 
Day 2 
(24 h) 
Day 3 
(48 h) 
Day 4 
(72 h) 
Day 5 
(96 h) 
Day 6   
 (120 h) 
Notes  
Hours (h) 
relate to PK 
sampling post 
last dose 
Pre-
dose 
0  
1 
2 
3  
4 
5 
6  
7 
8  
9  
10 
12 
16 
one week 
prior to re-
admission to 
the unit. For 
further detail 
see Appendix 
7and Section 
8.1.3. 
Drug/alcohol/cotinine 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Haematology/Chemistry
/ Urine tests 
 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
X 
X 
For further 
detail, see 
Section 
Appendix 2 
VH3739937 Dose 
Administration 
 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Randomizatio
n to occur on 
Day 1 prior to 
dosing. 
For meal 
instructions 
prior to dose, 
see Section 
5.3.1 
 
Meals  
 
Per site usual practice 
Plasma PK Sampling 
 
  
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
In Cohort 1, 
4mL of blood 
will be 
collected for 
analysis at 
each 
timepoint. In 
Cohort 2, 2 
mL of blood 


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Procedure 
Day -2 
Day -1 
Day 1 (Hours) 
Day 2 
(24 h) 
Day 3 
(48 h) 
Day 4 
(72 h) 
Day 5 
(96 h) 
Day 6   
 (120 h) 
Notes  
Hours (h) 
relate to PK 
sampling post 
last dose 
Pre-
dose 
0  
1 
2 
3  
4 
5 
6  
7 
8  
9  
10 
12 
16 
will be 
collected at 
each visit.  
For further 
detail, see 
Section 8.4. 
Urine PK Sampling  
 
 
X 
 
<==========================================================================> 
 
Pre-dose 
urine can be 
collected up 
to 3.5 h pre-
dose. 
Afterward 
urine will be 
collected over 
24 h 
collection 
periods as 
follows: 0-24 
h, 24-48 h, 48 
– 72 h, 72 – 
96 h in Cohort 
2 Period 3 
only. For 
further detail, 
see Section 
8.4. 
SAE Review 
<====================================================================================================> 
All SAEs will 
be collected 
from 
screening 
until follow up 
visit 


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Procedure 
Day -2 
Day -1 
Day 1 (Hours) 
Day 2 
(24 h) 
Day 3 
(48 h) 
Day 4 
(72 h) 
Day 5 
(96 h) 
Day 6   
 (120 h) 
Notes  
Hours (h) 
relate to PK 
sampling post 
last dose 
Pre-
dose 
0  
1 
2 
3  
4 
5 
6  
7 
8  
9  
10 
12 
16 
AE Review 
 
 
<===========================================================================================> 
All AEs will be 
collected from 
first dose until 
follow up visit 
Concomitant Medication 
Review 
<====================================================================================================> 
 
 


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Table 2 continued 
Part 1 SAD Cohorts 1 and 2 Periods 1 through 4 – Outpatient Visit 
Procedure 
Day  
Notes 
Hours (h) relate to PK sampling post 
last dose 
9 (192 h)   
12 (264 h)  
16 (360 h)  
Outpatient Visit 
X 
X 
X 
 
Brief Physical Exam 
X 
 
X 
  
 
X 
  
Brief physical examinations may be 
made full and laboratory procedures 
may be repeated if needed at the 
discretion of the PI. 
Vital signs 
X 
X 
X 
For further detail, see Section 8.1.2 
 
12-lead safety ECGs 
X 
X 
X 
For further detail, see Section 8.1.4 
Haematology/Chemistry/ 
Urine tests 
X 
X 
X 
For further detail, see Section 
Appendix 2 
Plasma PK Sampling 
X 
X 
X 
In Cohort 1, 4mL of blood will be 
collected for analysis at each timepoint. 
In Cohort 2, 2 mL of blood will be 
collected at each visit. For further detail, 
see Section 8.4. 
Urine PK Sampling 
X 
X 
X 
For Cohort 2 Period 3 only, fresh spot 
urine sample collection at each visit. 
Please see SRM for further detail.  
SAE/AE Review 
<=================================================================================> 
All SAEs will be collected from 
screening until follow up visit; All AEs 
will be collected from first dose until 
follow up visit 
Concomitant Medication 
Review 
<=================================================================================> 
 


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Table 3 
Part 2 Multiple ascending dose (MAD) Cohorts 3 and 4: Study Intervention - In Unit Duration 
Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 14 
3, 5, 7, 9, 11, 13 
  15 
(24 h) 
 
16 
(48 h) 
 
17 
(72 h) 
 
18 
(96 h) 
 
19 
(120 h) 
 
Hours (h) relate to PK sampling 
post last dose 
Admission to Unit 
X 
 
 
 
 
 
 
 
 
 
In a pandemic situation see 
Appendix 7. 
Discharge from Unit 
 
  
 
 
 
 
 
 
 
X 
In a pandemic situation see 
Appendix 7 
Brief Physical Exam 
 
X 
 
X (Day 6) 
 
X 
 
 
 
X 
Brief physical examinations may 
be made full and laboratory 
procedures may be repeated if 
needed at the discretion of the 
PI. 
CSSRs 
 
 
 
X (Day 12) 
 
 
 
 
 
X 
 
Weight, BMI 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
X 
X  
  
 
 
X 
 
X 
X 
Vital signs to be performed pre-
dose. Temperature will be 
monitored every day during 
study participation. For further 
detail, see Section 8.1.2 
12-lead safety ECGs 
 
X 
X 
X 
 
 
X (Day 3) 
X 
X 
X 
X 
X 
ECG should be performed pre-
dose on dosing days. ECG 
timepoints may be reduced in 
subsequent dosing groups. For 
further detail, see Section 8.1.4 
Continuous ECG (full 
time matched baseline 
on Day-1) 
 
X 
X 
X  
(Day 2 end of 24 h 
collection from Day 
1 and Day 14) 
 
X 
 (end of 
24 h 
collection 
from Day 
14) 
 
 
 
 
Continuous ECG monitoring 
from Day -1 to 24 h post dose on 
Day 1 and 14. ECG data 
extraction will coincide with PK 
sampling schedule at pre-dose, 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 
and 24 h post dose on Days 1, 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 14 
3, 5, 7, 9, 11, 13 
  15 
(24 h) 
 
16 
(48 h) 
 
17 
(72 h) 
 
18 
(96 h) 
 
19 
(120 h) 
 
Hours (h) relate to PK sampling 
post last dose 
2, 14 and 15 and on 
corresponding timepoints on 
Day -1. For further detail, see 
Section 8.1.4 
Testing for SARS CoV-2 
X 
 
 
X  
(Day 14) 
X  
(Day 7) 
 
 
 
 
X 
An additional SARS-CoV-2 test 
will be performed approximately 
one week prior to admission to 
the unit. Weekly SARS-CoV-2 
testing is required while in the 
unit (Days 7 and 14) and on 
discharge (Day 19). An 
approved molecular test (PCR) 
will be used. For further detail, 
see Appendix 7 and Section 
8.1.3. 
Drug/alcohol/cotinine 
screen 
X 
  
 
 
 
 
 
 
 
 
 
Haematology/Chemistry
/ Urine tests 
 
X  
X 
X  
 
 
X 
 
X 
X 
For further detail, see 
Appendix 2 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
Female participants only. For 
further detail see Appendix 2 
VH3739937 Dose 
Administration 
 
  
X 
X 
X 
 
 
 
 
 
Once-daily oral dose from Day 1 
to Day 14. Randomization to 
occur on Day 1 prior to dosing. 
For meal instructions prior to 
dose, see Section 5.3.1 
Meals 
Per site usual practice 
Plasma PK Sampling 
 
  
  
X 
X 
   
X 
 (Day 3, 11 and 
13) 
X 
X 
X 
 X 
X 
2mL of blood will be collected at 
pre-dose (within 15 mins prior to 
dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 
9, 10, 12, 16 and 24h post 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 14 
3, 5, 7, 9, 11, 13 
  15 
(24 h) 
 
16 
(48 h) 
 
17 
(72 h) 
 
18 
(96 h) 
 
19 
(120 h) 
 
Hours (h) relate to PK sampling 
post last dose 
  
dosing on Day 1 and Day 14. 
The 24 hour post Day 1 dose 
collection will be pre-dose on 
Day 2, the 24 hour post Day 14 
dose collection will be post dose 
on Day 15 (24 hours after the 
last dose). Samples will also be 
collected pre-dose on Days, 3, 
4, 6, 8, 10, 11,12, 13 and once 
each day on days 16 (48 hours 
post last dose),17(72 hours post 
last dose),18 (96 hours post last 
dose) and 19 (120 hours post 
last dose).  PK sampling 
timepoints may be reduced. For 
further detail, see Section 8.4 
Plasma Metabolite 
Sampling 
 
  
  
X 
 
X  
(Day 2 and Day 14) 
 
 
  
  
  
  
  
  
X 
  
  
  
  
Additional 2mL of blood will be 
collected at pre-dose (within 15 
mins prior to dosing) and at the 
same timepoints as Plasma PK 
samples on Days 1, 2, 14 and 
15 (as described above). For 
further detail, see Section 8.4 
Urine PK and Metabolite 
Sampling 
 
 
X 
X  
(Day 2 end of 24 h 
collection from    
Day 1 and on Day 
14) 
 
X (end of 
24 h 
collection 
from Day 
14) 
X 
X 
X 
X 
Collections at pre-dose (20 mL) 
(within 1 h prior to dosing) and 
from time 0 up to 24 h post 
dosing on Day 1 and from time 0 
to 24h post dosing on Day 14. 
Spot urine sample collection on 
Day 16, 17, 18, and 19 at the 
post dose timepoint utilized on 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 14 
3, 5, 7, 9, 11, 13 
  15 
(24 h) 
 
16 
(48 h) 
 
17 
(72 h) 
 
18 
(96 h) 
 
19 
(120 h) 
 
Hours (h) relate to PK sampling 
post last dose 
Day 1. For further detail, see 
Section 8.4 
SAE Review 
=====================================================================================> 
All SAEs will be collected from 
screening until follow up visit 
AE Review 
 
 
==========================================================================> 
All AEs will be collected from 
first dose until follow up visit 
Concomitant Medication 
Review 
<======================================================================================> 
 


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Table 3 continued 
Part 2 MAD Cohorts 3 and 4 – Outpatient Visit 
Procedure 
Day  
Notes  
Hours (h) relate to PK sampling post 
last dose 
22 (192 h)   
25 (264 h)  
29 (360 h)  
Outpatient Visit 
X 
X 
X 
 
Brief Physical Exam 
X 
 
X 
  
 
X 
  
Brief physical examinations may be 
made full and laboratory procedures 
may be repeated if needed at the 
discretion of the PI. 
Vital signs 
X 
X 
X 
For further detail, see Section 8.1.2 
 
12-lead safety ECGs 
X 
X 
X 
For further detail, see Section 8.1.4 
Haematology/Chemistry/ 
Urine tests 
X 
X 
X 
For further detail, see Appendix 2 
Plasma PK Sampling 
X 
X 
X 
About 2 mL of blood will be collected at 
each visit. 
Urine PK Sampling 
X 
X 
X 
Fresh spot urine sample collection at 
each visit. Please see SRM for further 
detail.  
SAE/AE Review 
<=================================================================================> 
All SAEs will be collected from 
screening until follow up visit; All AEs 
will be collected from first dose until 
follow up visit 
Concomitant Medication 
Review 
<=================================================================================> 
 
 


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Table 4 
Part 2 MAD Cohort 5: Study Intervention (Day-2 to Day 23) – In Unit Duration 
Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 
14, 16, 18 
3, 5, 7, 9, 11, 13, 
15, 17 
      19 
(24 h) 
 
20 
(48 h) 
 
21 
(72 h) 
 
22 
(96 h) 
 
23 
(120 h) 
 
 
Hours (h) relate to PK sampling 
post last dose 
Admission to Unit 
X 
 
 
 
 
 
 
 
 
 
In a pandemic situation see 
Appendix 7. 
Discharge from Unit 
 
  
 
 
 
 
 
 
 
X 
In a pandemic situation see 
Appendix 7 
Brief Physical Exam 
 
X 
 
X  
(Day 18) 
X  
(Day 9) 
 
 
 
 
X 
Brief physical examinations may 
be made full and laboratory 
procedures may be repeated if 
needed at the discretion of the PI. 
CSSRs 
 
 
 
X 
 (Day 18) 
X 
(Day 9) 
 
 
 
 
X 
 
Weight, BMI 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
X 
X  
X  
(Days 15 and 
17) 
 
 
 
X 
 
X 
X 
Vital signs to be performed pre-
dose. Temperature will be 
monitored every day during study 
participation. For further detail, 
see Section 8.1.2 
12-lead safety ECGs 
 
X 
X 
 
X 
 
 
X  
(Days 3, 15 and 
17) 
X 
X 
X 
X 
X 
ECG should be performed pre-
dose on dosing days. ECG 
timepoints may be reduced in 
subsequent dosing groups. For 
further detail, see Section 8.1.4 
Continuous ECG (full 
time matched baseline 
on Day-1) 
 
X 
X 
X  
(Day 2 - end of 24 
h collection from 
Day 1 and Day 14) 
X 
 (Day 15 - end of 
24 h collection 
from Day 14) 
 
 
 
 
 
Continuous ECG monitoring from 
Day -1 to 24 h post dose on Day 
1 and 14. ECG data extraction 
will coincide with PK sampling 
schedule at pre-dose, 1, 2, 3, 4, 
5, 6, 7, 8, 9, 10, 12, 16 and 24 h 
post dose on Days 1, 2, 14 and 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 
14, 16, 18 
3, 5, 7, 9, 11, 13, 
15, 17 
      19 
(24 h) 
 
20 
(48 h) 
 
21 
(72 h) 
 
22 
(96 h) 
 
23 
(120 h) 
 
 
Hours (h) relate to PK sampling 
post last dose 
15 and on corresponding 
timepoints on Day -1. For further 
detail, see Section 8.1.4 
Testing for SARS CoV-2 
X 
 
 
X  
(Day 14) 
X  
(Day 7) 
 
 
 
 
X 
An additional SARS-CoV-2 test 
will be performed approximately 
one week prior to admission to 
the unit. Weekly SARS-CoV-2 
testing is required while in the unit 
(Days 7, 14) and on discharge 
(Day 23). An approved molecular 
test (PCR) will be used. For 
further detail see Appendix 7 and 
Section 8.1.3 
Drug/alcohol/cotinine 
screen 
X 
  
 
 
 
 
 
 
 
 
 
Haematology/Chemistry/ 
Urine tests 
 
X  
X 
X  
X  
(Day 15) 
 
X 
 
X 
X 
For further detail, see Appendix 2 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
X 
Female participants only.  For 
further detail see Appendix 2 
VH3739937 Dose 
Administration 
 
  
X 
X 
X 
 
 
 
 
 
Once-daily oral dose from Day 1 
to Day 18. Randomization to 
occur on Day 1 prior to dosing. 
For meal instructions prior to 
dose, see Section 5.3.1 
Meals 
Per site usual practice 
 
Plasma PK Sampling 
 
  
  
X 
X 
   
X 
 (Days 3, 15, 17) 
  
X 
X 
X 
 X 
X 
2mL of blood will be collected 
pre-dose (within 15 mins prior to 
dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 
9, 10, 12, 16 and 24h post dosing 
on Days 1, 14 and Day 18. The 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 
14, 16, 18 
3, 5, 7, 9, 11, 13, 
15, 17 
      19 
(24 h) 
 
20 
(48 h) 
 
21 
(72 h) 
 
22 
(96 h) 
 
23 
(120 h) 
 
 
Hours (h) relate to PK sampling 
post last dose 
24 hour post Day 1 dose 
collection will be pre-dose on Day 
2, the 24 hour post Day 14 dose 
collection will be post-dose on 
Day 15 and the 24 hour post Day 
18 dose will be post dose on Day 
19 (24 hours after the last dose). 
At all other timepoints on dosing 
days, samples will be drawn pre-
dose prior to dose administration. 
On post dosing Days 20, 21, 22 
and 23 samples will be collected 
at the same time of the day as the 
post-dose collections on dosing 
days. PK sampling timepoints 
may be reduced. For further 
detail, see Section 8.4 
Plasma Metabolite 
Sampling 
 
  
  
X 
 
 
X 
(Days 2, 14 and 
18) 
 
  
 
  
  
X  
(Day 15)  
  
  
X 
  
  
  
  
Additional 2mL of blood will be 
collected pre-dose (within 15 
mins prior to dosing) and at the 
same timepoints as Plasma PK 
samples on Days 1, 2, 14, 15, 18 
and 19 (as described above). For 
further detail, see Section 8.4 
Urine PK and Metabolite 
Sampling 
 
 
X 
X  
(Day 2 end of 24 h 
collection from    
Days 1, 14 and 
Day 18) 
X  
(Day 15 end of 
24 h collection 
from Day 14)  
 
X       
(Day 19 
end of   
24 h 
collection 
X 
X 
X 
X 
Collections at pre-dose (40 mL) 
(within 1 h prior to dosing) and 
from time 0 up to 24 h post 
dosing on Days 1, 14 and 18. 
Spot urine sample collection on 


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Procedure 
Pre-
Treatment 
Days   
Treatment Days 
In House Post Treatment Days 
Notes 
-2 
-1 
1 
2, 4, 6, 8, 10, 12, 
14, 16, 18 
3, 5, 7, 9, 11, 13, 
15, 17 
      19 
(24 h) 
 
20 
(48 h) 
 
21 
(72 h) 
 
22 
(96 h) 
 
23 
(120 h) 
 
 
Hours (h) relate to PK sampling 
post last dose 
from Day 
18) 
Day 20, 21, 22, and 23. For 
further detail, see Section 8.4 
Bile Sampling 
(Enterotest or 
EnteroTracker) 
 
 
 
X  
(Day 18) 
 
 
 
 
 
 
Collection at pre-dose and post 
dose via Enterotest or 
Enterotracker. Enterotest or 
Enterotracker will be swallowed at 
2 h post dose. After approx. 6.5 h 
the string will be removed. For 
Further detail see Section 5.3.1 
SAE Review 
<=====================================================================================> 
All SAEs will be collected from 
screening until follow up visit  
AE Review 
 
 
<==========================================================================> 
All AEs will be collected from first 
dose until follow up visit 
Concomitant Medication 
Review 
<=====================================================================================> 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4 continued:  Part 2 MAD Cohort 5: Outpatient Visits  
 
Procedure 
Day  
Notes 
Hours (h) relate to PK sampling post 
last dose 
26 (192 h)   
29 (264 h)  
33 (360 h)  
Outpatient Visit 
X 
X 
X 
 
Brief Physical Exam 
X 
 
X 
  
 
X 
  
Brief physical examinations may be 
made full and laboratory procedures 
may be repeated if needed at the 
discretion of the PI. 
Vital signs 
X 
X 
X 
For further detail, see Section 8.1.2 
12-lead safety ECGs 
X 
X 
X 
For further detail, see Section 8.1.4 
Haematology/Chemistry/ 
Urine tests 
X 
X 
X 
For further detail, see Appendix 2 
Plasma PK Sampling 
X 
X 
X 
About 2 mL of blood will be collected at 
each visit. 
Urine PK Sampling 
X 
X 
X 
Fresh spot urine sample collection at 
each visit. Please see SRM for further 
detail.  
SAE/AE Review 
<=================================================================================> 
All SAEs will be collected from 
screening until follow up visit; All AEs 
will be collected from first dose until 
follow up visit 
Concomitant Medication 
Review 
<=================================================================================> 
 


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Table 5 
Part 2 Weekly MAD Cohort 6: Study Intervention – In Unit Duration 
Procedure 
Pre-
Treatment 
Days   
Week 1 
Week 2 
Week 3 
In House Post Treatment Days 
Notes 
Treatment 
Days 
Treatment 
Days 
Treatment 
Days 
-2 
-1 
 1 
2, 3, 4, 
5, 6, 7  
 8  
9, 10, 11, 
12, 13, 14 
15 
    16 
24h 
 
17 
48h 
 
18 
72h 
 
19 
96h 
 
20 
120h 
 
 
Hours (h) relate to PK sampling 
post last dose 
Admission to Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
In a pandemic situation see 
Appendix 7. 
Discharge from Unit 
 
  
 
 
 
 
 
 
 
 
 
X 
In a pandemic situation see 
Appendix 7 
Brief Physical Exam 
 
X 
 
X 
(Day 6) 
  
X 
(Day 9) 
X 
 
 
 
 
X 
Brief physical examinations may 
be made full and laboratory 
procedures may be repeated if 
needed at the discretion of the PI. 
CSSRs 
 
 
 
 
 
X 
(Day 12) 
 
 
 
 
 
X 
 
Weight, BMI 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
X 
X 
 (Days 2, 
4, and 6) 
 
X  
X 
(Days 10, 
12 and 
14) 
X 
X  
 
X 
 
X 
Vital signs to be performed pre-
dose. Temperature will be 
monitored every day during study 
participation. For further detail, 
see Section 8.1.2 
12-lead safety ECGs 
 
X 
X 
 
X  
 
X 
X  
X 
X 
X 
X 
X 
X 
ECG should be performed pre-
dose on dosing days. ECG 
timepoints may be reduced in 
subsequent dosing groups. For 
further detail, see Section 8.1.4 
Testing for SARS CoV-2 
X 
 
 
X  
(Day 7) 
  
X 
(Day 14) 
 
 
 
 
 
X 
An additional SARS-CoV-2 test 
will be performed approximately 
one week prior to admission to 
the unit. Weekly SARS-CoV-2 
testing is required while in the unit 
(Days 7, 14) and on discharge 
(Day 20). An approved molecular 


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Procedure 
Pre-
Treatment 
Days   
Week 1 
Week 2 
Week 3 
In House Post Treatment Days 
Notes 
Treatment 
Days 
Treatment 
Days 
Treatment 
Days 
-2 
-1 
 1 
2, 3, 4, 
5, 6, 7  
 8  
9, 10, 11, 
12, 13, 14 
15 
    16 
24h 
 
17 
48h 
 
18 
72h 
 
19 
96h 
 
20 
120h 
 
 
Hours (h) relate to PK sampling 
post last dose 
test (PCR) will be used. For 
further detail see Appendix 7 and 
Section 8.1.3 
Drug/alcohol/nicotine 
screen 
X 
  
 
 
 
 
 
 
 
 
 
 
 
Haematology/Chemistry/ 
Urine tests 
 
X  
X 
X  
(Days 2, 
4 and 6) 
 
X  
X 
(Days 9, 
11 and 
13) 
X 
 
X 
 
X 
X 
For further detail, see Appendix 2 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
  
Female participants only. For 
further detail see Appendix 2 
VH3739937 Dose 
Administration 
 
  
X 
 
X 
 
X 
 
 
 
 
 
Weekly oral dose on Days 1, 8 
and 15. Randomization to occur 
on Day 1 prior to dosing. For 
meal instructions prior to dose, 
see Section 5.3.1 
Meals 
Per site usual practice 
 
Plasma PK Sampling 
 
  
  
X 
X 
  X 
X 
X  
X 
X 
X 
 X 
X 
2mL of blood will be collected at 
pre-dose (within 15 mins prior to 
dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 
9, 10, 12, and 16 h on Days 1, 8 
and Day 15. The 24 h post day 1 
dose collection on Days 2, 9 and 
15 will be taken at post-dose 
collection timepoint. At all other 
timepoints on non-dosing days 
(Days 3, 4, 5, 6, 7, 10, 11, 12, 13, 
14, 16, 17, 18, 19, 20), samples 
will be drawn at the post-dose 


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Procedure 
Pre-
Treatment 
Days   
Week 1 
Week 2 
Week 3 
In House Post Treatment Days 
Notes 
Treatment 
Days 
Treatment 
Days 
Treatment 
Days 
-2 
-1 
 1 
2, 3, 4, 
5, 6, 7  
 8  
9, 10, 11, 
12, 13, 14 
15 
    16 
24h 
 
17 
48h 
 
18 
72h 
 
19 
96h 
 
20 
120h 
 
 
Hours (h) relate to PK sampling 
post last dose 
timepoint. For further detail, see 
Section 8.4 
Urine PK  
 
 
X 
X  
(Day 2, 
end of 
24hr 
collection 
from Day 
1)  
X 
X  
(Day 9, 
end of 
24hr 
collection 
from Day 
8) 
X 
X  
(Day 
16, 
end 
of 
24hr 
colle
ction 
from 
Day 
15) 
 
 
 
 
  Collections at pre-dose (20 mL) 
(within 1 h prior to dosing) and 
from time 0 up to 24 h post 
dosing on Days 1, 8 and 15. For 
further detail, see Section 8.4 
SAE Review 
<=====================================================================================> 
All SAEs will be collected from 
screening until follow up visit 
AE Review 
 
 
<==========================================================================> 
All AEs will be collected from first 
dose until follow up visit 
Concomitant Medication 
Review 
<=====================================================================================> 
 
 
 
 
 
 
 
 
 


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Table 5 continued:  Part 2 Weekly MAD Cohort 6: Outpatient Visit  
 
Procedure 
Day  
Notes 
Hours (h) relate to PK sampling post 
last dose 
23 (192 h)   
26 (264 h)  
30 (360 h)  
Outpatient Visit 
X 
X 
X 
 
Brief Physical Exam 
X 
 
X 
  
 
X 
  
Brief physical examinations may be 
made full and laboratory procedures 
may be repeated if needed at the 
discretion of the PI. 
Vital signs 
X 
X 
X 
For further detail, see Section 8.1.2 
 
12-lead safety ECGs 
X 
X 
X 
For further detail, see Section 8.1.4 
Haematology/Chemistry/ 
Urine tests 
X 
X 
X 
For further detail, see Appendix 2 
Plasma PK Sampling 
X 
X 
X 
About 2 mL of blood will be collected at 
each visit. 
Urine PK Sampling 
X 
X 
X 
Fresh spot urine sample collection at 
each visit. Please see SRM for further 
detail.  
SAE/AE Review 
<=================================================================================> 
All SAEs will be collected from 
screening until follow up visit; All AEs 
will be collected from first dose until 
follow up visit 
Concomitant Medication 
Review 
<=================================================================================> 
 
 
 
 
 
 
 


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Table 6 
Part 3 RBA Cohort 7: Study Intervention – In Unit Duration and Outpatient Visits  
Procedure 
Pre-
Treatment 
Days 
Treatment Periods 1 and 2 (Days) 
Treatment Period 3 only (Days) 
Notes 
 
-2 
 
-1 
 
1 
Washout 
1 
Washout 
Hours (h) relate to PK sampling 
post last dose 
2 
3 -5 
6 
9 
12 
16 
17-22 
2 
3-5 
6 
9 
12 
16 
Admission to 
Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For all treatment periods, 24 
day required wash out includes 
completion of re-admission to 
unit on Day -2 and Day -1 for 
subsequent treatment periods. 
Admission to unit will occur on 
Day-2 for all treatment periods.  
Discharge from 
clinic 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Discharge from unit at 
discretion of PI during 
pandemic 
Outpatient Visit 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
Brief Physical 
Exam 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
Brief physical examinations 
may be made full examinations 
if needed, at the discretion of 
the investigator 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Female participants only. For 
further detail see Appendix 2 


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Procedure 
Pre-
Treatment 
Days 
Treatment Periods 1 and 2 (Days) 
Treatment Period 3 only (Days) 
Notes 
 
-2 
 
-1 
 
1 
Washout 
1 
Washout 
Hours (h) relate to PK sampling 
post last dose 
2 
3 -5 
6 
9 
12 
16 
17-22 
2 
3-5 
6 
9 
12 
16 
SARS-CoV-2 
Test 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
An approved molecular test 
(PCR) will be used. If 
participants remain in unit 
during study treatment periods, 
weekly SARS-CoV-2 testing is 
required. If participants are 
discharged from unit on Day 6, 
SARS-CoV2 test will be 
required at discharge, 
approximately one week prior to 
re-admission to the unit for the 
following period and at Day -2. 
For further detail, see Appendix 
7 and Section 8.1.3 
Drug/alcohol/  
nicotine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse will 
be measured in triplicate pre-
dose on Day 1 in Periods 1-3. 
At all other timepoints, single 
blood pressure and pulse will 
be measured at pre-dose 
timepoint. Temperature will be 
monitored every day during 
study participation.   For further 
detail, see Section 8.1.2 
CSSRS 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 


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Procedure 
Pre-
Treatment 
Days 
Treatment Periods 1 and 2 (Days) 
Treatment Period 3 only (Days) 
Notes 
 
-2 
 
-1 
 
1 
Washout 
1 
Washout 
Hours (h) relate to PK sampling 
post last dose 
2 
3 -5 
6 
9 
12 
16 
17-22 
2 
3-5 
6 
9 
12 
16 
VH3739937 
Dose 
Administration 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Randomization to occur on Day 
1 prior to dosing. For meal 
instructions prior to dose, see 
Section 5.3.1 
12-Lead Safety 
ECGs 
 
X 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
All ECG timepoints on Day 1 in 
Periods 1-3 will be taken at pre-
dose, 2 h and 4 h post dose. 
Pre-dose ECGs in Periods 1-3 
will be taken in triplicate. For 
further detail, see Section 8.1.4 
Plasma PK 
Sampling 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
2mL of blood will be collected at 
pre-dose (within 15 mins prior 
to dosing) and 1, 2, 3, 4, 5, 6, 7, 
8, 9, 10, 12, 16, 24, 48, 72, 96, 
120,192, 264, 360 h post dose. 
For further detail, see Section 
8.4. Please see SRM for details 
of blood collection and 
processing. 
Haematology/ 
Chemistry/Urine 
Test 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
Day -1 assessments will be 
collected prior to dosing periods 
for all treatment periods. Day 2 
samples in each period to be 
collected 24 h post dose.  For 
further detail, see Appendix 2 
SAE review 
============================================================================================➔ All SAEs will be collected from 
screening until follow up visit 


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Procedure 
Pre-
Treatment 
Days 
Treatment Periods 1 and 2 (Days) 
Treatment Period 3 only (Days) 
Notes 
 
-2 
 
-1 
 
1 
Washout 
1 
Washout 
Hours (h) relate to PK sampling 
post last dose 
2 
3 -5 
6 
9 
12 
16 
17-22 
2 
3-5 
6 
9 
12 
16 
AE review 
 
 
==================================================================================➔ All AEs will be collected from 
first dose until follow up visit 
Concomitant 
medications 
=============================================================================================➔  


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
The inhibition of maturation and release of human immunodeficiency virus-1 
(HIV-1) is a novel target for drug development, distinct from viral protease, reverse 
transcriptase and integrase. There are no maturation inhibitors (MI) approved for the 
treatment of HIV infection. VH3739937 is a MI that displays in vitro evidence of low 
nanomolar potency against multiple HIV-1 Gag polymorphisms and a broad spectrum 
covering multiple HIV-1 subtypes, supporting compound development. This is a double-
blind (sponsor-unblinded), randomised, placebo-controlled, first-time-in-human (FTIH) 
study in a combined single- and multiple-dose protocol to investigate the safety, 
tolerability and PK of VH3739937 in healthy participants. This study is designed in three 
parts: i) to gain information on the safety, tolerability, and pharmacokinetic properties of 
VH3739937 when administered as powder-in-a-bottle (PiB); ii) the relative 
bioavailability (RBA) of the GSK3739937 PiB and GSK3739937 Tablet  and; iii) to 
evaluate the safety, tolerability and pharmacokinetic (PK) parameters of the tablet 
formulation when administered under fasting and fed conditions. This study will enable 
further clinical development of VH3739937, including a Phase IIA Proof of Concept 
(PoC) study in HIV-infected patients, a First-Time-in-Human study of the long acting 
formulation of VH3739937, as well as supporting the future studies of parenteral 
administration (subcutaneous and intramuscular routes) of a long acting formulation of 
VH3739937. 
 
2.2. 
Background 
It is estimated that approximately 38 million people are currently living with 
HIV/Acquired Immunodeficiency Syndrome (AIDS) and that the worldwide epidemic 
continues to grow at a rate of 1.7 million new infections and cause 770,000 deaths per 
year [Fact sheet, 2019].  Chronic HIV infection in adults continues to be characterized by 
increased development of resistant virus, increasing transmission of resistant virus and 
issues associated with long term toxicity of anti-retroviral therapy (ART).  The current 
paradigm in the treatment of HIV involves life-long therapy with multiple antiretrovirals. 
This dependency on medical therapy requires a need for continuous improvement on the 
durability, tolerability and convenience of all antiretroviral classes.   
Chronic exposure to combination anti-retroviral therapy (cART) has identified anti-
retroviral (ARV)-associated long-term toxicities (e.g. central nervous system (CNS) or 
cardiovascular (CV)/metabolic effects, renal disease, etc.), creating a need to address and 
prevent these co-morbidities. Regimens which avoid particular classes of agents may help 
avoid or manage comorbidities among people living with HIV (PLHIV) and the use of 2 
drug regimens have the potential to reduce long term toxicities by reducing ARV 
exposure. Treatment failure remains a continuing concern in clinical care due to the 
presence and emergence of resistant strains and tolerability issues. In addition, managing 
an ageing population of PLHIV with an increasing prevalence of comorbidities and 
polypharmacy requires ARVs with the potential for fewer drug-drug interactions. 


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VH3739937, an HIV-1 maturation inhibitor (MI) has a novel mechanisms of action 
(MoA) and has the potential to meet these required characteristics for future therapy.  
There is considerable interest in long acting antiretroviral therapy which allow less than 
daily dosing among PLHIV. Long acting (LA) regimens offer potential advantages over 
daily oral regimens including less frequent dosing, improved adherence, treatment 
satisfaction and outcomes.  
The inhibition of maturation and release of human immunodeficiency virus-1 (HIV-1) is 
a novel target for drug development, distinct from viral protease, reverse transcriptase or 
integrase. There are currently no MIs approved for the treatment of HIV infection. 
VH3739937 is a MI that displays in vitro evidence of low nanomolar potency against 
multiple HIV-1 Gag polymorphisms and a broad spectrum covering multiple HIV-1 
subtypes, supporting compound development and has the potential to be developed as a 
long acting formulation as well as an oral formulation.  It is anticipated the oral version 
will be used as an oral lead in to establish short term safety and tolerability prior to LA 
administration or to bridge periods where LA dosing is not possible. The oral version of 
VH3739937 will support the undertaking of the phase 2a POC study and drug-drug 
interaction studies.   
VH3739937 is a next-generation HIV MI with a similar chemical structure and profile to 
GSK3640254 which is being developed as an oral ARV. Both MIs have improved profile 
over prior developmental MIs as they (1) exhibit significantly improved pan-genotypic 
coverage and potency against polymorphic variants; (2) in vitro data suggest that both 
MIs exhibit a higher barrier to emergence of resistant viruses (except for A364V); (3) 
both MIs have improved potency in vitro toward all HIV-1 subtypes; and (4) it has a 
projected lower once-daily (QD) human dose. Summaries of the pre-clinical studies are 
included in the Clinical Investigator's Brochure (CIB) [GlaxoSmithKline Document 
Number 2019N421306_00]. 
2.2.1. 
Background Key Safety and PK data with Prior Maturation 
Inhibitors (GSK3532795 and GSK3640254) 
Bristol-Myers Squibb (BMS), and later ViiV Healthcare (VH), developed an HIV-1 MI 
(GSK3532795), which was studied through Phase 2b studies in both treatment-naïve 
(AI468038) and experienced (AI468048) HIV-1 infected adults. In study AI468038, a 
greater number of participants who received GSK3532795 experienced gastrointestinal 
(GI) intolerability (specifically G1-2 diarrhoea and abdominal pain). A detailed 
examination of all GI AEs (regardless of Grade/Relationship) revealed a relationship with 
dose [GlaxoSmithKline Document Number 2016N302783_00]. Ultimately, the rate of GI 
intolerability in the GSK3532795 dose groups in the Phase 2b study AI468038, helped 
lead to VH’s decision to end all clinical trials and not progress to Phase 3 studies. 
GI AEs were also previously observed in healthy participants in Phase 1 studies with 
varying doses, durations, and formulations of GSK3532795.  First, in AI468049, the rates 
of GI AEs ranged from 33-67% across cohorts (single oral doses of GSK3532795 60 mg 
– 180 mg with food) [GlaxoSmithKline Document Number 2016N297636_00].  Second, 
in AI468063, 65% of participants receiving GSK3532795 180 mg QD with food 


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developed diarrhoea [GlaxoSmithKline Document Number 2017N319618_00].  Finally, 
in AI468052, 29% of participants who received GSK3532795 180 mg once daily (QD) 
with food developed GI AEs. In all three studies, the most common GI AEs were 
abdominal pain and diarrhoea.  
Aside from mild-moderate GI intolerability, two SAEs occurred in phase I study 
AI468044 in healthy participants receiving supra-therapeutic doses of GSK3532795: one 
healthy participant had acute psychosis and another had suicidal ideation/homicidal 
ideation as diagnosed by a psychiatrist. These two participants received GSK3532795 
240 mg twice daily (BID) and 240 mg QD for 3 days with food, respectively. These 
events were not observed in any other clinical study with GSK3532795. The most 
frequent neuropsychiatric AEs in studies with GSK3532795 were headache, dizziness 
and sleep abnormalities (e.g. insomnia, abnormal dreams) [GlaxoSmithKline Document 
Number 2017N332341_00]. 
GSK3640254, was evaluated in a First time in human study (207187) and in a Phase 2a 
proof of concept study in HIV-1 infected, treatment-naïve patients. Study 207187 was 
carried out in two parts (Part 1 and Part 2).  Participants in Part 1 received single 
ascending doses of GSK3640254 (1-700 mg) and participants in Part 2 received repeated 
daily doses of GSK3640254 at different concentrations (50-320 mg) 
GSK3640254 did not show any major tolerability findings (including AEs, vital signs, 
ECG findings, or laboratory values) when given to healthy males in single doses (up to 
700 mg) or daily doses (up to 320 mg QD for 14 days), supporting further clinical 
development of GSK3640254. Three participants from Part 1 and one participant from 
Part 2 of the study were withdrawn due to adverse events. 
GI related AEs were reported in 6 of 16 participants from Part 1 and 13 of 56 participants 
from Part 2 of the study. All these events were mild in intensity. No dose/AE relationship 
and no major GI tolerability issues were observed in this study. 
Psychiatric AEs were reported in 2 of 16 participants from Part 1 and in 6 of 56 
participants from Part 2 of the study. All these events were mild (except 1 event of 
depression in Part 1 that was moderate in intensity in a participant with history of family 
stressors prior to study entry) and none were considered related to the study treatment. 
Neurologic AE of headache was reported in 6 participants from Part 1 and in 15 
participants from Part 2. There were no major GSK3640254 related neuro/psychiatric 
events observed. None of these events (except 1 in Part 2) were considered related to the 
study treatment. 
Skin tissue disorders AEs, contact dermatitis due to ECG leads were reported in 5 out of 
16 participants in Part 1. In Part 2 ,14 out of 56 participants reported skin related AEs, 
contact dermatitis due to ECG leads n=8, dry skin, eczema nummular, miliaria, pruritus 
rash and rash maculo-papular. All events were mild in intensity and none was considered 
related to study treatment. One event lead to study discontinuation (rash maculo-papular).  
Though there were a number of participants with ECG abnormalities in both parts of the 
study, none of these findings were considered clinically significant. There were no 


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clinically significant arrhythmias reported in either Part 1 or Part 2 of the study. No 
participants had a QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF) value of >500 msec or an increase from baseline >60 msec. A cardiodynamic 
evaluation of the multiple ascending dose portion of Study 207187 was undertaken based 
upon concentration vs change from pre-dose QT interval corrected (QTc) using 12-lead 
Holter ECGs an analysis by iCardiac/eRT. This indicated a weak relationship between 
QT prolongation and GSK3640254 plasma concentrations and indicated that an effect on 
QTcF can be excluded up to GSK3640254 plasma concentration of ~2000 
ng/mL[GlaxoSmithKline Document Number 2018N392814_01]. 
To characterize the population pharmacokinetics of VH3739937 and identify important 
determinants of variability, a population model was conducted as an alternate analysis 
approach to characterize the pharmacokinetics and the simulation was implemented to 
predicted the higher single dose and multiple dose cohort PK profile based on the model. 
The PK of VH3739937 following oral administration was adequately characterized by a 
linear one-compartment model with first-order absorption and first-order elimination, and 
with a dose factor and inter-individual variability on CL/F and on the magnitude of 
proportional residual error. The simulations for higher single dose 640 and 800 mg, 
multiple daily dose 50 and 100 mg and the multiple weekly dose 500 mg were conducted 
to predict the PK profile to obtain the Cmax and AUC for safety cover. More detailed 
information can be found in the Investigator’s Brochure Supplement [GlaxoSmithKline 
Document Number 2021 RPS_CLIN_004025]. 
2.3. 
Benefit/Risk Assessment 
Based upon pre-clinical studies and clinical studies of prior MIs (GSK3532795 and 
GSK3640254) the major potential risks are GI intolerability (e.g. abdominal pain and 
diarrhoea), gastric toxicity (effects on parietal cells and chief cells), prolongation of QTc, 
skin and subcutaneous tissue disorders (maculopapular rash) and neuropsychiatric safety. 
A preclinical toxicity finding observed microscopically in stomach (single-cell necrosis 
of parietal cells) was seen in animals at exposures of VH3739937 that will be tested in 
this study, however the microscopic finding was minimal and reversible in animals. As 
noted in Section 2.3.1, the GLP hERG invitro assay showed an atypical response 
(inhibition (~47%) at 2.306 - 0.231 equivalent to 0.073 µg/mL. This is consistent with the 
other non-clinical CV data which demonstrated high margin (see Section 2.3.1. for 
further detail).   
In a single-dose study of respiratory function in telemetered rats, VH3739937 resulted in 
mild reductions in respiratory rate and increased reversible pulmonary resistance. The 
protocol includes frequent monitoring of vital signs including respiratory rate and brief 
physical examinations including respiratory examination.  
The protocol will exclude potential participants from the study with any pre-existing 
psychiatric condition or positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered CSSRS. The CSSRS assessment will also 
be administered by a clinician (or qualified designee) during the on-treatment portion of 
the MAD only. 


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Thus, to ensure the overall safety of participants (including, but not limited to, the risk of 
GI intolerability, QTc prolongation, skin disorders and neuropsychiatric safety), this 
clinical trial will include healthy adults who will be actively monitored by receiving 
frequent clinical, ECG, and laboratory evaluations during their participation in the trial.  
In addition, consistent with Sponsor guidance for early phase studies, this study will be 
conducted in a hospital-based clinical research unit with prior experience with first-time-
in-human-trials, sufficient overnight facilities and immediate emergency care capabilities. 
ViiV Healthcare has assessed this study for any risks that may be posed to participants 
taking part. The proposed risk assessment and management plan for the study has been 
developed in accordance with the tenets of Food and Drug Administration (FDA) and 
European Medicines Agency (EMEA) guidance on strategies to identify and mitigate 
risks for FTIH clinical trials with investigational medicinal products.  
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of VH3739937 may be found in the IB 
[GlaxoSmithKline Document Number 2019N421306_00] and IB Supplement 
[GlaxoSmithKline Document Number 2021 RPS_CLIN_004025]. 


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [VH3739937] 
Cardiovascular (QT prolongation) 
Pre-clinically, VH3739937  
• In a definitive in vitro hERG assay, there 
was no hERG channel tail current inhibition 
at a concentration of 0.073 μg/mL in a 
protein free system and there was a flat 
level of hERG channel inhibition 
(approximately 46% to 48%) at 
concentrations of 2.306 μg/mL to 0.231 
μg/mL. This response was considered to be 
atypical and an half maximal inhibitory 
concentration (IC50) value was not 
estimated.  An in vitro cardiac ventricular 
wedge assay was negative for effects on 
QT interval or other ECG changes 
suggestive of effects on cardiac sodium or 
calcium channels at concentrations up to 
2.5 g.mL in a protein free system.   In a 
definitive cardiovascular telemetry study in 
dogs, VH3739937 did not have any effect 
on electrocardiogram at plasma 
concentration up to 9.82 µg/mL (1.47 
µg/mL free). A pivotal 1 month oral toxicity 
study in dogs was also negative for ECG 
changes at exposures up to 39.8 µg/mL 
(5.6 µg/mL free).  Weight of evidence 
 
• Protocol exclusion criteria based on ECG 
parameters and cardiac medical history. 
• Participants in the study will have a 24 hour 
holter monitor and continuous ECGs during 
treatment; they will also have frequent 
clinical and vital sign evaluations (see SoA 
table). 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
suggests a low potential for QT prolongation 
in humans at exposures up to the highest 
predicted mean maximum observed 
concentration (Cmax) of 3.76 µg/mL (0.26 
µg/mL free). 
• A cardiodynamic evaluation of the multiple 
ascending dose portion of study 207187 of 
GSK3640254 was undertaken based upon 
concentration vs change from pre-dose QTc 
using 12-lead Holter ECGs an analysis by 
iCardiac/eRT. This indicated a weak 
relationship between QT prolongation and 
GSK3640254 plasma concentrations and 
indicated that an effect on QTcF can be 
excluded up to GSK3640254 plasma 
concentration of ~2000 ng/mL 
 
Gastrointestinal intolerability  
• Clinical signs indicative of gastrointestinal 
intolerability (sporadic vomiting and 
abnormal faeces) occurred mainly in dogs 
at 30 mg/kg/day.  
 
• GSK3640254:  
- 
Low grade GI adverse effects were 
observed. The most frequent AEs were 
• Protocol exclusion criterion based on pre-
existing GI pathology or baseline GI 
signs/symptoms 
 
• Participants in the study will undergo 
intensive physical exam and laboratory 
testing. In addition, participants will undergo 
continuous evaluation for adverse events 
during their participation in the trial; there 
are clinical stopping criteria based upon 
incidence and intensity of treatment-
emergent AEs. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
abdominal pain and diarrhea in studies 
of GSK3640254.  
• GSK3532795: 
- 
Of note GI intolerability (predominately 
abdominal pain and diarrhea) was seen 
with a structurally related compound 
GSK3532795 which was evaluated 
through Phase 2b dosing.  
Gastric toxicity 
• Gastric toxicity findings were observed 
microscopically in stomach of single-cell 
necrosis of parietal cells and/or chief cells, 
decreased cellularity of parietal cells and 
other changes in appearance of chief cells 
and foveolar cells were present in preclinical 
species dosed for up to 4 weeks. These 
findings were reversible.  
• Based on preclinical toxicity studies, gastric 
findings were reversible. Gastric toxicity will 
be investigated in a phase 2b substudy of 
GSK3640254 
 
 
Neurologic/psychiatric safety 
• Two psychiatric SAEs in previous MI 
GSK3532795 clinical program (acute 
psychosis, homicidal/suicidal ideation) at 
supratherapeutic doses were seen in 
healthy participants in TQT study. 
 
• Psychiatric adverse events were reported 
infrequently in the FTiH study of 
GSK3640254 and were of low grade.  
• Protocol exclusion criterion based on any 
pre-existing psychiatric condition (including 
assessment using the CSSRS) for 
participants in the study. 
 
• Participants in the study will undergo 
intensive physical exam and laboratory 
testing. In addition, participants will undergo 
continuous evaluation for adverse events 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
• From a Neurologic and Psychiatric AE 
summary and PK/pharmacodynamic (PD) 
analysis for GSK3532795 across all studies 
mild G1 headache and G1 sleep 
abnormalities were the predominant AEs, 
with a trend for increasing neurologic and 
psychiatric AEs with increasing dose (based 
on TQT and P2b studies). No exposure-
response relationship seen for select 
neurologic and psychiatric AEs (based on 
TQT and P2b studies) 
 
• CNS penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly 
low brain distribution/penetration 
 
 
during their participation in the trial; there 
are clinical stopping criteria based upon 
incidence and intensity of treatment-
emergent AEs.  
 
• Participants will be in house throughout the 
study to ensure rapid diagnosis and 
management of any potential event. 
 
• Finally, participants in the RBA and FE will 
have CSSRS assessment at Day -1 and 
discharge, participants in SAD will have 
CSSRS assessment at discharge, and 
participants in the MAD will have 
assessment via a clinician (or qualified 
designee) administered CSSRS during the 
on-treatment portion of the study. In the 
event of a positive (abnormal) response 
confirmed by the investigator, the 
participant will discontinue from the trial and 
the PI/sub-investigator (SI) will arrange for 
urgent specialist psychiatric evaluation and 
management. 
Skin and subcutaneous tissue disorders  
• Across GSK3640254 clinical trials, AEs 
leading to discontinuation have included 
urticaria and maculopapular rash. 
 
• Participants will undergo continuous 
evaluation for adverse events during their 
participation in the trial supplemented by the 
use of physical exams. 
 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• Protocol includes individual participant 
stopping criteria, including:  
o A grade ≥2 rash with concurrent fever 
with or without concurrent elevations in 
liver biochemistry reasonably 
attributable to dosing with VH3739937, 
in the opinion of the Investigator.   
 


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2.3.2. 
Benefit Assessment 
This is a study in healthy participants; no medical benefit will be derived by participant’s 
participation.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Given the preclinical profile of VH3739937, the clinical profile of structurally similar 
MIs (GSK3532795 and GSK3640254), and the planned clinical procedures and 
evaluations in this study, the potential risks to participants receiving VH3739937 are low, 
evaluable, and manageable. 
2.3.4. 
Acute Monitoring in FTIH Studies 
Consistent with GlaxoSmithKline (GSK)/VH Guidance and Committee for Medicinal 
Products for Human Use (CHMP) guidelines for early phase studies, the study will be 
conducted in an accredited Phase 1 Clinical Research Unit(s) with previous experience 
with first-time-in-human trials and immediate access to hospital facilities for the 
treatment of medical emergencies. 
There will be continuous medical monitoring during the in-house period for all 
participants as detailed in the SoA for this study.   
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To investigate the safety and tolerability 
of VH3739937 following single, repeated 
daily, and weekly oral administration in 
healthy participants (Part 1 & 2) 
• 
To assess the safety and tolerability of 
VH3739937 following single oral 
administration in healthy participants 
under fasted or fed (moderate calorie and 
fat) conditions (Part 3) 
• 
To evaluate the relative bioavailability 
(RBA) of GSK3739937 powder-in-bottle 
(PiB) versus GSK3739937 Tablet and the 
effect of food on the PK of GSK3739937 
Tablets and GSK3739937 PiB (Part 3) 
VH3739937 safety parameters:  
• Adverse events; post baseline values and 
changes over time of clinical laboratory 
evaluations (haematology, clinical 
chemistry, urinalysis), vital signs, and ECG 
parameters from pre-dose values  
(Part 1, 2 & 3) 
 
 
 
• Derived PK parameters for VH3739937 
Part 3 (single dose):  AUC (0-24), AUC(0-inf), 
Cmax 
Secondary 
• 
To describe the PK profile of VH3739937 
following single (Part 1 & 3), repeated 
Derived PK parameters for VH3739937: 


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Objectives 
Endpoints 
daily and weekly (Part 2) oral 
administration in healthy participants 
 
 
 
• Part 1 (single dose): AUC(0-24), AUC(0-t) , 
AUC(0-inf) , Cmax, C24, tmax, tlag, t1/2, Clast, tlast, 
CL/F 
 
• Part 2 (repeated once daily [QD] dose): 
o Day 1: AUC (0-24), Cmax, C24, tmax, tlag 
o Day 14 (Cohorts 3 and 4): AUC(0-), 
Cmax, C, tmax, t1/2, and CL/F 
o Day 18 (Cohort 5): AUC(0-), Cmax, C, 
tmax, t1/2, and CL/F 
• Part 2 (repeated once weekly [QW] dose: 
o Day 1 (Cohort 6): AUC (0-168), Cmax, 
C168, tmax, tlag 
o Day 15 (Cohort 6): AUC(0-t), Cmax, Ct, 
tmax, t1/2, and CL/F 
 
• Part 3 (single dose): C24, tmax, tlag, t1/2, Clast, 
tlast, CL/F 
 
 
• 
To examine dose proportionality following 
single and repeated doses of      
VH3739937 (Part 1 & 2) 
Derived PK parameters for VH3739937: 
• 
Part 1 (single dose): AUC(0-inf), Cmax.  
• 
Part 2 (repeated dose): AUC(0-), Cmax, C 
• 
To predict the accumulation from single 
dose data (Part 1) and assess 
accumulation of VH3739937 after repeat 
doses (Part 2 at steady state) 
Accumulation indices for PK parameters for 
VH3739937: 
• 
Part 2 (repeated dose): 
Observed accumulation ratios: RAUC(0-) , 
R(Cmax),  R (C) 
• 
To assess time to steady-state of 
VH3739937 (Part 2) 
Derived PK parameters for VH3739937: 
• Part 2 (repeated dose):  
o Cohorts 3 and 4: Pre-dose 
concentrations on Day 2-14 
o Cohort 5: Pre-dose concentrations on 
Day 2-18  
Exploratory 
• To assess the exposure response 
relationship between VH3739937 and 
safety parameter, including QTcF following 
single and repeated administration (Part 1 
& 2) 
• Change-from-baseline QTcF (∆QTcF) 


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Objectives 
Endpoints 
• To collect plasma and urine samples for 
analysis of metabolites of VH3739937 
• Metabolites of VH3739937 in plasma and 
urine.  The analyses will be conducted and 
reported separately from this protocol.  
• To characterize renal excretion of 
VH3739937, as data permits  
• Urinary recovery of VH3739937 (Ae[0-x]), 
Ae[0-] and Ae[0-t]) and renal clearance 
(CLr) 
• To collect duodenal bile for analysis of 
metabolites of VH3739937 (Part 2, Cohort 
5 only) 
• Metabolites of VH3739937 in duodenal 
bile. The analyses will be conducted and 
reported separately from this protocol  
AUC(0-24) = Area under the plasma concentration time curve from zero (pre-dose) to 24; AUC(0-t) = Area 
under the plasma concentration time curve from zero (pre-dose) to t; AUC(0-inf) = Area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time; AUC(0-) = Area under 
the curve (Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing 
interval at steady state); Cmax = Maximum observed concentration; C24 = Drug concentration at 24 hours 
post-dose;  Clast = last observable concentration; tlast = time of last observable concentration; C (or Ctrough) = 
trough serum concentration; CL/F= Apparent oral clearance; ECG= Electrocardiogram; PiB = powder-in-
bottle; RAUC(0-) = Accumulation ratio of area under the concentration-time curve over the dosing interval; 
R(Cmax) = Ratio of maximum observed concentration; R (C) = Ratio of concentration over the dosing 
interval; RBA = relative bioavailability; tmax = Time of occurrence of Cmax; t1/2 = Apparent terminal phase 
half-life; tlag = lag time. 
 
Note: The exploratory endpoints may be analyzed upon the clinical development 
continuation of VH3739937. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-
controlled, single- and repeat-dose escalation study including a weekly oral dose MAD 
cohort and a RBA and FE cohort to investigate the safety, tolerability and PK of 
VH3739937 in healthy participants. 
 
As described in Figure 3 below, in Part 1, the proposed dosing schedule is designed to 
investigate single ascending oral doses of VH3739937 initially in Cohorts 1 and 2. Then, 
at a suitable cross-over point (described below), Part 2 will involve 4 cohorts of multiple 
ascending dosing of oral VH3739937 when administered:   
• once daily for 14 days (Cohorts 3 and 4);  
• once daily for 18 days (Cohort 5); and  
• three oral doses administered at weekly intervals over two weeks (Cohort 6) 
(Figure 3).    
In Part 3, the RBA and FE (Cohort 7) will include a randomized, open-label, single dose, 
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with GSK3739937 Tablet  and to assess the effect of food (fasted or fed (under moderate 
calorie and fat conditions)) upon the safety, tolerability and PK of the GSK3739937 
Tablet  (Figure 4).  All doses will be administered following a standardized meal for each 
dosing period that contains approximately 600 calories with approximately 30% of 
calories from fat (unless otherwise indicated in Part 3 dosing in fasted condition).   
Overall, approximately 76 participants will be randomly assigned to study intervention. 
In Part 1, approximately 18 participants will be randomized with approximately 9 
participants within each of Cohort 1 and Cohort 2.  Part 1 will include an additional 
higher dose treatment period (800 mg) evaluated in approximately 9 participants as 
supported by emerging data.  In Part 2, approximately 40 participants will be randomized 
with approximately 10 participants within each of Cohorts 3 to 6. In Part 3, 
approximately 18 participants will be treated to ensure that 12 evaluable participants 
complete Cohort 7. 
All participants will have a screening visit within 28 days prior to first dose and a follow-
up visit approximately 28 days after the last dose.  All dosing will be conducted in a 
hospital based inpatient clinical trial unit.  Study participants will be confined to the 
clinic from Day -2 until discharge.  Additional outpatient visits will be required for all 
study parts. Flexibility of visit scheduling may be required if a pandemic situation applies 
(see Appendix 7).  Otherwise, study assessments will be performed as indicated in the 
SoA presented in this protocol.    
A summary of the overall study design, including proposed doses, sample size, and order, 
is presented in Figure 3 and Figure 4 below.  
Figure 3 
Phase 1 Study in Healthy Participants using planned doses of 
VH3739937 Part 1 and Part 2 
 
 
A=Active; P=Placebo 
QD = once daily; QW = once weekly 
*= Period 4 may include participants from both Cohorts 1 and 2 
Highlighted cohorts and treatment periods denotes completed 


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The doses shown in Figure 3 above are intended to demonstrate general concepts relating 
to factors of escalation. The modelling and simulation implemented using the data 
currently available following oral administration of a suspension formulation in the fed 
state indicated the predicted efficacious dose for the daily dose is 25 mg and the weekly 
dose is 500 mg.  Due to the observed half-life of ~90 h, the anticipated accumulation ratio 
following repeated daily and weekly doses is ~6-fold and 1.3-fold, respectively.  Dosing 
will be conducted in accordance with safety and PK stopping criteria (Section 7.1.4). 
 In Part 1, dose escalation will be determined by ViiV Healthcare (VH)/GlaxoSmithKline 
(GSK) study team and the Principal Investigator (PI) and guided by safety data and PK 
stopping criteria. Post-dose safety and PK data through Day 16 from a minimum of 4 
participants receiving VH3739937 are required for dose escalation in Part 1. The suitable 
crossover point from Part 1 to Part 2 referenced in the above text was determined once 
the single dose safety and preliminary PK data for the anticipated minimally effective 
dose was evaluated in Part 1 single ascending dose (SAD) and the maximum exposure for 
the MAD dose was covered by the SAD certain dose level.  In Part 2, Cohorts 3 and 4, 
dose escalation will be determined by the VH/GSK study team and the PI and guided by 
the safety and PK data (minimally up to Day 29, 15 days following the Day 14 dose) 
from the previous dosing Cohort(s).  Dose escalation from Cohort 5 will be similarly 
guided by safety and PK data minimally up to Day 33, 15 days following the Day 18 
dose.  
 
Based on human PK predicted from preclinical species, assuming an average 
bioavailability of ~14% and dose proportionality as well as predicted moderate between-
participant PK variability, the highest dose to be assessed in Part 1 was anticipated to be 
~640 mg QD. However, as indicated by data evaluated for Part 1 Treatment Periods 
through 640 mg, VH3739937 exposures are lower than predicted, therefore an additional 
higher dose SAD treatment period will be evaluated. This higher dose will be conducted 
in accordance with safety and PK stopping criteria. 
Study Design Details Part 1 (SAD): 
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts each of approximately 9 healthy participants. Each of these two cohorts 
may contain a minimum of three escalating doses of VH3739937 through to 640 mg. An 
additional 800 mg dose will be evaluated as this was indicated following review of safety 
and PK data from participants dosed up to 640 mg.   The interlocking design shown in 
Figure 3 and the randomization sequence in Table 7 will allow the 9 participants in each 
cohort to potentially receive one of the lower and one of the higher doses of VH3739937.  
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy with 
alternating ascending doses (Table 7).   In each escalating dose period, 6 participants will 
be randomized to receive VH3739937 and 3 participants will be randomized to receive 
placebo. Participants in either Cohort will be assigned to one of the three treatment 
sequences, and each participant will receive placebo at least once. When the 800 mg dose 
is evaluated, 6 participants from both Cohorts 1 and 2 will be randomized to receive 
VH3739937 and 3 participants will be randomized to receive placebo, independent of 
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Details of the starting dose and dose escalation can be found in Section 4.3 
Table 7 
Description of treatment sequences in Cohort 1 and Cohort 2 
Periods 1, 2, and 3 
Cohort 1 
Period 1 
Period 2 
Period 3 
Sequence 1 
Placebo 
Dose 3 
Dose 5 
Sequence 2 
Dose 1 
Placebo 
Dose 5 
Sequence 3 
Dose 1 
Dose 3 
Placebo 
 
Cohort 2 
Period 1 
Period 2 
Period 3 
Sequence 1 
Placebo 
Dose 4 
Dose 6 
Sequence 2 
Dose 2 
Placebo 
Dose 6 
Sequence 3 
Dose 2 
Dose 4 
Placebo 
 
 
For Part 1, 24-hour continuous Holter/ ECG recordings will be collected on the day 
before dosing (Day -1), and Day 1 for extraction of ECGs paired with PK sampling. 
 
Participants in Part 1 will have a screening visit within 28 days prior to the first dose and 
a follow-up visit approximately 28 days after the last dose.  Flexibility of visit scheduling 
may be required if a pandemic situation applies (see Appendix 7).  Otherwise, study 
assessments will be performed as indicated in the SoA.  Study participants will be 
confined to the clinic from Day −2 until discharge.  Additional outpatient visits will be 
required on Days 9, 12 and 16.  Duration of study participation in Part 1 may be a 
minimum of approximately 27 weeks for SAD treatment periods 1 to 3. However, in Part 
1, study duration will be extended up to approximately 31 weeks to evaluate a higher 
dose (800 mg) for participants included in this dose period. Participants who have 
completed Part 1 may be able to re-enroll to complete 800 mg treatment period. To 
ensure safety, participants will need to go through re-eligibility assessments.  
Part 1 SAD: Dose Escalation 
Dose escalation in Part 1 will be determined by the Dose Escalation Committee 
(VH/GSK study team and the PI) based on the double-blind (sponsor-unblinded) safety 
data and the PK data from the current and previous dose(s) according to the dose 
escalation charter.  Dose escalation will generally not exceed approximately 3-fold 
between doses up to approximately the predicted minimally effective dose and will not 
exceed 2-fold thereafter.   However, if after the first SAD dose, the exposures are 
significantly different from the predicted level, the second dose or the sample collection 


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schedule will be re-estimated and a different fold increase may be used. Post-dose safety 
and PK data through Day 16 from a minimum of 4 participants receiving VH3739937 are 
required for dose escalation in Part 1.  Dose escalation will be guided by safety as well as 
the SAD PK stopping criteria (see Section 7.1.4). 
 
Due to the alternating dosing periods between Cohort 1 and Cohort 2, a participant in 
either cohort will receive the next dose after approximately 3 or 4 weeks. 
Study design details Part 2 (MAD): 
Part 2 consists of approximately 4 ascending repeat-dose cohorts (Cohorts 3 to 6), each 
with 10 participants who will receive a once-daily dose of VH3739937 or placebo (PBO) 
for 14 days (Cohort 3 [25 mg] and Cohort 4 [50 mg]), or for 18 days (Cohort 5 [100 mg]) 
or three oral doses at weekly intervals over two weeks (Cohort 6 [500 mg]).   
The duration of dosing in Cohort 5 is to support up to 18-day dosing as an oral lead for 
the future SAD and MAD studies of the long acting formulation of VH3739937. This 
duration is to allow the identification of any early drug hypersensitivity reactions (HSR) 
which may occur before the administration of the long acting formulation. In each 
escalating dose cohort, 7 participants will be randomized to receive VH3739937 and 3 
participants will be randomized to receive PBO.  Details of the starting dose and dose 
escalations in Part 2 (MAD) are provided in Section 4.3.   
Part 2 of the study was initiated once the single dose safety and preliminary PK data were 
evaluated in the SAD and the maximum exposure for the first MAD dose was covered by 
the SAD certain dose level. The potential minimally effective daily oral dose for 
VH3739937 with the suspension formulation was determined by the modeling and 
simulation utilising data for all doses in Part 1, as 25 mg, and is anticipated to be that 
which is predicted to provide a steady state C ≥ 0.258 g/mL in 95% of participants. 
More detailed information may be found in the IB Supplement [GlaxoSmithKline 
Document Number 2021 RPS_CLIN_004025].    
Dose escalation in the MAD will not exceed 2-fold between cohorts 3 to 5 and will be 
driven by safety and PK stopping criteria (see Section 7.1.4). The 500 mg dose included 
in the MAD Cohort 6 was determined following modeling and simulation of PK data 
acquired in SAD treatment periods through to 640mg and in MAD Cohort 3.  In addition, 
a dose will not be assessed in the MAD until the anticipated steady-state exposure (Cmax 
and AUC(0-) on Day 14) for that dose have been evaluated and shown not to have met 
safety stopping criteria in the SAD portion of the study (Part 1).  
For Part 2 MAD Cohorts 3, 4 and 5, 24-hour continuous Holter/ECG recordings will be 
collected, on the day before the first dose (Day -1), Day 1, and Day 14 for extraction of 
ECGs paired with PK sampling.  In addition, 12-Lead ECGs will be collected for Part 2 
at timepoints indicated in the SoA. 
Participants in Part 2 will have a screening visit within 28 days prior to first dose and a 
follow-up visit approximately 28 days after the last dose.  Flexibility of visit scheduling 
may be required if a pandemic situation applies (see Appendix 7).  Otherwise, study 


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assessments will be performed as indicated in SoA. Study participants will be confined to 
the clinic from Day −2 until discharge with requirement to complete all scheduled 
outpatient visits. Maximum duration of study participation from admission into the unit 
until completion of follow visit will be approximately 5 weeks. 
Part 2 MAD: Dose Escalation 
Dose escalation in Part 2 will be determined by the VH/GSK study team and the PI based 
on the double-blind (sponsor-unblinded) safety and PK data (minimally up to 15 days 
following the last dose) from the previous dosing Cohort (s).   Specifically, safety and PK 
data through Day 29 in Cohorts 3 and 4 and through Day 33 in Cohort 5 from a minimum 
of five participants receiving active drug will be required for dose escalation. 
Part 3 (RBA FE)  
Part 3 will involve a randomized, open-label, single-dose, 3-period crossover optional 
Cohort 7 to compare the RBA of the GSK3739937 PiB with GSK3739937 Tablet and to 
assess the effect of food on the safety, tolerability and PK of GSK3739937 Tablet  in 
healthy participants. In Part 3, approximately 18 participants will be treated to ensure that 
approximately 12 evaluable participants complete Cohort 7.  If participants prematurely 
discontinue Part 3, additional participants may be randomized after consultation with the 
sponsor to ensure that approximately 12 evaluable participants complete the study. 
 
Part 3 will consist of a screening period and 3 sequential treatment periods with a single 
dose of study intervention per treatment period.  
Prior to dosing on Day 1 of Period 1, participants will be randomly assigned to 1 of 3 
treatment sequences (ABC, BAC, or CAB). Participants will receive each of the 
following treatments administered as 1 treatment per period: 
• Treatment A: GSK3739937 PiB, 100 mg (administered as oral suspension) 
administered under moderate fat conditions (reference) 
 
• Treatment B: GSK3739937 Tablet, 100 mg (single dose given as 100 mg 
tablet(s)) administered under moderate fat conditions (test) 
 
• Treatment C: GSK3739937 Tablet, 100 mg (single dose given as 100 mg 
tablet(s)) 
administered under fasted conditions (reference). 
 
To ensure adequate washout, there will be at least 24 days between each dose of study 
intervention, with an allowance window of 4 hours (i.e., 24 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic.  
 


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Figure 4 
Phase 1 Study in Healthy Participants using planned doses of 
VH3739937 Part 3 
 
 
For treatments administered in the fed state, participants will fast overnight for at least 
9.5 hours prior to dosing and will receive a moderate fat (Treatments A and B) meal 25 
minutes prior to dosing. Dose administration will occur within 5 minutes of completion 
of meal consumption. Participants will not receive any further food until 4 hours after 
dosing. Treatment C will be administered in the fasted state. Participants will fast 
overnight for at least 9.5 hours prior to dosing and until 4 hours after dosing. 
 
Pharmacokinetic blood samples for the analysis of VH3739937 will be collected prior to 
dosing (0 hour) on Day 1 and up to 360 h hours post-dose in Periods 1, 2, and 3.  
Additional outpatient visits up to approximately Day 16 post each Treatment A, B and C 
will be required for collecting necessary PK and safety assessments.   
 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings. 
 
In Part 3, assessments will be performed as indicated in the SoA. Participants will be 
confined to the clinic from Day −2 until discharge on Day 6 of each treatment period. 
Participants are required to complete all outpatient visits during study conduct. Re-
admission to the unit will occur on Day -2 for Treatment Periods 2 and 3. A washout 
period of 24 days is required during treatment periods 1 and 2 prior to dosing in 
subsequent treatment periods. The duration of Part 3, including Screening, is 
approximately 16 weeks. 
 
4.2. 
Scientific Rationale for Study Design 
This is a first time in human study that will assess the safety, tolerability, and PK of 
VH3739937, an HIV-1 MI. The data gathered will inform subsequent clinical trials for 
VH3739937, including a Phase 2a POC study in HIV-1-infected participants as well as a 
FTiH study of VH3739937 administered parenterally (subcutaneously or 
intramuscularly). 
All doses of VH3739937 in this study will be administered in the fed state with dosing 
occurring within 15 minutes of completing a standardized moderate fat meal, unless 
otherwise indicated in Part 3 Treatment C (i.e. within 5 minutes after completing the 


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meal).  Data with previous MIs, GSK3532795 and GSK3640254, demonstrated that food 
was necessary to achieve dose proportional PK and target efficacious concentrations (see 
Section 2.2.1.). Given the structural similarities, including solubility limitations, between 
GSK3532795, GSK3640254 and VH3739937, administration of VH3739937 with food 
in this study is expected to enhance both bioavailability and the likelihood for linear PK, 
allowing for a rigorous assessment of safety and tolerability across a larger exposure 
range than would be allowed in the fasted state. Finally, VH intends to administer 
VH3739937 in the fed state in a future Phase 2a POC study in HIV-infected participants; 
the current study will assess the safety, tolerability, and PK of VH3739937 under the 
same conditions in healthy participants prior to dosing in HIV-infected participants. The 
relative bioavailability cohort is planned to assess the impact of the fasted and fed state 
on VH3739937 bioavailability. 
In Part 2 of the study (MAD), doses up to 4 times the minimally anticipated effective 
dose following oral administration of the suspension formulation (25 mg) are planned to 
be evaluated in Cohorts 3 to 5 and a higher 500 mg weekly dose will be evaluated in 
Cohort 6. In future studies in HIV-1-infected participants, these doses/exposures may be 
evaluated to understand the relationship between VH3739937 exposures and efficacy, 
duration of response, and resistance development.  Furthermore, assessment of this 
dose/exposure range (anticipated to be the therapeutic exposure range in the target 
population) in healthy participants will inform safety and tolerability prior to exposing a 
more vulnerable HIV-1-infected population to VH3739937 and will inform risk 
mitigation strategies for potential drug interactions. 
This dose/exposure range in healthy participants is clinically reasonable based upon the 
preclinical profile of VH3739937 and the clinical profile of prior MIs (GSK3640254 and 
GSK3532795), and the planned inpatient and outpatient evaluation for potential treatment 
emergent risks: including QT prolongation, GI intolerability and neuropsychiatric safety 
– which will be frequently monitored in this limited dosing duration setting. The 
preliminary data observed to date in this study (212548) through 640 mg in the SAD and 
25 mg QD for 14 days in the MAD have not highlighted a significant safety concern. 
Phase 1-2a studies with GSK3640254 have not evaluated for the presence of gastric 
toxicity in humans; thus, it is unclear if any of the GI AEs observed in any clinical trial 
were representative of, associated with, or resulted from gastric toxicity (if present). 
However, a currently active Phase 2b study of GSK3640254 includes a sub-study to 
assess the potential for GI toxicity.  
 
4.3. 
Justification for Dose 
4.3.1. 
Predicted Human Pharmacokinetics 
The pharmacokinetic profile for VH3739937 in humans was predicted using allometric 
scaling across all species (mouse, rat, dog, and monkey), and was combined with Css-
MRT modeling to obtain the predicted human PK profile [GlaxoSmithKline Document 
Number 2020N427033_00].  Using this method, the intravenous (IV) plasma clearance in 
humans for VH3739937 is projected to be low (0.12 mL/min/kg) and the intravenous 
volume of distribution was predicted to be 0.25 L/kg. The elimination half-life was 


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anticipated to be around 24 hours, leading to an approximate 2-fold anticipated 
accumulation with once daily dosing. The mean oral bioavailability in animals was 
approximately 12% (based on simultaneous fitting of the IV and oral animal data using 
compartmental modeling) and assumed for exposure projections in humans. 
4.3.2. 
Predicted Human Effective Dose  
Trough concentrations (C) are typically the PK parameter of interest for efficacy for 
other antiretroviral classes such as protease inhibitors and integrase inhibitors. The target 
C for VH3739937 was established using the average of 3-times the protein binding-
adjusted EC90 (3xPBA-EC90) for a small library of 6 Gag/Pr genotyped viruses less 
sensitive to a precursor maturation inhibitor GSK3640254. These viruses exhibited an 
average 3xPBA-EC90 of 312 nM (0.258 g/mL).  A similar 3xPBA-EC90 value was 
observed towards 370 virus (309 nM). The predicted dose that achieves a C at steady-
state ≥ target concentration in ~ 95% of the simulated subjects will be selected as the 
minimal effective dose. 
Prior to study initiation, the rationale for estimation of the minimally effective dose and 
associated PK parameters was as follows:   
The potential minimal effective dose for VH3739937 was estimated using the predicted 
human PK profile, assuming 50% between subject variability (IIV) on CL, V2 and Ka, 
the same parameters for which moderate to high IIV was estimated in a preliminary 
population PK model for GSK3640254, based on data from a FTIH study profile 
[GlaxoSmithKline Document Number 2020N427033_00].  This led to the prediction of a 
likely minimally effective once daily dose of approximately 80 mg. At this dose, the 
mean repeat-dose Cmax is predicted to be approximately 0.94 g/mL, mean C is 
predicted to be approximately 0.68 g/mL and mean AUC is predicted to be 
approximately 20.1 g*h/mL (Table 10). The anticipated steady-state mean AUC is 1.27-
fold lower than the no observed adverse effect level (NOAEL) in the rat (25.5 g*h/mL), 
4.79-fold lower than the lowest observed adverse effect level (LOAEL) in the rat (96.2 
g*h/mL), and 2.58-fold lower than the LOAEL in the dog (51.9 g*h/mL). 
 
However, during the course of study 212548 conduct, modelling and simulation of PK 
data from SAD treatment Periods 10 mg, 30 mg, 80 mg, 160 mg, 320 mg and 640 mg 
have led to the revision of the estimation of the predicted minimally effective dose and 
associated PK parameters. More detailed information may be found in the IB Supplement 
[GlaxoSmithKline Document Number 2021 RPS_CLIN_004025].   
4.3.3. 
 Part 1 (SAD) Starting Dose and Dose Escalation  
The starting oral dose of VH3739937 in the SAD will be 10 mg. Assuming a 10-fold 
safety factor and a body weight of 70 kg, this starting dose is lower than that calculated 
based on the NOAEL in rat of 10 mg/kg/day (maximum recommended starting dose 
[MRSD] = 11.3 mg) and the LOAEL in dog of 3 mg/kg (MRSD = 11.7 mg), in the 
absence of a NOAEL in dog [FDA/CDER, 2005]. Although a NOAEL was not 
established in the 4-week dog study due to the presence of gastric toxicity at all doses, the 
gastric findings at 3 mg/kg/day (LOAEL) were minimal in severity and reversible. 


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Based on the predicted human PK, a 10 mg dose would provide a mean AUC(0-inf) of 
2.58 g*h/mL and a mean Cmax of 0.0454 g/mL. This predicted AUC(0-inf) is ~10-
fold lower than that observed in the rat at the NOAEL (25.5 g*h/mL), 20.1-fold lower 
than that observed in the dog at the LOAEL (51.9 g*h/mL), and 37.3-fold lower than 
that observed in the rat LOAEL  (96.2 g*h/mL).  
Dose escalations in Part 1 (SAD) will be governed in real-time by safety and PK stopping 
criteria (see Section 7.1.4. and Section 7.1.5).  Based on the assumptions described 
above, the top dose anticipated in Part 1 was a single dose of 640 mg.  However, 
following review and evaluation of emerging available PK and safety data, a higher SAD 
dose of 800 mg was selected for evaluation in Cohort 1, Period 4.  Observed exposures 
were lower than that projected and review of preliminary safety data from the SAD 10mg 
through to 640mg dose and the MAD 25mg dose, supported escalation to the 800mg 
dose.  These preliminary PK and safety data are summarised in the IB Supplement 
[GlaxoSmithKline Document Number 2021 RPS_CLIN_004025]. The predicted median 
Cmax for 800 mg dose was 1.60 g/mL.  This higher 800mg dose will be in accordance 
with SAD PK stopping criteria.  Based on the data collected from the observed doses so 
far in the study, the probability of any SAD participant having a Cmax > 21 µg/mL is 
extremely low. 
4.3.4. 
Part 2 (MAD) Starting Dose and Dose Escalation  
The initial dose in the MAD (Cohort 3) was approximately equal to the likely minimally 
effective dose, re-estimated at 25 mg based on the clinical PK data following oral 
administration of the suspension formulation collected in the early doses of Part 1.  Dose 
escalation in the MAD will not exceed 2-fold between daily dosing cohorts 4 and 5 and 
will be governed by both safety and MAD PK stopping criteria (see Section 7.1.4 and 
Section 7.1.5). Based on emerging PK data in Part 1, the once weekly (QW) dosing 
Cohort 6 will be dosed at 500 mg.  Given different assumptions for the between 
participant AUC variability (%CVb) and the current human PK prediction, the 
probability of any participant AUC(0-) in the MAD above 96.2 g/mL, the LOAEL 
exposure in rat, are illustrated in Table 8.  Similarly, the probability of any participant 
AUC(0-24) which cover the maximum exposure in the MAD Cohort 6 above 96.2 
mg/mL is illustrated in Table 9. 
 
Table 8 
Probability of any MAD participant (AUC(0-)  >96.2 µg*h/mL) for 
potential QD doses 
AUC variability 
Potential VH3739937 QD MAD Doses 
%CVb1 
25 mg 
50 mg 
100 mg 
25 
0 
0 
<0.001 
35 
0 
0 
0.003 
50 
0 
<0.001 
0.028 
Note: 1, %CVb: between-participant coefficient of variation 


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Table 9 
Probability of any MAD participant (AUC(0-)  >96.2 µg*h/mL and 
(Cmax >21 µg/mL)) for 500 mg QW dose 
AUC variability 
(%CVb1) 
Cmax Variability 
(%CVb1) 
Any Participant (AUC >96.2 µg*h/mL or 
Cmax >21 µg/mL) 
25 
25 
0 
Note: 1, %CVb: between-participant coefficient of variation 
Given the results in the tables above, it is unlikely that any subject exceeds the safety 
thresholds in the QD or QW MAD portions of the study. 
4.3.5. 
Part 3 RBA Dose Selection  
The relative bioavailability of a 100 mg tablet formulation will be assessed in Part 3, 
using the PiB formulation as a reference. A 100 mg unit tablet dose was chosen as a 
reasonable representative dose for this assessment, given available PiB pharmacokinetic 
data and projected clinical doses (25 mg QD or 500 mg QW).  
Although no definitive preclinical data on solid dose bioavailability is available, it is 
unlikely that moving to a tablet will result in significantly higher exposure (as Cmax or 
AUC) relative to a 100 mg PiB dose. Given doses of up to 640 mg PIB have been safely 
administered in Part 1, there is no perceived safety risk. 
4.3.6. 
Dose Escalation Committee (DEC) 
This study will utilize a dose escalation committee made up of at least the following: 
Sponsor and Site staff (including safety physicians and clinicians, PI, Sub-Investigator, 
Medical Monitor, clinical pharmacokineticist/pharmacologist, data manager, 
pharmacovigilance, and statistician) and/or their delegates. The committee will evaluate 
data including but not limited to: AEs, vital signs, laboratory findings, ECG parameters, 
and PK data.  The DEC will meet when data are available from a minimum of 4 active 
treated participants through Day 16 assessments in Part 1, and from a minimum of 5 
active treated participants through Day 29 assessments in Part 2 Cohorts 3 and 4, and 
similarly through Day 33 assessments in Cohort 5.  A dose escalation plan will document 
the structure and function of the DEC.  This plan is included in the Dose Escalation 
Charter which will also specify the safety and PK requirements for the DEC prior to 
making a dose escalation decision.  The blinding of personnel is discussed in Section 6.4. 
4.3.7. 
Anticipated Exposure and Safety Cover for a Range of Potential 
Doses 
Projected steady-state exposures of GSK3739937 from potential doses in Part 2 are 
compared to target efficacious concentrations and preclinical toxicity exposures in Table 
10.  Projected steady-state PK for a range of potential QD (50-100 mg) or QW (500 mg) 
doses following fed administration and comparison to efficacy target and preclinical 
exposure in Table 11.  Predicted human exposure following multiple doses can be 
compared to the NOAEL and LOAEL in rats, the Cmax from the dog CV study and to 
LOAEL in dogs.  Findings in both species were GI related, limited and reversible (see 


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Section 2.3.1 and the Clinical Investor Brochure [GlaxoSmithKline Document Number 
2019N421306_00] for further details). 
 
Importantly, the doses listed here are intended to demonstrate general concepts relating to 
factors of escalation. The specific doses in the SAD and MAD portions are subject to 
change based upon emerging clinical and PK data gathered in this study. As described 
above, dose escalations will be governed in real-time by safety and PK. A dose which has 
met formal clinical, QT, and PK stopping criteria (see Section 7) will not be repeated in 
the SAD or MAD. 
Table 10 
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and 
preclinical exposure  
 
 Parameter 
10 mg  
30 mg  
80 mg 
160 mg 
320 mg 
C, µg/mL 
Mean 
0.085 
0.255 
0.68 
1.36 
2.72 
Lower bound of 90% CI 
0.036 
0.107 
0.28 
0.57 
1.14 
C/Ctarget (0.258 g/mL) 
 
 
 
 
 
Lower bound of 90% CI 
0.140 
0.421 
1.12 
2.24 
4.49 
Cmax Day 14, µg/mL 
 
 
 
 
 
Mean 
0.117 
0.352 
0.939 
1.88 
3.76 
Upper bound of 80% CI a 
0.207 
0.620 
1.65 
3.31 
6.61 
Cmax Cover withb 
 
 
 
 
 
Dog 1-month GLP study (39.8 g/mL)c 
729 
242 
90.8 
45.4 
22.7 
Dog CV study (9.82 g/mL)d 
180 
59.8 
22.4 
11.2 
5.60 
Mean AUC, µg*h/mL 
 
 
 
 
 
Mean 
2.51 
7.52 
20.1 
40.1 
80.2 
Upper bound of 80% CI a 
4.63 
13.9 
37.0 
74.1 
148 
AUC Cover withb 
 
 
 
 
 
Rat NOAEL (25.5 g*h/mL) 
10.16 
3.39 
1.27 
0.636 
0.318 
Rat LOAEL (96.2 g/mL) 
38.3 
12.8 
4.79 
2.40 
1.20 
Dog LOAEL (51.9 g/mL) 
20.7 
6.90 
2.58 
1.29 
0.647 
a. 
The upper bound of the 80% CI is presented to capture the likely highest PK values in 6 subjects. 
b. The Cmax and AUC cover were computed as the ratio of Cmax or AUC in animal divided by the mean 
Cmax or AUC predicted in human.  
c. 
Equivalent to 85.3 g/mL in human (based on 85% and 93% protein binding in dog and human, 
respectively).  
d. Equivalent to 21.0 g/mL in human (based on 85% and 93% protein binding in dog and human, 
respectively). 
 
 


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Table 11 
Projected steady-state PK for a range of potential QD (50-100 mg) or 
QW 500 mg) doses following fed administration and comparison to 
efficacy target and preclinical exposure  
 Parameter 
 
50 mg  100 mg 
500e mg 
C, µg/mL 
 
Median 
 
0.905 
1.57 
0.429 
Lower bound of 90% CI 
 
0.557 
1.01 
0.253 
C/Ctarget (0.258 g/mL) 
 
 
 
 
 
 
 
 
Lower bound of 90% CI 
 
2.16 
3.91 
0.981 
Cmax after last dose, µg/mL 
 
 
 
 
Median 
 
0.968 
1.72 
1.5 
Upper bound of 90% CI a 
 
1.53 
2.65 
2.07 
Cmax Cover withb 
 
 
 
 
Dog 1-month GLP study (39.8 g/mL)c 
 
88.1 
49.6 
58.8 
Dog CV study (9.82 g/mL)d 
 
21.7 
12.2 
14.5 
Mean AUC, µg*h/mL 
 
 
 
 
Median 
 
22.7 
39.8 
31.3 
Upper bound of 90% CI a 
 
36.1 
62.0 
45.5 
AUC Cover withb 
 
 
 
 
Rat NOAEL (25.5 g*h/mL) 
 
1.12 
0.641 
0.815 
Rat LOAEL (96.2 g/mL) 
 
4.24 
2.42 
3.07 
Dog LOAEL (51.9 g/mL) 
 
2.29 
1.30 
1.66 
 
a. 
The upper bound of the 95% PI is presented to capture the likely highest PK values. 
b. The Cmax and AUC cover were computed as the ratio of Cmax or AUC in animal divided by the 
median Cmax or AUC predicted in human.  
c. 
Equivalent to 85.3 g/mL in human (based on 85% and 93% protein binding in dog and human, 
respectively).  
d. Equivalent to 21.0 g/mL in human (based on 85% and 93% protein binding in dog and human, 
respectively). 
e. 
The weekly dose 500 mg 
f. 
the maximum 24 hour AUC were calculated from 0-24h after the last dose to match the daily safety 
limit 96.2 ug*h/mL 
 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit and the last scheduled procedure shown in the 
SoA 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent. 
 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISICS 
2. Participants who are overtly healthy as determined by the investigator or medically 
qualified designee based on a medical evaluation including medical history, 
physical examination, laboratory tests, and cardiac monitoring (history and ECG). 
 
3. Participants who are negative on two consecutive tests for SARs-CoV-2, performed 
at Screening, on admission and (re-)admission to the Phase I unit, using an 
approved molecular test (PCR). 
4. Participants who are able to understand and comply with protocol requirements and 
timetables, instructions, and protocol-stated restrictions. 
 
WEIGHT 
5. Body weight ≥50.0 kg (110 lbs.) for men and ≥45.0 kg (99 lbs) for women and 
body mass index within the range 18.5 to 32.0 kg/m2 (inclusive). 
 
SEX 
6. Male and/or female 
Male participants: 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 5 days, corresponding to time needed to 
eliminate study intervention(s) (e.g. 5 terminal half-lives) plus an additional 90 
days (a spermatogenesis cycle) after the last dose of study intervention:  
• Refrain from donating sperm 
PLUS either:  
• 
Be abstinent from heterosexual or homosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent  


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OR 
• 
Must agree to use a male condom  
AND 
And female partner to use an additional highly effective contraceptive method 
with a failure rate of <1% per year as described in Appendix 4 
       OR 
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  
• Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person.  
 Female participants:  
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and is not a woman of childbearing potential (WOCBP) as defined in Appendix 4. 
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 2. 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
 
INFORMED CONSENT 
7. Capable of giving signed informed consent as described in Appendix 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. Signs and symptoms which in the opinion of the investigator are suggestive of 
COVID-19 (i.e. fever, cough etc) within 14 days of inpatient admission 
 
2. Contact with known COVID-19 positive person/s in the 14 days prior to inpatient 
admission 
3. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly 
altering the absorption, distribution, metabolism, or elimination of drugs; 


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constituting a risk when taking the study intervention or interfering with the 
interpretation of data 
4. Pre-existing clinically relevant, in the opinion of the PI, gastro-intestinal pathology 
or diagnosis – e.g. irritable bowel syndrome, inflammatory bowel disease, and/or 
significant baseline signs and symptoms. 
5. Medical history of cardiac arrhythmias or cardiac disease or a family and personal 
history of long QT syndrome. 
6. Any known or suspected pre-existing psychiatric condition 
7. Any positive (abnormal) response confirmed by the investigator or clinician (or 
qualified designee) administered CSSRS at screening  
8. Any other clinical condition (including but not limited to active substance use) or 
prior therapy that, in the opinion of the Investigator, would make the participant 
unsuitable for the study; unable to comply with dosing requirements; or unable to 
comply with study visits; or a condition that could affect the absorption, 
distribution, metabolism or excretion of the drug. 
9. Estimated Glomerular Filtration Rate (eGFR) <90 mL/min or serum creatinine 
>1.1 x ULN. 
10. Hemoglobin <12.5 g/dL for men and <11 g/dL for women 
11. Alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.1x upper 
limit of normal (ULN)  
12. Bilirubin >1.1xULN (isolated bilirubin >1.1xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).  
13. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones) 
14. Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the 
past 3 months (does not include ST segment changes associated with re-
polarization), symptomatic bradycardia, non-sustained or sustained atrial 
arrhythmias, non-sustained or sustained ventricular tachycardia (3 consecutive 
ventricular ectopic beats), second-degree atrioventricular block Mobitz Type II, 
third-degree atrioventricular block, complete heart block, or conduction 
abnormality (including but not specific to left or right complete bundle branch; 
AV block [2nd degree or higher]; WPW syndrome), Sinus Pauses > 3 seconds, 
which, in the opinion of the investigator or VH/GSK Medical Monitor, will 
interfere with the safety for the individual participant. 
15. Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility 
determination): 
 
Males 
Females 
Heart rate 
<45 or >100 bpm 
<50 or >100 bpm 
PR interval 
<120 or >220 msec 
QRS duration 
<70 or >120 msec 
QTcF interval  
>450 msec 
Note:  
• A heart rate from 100 to 110 bpm can be rechecked by ECG or vitals within 30 
minutes to verify eligibility. 


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• The QTc is the QT interval corrected for heart rate according to QTcF, and/or 
another method, machine-read or manually over-read. 
• The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject will be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial. 
 
PRIOR/CONCOMITANT THERAPY 
16. Past or intended use of over-the-counter or prescription medication [including 
cytochrome p450 enzyme inducers or inhibitors, vitamins, herbal and dietary 
supplements (including St. John’s Wort)] within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to dosing and 
for the duration of the study, unless in the opinion of the Investigator and Sponsor, 
the medication will not interfere with the study medications, procedures, or 
compromise participant safety [Specific medications, such as paracetamol listed in 
Section 6.6 may be allowed]. 
17. Unwillingness to abstain from ingestion of any food or drink containing grapefruit 
and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior 
to the first dose of study treatment(s) or until the end of the study. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
18. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 56 days 
19. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day 
20. Current enrolment or past participation within the last 30 days, 5 half-lives or twice 
the duration of the biological effect of the investigational product (whichever is 
longer) before signing of consent in this or any other clinical study involving an 
investigational study intervention or any other type of medical research 
 
DIAGNOSTIC ASSESSMENTS  
21. Presence of HBsAg at screening or within 3 months prior to first dose of study 
intervention 
22. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
first dose of study intervention. 


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NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) 
test is obtained 
23. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention 
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing 
24. Positive pre-study drug/alcohol screen 
25. Positive HIV antibody/antigen test 
26. Regular use of known drugs of abuse 
OTHER EXCLUSIONS 
27. Regular alcohol consumption within 6 months prior to the study defined as:  
• 
An average weekly intake of >14 units for males or >7 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 (25 mL) measure of spirits.  
28. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- 
or nicotine-containing products (e.g. nicotine patches or vaporizing devices) 
within 6 months prior to screening and at admission. 
29. Sensitivity to any of the study interventions, or components thereof, or drug or 
other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study 
  
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or their fruit juices within 7 
days before the start of study intervention until the end of the study. 
• 
In Part 1 and 2, participants will refrain from water intake between 1-hour pre and 1-
hour post dosing. No water intake restrictions at other times.  
• 
All doses of VH3739937 in Part 1, Part 2, and Part 3 (Treatments A and B only) in 
this study will be administered in the fed state (moderate fat).  The participants in 
Part 1, Part 2 and Part 3 (Treatments A and B) will fast for at least 9.5 hours prior to 
dosing and will receive a standardized moderate fat meal 25 minutes prior to dosing. 
Participants will eat this meal in up to 25 minutes with dose administration to occur 
within 5 minutes of completion of meal consumption. Participants will not receive 
any further food until 4 hours post-dose. The standardized moderate fat meal will 
contain about 600 calories with approximately 30% of them coming from fat.  


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• 
Meal times should be approximately uniform across all treatment periods. The food 
content of meals must be identical on serial PK sampling days. At all other times, 
meals will follow site usual practice. 
• 
The participants in Part 3 (Treatment C) will be administered study intervention in 
the fasted state. The participants will fast overnight for at least 9.5 hours prior to 
dosing and until 4 hours after dosing. No water is allowed from 2 hours prior to 
dosing until 2 hours after dosing except for the glass of water needed to administer 
the study medication (e.g. 240 mL). Water is allowed ad libitum at all other times.   
• 
In MAD Cohort 5 Day 18 only, participants will undergo biliary metabolism testing 
using the Enterotest or EnteroTracker for analysis of VH3739937 and its 
metabolites.  The duodenal bile sample collected from placebo-dosed participants in 
this same cohort will be considered as the control sample. The string as a capsule 
device will be swallowed by fasted participants at approximately 2 hours after dosing 
on Day 18 of dosing and removed at approximately 6.5 hours post dose.  
• 
Additional details on the Bile Sample Collection, Food Cue, EnteroTest or 
EnteroTrack placement, bile sample storage and shipment procedures can be found 
in the study reference manual (SRM). 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before the start of dosing 
until after collection of the final PK and/or pharmacodynamic sample.  
• 
Use of alcohol or tobacco products will not be allowed from screening until after the 
final follow-up visit. 
• 
Participants must have a negative drug test at screening and admission to the clinical 
unit and must abstain from recreational drug use from screening until after the final 
follow-up visit. 
 
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). 
 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs. 


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Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.   
 
Participants in a pandemic situation who meet all eligibility criteria at screening but no 
longer remain within the screening window prior to study admission on Day -2, may have 
all screening procedures repeated (see Appendix 7).  In this situation rescreened 
participants should be assigned a new participant number from that assigned at the initial 
screening. 
 
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.  The active investigation interventions used in study 212548 are 
GSK3733937 Powder in bottle (PiB) and GSK3733937 Tablet, 100 mg (can also be 
referred to as VH3733973 PiB  and VH 3739937 Tablet, 100 mg) 
6.1. 
Study Intervention(s) Administered 
Intervention 
Name 
GSK3739937 Powder-in-Bottle 
(PiB) 
Placebo for GSK3739937 
PiB 
GSK3739937 Tablet1 
Dose 
Formulation 
Powder-in-bottle for 
reconstitution with 50 mL of 
vehicle (0.5% Hypromellose in 
Sterile Water for Irrigation) 
50 mL of vehicle (0.5% 
Hypromellose in Sterile 
Water for Irrigation) 
Tablet 
Unit Dose 
Strength(s) 
Oral Suspension of 
VH3739937  
N/A 
100 mg tablet 
Route of 
Administration 
Oral 
Oral 
Oral 
Dosing 
Instructions 
Each dose to be reconstituted 
with 50 mL vehicle followed by 
additional rinses with 
vehicle/Sterile Water for 
Irrigation. The maximum 
volume of vehicle will not 
exceed 120 mL/daily.  The 
volume of vehicle / Sterile 
Water for irrigation rinses will 
vary across the GSK3739937 
doses, volume of vehicle / 
Sterile water for irrigation for 
the placebo will also vary to 
match that of the GSK3739937 
dose.  Further detail can be 
found in the SRM. 
50 mL of vehicle followed by 
additional vehicle/Sterile 
Water for Irrigation rinses. 
The maximum volume of 
vehicle will not exceed 120 
mL/daily.  The volume of 
vehicle / Sterile Water for 
irrigation rinses will vary 
across the GSK3739937 
doses, volume of vehicle / 
Sterile water for irrigation for 
the placebo will also vary to 
match that of the 
GSK3739937 dose.  Further 
detail can be found in the 
SRM. 
Study intervention will be 
administered by the study 
personnel during each 
dosing day with 240 ml of 
water 
Sourcing 
GSK3739937 provided as Bulk 
Powder and Hypromellose 
Hypromellose provided 
centrally by the Sponsor, 
Provided in bulk by the 
Sponsor 


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provided centrally by the 
Sponsor. Sterile Water for 
irrigation provided by the site  
Sterile Water for irrigation 
provided by the site 
Packaging and 
Labeling 
 
Study Intervention will be 
provided in amber glass bottle. 
Each bottle will be covered to 
obscure the appearance of the 
study intervention. Each bottle 
will be labeled as required per 
country requirement. 
Study Intervention will be 
provided in amber glass 
bottle. Each bottle will be 
covered to obscure the 
appearance of the study 
intervention. Each bottle will 
be labeled as required per 
country requirement. 
Study Intervention will be 
provided in bulk by Sponsor. 
The investigator will package 
in high-density polyethylene 
bottles. Each bottle will be 
labelled as required per 
country requirement". 
  1Use of GSK3739937 Tablet will be in Part 3, RBA and FE Cohort 7 only 
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. Further 
guidance can be found in the SRM.  
• 
An unblinded pharmacist or designee will prepare blinded study intervention and 
provide to authorize study staff for administration. Each bottle will be covered to 
obscure the appearance of the study intervention. The blinded drug product and 
placebo will be administered by site staff not involved with assessments.  For details 
of the blinding approach refer to the SRM.   
• 
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. In the case of unintentional 
occupational exposure notify the Study Sponsor Medical Monitor and/or Sponsor 
study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.  


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6.3. 
Method of Treatment Assignment 
Participants will be assigned to study treatment in accordance with the randomization 
schedules generated by the Sponsor or their delegate, prior to the start of the study, using 
the GSK validated randomization software RANDALL NG.  Randomization and study 
treatment assignment will be facilitated by the interactive response technology (IRT) 
through the central Randomization and Medication Ordering System Next Generation 
(RAMOS NG) for Part 1 Cohorts 1 and 2, treatment periods 1, 2 and 3, and Part 2 
Cohorts 3, 4 and 5.  Each participant scheduled to receive study intervention will receive 
a treatment allocation number when randomized.  For Part 1, higher dose SAD (800 mg) 
Treatment Period 4, Part 2 MAD Cohort 6, and Part 3 RBA and FE, RAMOS NG will not 
be used (see Section 6.4 for additional details).  
 
Study intervention will be dispensed at the study visits summarized in the SoA 
 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomized in a 2:1 ratio to receive study treatment (VH3739937 
active drug:placebo) within Part 1 and in a 7:3 ratio in Part 2. Participants in Cohort 1 and 
Cohort 2 will follow the same randomization strategy with alternating ascending doses).  
Participants in either Cohort will be assigned to one of the three treatment sequences, and 
each participant will receive placebo once. In SAD treatment period 4 (800 mg), 6 
participants will be randomized to receive VH3739937 and 3 participants will be 
randomized to receive placebo, independent of which prior doses they received. 
Investigators unless specified above will remain blinded to each participant’s assigned 
study treatment throughout the course of the study. Part 3, the RBA and FE Cohort 7, will 
be open label and all 12 evaluable participants will receive VH3739937. 
 
Part 1 and Part 2 will be a double-blind study with participants and the site staff blinded 
with the following exception: due to the different appearance of VH3739937 PiB and 
placebo for VH3739937 PiB; an unblinded pharmacist at the site who will prepare the 
blinded drug product and blinded placebo. The blinded drug product and placebo will be 
administered by designated unblinded site staff who must not be involved with 
assessments. The sponsor will be unblinded.  For dose escalation, the Sponsor study team 
physicians, statistician, and clinical pharmacokinetic staff and/or their delegate will have 
access to unblinded data.  The Sponsor will present data at DEC meetings in a blinded 
fashion when interacting with site staff.  Other Sponsor staff will remain blinded unless 
unblinding becomes necessary.  The blind may be broken if, in the opinion of the 
investigator, it is in the participant’s best interest for the investigator to know the study 
treatment assignment.  The Sponsor study team must be notified before the blind is 
broken unless identification of the study treatment is required for a medical emergency in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition.  In this case, the Sponsor study team must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF, as applicable. The 
RAMOS NG system will be programmed with blind-breaking instructions for Part 1 


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Cohorts 1 and 2, treatment periods 1, 2 and 3 and Part 2 Cohorts 3, 4 and 5 in case of an 
emergency. 
For Part 1, higher dose SAD (800 mg dose), Part 2 Cohort 6, and Part 3 RBA and FE 
Cohort 7, RAMOS NG will not be used.  A paper randomization list will be 
electronically sent to the unblinded site pharmacist or designee by GSK study statistician 
prior to Day 1 to permit sufficient time for pharmacy to prepare study intervention in 
advance. Access to randomization codes is limited to only those authorized by unblinded 
site pharmacist in order to maintain the integrity of the treatment blind. The pharmacy 
has restricted access and can only be accessible to authorized personnel.  The 
randomization list is stored on a password protected computer or a restricted access 
pharmacy.  The unblinded study monitor will confirm that codes are securely kept locked 
in a limited access area to preserve the integrity of the treatment blind prior to site 
initiation. GSK no longer has the capability to support generation of individual 
randomization envelopes for studies and therefore an alternative strategy will be 
employed to maintain investigator blinding for higher dose SAD (800 mg), Part 2 Cohort 
6, and Part 3 RBA and FE Cohort 7.  Upon receipt, the copy of the randomization list per 
cohort will be transferred to a locked cabinet at the nurses’ station.  In the event of 
emergency unblinding, a member of the Parexel staff will retrieve and open the random 
list for the cohort and unblind the specific participant without revealing any further 
unblinding information to study staff.  The unblinding staff shall be prohibited from 
working on the study. 
 
The unblinded study monitor will confirm unblinded site staff will maintain study 
documentation that would unblind the blinded site staff in a separate, limited access 
location. The unblinded study monitors will ensure that any essential documents 
containing information that could potentially reveal the blind (ie., IP Accountability, 
Reconciliation, and Destruction Form) are maintained in a limited access location on site 
until they can be combined with the sponsor TMF for archiving. 
Unblinded monitors, and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study treatment records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF. 
Sponsor’s Global Clinical Safety and Pharmacovigilance (GCSP) 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 Sponsor policy. 
Any instance of unblinding will be documented in the study TMF. 


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6.5. 
Study Intervention Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• 
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.  Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. Participants 
will not be allowed to use the bathroom at least 1hr after dose.  
 
6.6. 
Concomitant Therapy 
Participants must abstain from taking prescription or non-prescription drugs (including 
Cytochrome P450 (CYP) inducers and inhibitors, vitamins 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 follow-up visit, unless, in the opinion of the investigator and sponsor, the medication 
will not interfere with the study.  
Permitted Medications are as follows: 
• Paracetamol/Acetaminophen, at doses of ≤2 grams/day, is permitted for use at any 
time during the study 
• In the event of irritation from ECG leads, up to 2.5% topical hydrocortisone may 
be used at the discretion of the investigator 
• Vaccination with an approved vaccine for SARS-CoV-2 prior to or during study 
participation (see SRM for detailed guidance on acceptable timing for 
vaccination) 
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Sponsor Medical Monitor 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be reviewed with the Study Sponsor 
Medical Monitor and recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 


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The Medical Monitor will be contacted if there are any questions regarding concomitant 
or prior therapy. 
6.7. 
Dose Modification 
The decision to proceed to the next dose level in both Part 1 (SAD) and Part 2 (MAD) 
will be made by the DEC, based on safety, tolerability, and preliminary PK data obtained 
from the prior dose level(s) as described in the Dose Escalation Committee Charter. 
Criteria for discontinuation of dose escalation also apply to discontinuation of dosing 
within the cohort in which a toxicity occurs.  
 
6.8. 
Intervention after the End of the Study 
Since only healthy participants are eligible for study participation, no additional treatment 
from Sponsor, including VH3739937, will be provided after the completion of the study.  
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
A participant may be withdrawn from the study at any time:  
• At his or her own request 
• At the discretion of the Investigator in consultation with the Study Sponsor 
Medical Monitor for safety (including lab abnormalities or intercurrent illness), 
psychiatric, compliance, or administrative reasons.   
• Emergence of any positive (abnormal) response confirmed by the investigator or a 
clinician (or qualified designee) administered CSSRS during the on-treatment 
phase (MAD only). 
• ≥ Grade 3 AE (or clinically significant laboratory abnormality) suspected to be 
related to VH3739937 
• A SAE, regardless of its severity, that is considered be clinically significant and 
reasonably attributable to dosing with VH3739937, in the opinion of the 
Investigator.   
• A grade ≥2 rash with concurrent fever with or without concurrent elevations in 
liver biochemistry reasonably attributable to dosing with VH3739937, in the 
opinion of the Investigator.   
• Termination of the study by the Sponsor. Safety data will be reviewed by the 
Sponsor in-stream by single case and collectively.  If a safety concerns arises, a 
decision about continuation of the study will be made.  
• Loss of ability to freely provide consent due to incarceration or involuntary 
treatment of either a psychiatric or physical (eg, infectious disease) illness 
• Unblinding of unauthorized Site Staff, including the PI, for any reason 


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• Repeat non-adherence by the participant with the requirements of the protocol or 
treatment (as determined by Investigator in consultation with the Study Sponsor 
Medical Monitor) 
• Pregnancy (Section 10.4.3) 
• PK stopping criteria is met (Section 7.1.4) 
• Clinical criteria for stopping study is met (Section 7.1.5) 
 
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. 
If a participant chooses to withdraw from the study, he/she will complete a follow-up 
visit as per SoA. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.  
Discontinuation of study intervention for abnormal liver tests is required when: 
• A participant meets one of the conditions outlined in Figure 5 below. 
• When in the presence of abnormal liver chemistries not meeting protocol-
specified stopping rules, the investigator believes study intervention 
discontinuation is in the best interest of the participant.  
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met: 


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Figure 5 
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 
Details of Liver Safety Required Actions and Follow-Up Assessments can be found in 
Appendix 5. 
7.1.1.1. 
Study Intervention Restart or Rechallenge after liver stopping 
criteria met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.2. 
QTc Stopping Criteria 
The QTcF must be used for each individual participant to determine eligibility for and 
discontinuation from the study.  This formula may not be changed or substituted once the 
participant has been enrolled. 
The QTcF stopping criteria is based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.   
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.   
• QTcF >500 msec, 
• Change from baseline:  QTcF>60 msec 
 
See the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*


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7.1.3. 
Temporary Discontinuation 
Temporary discontinuation in this study is not allowed. 
7.1.4. 
PK Stopping Criteria for SAD and MAD 
In the SAD, the PK stopping criteria are based on mitigating any potential for Cmax 
mediated effects on ECG parameters.  There were no ECG or other CV effects in a good 
laboratory practice (GLP) single-dose CV study in telemeterized dogs (Cmax = 9.82 
µg/mL) and a 1-month GLP study in dogs (Cmax = 39.8).  The stopping criteria is 
conservatively based on lower Cmax in the CV study in telemeterized dogs where there 
were no CV effects (9.82 µg/mL), equivalent to 21 µg/mL, when adjusted for protein 
binding.  Protein binding is higher in human (93%) compared to dog (85%).  If safety or 
PK stopping criteria are not met for the current/prior doses, dose escalation in Part 1 
(SAD) will be stopped in the event that the Bayesian predicted probability is >50% that 
any participant’s Cmax for the next subsequent dose will exceed 21 µg/mL (the SAD PK 
stopping criteria). 
In the MAD, the PK stopping criteria are based on AUC exposures where VH3739937-
related microscopic findings were observed in the stomach of rats and dogs in the GLP 1-
month oral toxicity studies.  Corresponding Cmax exposures are expected to be below 21 
µg/mL.  A NOAEL was identified for microscopic findings in the stomach of rats at 10 
mg/kg/day and a LOAEL in rats was identified at 40 mg/kg/day.  A NOAEL for 
microscopic findings in the stomach of dogs was not identified and the LOAEL in dogs 
was 3 mg/kg/day.  At the LOAEL in rats and dogs, VH3739937 was well tolerated and 
resulted in minimal, reversible single cell necrosis of parietal cells and chief cells.  
Exposure at the LOAEL in rats was AUC = 96.2 ug*h/mL and in the dog was AUC = 
51.9 µg*h/mL.  The LOAEL in rats was chosen as the PK stopping criteria, and exposure 
is approximately 4-fold higher than the AUC in rats at the NOAEL dose of 10 mg/kg/day. 
The selection of the higher LOAEL AUC from the two preclinical species arises from the 
need to achieve sufficiently high exposures for cardiodynamic assessment of the TQT 
prolongation risk and mitigate the need for a TQT study. In the absence of data on the 
effect of intrinsic and extrinsic factors on the PK of VH3739937, and at the time of study 
initiation, the typical targeted doses were ~4x the minimal predicted efficacious dose.  
 
Dose escalation in Part 2 (MAD) will be stopped in the event that safety or PK stopping 
criteria are not met, but if the Bayesian predicted probability is >50% that any 
participant’s AUC(0-) on Day 14 in the subsequent Cohort 3 and 4, or on Day 18 in 
Cohort 5, or on or prior to Day 21 in Cohort 6 will exceed the MAD PK stopping criteria. 
In the event this occurs, the dose for the next cohort may be reduced such that the 
Bayesian predicted probability that any participant’s AUC(0-) and the Cmax on Day 14 
in the subsequent dose will exceed the MAD PK stopping criteria is ≤50%.  
 
7.1.5. 
Clinical Criteria for Stopping the Study 
Safety parameters and the available pharmacokinetic parameters from the previous 
cohorts will be fully assessed by the DEC before the next cohort is dosed. Any trends 


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towards drug-related changes will be fully evaluated. The decision to dose escalate will 
be based on the nature, severity and frequency of any safety and/or tolerability 
observations. The decision to dose escalate may be delayed to allow the collection of 
additional safety data if clinically indicated.  
If the following number of participants, within the ongoing cohort of 7 active 
participants, develops clinically significant changes in safety parameters not listed above 
or significant AEs thought to be drug related, the dose escalation will be paused until all 
of the cumulative safety data is reviewed by the DEC and the VSLC: The VSLC is 
comprised of senior representatives from various departments, including clinical 
development, toxicology, pharmacovigilance, epidemiology, and medical affairs. 
However, if any of the criteria are met, an optional cohort may be introduced to assess a 
lower tolerated dose.  
• One participant experiences an AE of Grade 4 intensity or a Grade 4 clinically 
significant laboratory abnormality assessed as related to VH3739937, as reported 
by the PI. 
• One participant experiences a Serious Adverse Event (SAE) or death assessed as 
related to VH3739937, as reported by the PI. 
• If greater than 25% of participants within the same Period (SAD) or Cohort 
(MAD) receiving VH3739937 have a ≥ Grade 3 intensity AE or lab abnormality 
(with the exception of asymptomatic changes in lipid panel) or a ≥ Grade 2 
intensity rash with concurrent fever, transaminase elevation or eosinophilia. 
• 2 participants with confirmed QTcF ≥500 msec or a change from baseline of 
QTcF>60 msec, within the same Period (SAD) or Cohort (MAD) 
• 2 participants with clinically significant, in the opinion of the PI, arrhythmias 
within the same Period (SAD) or Cohort (MAD) 
 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. Please see SRM for further 
detail.  
• 
Please see SoA for data to be collected at the time of study discontinuation if 
occurs prior to discharge from unit, and if study discontinuation occurs post 
discharge from unit, and follow-up and for any further evaluations that need to 
be completed.   
• 
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. 


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• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
 
7.3. 
Lost to Follow Up 
• 
Participants will be expected to be resident in the Phase I unit as per SoA.  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 will continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical 
record. 
• 
Should the participant continue to be unreachable, he/she will be considered 
to have withdrawn from the study with a primary reason of lost to follow-
up.  
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA 
• 
Immediate safety concerns will be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant will continue or 
discontinue study intervention. 
• 
All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA 
 


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8.1. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA 
8.1.1. 
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). 
• 
Height and weight will be measured and recorded as indicated in the SoA 
• 
Investigators will pay special attention to clinical signs related to previous 
serious illnesses. 
8.1.2. 
Vital Signs 
• 
Single oral temperature, pulse rate, respiratory rate and blood pressure will be 
assessed. 
• 
All blood pressure and pulse measurements will be assessed in semi-supine 
position with a completely automated device. Manual techniques will be used 
only if an automated device is not available. 
• 
Blood pressure and pulse measurements will be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). In addition, 
temperature will be monitored daily during study participation. 
• 
Additional details can be found in the SRM. 
 
8.1.3. 
Screening for COVID-19 Infection 
• Study participants will be monitored at Screening and daily while inpatients for 
COVID-19 symptoms.  Investigator(s) should utilise the World Health 
Organisation (WHO)_Case Definitions to classify COVID-19 cases [World 
Health Organisation, 2020].  While outpatients, participants should report to the 
unit any symptoms suggestive of COVID-19.  All participants who experience 
symptoms suggestive of COVID-19 should be isolated in the unit or at home and 
tested for SARS-CoV-2 using an approved molecular test (PCR).  The 
investigator should consider any participant testing positive for SARS-CoV-2 
being discontinued from study drug if COVID-19 symptoms are moderate to 
severe. Appropriate contact tracing for all participants testing positive will be 
performed within the unit.  This should be done in accordance with local 


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legislation and guidelines. Appropriate follow up should be implemented for 
participants who discontinue study due to COVID-19.   
• Following Screening, all study participants will be admitted to the Phase I unit on 
Day -2 and tested for SARS-CoV-2. 
• Participants in the Part 1 SAD treatment periods 2, 3 or 4 (if included) and in the 
RBA FE Cohort 7 will be tested for SARS-CoV-2 approximately one week prior 
to re-admission, at admission, and on re-admission to the unit as per the SoA. In 
addition all participants in Part 2 MAD Cohorts 3,4,5 and 6 will be tested for 
SARS-CoV-2 weekly while in the Phase I unit and at discharge.   
• 
All study participants should be tested again for SARS-CoV-2 using an 
approved molecular test (PCR) prior to leaving the unit.   
 
8.1.4. 
Electrocardiograms 
• 
In Part 1, 12-Lead ECG will be performed on Day-1, Day 1 at pre-dose, and 1, 
2, 4, 6, 12 and 16 hours post-dose.  At all other timepoints, ECG will be 
performed at the pre-dose timepoint.  
• 
In Part 2, 12-Lead ECG will be performed at the pre-dose timepoint at all 
timepoints indicated in SoA.  
• 
In Part 3, 12-Lead ECG should be performed on Day 1 in Periods 1-3 at pre-
dose, 2 h, and h post dose. Pre-dose ECGs in Periods 1-3 will be taken in 
triplicate. 
• 
Triplicate 12-lead ECG recordings will be obtained after the participant has been 
in a semi-supine position for at least 5 minutes using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  Participant eligibility will be based upon triplicate ECG recordings. 
Single recordings will be made at all other timepoints.  
• 
At each time point at which triplicate ECG are required, 3 individual ECG 
tracings will be obtained as closely as possible in succession, but no more than 
2 minutes apart. The full set of triplicates should be completed in less than 4 
minutes. 
• 
If any abnormalities in ECG interval are noted (including prolongation of the 
QT interval), ECGs will be repeated in triplicate with recordings over a 5 minute 
time period.  Refer to Section 7.1.2 for QTc Stopping Criteria and additional 
QTc readings that may be necessary. 
• 
At least one of these ECGs will be available and reviewed by the PI on site to 
evaluate for QT prolongation to ensure subject safety. Additional safety ECGs 
beyond those described in the SoA may be printed at the discretion of the PI if 
prolongation in QT interval is suspected. 
• 
Safety ECGs may be printed from the Global Instrumentation Holter device (see 
below).  ECG parameters from safety ECGs will not be collected unless as part 


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of an observed adverse events. Refer to Section 7.1.2 for QTc Stopping Criteria 
and additional QTc readings that may be necessary.  
• 
At timepoints for ECG extraction from Holter recordings, participants will be 
semi-supinely resting for at least 10 minutes.  
• 
Once human data (eg Cmax) is known, the number of ECG time points may be 
reduced in subsequent dosing groups. 
• 
Additional detail can be found in the SRM. 
 
8.1.4.1. 
Cardiodynamic assessment (ECGs extracted from Holter recordings) 
The frequency of ECG data in the SAD and MAD arises from emerging literature 
suggesting frequent QT evaluation early in development may mitigate the need for a 
formal TQT study [Darpo, 2014].  ECGs will be extracted as shown in the SoA from the 
SAD and the MAD component of the study. Should clinical development of VH3739937 
continue, an exploratory objective of this study is to assess the exposure-response 
relationship between VH3739937 and QTcF following single and repeat dose 
administration.  
The 12-lead Holter and ECG equipment will be used and may be supplied and supported 
by eREsearchTechnology, Inc. (ERT) or the contract research organization (CRO).  All 
ECG data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R 
ECG continuous 12 lead digital recorder.  The continuous 12-lead digital ECG data will 
be stored onto SD memory cards.  ECGs to be used in the analyses will be selected by 
pre-determined time points as defined in the SoA, and will be read centrally by ERT, Inc. 
 
The following principals will be followed in ERT’s core laboratory: 
 
▪ ECG analysts are blinded to the subject, visit and treatment allocation 
▪ Baseline and on-treatment ECGs for a particular subject will be over-read on the 
same lead and will be analyzed by the same reader. 
▪ The primary analysis lead is lead II.  If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire subject data set. 
 
The following is a brief description of ECG analysis methods utilized by ERT’s core 
laboratory. 
TQT Plus ECG Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer-assisted and statistical process 
utilized by ERT, Inc. The method enables extraction of ECGs with the lowest heart rate 
(HR) variability and noise within the protocol-specified extraction time window (e.g., the 
HR and QT changes from beat-to-beat in the range of <10%). At each protocol-specified 
timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG window” 
(typically, the last 5 minutes of the 15-minute period when the subject is maintained in a 
supine or semi-recumbent quiet position). 


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High-Precision QT Analysis 
High-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates.  Statistical quality control procedures are used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria, including: 
 
▪ QT or QTc values exceeding or below certain thresholds (biologically unlikely). 
▪ RR values exceeding or below certain thresholds (biologically unlikely). 
▪ Rapid changes in QT, QTc or RR from beat to beat. 
 
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” is performed using COMPAS software.  All 
low confidence beats are reviewed manually and adjudicated using pass-fail criteria.  The 
final QC assessment is performed by a cardiologist.  The beats found acceptable by 
manual review are included in the analysis.  The median QT, QTc, and RR value from 
each extracted replicate is calculated, and then the mean of all available medians from a 
nominal timepoint is used as the subject’s reportable value at that timepoint. 
 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals 
will be performed manually in 3 of the 10 ECG replicates at each timepoint.  Each 
fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) 
is electronically marked. 
 
Table 12 
T-wave morphology categories (assessed manually) 
Category 
Description 
Normal T-wave 
Any T-wave not meeting any criterion below 
Flat T-waves 
T amplitude < 1 mm (either positive or negative) including flat isoelectric line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending 
arm of the positive T-wave 
Biphasic 
T-wave that contains a second component with an opposite phase that is at least 
0.1 mV deep (both positive and negative/positive and polyphasic T-waves 
included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notches 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending 
arm of the negative T-wave 
In addition to the T-wave categorical analysis, the presence of abnormal U-waves is 
noted. 
 
8.1.5. 
Clinical Safety Laboratory Assessments 
• 
Refer to 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 relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
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• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 28 days after the last dose of study 
intervention will be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
All protocol- required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the laboratory manual and the SoA 
 
8.1.6. 
Suicidal Ideation and Behaviour Risk Monitoring 
VH3739937 is not thought to penetrate the CNS and is not being developed for a 
neurologic or psychiatric condition. Based upon the clinical data from the VH3532795 
clinical program, where two healthy volunteers reported CNS SAEs at supratherapeutic 
doses, participants will be excluded based on any pre-existing psychiatric condition 
(including assessment using the CSSRS). 
In addition, participants in the study will have assessment by the CSSRS during the on-
treatment phase of the study (see SoA for details).  As described in Section 7.1, any 
positive (abnormal) response confirmed by the investigator during the on-treatment phase 
will result in their discontinuation.  In either case (screening or on-treatment) of positive 
(abnormal) response confirmed by the investigator, the PI/SI will arrange for urgent 
specialist psychiatric evaluation and management. 
 
The definitions of behavioural suicidal events used in this scale are based on those used 
in the Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
behaviour, suicidal ideation, and intensity of ideation.  Screening visit questions will be 
in relation to lifetime experiences and current experiences (within the past 2 months) and 
all subsequent questioning in relation to the last assessment. Please see the SRM for 
further details. 
 
8.2. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
As described in Appendix 3 and Appendix 6, intensity of AEs (and lab abnormalities) 
will be graded using the division of AIDS (DAIDS) Grading table. While the study 
population will consist of HIV-1 seronegative healthy volunteers, the DAIDS criteria will 
be used in later clinical trials (Phase 2a and beyond).  Additionally, the DAIDS criteria 
have a more conservative grading scale relative to others. Thus, participant safety 
evaluation and monitoring will be more conservative. 
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 


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following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention and/or study 
(see Section 7).  
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signing of the informed consent form until 
the follow-up visit at the time points specified in the SoA However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a 
ViiV/GSK product will be recorded from the time a participant consents to 
participate in the study. 
• All AEs will be collected from the start of intervention until the follow-up visit at 
the time points specified in the SoA 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance will 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. For further detail, please see Appendix 3 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.2.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.  
8.2.3. 
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 7.3.).  Further information on follow-up procedures is given in 
Appendix 3. 


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8.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
 
8.2.5. 
Pregnancy 
• 
Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 5 
days [at least 5 terminal half-lives] after last dose of study intervention. 
• 
If a pregnancy is reported, the investigator will inform GSK within 24 hours of 
learning of the pregnancy and will follow the procedures outlined in Appendix 4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
 
8.3. 
Treatment of Overdose 
For this study, any dose of VH3739937 greater than a planned dose level within a 20-
hour time period will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose.  The investigator will 
use clinical judgment to treat any overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 5 days). 


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3. Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant.  No dose 
modifications are permitted without prior discussion and consent from the DEC. 
8.4. 
Pharmacokinetics 
• Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of VH3739937 at timepoints specified in the SoA.  
Details of blood collection and processing of PK samples are detailed in the SRM. 
• Whole blood samples of additional approximately 2 mL will be collected in SAD 
cohort 1 only for acidification purpose. Concentrations from acidified samples 
will be compared to concentrations from non-acidified samples and will be 
reported as exploratory data.     
• The number of PK sampling time points may be reduced in the initial MAD 
cohort as well as further in subsequent MAD dosing groups once human PK data 
are available in the SAD as well as in the initial MAD cohorts. 
• An additional 2 mL of whole blood samples will be collected for metabolite 
profiling of VH3739937 at the same timepoints as the PK samples on Day 1, Day 
2, Day 14, Day 15 in MAD cohorts 3, 4 and 5, and on Day 18, and Day 19 in the 
MAD cohort 5 only, as specified in the SoA. The results will be reported under a 
separate protocol. Details of blood collection and processing are detailed in the 
SRM.  
• A maximum of 10 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. 
Instructions for the collection, processing, handling and shipping procedures of 
biological samples will be provided in the SRM. The actual date and time (24-
hour clock time) of each sample will be recorded.   
• In Part 1, Cohort 2 Period 3 only, pre-dose urine can be collected up to 3.5 h pre-
dose for analysis of VH3739937 renal excretion. Afterward urine will be collected 
for analysis of VH3739937 renal excretion over 24 h collection periods as 
follows:  0-24 h, 24-48 h, 48-72 h, 72-96 h.  Fresh spot urine collection will be 
taken at each outpatient visit. For further detail, please see SRM. 
• In Part 2, urine PK and metabolite samples for analysis of VH3739937  will be 
collected at pre-dose (20 mL) (within 1 h prior to dosing) and from time 0 up to24 
h post dosing on Day 1 and from time 0 to 24 h post dosing on Day 14 in MAD 
Cohorts 3 and 4.  Spot urine sample collection on Day 16, 17 18, and 19 at post 
dose timepoint used on Day 1.  Fresh spot urine collection will be taken at each 
outpatient visit for urine PK sampling for analysis of VH3739937.  


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• In Part 2, Cohort 5, urine PK and metabolite samples for analysis of VH3739937  
will be collected at pre-dose (40 mL) (within 1 h prior to dosing) and from time 0 
up to 24 h post dosing on Days 1, 14 and 18.  Spot urine sample collection on Day 
20, 21, 22, and 23 at the post dose timepoint on Day 1.  Fresh spot urine 
collection will be taken at each outpatient visit for urine PK sampling for analysis 
of VH3739937.  
• In Part 2, Cohort 6, urine PK samples for analysis of VH3739937 will be 
collected at pre-dose (20 mL) (within 1 h prior to dosing) and from time 0 up to 
24 h post dosing on Days 1, 8 and 15.  Fresh spot urine collection will be taken at 
each outpatient visit for urine PK sampling for analysis of VH3739937.  
• After PK analysis, aliquots of 200 mL pooled urine samples (0-24 h) will be used 
for metabolite profiling. A maximum of 2 urine samples may be collected at 
additional time points during the study if warranted and agreed upon between the 
investigator and the sponsor. The actual start and stop date and time (24-h clock 
time) as well as collected volume over 24 h will be recorded for urine sample. 
Details of PK urine sample collection, processing and handling, storage 
procedures and shipping procedures are detailed in the SRM 
• Duodenal bile samples will be collected on Day 18 only for the analysis of 
VH3739937 and its metabolites for participants in MAD Cohort 5 only.  
• The EnteroTest or EnteroTracker will be swallowed 2 h post-dose. After 
approximately 6.5 h the bile string will be removed. Bile fluid is recovered on a 
highly absorbent nylon line which is contained within a weighted gelatin capsule. 
The 140 cm EnteroTest line or 90 cm EnteroTracker line unwinds after capsule 
swallowing as the capsule dissolves in the stomach and the line then passes into 
the duodenum. During withdrawal, the weighted section of the capsule separates 
from the line and passes in the stool. Additional details of the bile 
EnteroTest/EnteroTracker sample collection, processing, storage and shipping 
procedures are provided in the SRM. 
• The metabolite profiling of the plasma, bile and urine samples will be conducted 
under separate protocols and the results are reported separately according to the 
protocols.   
• Residual plasma and urine samples from all cohorts after PK bioanalysis may be 
used for metabolite identification and profiling purpose.   
• Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
• For Part 3, samples collected for VH3739937 plasma concentration may also be 
used to evaluate safety aspects related to concerns arising during or after the 
study. Once the plasma has been analysed for VH3739937, any remaining plasma 
may be analysed for other compound-related metabolites and the results reported 
under a separate protocol.  
 


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8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics 
A genetic sample is not required in this study. 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No formal statistical hypotheses are to be tested. 
9.2. 
Sample Size Determination 
9.2.1 
Sample Size Assumptions 
Parts 1 and 2  
Sample size is based on feasibility. No formal calculation of power or sample size (i.e., 
sample size sensitivity or robustness) for Parts 1 and 2 of the study has been performed. 
A sample size of approximately 9 participants (6 active: 3 placebo) per dose-cohort 
should be sufficient to provide useful estimates of both inter- and intra-participant 
variability for VH3739937, PK parameters, and initial safety assessment. 
 
Sample size re-estimation is not planned.  
 
Data will be reviewed by the DEC prior to each dose escalation; no other interim analysis 
is planned. 
 
Part 3  
This is the first study which will evaluate the pharmacokinetic properties of VH3739937 
in humans following oral administration of suspension and tablet formulations. Results 
from previous PK studies for GSK3640254 (a similar compound to VH3739937), and 
observed preliminary data from Part 1 of the study suggest that 25% is a conservative 
estimate for percent within subject coefficient of variation (%CVw) of Cmax and 
AUC(0-t) and will therefore be used to assess the precision (i.e. half width of the 90% 
confidence interval on the log and ratio scale) potential sample sizes of this three period 
crossover RBA/FE study. Assuming a within participant coefficient of variation of 25% 
and a sample size of 12 participants, it is estimated that the half width of the 90% 
confidence interval for the formulation difference on the log-scale will be within 0.173 of 
the point estimate (assumed to be 1.0). If the point estimate of the ratio of geometric 
means is assumed to be 1.0, then the 90% confidence interval will be approximately 
(0.841, 1.189) on the original scale.  
 


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Since tablet formulation and amount of food consumed may change the exposure to 
VH3739937, a range of point estimates for true ratio of 0.9, 1.0, and 1.1 were used in 
combination with sample sizes ranging from 12 to 18. The resulting estimated 90% 
confidence intervals are shown in Table 13 below. 
 
Table 13 
90% Confidence Intervals for RBA/FE of VH3739937 
 
n 
%CVw 
Point Estimate 
90% CI 
12 
25 
0.9 
(0.757, 1.070) 
12 
25 
1 
(0.841, 1.189) 
12 
25 
1.1 
(0.925, 1.308) 
15 
25 
0.9 
(0.772, 1.049) 
15 
25 
1 
(0.858, 1.166) 
15 
25 
1.1 
(0.944, 1.282) 
18 
25 
0.9 
(0.783, 1.034) 
18 
25 
1 
(0.870, 1.149) 
18 
25 
1.1 
(0.957, 1.264) 
 
9.2.2 
Sample Size Sensitivity 
To assess the sensitivity of sample size to within participant variability of the PK 
parameters, point estimates and 90% confidence intervals for a sample size of 12 
participants with a true ratio of 1.0 were calculated for %CVw values ranging from 15% 
to 35% were also considered and shown in Table 14 below. 
Table 14 
Sample Size Sensitivity for RBA/FE of VH3739937 
N 
%CVw 
Point Estimate 
90% CI 
12 
15 
0.9 
(0.810, 1.000) 
12 
25 
0.9 
(0.757, 1.070) 
12 
35 
0.9 
(0.708, 1.143) 
12 
15 
1 
(0.900, 1.111) 


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N 
%CVw 
Point Estimate 
90% CI 
12 
25 
1 
(0.841, 1.189) 
12 
35 
1 
(0.787, 1.270) 
 
Approximately 18 participants will be enrolled to ensure that approximately 12 evaluable 
participants complete the study.   
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All participants who sign the ICF 
Safety 
All participants who received at least 1 dose of study intervention. Participants 
will be analyzed according to the intervention they received. 
Pharmacokinetic Concentration  
 
The PK Concentration Population will include all participants who undergo 
plasma PK sampling and have evaluable PK assay results. This population will 
be used for the concentration listing. 
Pharmacokinetic Parameter 
The PK Parameter Population will include all participants who undergo plasma 
PK sampling and have evaluable PK parameters estimated. This population will 
be used for PK parameter listing, plotting of the concentration-time data and PK 
parameter summary. 
9.4. 
Statistical Analyses 
9.4.1. 
Safety Analyses 
All safety analyses will be performed on the Safety Population and details will be 
provided in the Reporting and Analysis Plan (RAP).  
Endpoint 
Statistical Analysis Methods 
Primary 
Safety data will be presented in tabular and or graphic format and summarized descriptively 
accordingly to GSK’s Integrated Data Standards Library (IDSL) standards 
Exploratory 
Will be described in the reporting and analysis plan  
 
AEs will be tabulated using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred terms. The number and percentage of participants experiencing each specific 
AEs (All AEs, Grade 2 or higher, and SAEs) will be tabulated by severity and by 
relationship to study product. For the calculations in these tables, each participant’s AEs 
will be counted once under the maximum severity or the strongest relationship to study 
product. AEs leading to withdrawal will also be summarized by treatment. 


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9.4.2. 
Other Analyses 
PK and pharmacodynamic exploratory analyses will be described in the reporting and 
analysis plan. The population PK analysis and pharmacodynamic analyses will be 
presented separately from the main clinical study report (CSR).  
Additionally, special statistical and data analysis considerations may be warranted in the 
event that the COVID-19 or related epidemics or natural disasters may affect the study 
and data integrity. To the extent possible, these will be described in the study RAP. 
9.4.3. 
Pharmacokinetic Analyses 
Plasma VH3739937 concentration-time data will be analyzed by noncompartmental 
methods using WinNonlin Professional 5.2 or higher, Phoenix (Pharsight Corporation) or 
comparable software.  The various analyses will be conducted as permitted by data 
available. Individual plasma PK parameters for each participant and dosing group will be 
determined, including:   
• Part 1 (single dose): AUC(0-24), AUC(0-), AUC(0-inf), Cmax, C24, tmax, tlag, t1/2, Clast, 
tlast, CL/F.   
• Part 2 (repeated once daily [QD] dose):  
o Day 1: AUC(0-24), Cmax, C24, tmax, tlag 
o Day 14 (Cohort 3 and 4): AUC(0-), Cmax, C, tmax, t1/2, and CL/F 
o Day 18 (Cohort 5): AUC(0-t), Cmax, Ct, tmax, t1/2, and CL/F 
• Part 2 (repeated once weekly [QW] dose): 
o Day 1 (Cohort 6): AUC (0-168), Cmax, C168, tmax, tlag 
o Day 15 (Cohort 6): AUC(0-t), Cmax, Ct, tmax, t1/2, and CL/F 
• Part 3 (Single Dose Relative Bioavailability):  
o AUC (0-24), AUC(0-inf), Cmax, C24, tmax, tlag, t1/2, Clast, tlast, CL/F 
 
 
9.4.4. 
Statistical Analysis of Pharmacokinetic Data 
• Statistical analyses of the pharmacokinetic parameter data will be the 
responsibility of Clinical Statistics, GSK. 
• Plasma VH3739937 concentrations and PK data will be summarized by treatment 
and listed by participant. Unless stated otherwise, descriptive summaries will 
include number (n), mean, standard deviation (SD), coefficient of variation 
(%CV), median, minimum, and maximum for continuous variables, n and percent 
(%) for categorical variables, and geometric mean, 95% confidence interval (CI), 
and the between-participant CV (%CVb) for the log-transformed PK parameters. 
• Dose proportionality of selected single and repeated dose PK parameters will be 
assessed by the power model. 


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• Accumulation will also be: 
o Predicting from single dose data (Part 1) based on AUC as follows: Rp = 
AUC(0-) day 1/ AUC(0-) day 1 
o Evaluated for each treatment by determining the ratio of Day 14 for cohort 
3 and 4, Day 18 for cohort 5, and Day 15 for cohort 6 (Part 2) to Day 1 
AUC(0-) (R(AUC(0-)), Cmax (R(Cmax)), and C (R(C)). C24 on Day 
1 will be taken as the C on that day. 
• Assessment of steady-state VH3739937 concentrations will be assessed in Part 2 
by estimating the slope of pre-dose concentrations on Days 2-14 for Cohorts 3 
and 4, Days 2-18 for Cohort 5 and Days 2-15 for Cohort 6.  The final assessment 
of the slope will be determined by at least the last 3 pre-dose concentrations.   
• Part 3 
For the assessment of relative bioavailability of formulation and food effect (if 
conducted), the loge-transformed PK parameters will be analysed as data permits 
using separate mixed effect models with a fixed effect term for fed vs. fasted and 
tablet vs PiB. Participant will be treated as a random effect in each model. Point 
estimates and their associated 90% CIs will be calculated for the difference in 
AUC (0-24), AUC(0-inf), and Cmax for the tablet vs PiB and fed vs fasted 
comparisons. The point estimates and their associated 90% CIs will then be back-
transformed to provide point estimates and 90% CIs for the ratios of tablet vs PiB 
and fed vs fasted in PK parameter values on the original scale.  
•  Full details of the statistical analysis of PK data will be described in the RAP. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
• Pharmacokinetics/Pharmacodynamic (PK/PD) analyses will be performed only if 
the VH3739937 development project is progressing forward. The end point for 
the potential impact of VH3739937 on cardiac repolarization will be the change-
from-baseline QTcF (∆QTc). A modelling approach will be used to describe the 
relationship between VH3739937 concentration and QTc data.  
• The details of the PK/PD analysis will be described in the RAP or in a separate 
analysis plan if the analysis is reported separately. 
9.5. 
Interim Analyses 
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available pharmacokinetic data will be reviewed internally at the Dose Escalation 
Committee (ViiV/GSK) prior to each dose escalation or administration and according to 
the dose escalation charter. Safety data (labs, vital signs, ECG, AEs, SAEs) will be 
reviewed by the PI/Sub-I and ViiV/GSK study team after completion of each dose level. 
Dose escalation can only occur after PI/Sub-I and ViiV/GSK study team has found that 
the safety, PK profiles are supportive to proceed with the evaluation of the next highest 
dose level. 


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At each dose, the Bayesian probability of an individual exceeding the Cmax threshold in 
Part 1 and the Bayesian probability of an individual exceeding the AUC threshold in Part 
2 will be calculated and compared with 50%. This will be used to help selection of the 
next dose together with safety and tolerability data. The Bayesian probability will be 
based on Whitehead’s model shown below [Whitehead, 2001] using non-informative 
prior for model parameters. 
 
 
[1] 
Where yij is log-PK of i-th participant to j-th dose, dij is j-th log-dose administered to i-th 
participant. θ1 and θ2 are population intercept and slope, respectively. si is random effect 
of i -th participant and 
 is random error of i -th participant in j-th dose. 
When intra-participant variability cannot be estimated during PK predictions in Part 1 
(i.e., early on in the study when there is not sufficient information to estimate intra-
participant variability) and for conducting prediction of all doses in Part 2, the same 
Whitehead’s model will be used for Bayesian probability calculations as below. 
 
[2] 
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th participant. θ1 
and θ2 are population intercept and slope, respectively and i is random error of i-th 
participant. 
Bayesian model Operating Characteristics (OC) 
In this part, we want to explore the operating characteristics of the possibility of 
escalating to the 800 mg dose in the SAD portion of the study. Given different 
assumptions of with-in and between participant Cmax variability (CV%), and assuming 
dose proportionality (slope=1), data for 1000 trials were simulated based on Whitehead’s 
model [1]. Each simulated trial contains Cmax values for 6 subjects on treatment for 
doses ranging from 10 mg to 640 mg in SAD cohort 1 and cohort 2.  
For each simulated trial, we fit the mixed effect Bayesian model based on mode [1]. 
Using the following procedure, we calculated the Bayesian probability of an individual 
exceeding the Cmax threshold:  
10,000 iterations were simulated in the MCMC procedure. In each iteration, we obtained 
the estimated parameters 𝜃̂1, 𝜃̂2, 𝑠̂𝑖 (𝑖= 1,2, … , 6) and   𝜎̂2(the estimated standard 
deviation of 𝜖𝑖𝑗), Based on the estimation, a random sample for each subject, which 
represented the simulated exposure in the 800 mg dose, was drawn from the distribution 
𝑁(𝜃̂1 + 𝜃̂2 × 800 + 𝑠𝑖, 𝜎̂2).   We counted the number of iterations 𝑁 with any simulated 
exposure exceeding the Cmax threshold log(21). The Bayesian probability was calculated 
as 1 −
𝑁
10,000. .  


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For each trial, the Bayesian probability of the 800 mg dose exceeding the Cmax threshold 
of log(21) was calculated and compared with different thresholds (40%, 50% or 60%).  
Results showed that all simulated trials had a probability less than 40%, 50%, and 60% in 
situations with high variability (%CVw = 50, %CVb = 50) as well as scenarios with low 
variability (%CVw = 12.5, %CVb = 25). These results indicate that the probability of 
escalating to 800 mg in the SAD is high.  
Additional simulations were conducted to determine the probability of escalating to 100 
mg during the Part 2 of the study (MAD QD dosing).  1000 simulated trials were 
produced for each value of %CVb (25, 35, and 50), using a predicted 24-hour steady state 
AUC of 39.8 µg*h/mL. More detailed information may be found in the IB Supplement 
[GlaxoSmithKline Document Number 2021 RPS_CLIN_004025].  For each trial, the 
Bayesian probability of the 100 mg MAD QD dose producing an 24 hour steady state 
AUC above log(96.2) was calculated. This value was compared to potential evidence 
thresholds of 40%, 50%, and 60%.  Table 15 shows the probability of a simulated trial 
having a Bayesian predictive probability of exceeding the AUC safety threshold of 
log(96.2) less than the various threshold values under the chosen values of CVb.  
Table 15 
Percentage of simulated trials of 100 QD dosing with Bayesian 
predicted probability of 24hr steady state AUC under safety 
threshold of log(96.2) across probability thresholds 
AUC Variability 
Probability Threshold 
%CVb  
40% 
50% 
60% 
25 
0.995 
0.999 
1 
35 
0.934 
0.967 
0.986 
50 
0.791 
0.880 
0.927 
 
These results indicate that the probability of escalating to 100 mg during the MAD QD 
dosing portion of the study is high.  
Finally, simulations were performed to assess the probability of any participant having an 
24 hour steady state AUC above log(96.2) or a Cmax above log(21) during the weekly 
MAD dosing portion of the study. It is anticipated that a 500 mg weekly dose will 
produce a steady state maximum daily AUC of 31.2 µg*h/mL. Under this assumption, 
1000 simulated trials were produced for each value of %CVb (25, 35, 5). Each simulated 
trial included 7 participants dosed at 500 mg. No simulated trial produced any participant 
who had either an AUC above log(96.2) or a Cmax above log (21). Therefore, the 
probability of a subject exceeding the safety threshold during the weekly dosing portion 
of the study is low.   
9.6. 
Final Analyses  
Final analysis will be performed after the completion of the study and final datasets 
authorization. 
 


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Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by participant, treatment and day; summaries will be 
presented by treatment, day, and time for each part. 
 
Unless stated otherwise, descriptive summaries will include n, mean, SD, %CV, median, 
minimum, and maximum, geometric mean with associated 95% CI, and the %CVb for 
continuous variables, whereas n and percent will be used as summary statistics for 
categorical variables. 


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


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.5. 
Committees Structure 
This study will be reviewed and approved by an Internal Review Committee prior to 
initiation. 
10.1.6. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  


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• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
10.1.7. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• 
ViiV/GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
ViiV/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. 
• 
ViiV/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 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.8. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 


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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 and/or Task Order 
between ViiV/GSK and the study site. 
• 
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). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 15 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
• 
Quality tolerance limits (QTLs) will be pre-defined in the QTL report to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during the study and 
deviations from the QTLs and remedial actions taken will be summarized in the 
clinical study report. 
10.1.9. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
The clinical site in this study, utilizes a validated proprietary bedside data 
capture system to retain the source data.  


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10.1.10. 
Study and Site Closure 
ViiV/GSK or its designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 16 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. 
• Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• Pregnancy testing (urine or serum as required by local regulations) will be 
conducted at monthly intervals during intervention and at the end of relevant 
systemic exposure. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study. 
Table 16 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes 
White Blood Cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Clinical Chemistry1 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium, Chloride, 
Bicarb 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium, 
Magnesium, 
Phosphate 
Alkaline phosphatase 
Amylase 
Lipase 
Fasting Lipid Panel 
(Cholesterol, 
Triglycerides, high-
density lipoprotein 
[HDL], low-density 
lipoprotein [LDL])  
Serum creatine 
phosphokinase (CPK) 
 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 


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Laboratory 
Assessments 
Parameters 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• 
Serum alcohol and urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed)  
• 
Fourth generation serology test for HIV-1, hepatitis B surface antigen [HbsAg], and 
hepatitis C virus antibody)] 
• 
The results of each test must be entered into the CRF. 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 5 All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
 
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. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
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. 


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• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment will be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 


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may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
10.3.3. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category 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. 
 
 


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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 ViiV/GSK. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to ViiV/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 
ViiV/GSK to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide ViiV/GSK with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to ViiV/GSK within 24 hours 
of receipt of the information. 
 


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10.3.4. 
Reporting of SAE to ViiV/GSK 
SAE Reporting to ViiV/GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to ViiV/GSK will be the electronic 
data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement >40 IU/L or mIU/mL is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment. 
 
 


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10.4.2. 
Highly Effective Methods of Contraception 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, 121ymptom-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for the 
study. Male condom and female condom should not be used together (due to risk of failure with friction) 


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10.4.3. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive VH3739937 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Female Participants who become pregnant  
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant’s pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
• 
Any female participant who becomes pregnant while participating will discontinue 
study intervention and be withdrawn from the study. 


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments  
Table 17 
Phase I liver chemistry stopping criteria and required follow up 
assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin  2xULN or INR 
>1.5 
• Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours 
• Monitor participant(s) twice weekly until 
liver chemistries resolve, stabilise or return 
to within baseline 
• A specialist or hepatology consultation is 
recommended 
• Viral hepatitis serology3 
• 
Obtain international normalized ratio 
(INR) and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic  
analysis, obtained as soon as possible in 
relation to last dose4  
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 


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Liver Chemistry Stopping Criteria  
 
 
If ALT≥3xULN AND bilirubin < 2xULN and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours 
• Monitor participant(s) weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
 
 
If ALT≥3xULN AND bilirubin  2xULN or 
INR >1.5: 
• 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 and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants 
3. Includes: Hepatitis A immunoglobulin (gM) antibody; HbsAg and HbcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM. .  


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10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events Corrected 
Version 2.1, July 2017 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized 
for AE reporting. A grading (severity) scale is provided for each AE term. For more 
information, please refer to the DAIDS grading table Version 2.1, July 2017 at 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). 
 


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10.7. 
Appendix 7: Permissible Procedures During COVID-19 
Pandemic 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits.  Based on these challenges, 
it may be necessary to adopt additional measures and procedures to protect participant 
safety, and to allow flexibility to facilitate conduct of the study.  
Permissible changes to procedures during the COVID-19 pandemic if deemed necessary 
by the investigator are outlined below. The investigator should discuss with the medical 
monitor the rationale prior to these changes being implemented for a participant(s). Any 
change implemented will be documented in each participant’s medical notes and in the 
eCRF as a COVID-19 related protocol deviation. 
 
1) Participants previously deemed eligible during the screening period unable to 
attend within the allowable screening window due to COVID-19 may be 
rescreened.  The most recent screening data will be used to determine study 
eligibility.  
2) Duration of admission to the clinic may be extended if deemed necessary by the 
investigator due to the COVID-19 pandemic. 
3) Duration of study participation may be extended as a result of a pandemic 
restrictions. Parexel staff shall continue to monitor participant status via phone 
call until participant is able to return and complete protocol required study 
procedures. 
4) Participants are required to have two negative SARs-CoV-2 PCR tests prior to/on 
each (re-)admission to the unit. Participants will also undergo weekly testing 
while on the unit and on discharge as appropriate. Additional testing for SARS-
CoV-2 may be introduced to the SoA at different times if deemed necessary by 
the investigator and/or sponsor. 
 
If a participant has suspected COVID-19, or tests positive for COVID-19, or has potential 
COVID19 exposure while enrolled in the study, the Investigator must assess the impact 
of this disease/situation on the benefit/risk for the participant/(s) to continue in the study, 
as well as compliance with protocol withdrawal criteria.  Adverse events related to 
COVID-19 should continue to be evaluated as to whether they meet SAE criteria as 
defined in Section 10.3.2, and if so, reported in line with the SAE reporting requirements 
(Section 10.3.4). Investigator(s) should utilise the WHO Case Definitions to classify 
COVID-19 cases [World Health Organisation 2020].  The Sponsor recognises that 
COVID-19 case definitions may evolve during the study period, the most recent edition 
should be consulted for each case.    For all AEs or SAEs related to COVID-19, details 
should also be entered into the specific COVID-19 eCRF.  The study site should contact 
the study Medical Monitor for questions related to definitions and reporting, and 
decisions around impact to study drug continuation in the setting of clinically defined 
mild COVID-19 infection.  


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All cases of COVID-19 must be properly documented in the participant’s medical chart. 
Any participant withdrawing due to COVID-19 disease symptoms/diagnosis may be 
replaced following discussion between the Investigator and Sponsor. 
 


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10.8. 
Appendix 8: Abbreviations and Trademarks 
µg 
Micrograms 
∆QTcF 
Change-from-baseline QTcF 
%CV 
Coefficient of variation 
%CVw 
Within-participant coefficient of variation 
%CVb 
Between-participant coefficient of variation 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ARV 
Anti-retroviral 
ART 
Anti-retroviral therapy 
ALT 
Alanine transaminase 
AST 
Aspartate Aminotransferase 
AUC(0-) 
 
Area under the curve (Area under the 
plasma drug concentration-time curve from 
pre-dose to the end of the dosing interval at 
steady state)  
AUC(0-24) 
Area under the plasma concentration time 
curve from zero to 24 
AUC(0-inf) 
Area under the concentration-time curve 
from time zero (pre-dose) extrapolated to 
infinite time 
AUC(0-t) 
Area under the plasma concentration time 
curve from zero (pre-dose) to t 
BID 
Twice daily 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
bps 
Beats per minute 
BUN 
Blood urea nitrogen 
C 
Trough serum concentration 
C24 
Drug concentration at 24 hours post-dose 
cART 
Combination anti-retroviral therapy 
CHMP 
Committee for Medicinal Products for 
Human Use 
CI 
Confidence interval 
CIB 
Clinical Investigator’s Brochure  


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CIOMS 
Council for International Organizations of 
Medical Sciences 
CL/F 
Apparent oral clearance  
Clast 
Last observable concentration 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
Disease caused by corona virus SARS-
CoV-2 first observed in 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CSSRS 
Columbia Suicide Severity Rating Scale 
CTFG 
Clinical Trial Facilitation Group 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DAIDS 
Division of AIDS 
DEC 
Dose Escalation Committee 
dL 
Decilitre 
ECG 
Electrocardiogram  
eGFR 
Estimated Glomerular Filtration Rate 
EMEA 
European Medicines Agency 
ERT 
eResearch Technology, Inc 
FDA 
Food and Drug Administration  
FE 
Food Effect 
FSH 
Follicle stimulating hormone 
FTIH 
First-time-in-human 
g 
Grams 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and 
Pharmacovigilance  
GI 
Gastrointestinal 


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GLP 
Good laboratory practice 
GSK 
GlaxoSmithKline  
h 
Hours 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C 
HDL 
High-density lipoprotein 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and 
Accountability Act 
HIV-1 
Human immunodeficiency virus-1 
HPMC 
Hydroxypropyl methyl cellulose 
HR 
Heart Rate 
HRT 
Hormone Replacement Therapy 
HSR 
Hypersensitivity reactions 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form  
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee  
IgG 
Immunoglobulin G 
IIV 
Inter-Individual Variability 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board  
IRT 
Interactive Response Technology 
IU 
International Unit 
IUD 
Intrauterine Device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
kg 
Kilograms 
L 
Litres 
LA 
Long Acting 
LAM 
Lactational amenorrhoea method 
LDH 
Lactate dehydrogenase 


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LDL 
Low-density lipoprotein 
LOAEL 
Lowest observed adverse effect level 
m2 
Meter square 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Maturation inhibitors 
mins 
Minutes 
mIU 
milli-international units 
mL 
Milliliter 
MOA 
Mechanisms of action 
MRSD 
Maximum Recommended Starting Dose 
MSDS 
Material Safety Data Sheet  
msec 
Milliseconds 
ng 
Nanograms 
NOAEL 
No observed adverse effect level 
OC 
Operating Characteristics 
PBA 
Protein Binding Adjusted 
PBO 
Placebo 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic  
PI 
Principal Investigator  
PiB 
Powder-in-bottle 
PK 
Pharmacokinetic  
PLHIV 
People living with HIV 
POC 
Proof of Concept 
QD 
Once Daily 
QTc 
QT interval corrected 
QTcF 
QT interval corrected for heart rate 
according to Fridericia’s formula 
QTL 
Quality tolerance limit 


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QW 
Weekly Dosing 
RAP 
Reporting and Analysis Plan  
RAMOS NG 
Randomization and Medication Ordering 
System Next Generation 
RBA 
Relative Bioavailability 
RBC 
Red blood cell 
R (C) 
Ratio of concentration over the dosing 
interval 
RAUC(0-) 
Accumulation ratio of area under the 
concentration-time curve over the dosing 
interval 
R(Cmax) 
Ratio of maximum observed concentration 
Rp 
Predicted accumulation ratio 
RNA 
Ribonucleic acid 
SAD 
Single ascending dose 
SAE 
Serious Adverse Event  
SARS-CoV-2 
SARS Coronavirus-2 
SD 
Standard deviation  
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Oxaloacetic Transaminase 
SI 
Sub-investigator 
SOA 
Schedule of activities 
SRM 
Study Reference Manual  
SUSAR 
Suspected unexpected serious adverse 
reactions 
t1/2 
Apparent terminal phase half-life  
tlast 
Time of last observable concentration 
tlag 
Lag time 
Tmax 
Time of occurrence of Cmax  
TOC 
Table of Contents 
ULN 
Upper limit of normal  
VH 
ViiV Healthcare 
WBC 
White blood cells 
WHO 
World Health Organisation 


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WOCBP 
Women of Childbearing Potential  
 
Trademark Information 
Trademarks of ViiV Healthcare 
 
Trademarks not owned by the ViiV 
Healthcare 
NONE 
 
DAIDS 
 
 
Phoenix 
 
 
WinNonlin 


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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 [01] 11-JUN-2020 
Overall Rationale for the Amendment: Amendment 01 was generated to remove 
Sodium Stearyl Fumarate from the placebo formulation, to clarify administration for 
study interventions and maintenance of the blind.  Revisions were made to the study 
eligibility criteria and safety assessments in response to the FDA’s feedback and to 
mitigate the potential risks for study conduct during the COVID-19 pandemic.  Given the 
absence of benefit to study participants, the exclusion criteria and the criteria for 
individual subject discontinuation, dose escalation and stopping the study were revised to 
be more conservative.  Revisions were made to improve accuracy of the study risk 
assessment and the pharmacokinetic analyses.  


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Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Included the EudraCT 
number for this study  
The EudraCT number had been 
obtained 
1.2 Schedule of Activities 
(SOA) 
SOA for the SAD and MAD 
revised to include 
monitoring of temperature 
on each day of study 
participation and SARS 
CoV-2 testing at Screening, 
on admission to the Phase I 
unit and on day of discharge 
from the unit. 
Revision to clarify that ECG 
and vital signs are collected 
pre-dose and that bile 
sampling will be performed 
post-dose 
To mitigate risk to study conduct 
during the COVID-19 pandemic 
and to clarify scheduled activities 
2.3.1 Risk Assessment 
Included updated 
information for 
gastrointestinal events and 
included Skin and 
Subcutaneous Tissue 
Disorders as a new risk 
category  
Inclusions to ensure accuracy of 
this section 
2.3.4 Acute Monitoring in 
FTIH Studies 
Revised to state this study 
may be conducted in more 
than one Phase I Unit 
Improve clarity of information in 
this section 
5.1 Inclusion Criteria 
 Included a new criterion for 
participants to have two 
consecutive negative tests 
for SARS CoV-2 at 
Screening and on admission  
To mitigate risk to study conduct 
during the COVID-19 pandemic 
5.2 Exclusion Criteria 
Included two new criteria 
excluding participants 
having signs and symptoms 
suggestive of COVID-19 
and participants who had 
contact with a known 
COVID-19 positive person/s 
within 14 days prior to 
admission  
Included new criterion and 
revised existing criterion 
 To mitigate risk to study conduct 
during the COVID-19 pandemic.   
Exclusionary laboratory criteria 
expanded and made more 
conservative to facilitate 
improved assessment of a 
potential safety signal 


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Section # and Name 
Description of Change 
Brief Rationale 
addressing laboratory 
parameters for 
haemoglobin, liver and renal 
function. Extended 
exclusion criterion 
addressing prior and 
concomitant therapy to 
include cytochrome p450 
enzyme inducers or 
inhibitors. 
6.1 Study Intervention(s) 
Administered  
Revision to details of Study 
Interventions  
Removal of Sodium Stearyl 
Fumarate from the placebo  
6.2 
Preparation/Handling/Storage 
/Accountability 
Revision to clarify 
maintenance of the blind 
The revised placebo 
formulations may be 
distinguished visually from the 
active GSK3739937 formulation 
6.3 Method of Treatment 
Assignment 
Revised to improve clarity 
on use of RAMOS NG for 
study randomisation and on 
emergency unblinding 
procedures 
Implementation of use of 
RAMOS NG for randomisation of 
participants 
6.4 Measures to Minimize 
bias: Randomization and 
Blinding 
Revision to the method of 
administration of study 
interventions. Included 
additional information 
regarding unblinding in an 
emergency situation. 
To minimise unblinding due to 
visual differences between the 
active GSK3739937 and placebo 
formulations. Extended 
information provided to address 
unblinding. 
6.6 Concomitant Therapy 
Revised to include 
cytochrome P450 (CYP) 
inducers and inhibitors as 
prohibited medications  
Possible interaction of 
GSK3739937 with CYP inhibitors 
and inducers has not yet been 
excluded 
6.7 Dose Modification 
Revised to clarify that 
criteria for discontinuation of 
dose escalation also apply 
to discontinuation of dosing 
within the cohort in which a 
toxicity occurs 
Revision to include additional 
detail regarding dosing and dose 
escalation 
7.1 Discontinuation of Study 
Intervention 
Included an additional 
criterion for discontinuation 
of the study intervention and 
Inclusion of more conservative 
criteria for discontinuation of the 
study intervention and for 


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Section # and Name 
Description of Change 
Brief Rationale 
in 7.1.5 ‘Clinical criteria for 
stopping the Study’ 
extended the criteria cited 
that would lead to pausing 
or stopping the study 
pausing or stopping the study 
8.1 Safety Assessments 
8.1.1. ‘Physical 
Examination’ revised for 
clarity.  
8.1.2 ‘Vital Signs’ was 
revised to include 
temperature monitoring 
daily for study participants.  
A new sub-Section 8.1.3 
‘Screening for COVID-19’ 
was included 
8.1.4 ‘Electrocardiograms’ 
revised to state a semi-
supine position for Holter 
recordings 
To mitigate risk to study conduct 
during the COVID-19 pandemic 
and revision of 8.1.1 and 8.1.4. 
to assist clarity and study 
conduct 
9.4.3 Pharmacokinetic 
Analysis 
Revised to correct 
pharmacokinetic analyses in 
Part 2. 
Revision made to be consistent 
with study objectives 
9.4.4 Statistical Analysis of 
Pharmacokinetic Data 
Revised to be consistent 
with the revision to 
pharmacokinetic analyses in 
Section 9.4.3 
Revised for accuracy and to be 
consistent with Section 9.4.3 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Revised to remove urine 
test for pregnancy and to 
include the 4th generation 
serologic test for HIV-1 
Revised for accuracy and clarity 
10.7 Appendix 7: 
Permissable Procedures 
During COVID-19 Pandemic 
Revised to clarify evaluation 
and reporting of adverse 
events and serious adverse 
events related to COVID-19 
and reference to the World 
Health Organisation case 
definitions for COVID-19 
Improve clarity on the 
procedures and guidance 
provided  
10.8 Appendix 8: 
Abbreviations and 
Trademarks 
Revised to include the 
abbreviations included in 
revisions in this protocol 
amendment  
Inclusion of all abbreviations 
cited  


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11. 
REFERENCES 
Darpo B., Garnett C., Benson C.T., Keirns J., Leishman D., et. al.  Cardiac safety 
research consortium: Can the thorough QT/QTc study be replaced by early QT 
assessment in routine clinical pharmacology studies? Scientific update and a research 
proposal for a path forward. Am Heart J 2014; 168:262-72. 
Fact sheet: United Nations AIDS. Global HIV & AIDS statistics. 2019 fact sheet; 
Available at http://www.unaids.org/en/resources/fact-sheet. Accessed 16-APR-2020 
GlaxoSmithKline Document Number 2016N297636_00. Clinical Study Report AI468049 
(206221). Completion Date: 15 August 2016. 
GlaxoSmithKline Document Number 2016N302783_00.  Clinical Study Report 
AI468038 (205891). Completion Date: 26 May 2016. 
GlaxoSmithKline Document Number 2017N319618_00. Clinical Study Report AI468063 
(206294). Completion Date: 23-December 2015. 
GlaxoSmithKline Document Number 2017N332341_00. Clinical Study Report AI468044 
(206220). Completion Date: 14-October 2016. 
GlaxoSmithKline Document Number 2018N392814_01. Clinical Study Report (207187). 
Completion Date: 9-September 2018. 
GlaxoSmithKline Document Number 2019N421306_00.  GSK3739937 Investigator’s 
Brochure_2019_Version00_GSK3739937. Effective Date: March 2020. 
GlaxoSmithKline Document Number 2020N427033_00.  Modeling and Simulation 
Analysis Report to predict the Pharmacokinetics and Pharmacodynamics of GSK3739937 
for FTIH Study. Effective Date: 05-March-2020. 
GlaxoSmithKline Document Number RPS_CLIN_004025.  GSK3739937 Investigator’s 
Brochure Supplement 02_2021_Version00_GSK3739937. Effective Date: March 2021. 
Guidance for Industry estimating the maximum safe starting dose in initial clinical trials 
for therapeutics in adult healthy volunteers. FDA/CDER., July 2005. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007; 
164:1035-1043. 
Whitehead J. et al., Easy-to-implement Bayesian methods for dose-escalation studies in 
healthy participants, Biostatistics, 2, 47cs, 2, 47v 2001. 
World Health Organisation March 2020: Global surveillance for COVID-19 caused by 
human infection with COVID-19 virus. Interim 


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guidance.https://www.who.int/publications-detail/global-surveillance-for-human-
infection-with-novel-coronavirus-(2019-ncov)  Link accessed on 3rd June 2020 

SAP_001.pdf: 
 
 
Reporting and Analysis Plan 
 
 
Study ID: 212548 
Official Title of Study: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-
Controlled, Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability 
and Pharmacokinetics of GSK3739937 in Healthy Participants 
IND Number: 147773 
EudraCT Number: 2020-002834-34 
Date of document: 21-September-2021 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
212548 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for Study 212548: A Double-
Blind (Sponsor Unblinded), Randomized, Placebo-
Controlled, Single and Repeated Dose Escalation Study to 
Investigate the Safety, Tolerability and Pharmacokinetics of 
GSK3739937 in Healthy Participants 
Compound Number  : VH3739937 (also known as GSK3739937) 
Clinical Study 
Identifier 
: 212548 
Effective Date  
: Refer to Document date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 212548 
• 
This RAP is intended to describe the safety, tolerability, and pharmacokinetic 
analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable. 
 
 
RAP Author(s): 
Author 
Date 
Lead 
 
 
21-SEP-2021 
Principal Statistician (Development Biostatistics) 
Co-Authors 
 
 
  
21-SEP-2021 
Senior Programmer (Development Biostatistics)  
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


 
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RAP Team Reviews: 
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer 
Date 
 
21-SEP-2021 
Manager (Clinical Pharmacology Modelling and Simulation) 
  
Clinical Development Director (ViiV Clinical Development) 
21-SEP-2021 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Veeva Vault TMF eSignature) 
Approver 
Date 
 
21-SEP-2021 
Statistics Leader (Development Clinical Statistics) 
 (Line manager for 
) 
21-SEP-2021 
Programming Manager (Development Biostatistics) 
 
Approval Delegated to:  
 (Project Programmer) 
Programming Leader (Development Biostatistics) 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) ......................................... 7 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Analyses ..................................................................................... 13 
2.4.1. 
Part 1 (SAD) and 2 (MAD) ........................................................... 13 
2.4.2. 
Part 3 (RBA) ................................................................................ 13 
3. 
PLANNED ANALYSES .......................................................................................... 14 
3.1. 
Interim Analyses ......................................................................................... 14 
3.2. 
Final Analyses ............................................................................................ 14 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Baseline Definitions .................................................................................... 17 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 18 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
7. 
SAFETY ANALYSES ............................................................................................. 20 
7.1. 
Adverse Events Analyses ........................................................................... 20 
7.2. 
Clinical Laboratory Analyses ....................................................................... 20 
7.3. 
Other Safety Analyses ................................................................................ 21 
8. 
PHARMACOKINETIC ANALYSES ......................................................................... 22 
8.1. 
Primary Pharmacokinetic Analyses ............................................................. 22 
8.1.1. 
Endpoint / Variables ..................................................................... 22 
8.1.1.1. 
Drug Concentration Measures .................................... 22 
8.1.1.2. 
Derived Pharmacokinetic Parameters......................... 22 
8.1.2. 
Summary Measure ...................................................................... 23 
8.1.3. 
Population of Interest ................................................................... 24 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 24 
8.1.5. 
Statistical Analyses / Methods ..................................................... 24 
8.1.5.1. 
Statistical Methodology Specification .......................... 24 
8.1.5.1.1. 
Dose Proportionality (Power 
Model) .................................................... 24 
8.1.5.1.2. 
Accumulation Ratio ................................. 25 
8.1.5.1.3. 
Assessment of Steady State ................... 27 
8.1.5.1.4. 
Relative Bioavailability and Food 
Effect ...................................................... 28 
8.2. 
Exploratory Pharmacokinetic Analyses ....................................................... 29 


 
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9. 
POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 30 
10. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 31 
11. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 32 
11.1. 
Study Population ......................................................................................... 32 
11.1.1. 
Subject Disposition ...................................................................... 32 
11.1.2. 
Protocol Deviations ...................................................................... 32 
11.1.3. 
Additional Displays for Participants with a COVID-19 
Infection ....................................................................................... 32 
11.2. 
Safety ......................................................................................................... 32 
11.2.1. 
Assessment of COVID-19 AEs .................................................... 32 
11.2.2. 
Impact of COVID-19 Pandemic on Safety Results ....................... 32 
12. REFERENCES ....................................................................................................... 33 
13. APPENDICES ........................................................................................................ 34 
13.1. 
Appendix 1: Exclusions from Analysis Populations ..................................... 34 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 35 
13.2.1. 
Protocol Defined Schedule of Events ........................................... 35 
13.3. 
Appendix 3: Assessment Windows ............................................................. 36 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 36 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 37 
13.4.1. 
Study Phases .............................................................................. 37 
13.4.1.1. Study Phases for Concomitant Medication ................. 37 
13.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 37 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 38 
13.5.1. 
Reporting Process ....................................................................... 38 
13.5.2. 
Reporting Standards .................................................................... 38 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 39 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 40 
13.6.1. 
General ........................................................................................ 40 
13.6.2. 
Study Population .......................................................................... 40 
13.6.3. 
Safety .......................................................................................... 40 
13.6.4. 
Pharmacokinetic .......................................................................... 41 
13.6.5. 
Pharmacodynamic ....................................................................... 41 
13.6.6. 
Laboratory ................................................................................... 41 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 42 
13.7.1. 
Premature Withdrawals ................................................................ 42 
13.7.2. 
Handling of Missing Data ............................................................. 42 
13.7.2.1. Handling of Missing and Partial Dates ........................ 42 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 44 
13.8.1. 
Laboratory Values ........................................................................ 44 
13.8.2. 
Urinalysis Values ......................................................................... 44 
13.8.3. 
ECG ............................................................................................. 44 
13.8.4. 
Vital Signs .................................................................................... 45 
13.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 46 
13.9.1. 
Abbreviations ............................................................................... 46 
13.9.2. 
Trademarks ................................................................................. 47 
13.10. Appendix 10: List of Data Displays.............................................................. 48 
13.10.1. Data Display Numbering .............................................................. 48 


 
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13.10.2. Mock Example Shell Referencing ................................................ 48 
13.10.3. Deliverables ................................................................................. 48 
13.10.4. Study Population Tables .............................................................. 49 
13.10.5. Safety Tables ............................................................................... 53 
13.10.6. Pharmacokinetic Tables ............................................................... 59 
13.10.7. Pharmacokinetic Figures ............................................................. 62 
13.10.8. ICH Listings ................................................................................. 68 
13.10.9. Non-ICH Listings .......................................................................... 70 
13.11. Appendix 11: Example Mock Shells for Data Displays ................................ 72 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 212548/02. Note that GSK3739937 is 
also known as VH3739937 and will be referred to as VH3739937 for the remainder of 
this document. 
Protocol Revision Chronology: 
212548/00 
20-APR-2020 
Original 
212548/01 
11-JUN-2020 
Amendment 01 was generated to remove Sodium 
Stearyl Fumarate from the placebo formulation, to 
clarify administration for study interventions and 
maintenance of the blind. Revisions were made to 
the study eligibility criteria and safety 
assessments in response to the FDA’s feedback 
and to mitigate the potential risks for study 
conduct during the COVID-19 pandemic. Given 
the absence of benefit to study participants, the 
exclusion criteria and the criteria for individual 
subject discontinuation, dose escalation and 
stopping the study were revised to be more 
conservative. Revisions were made to improve 
accuracy of the study risk assessment and the 
pharmacokinetic analyses. 
212548/02 
16-MAR-2021 Updates made following acquisition of clinical 
pharmacology data in Part 1, the Single 
Ascending Dose (SAD) 10 mg, 30 mg, 80 mg, 
160 mg, 320 mg and 640mg treatment 
periods and Multiple Ascending Dose (MAD) 
Cohort 3; 25 mg to: 
• extend the period of post dosing assessment to 
include outpatient visits in the 
study; 
• include a higher dose SAD treatment period 
(800 mg); 
• revise the duration of dosing in MAD Cohort 5 
(100 mg); and 
• inclusion of an additional MAD Cohort 6 (500 
mg) to evaluate weekly oral 
dosing. 
Part 3 of the study was included to evaluate the 
relative bioavailability (RBA) of 


 
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VH3739937 when administered as VH3739937 
powder-in-a-bottle (PiB) or as 
VH3739937 100 mg Tablet under fasted and fed 
(moderate fat) conditions. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in most recent version of the protocol Amendment 2 (212548/02) [(Dated: 16-
Mar-2021)] which introduced Part 3 (relative bioavailability and food effect).  
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To investigate the safety and 
tolerability of VH3739937 
following single and repeated 
daily and weekly oral 
administration in healthy 
participants (Part 1 & 2) 
• To assess the safety and 
tolerability of VH3739937 
following single oral 
administration in healthy 
participants under fasted or fed 
(moderate calorie and fat) 
conditions (Part 3) 
• To evaluate the relative 
bioavailability (RBA) of 
VH3739937 powder in bottle 
(PiB) versus VH3739937 tablet 
and the effect of food on the PK 
of VH3739937 tablets and 
VH3739937 PiB (Part 3) 
 
VH3739937 safety parameters:  
• Adverse events; post baseline values and 
changes over time of clinical laboratory 
evaluations (haematology, clinical chemistry, 
urinalysis), vital signs, and ECG parameters 
from pre-dose values (Part 1, 2, and 3) 
 
• Derived PK parameters for VH3739937, as 
data permits: Part 3 (single dose):  AUC (0-24), 
AUC(0-inf), Cmax, 
Secondary Objectives 
Secondary Endpoints 
• 
To describe the PK profile of 
VH3739937 following single 
(Part 1 and 3) and repeated daily 
and weekly oral administration in 
healthy participants (Part 2), as 
data permits 
Derived PK parameters for VH3739937, as data 
permits: 
• Part 1 (single dose): AUC(0-24), AUC(0-t) , AUC(0-inf) , 
Cmax, C24, tmax, tlag, t1/2, Clast, tlast, CL/F 
 
• Part 2 (repeated once daily [QD] dose): 


 
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Objectives 
Endpoints 
 
o Day 1: AUC (0-24), Cmax, C24, tmax, tlag 
o Day 14 (Cohorts 3 and 4): AUC(0-), Cmax, C, 
tmax, t1/2, and CL/F 
o Day 14 (Cohort 5): AUC(0-), Cmax, C, tmax 
o Day 18 (Cohort 5): AUC(0-), Cmax, C, tmax, t1/2, 
and CL/F 
• Part 2 (repeated once weekly [QW] dose, as data 
permits: 
o Day 1 (Cohort 6): AUC (0-168), Cmax, C168, tmax, 
tlag 
o Day 8 (Cohort 6): AUC (0-168), Cmax, C168, tmax 
o Day 15 (Cohort 6): AUC(0-t), Cmax, C,, tmax, t1/2, 
and CL/F 
 
• Part 3 (single dose): AUC (0-24), AUC(0-inf), Cmax, C24, 
tmax, tlag, t1/2, Clast, tlast, CL/F 
 
 
• 
To examine dose proportionality 
following single and repeated 
doses of      VH3739937 (Part 1 & 
2), as data permits 
Derived PK parameters for VH3739937, as data 
permits: 
• 
Part 1 (single dose): AUC(0-inf), Cmax.  
• 
Part 2 (repeated dose): AUC(0-), Cmax, C 
• 
To predict the accumulation from 
single dose data (Part 1) and 
assess accumulation of 
VH3739937 after repeat doses 
(Part 2 at steady state), as data 
permits  
Accumulation indices for PK parameters for 
VH3739937, as data permits: 
• 
Part 1 (single dose): predicted accumulation ratio 
Rp based on AUC 
• 
Part 2 (repeated dose): observed accumulation 
ratios: RAUC(0-) , R(Cmax),  R(C) 
• To assess time to steady-state of 
VH3739937 (Part 2) 
Derived PK parameters for VH3739937, as data 
permits: 
• Part 2 (repeated dose):  
o Cohorts 3 and 4: Pre-dose concentrations on 
Day 2-14 
o Cohort 5: Pre-dose concentrations on Day 2-18 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess the exposure response 
relationship between VH3739937 
and safety parameter, including 
QTcF following single and 
repeated administration (Part 1 & 
2) 
• 
Change-from-baseline QTcF (∆QTcF) 


 
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Objectives 
Endpoints 
• 
To collect plasma and urine 
samples for analysis of 
metabolites of VH3739937 
• 
Metabolites of VH3739937 in plasma and urine.  
The analyses will be conducted and reported 
separately from this protocol.  
• 
To characterize renal excretion of 
VH3739937, as data permits  
• 
Urinary recovery of VH3739937 (Ae[0-x]), Ae[0-] 
and Ae[0-t]) and renal clearance (CLr) 
• 
To collect duodenal bile for 
analysis of metabolites of 
VH3739937 (Part 2, Cohort 5 
only) 
• 
Metabolites of VH3739937 in duodenal bile. The 
analyses will be conducted and reported separately 
from this protocol  
• 
Note: The exploratory endpoints may be analyzed once VH3739937 clinical development continues. 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
 
Note: Box color has no interpretation 
 
Design 
Features 
• 
This is a three-part, Phase 1, double-blind (sponsor-unblinded), randomized, 
placebo controlled, single- and repeat-dose escalation study and relative 
bioavailability/food effect study. 
Part 1 (SAD): 
• 
The SAD portion of the study will be conducted in an interlocking crossover fashion 
with two separate cohorts of 9 healthy participants each. Each of these two cohorts 
may contain a minimum of three escalating doses of VH3739937 through to 800mg 
• 
In each escalating period and Cohort, 6 participants will be randomized to 
VH3739937 and 3 participants will be randomized to placebo.  
• 
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy 
with alternating ascending doses with 3-period crossover, placebo-controlled. 
• 
To reduce operational complexity, the 800 mg SAD dose will use new participants 
who were not exposed to previous lower doses of VH3739937 
 
Part 2 (MAD): 
• 
Part 2 consists of approximately 3 ascending repeat-dose daily administration 
cohorts (Cohorts 3 to 5), and one repeat-dose weekly administration cohort (Cohort 
6) each with 10 participants who will receive a once-daily dose of VH3739937 or 


 
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Overview of Study Design and Key Features 
placebo (PBO) for 14 consecutive days (cohorts 3 and 4), or for 18 consecutive 
days (cohort 5).  Participants in Cohort 6 will receive one dose per week for 3 
consecutive weeks.  
• 
The duration of dosing in Cohort 5 is to support up to 18-day dosing as an oral lead 
in for the future SAD and MAD studies of the long acting formulation of VH3739937. 
This duration is to potentially allow the identification of any early drug 
hypersensitivity reactions (HSR) which may occur before the administration of the 
long acting formulation.  
• 
In each escalating dose cohort, 7 participants will be randomized to receive 
VH3739937 and 3 participants will be randomized to receive PBO 
 
Part 3 (RBA/FE) 
• 
Part 3 is a randomized, open-label, single-dose, 3-period crossover Cohort 7 to 
compare the RBA of the PiB formulation of VH3739937 with the tablet formulation 
and to assess the effect of food on the safety, tolerability and PK of the tablet 
formulation in  healthy participants.  
• 
In Part 3, approximately 18 participants will be treated to ensure that 12 evaluable 
participants complete Cohort 7.   
  
Dosing 
Part 1 (SAD): 
• 
In Part 1 participants will receive a single dose of VH3739937 
• 
Dose escalation in Part 1 will be determined by the Dose Escalation Committee 
based on the double-blind (sponsor-unblinded) safety data and the PK data from 
the current and previous dose(s).  
• 
Dose escalation will not exceed approximately 3-fold between doses up 
to approximately the predicted minimally effective dose and will not exceed 2-fold 
thereafter.  
• 
Dose escalation in Part 1 will require (from the current dosing group) at least 
24 hours of safety and PK data from 4 participants receiving active drug. Dose 
escalation will be guided by safety and the SAD PK stopping criteria (see Protocol 
Section 8).  
• 
Due to the alternating dosing periods between Cohort 1 and Cohort 2, a participant 
in either cohort will receive the next dose after approximately 3 or 4 weeks. 
 
Part 2 (MAD): 
• 
In Part 2 participants will receive a single dose of VH3739937 each day for either 14 
days (Cohorts 3 and 4) 18 days (Cohort 5), or once weekly for 3 weeks (Cohort 6) 
• 
Part 2 (MAD) of the study will be initiated once the single dose safety and 
preliminary PK data for the anticipated minimally effective dose has been evaluated 
in the SAD. 
• 
The potential minimally effective dose for VH3739937, noted as 25 mg, is 
anticipated to be that which is predicted to provide a steady state Ctrough ≥ 
0.258g/mL in 95% of participants and will be re-estimated based on the PK data 
collected in the early doses in Part 1.  
• 
Dose escalation in Part 2 will be determined by the VH/GSK study team and the PI 
based on the double-blind (sponsor-unblinded) safety and PK data (minimally up to 
24 h post Day 14 dose) from the current and previous dosing cohort(s). Specifically, 
14 days of safety and PK data (minimally up to 24 h post Day 14 dose) from a 
minimum of five participants in current cohort receiving active drug will be required 
for dose escalation 


 
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Overview of Study Design and Key Features 
 
Part 3 (RBA/FE) 
• 
Participants will receive each of the following treatments administered as 1 
treatment per period: 
o Treatment A: VH3739937 PiB, 100 mg (single dose oral suspension of 
VH3739937 dispersion) administered under moderate fat conditions 
(reference) 
o Treatment B: VH3739937 Tablet, 100 mg (single dose given as a 100 mg 
tablet(s)) administered under moderate fat conditions (test) 
o Treatment C: VH3739937 Tablet, 100 mg (single dose given as 100 mg 
tablet(s)) administered under fasted conditions (reference). 
 
• 
To ensure adequate washout, there will be at least 24 days between each dose of 
study intervention, with an allowance window of 4 hours (i.e., 24 days minus 4 
hours) to allow flexibility in scheduling participants for dosing at the clinic.  
 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
Part 1 (SAD): 
• 
Participants in either Cohort 1 or Cohort 2 will be assigned to 1 of the 3 treatment 
sequences in a cross-over, and each participant will receive placebo once. 
  
 
• 
When the 800 mg dose is evaluated, 9 new participants, who were not previously 
exposed to any dose of VH3739937 will be enrolled in the study. Six participants 
randomized to receive VH3739937 and 3 participants will be randomized to receive 
placebo. 
 
Part 2 (MAD): 
• 
In Cohorts 3 to 5, 10 participants per cohort (active/PBO=7/3) will receive a once-
daily dose of VH3739937 or PBO for 14 days (Cohort 3 and 4) or 18 days (Cohort 
5) 
• 
In Cohort 6, 10 participants (active/PBO=7/3) will receive a once-weekly dose of 
500 mg VH3739937 or PBO over the course of 14 days (Doses on Day 1, 8, and 
15) 
 
 


 
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Overview of Study Design and Key Features 
Part 3 (RBA/FE): 
• 
In Part 3 participants will randomly be assigned to a receive a random sequence of 
the following treatments: 
o Treatment A: VH3739937 PiB, 100 mg (administered as oral suspension 
under moderate fat conditions (reference) 
o Treatment B: VH3739937 Tablet, 100 mg (single dose given as a 100 mg 
tablet(s)) administered under moderate fat conditions (test) 
o Treatment C: VH3739937 Tablet, 100 mg (single dose given as 100 mg 
tablet(s)) administered under fasted conditions (reference) 
• 
In Part 3, participants will be assigned to one of three sequences according to a 
Latin square design. The three sequences are: 
o A/B/C 
o B/C/A 
o C/A/B 
 
Interim 
Analysis 
• 
All preliminary safety, tolerability, and available PK data will be reviewed internally 
at ViiV/GSK prior to each dose escalation. Safety data (labs, vital signs, ECG, AEs, 
SAEs) will be 
reviewed by the PI/Sub-I and ViiV/GSK study team after completion of each dose 
level. 
• 
Dose escalation can only occur after DEC has found that the safety and PK profiles 
are supportive to proceed with the evaluation of the next higher dose level (See 
Protocol Section 4.3.6 Dose Escalation Committee). 
2.4. 
Statistical Analyses 
2.4.1. 
Part 1 (SAD) and 2 (MAD) 
The main purpose of Parts 1 and 2 of study is to assess the safety, tolerability and PK of 
single and repeated oral doses of VH3739937 in healthy volunteers. A mixed model will 
be used to assess whether participants in Part 2 achieved steady state as described in 
Section 8.1.5.1.  
2.4.2. 
Part 3 (RBA) 
The purpose of Part 3 is to evaluate the relative bioavailability and food effect of two 
differing formulations of VH3739937 (tablet vs. powder in a bottle). For the assessment 
of relative bioavailability of formulation and food effect the log-transformed PK 
parameters will be analysed as data permits using separate mixed effect models with 
fixed effect terms for fed vs. fasted and tablet vs PiB. Participant will be treated as a 
random effect in each model. Point estimates and their associated 90% CIs will be 
calculated for the difference in AUC (0-24), AUC(0-inf), and Cmax for the tablet vs PiB and 
fed vs fasted comparisons. The point estimates and their associated 90% CIs will then be 
back-transformed to provide point estimates and 90% CIs for the ratios of tablet vs PiB 
and fed vs fasted in PK parameter values on the original scale.  
No formal statistical hypothesis will be tested. The mixed model will be used to estimate 
relative bioavailability and food effect but will not be used to justify statistical 
bioequivalence.  


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available pharmacokinetic data will be reviewed internally at the Dose Escalation 
Committee (ViiV/GSK) prior to each dose escalation or administration and according to 
the dose escalation charter. Safety data (labs, vital signs, ECG, AEs, SAEs) will be 
reviewed by the PI/Sub-I and ViiV/GSK study team after completion of each dose level. 
Dose escalation can only occur after PI/Sub-I and ViiV/GSK study team has found that 
the safety, PK profiles are supportive to proceed with the evaluation of the next highest 
dose level. 
At each dose, the Bayesian probability of an individual exceeding the Cmax threshold in 
Part 1 and the Bayesian probability of an individual exceeding the AUC threshold in Part 
2 will be calculated and compared with 50%. This will be used to help selection of the 
next dose together with safety and tolerability data. The Bayesian probability will be 
based on Whitehead’s model shown below [Whitehead, 2001] using non-informative 
prior for model parameters. 
𝑦𝑖𝑗= 𝜃1 + 𝜃2 𝑑𝑖𝑗+ 𝑠𝑖+ 𝜖𝑖𝑗 
Where yij is log-PK of i-th participant to j-th dose, dij is j-th log-dose administered to i-th 
participant. θ1 and θ2 are population intercept and slope, respectively. si is random effect 
of i -th participant and 
 is random error of i -th participant in j-th dose. 
When intra-participant variability cannot be estimated during PK predictions in Part 1 
(i.e., early on in the study when there is not sufficient information to estimate intra-
participant variability) and for conducting prediction of all doses in Part 2, the same 
Whitehead’s model will be used for Bayesian probability calculations as below. 
𝑦𝑖= 𝜃1 + 𝜃2 𝑑𝑖+ 𝜖𝑖 
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th participant. θ1 
and θ2 are population intercept and slope, respectively and i is random error of i-th 
participant. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study Population 
Enrolled  
• 
All participants who passed screening and entered the 
study.  
• 
Note screening failures (who never passed screening 
even if rescreened) and participants screened but 
never enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study. 
• 
Study Population 
Safety 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
Participants will be analyzed according to the 
intervention they received. 
• 
Study Population 
• 
Safety  
Pharmacokinetic 
(PK)  
• 
The PK Population will include all participants who 
undergo plasma or urine PK sampling and have 
evaluable PK assay results. 
• 
PK analyses 
Refer to Appendix 10 which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Separately, any important deviations which result in exclusion from analysis populations 
and events that result in exclusion from analysis populations will be listed.  
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan v1.0 June 2020 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis populations are captured and categorised on the protocol deviations 
dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
summary will be based on data as recorded on the inclusion/exclusion page of the eCRF. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment comparisons of relative bioavailability and food effect will be displayed as 
follows using the descriptors respectively: 
1. (B vs. A): VH3739937 X 100 mg (single dose given as 100 mg tablet(s)) 
administered under moderate fat conditions (test) vs. VH3739937 X 100 mg (single 
dose oral suspension of VH3739937 dispersion) administered under moderate fat 
conditions (reference)  
2. (B vs. C): VH3739937 X 100 mg (single dose given as 100 mg tablet(s)) 
administered under moderate fat conditions (test) vs. VH3739937 X 100 mg (single 
dose given as 100 mg tablet(s)) administered under fasted conditions (reference).  
 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
Part 1 
P 
Placebo 
SD PBO 
1 
D1 
GSK3739937 Dose Level 1 
SD 10mg 
2 
D2 
GSK3739937 Dose Level 2 
SD 30mg 
3 
D3 
GSK3739937 Dose Level 3 
SD 80mg 
4 
D4 
GSK3739937 Dose Level 4 
SD 160mg 
5 
D5 
GSK3739937 Dose Level 5 
SD 320mg 
6 
D6 
GSK3739937 Dose Level 6 
SD 640mg 
7 
D7 
GSK3739937 Dose Level 7 800 
mg 
SD 800mg 
8 
Part 2 
RP 
Placebo Repeated Dose 
QD PBO 
9 
R1 
GSK3739937 Repeat Dose Level 
1 
QD 25mg 
10 
R2 
GSK3739937 Repeat Dose Level 
2 
QD 50mg 
11 
R3 
GSK3739937 Repeat Dose Level 
3 
QD 100 mg 
12 
WP 
Weekly Placebo 
QW PBO 
13 
W1 
GSK3739937 Weekly Repeat 
Dose 500 mg 
QW 500mg 
14 
Part 3 
A 
GSK3739937 PiB Fed 100 mg 
PiB Fed 
15 
B 
GSK3739937 Tablet Fed 100 mg 
Tablet Fed  
16 
C 
GSK3739937 Tablet Fasted 100 
mg 
Tablet Fasted 
17 
NOTES: 
• 
Order represents treatments being presented in TFL, as appropriate. 
 


 
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5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
 
Part 1 (SAD Cohorts 1 and 2) 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Lab 
X 
X 
 
Day -1 
ECG 
X 
X 
X 
Day 1 (Pre-Dose) 
Vital Signs  
X 
X 
X 
Day 1 (Pre-Dose) 
 
Part 2 (MAD Cohorts 3, 4, 5, and 6) 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Lab 
X 
X 
X 
Day 1 (Pre-Dose) 
ECG 
X 
X 
X 
Day 1(Pre-Dose) 
Vital Signs  
X 
X 
X 
Day 1 (Pre-Dose) 
 
Part 3 (RBA/FE) 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Lab 
X 
X 
 
Day -1 
ECG 
X 
X 
X 
Day 1 (Pre-Dose) 
Vital Signs  
X 
X 
X 
Day 1 (Pre-Dose) 
 
On Day 1 triplicate pre-dose ECGs will be performed. The baseline for every ECG 
parameter will be calculated as the average of that parameter’s values from the Day 1 
pre-dose triplicate ECG reading 


 
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On Day 1 three readings of blood pressure and pulse will be taken. The first reading will 
be rejected. The average of the second and third readings (as recorded in the CRF) will 
serve as baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
For Part 3, baseline will be rederived for each period. 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.5 
Appendix 5: Data Display Standards & Handling Conventions 
13.6 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.8 
Appendix 8: Values of Potential Clinical Importance 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified.  
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 10. 


 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the safety population, unless otherwise specified. 
Safety data are the primary endpoints of the study, will be presented in tabular format and 
summarized descriptively accordingly to GSK’s Integrated Data Standards Library 
(IDSL) standards. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10 Adverse Events of Special Interest 
Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. While 
VH3739937 does not have a defined list of AESI, the AESI for the similar compound 
GSK3640254 will be used for this study. Further details of specific SOCs and SMQs for 
AESI of GS3640254 are maintained by that compound’s SRT. The list broadly includes 
the following items: 
• QT prolongation 
• GI intolerability/toxicity 
• Psychiatric events 
o Suicidal ideation/behaviour 
o Depression 
o Bipolar disorder Psychosis 
o Anxiety 
o Sleep disorders 
o Nervous system disorders 
The details of the planned displays are provided in Appendix 10 
7.2. 
Clinical Laboratory Analyses 
The safety analyses will be based on the Safety population, presented by treatment group 
unless otherwise specified. 
The ADLB dataset will be used, which contains the data that is available at a particular 
timepoint, with no imputation for missing values, unless otherwise stated in Appendix 7. 
Laboratory values, and change from baseline for haematology, clinical chemistry, and 
liver function parameters will be summarized by visit and by treatment group, based on 
GSK Core Data Standards. Laboratory values for haematology, clinical chemistry, liver 
function, and urinalysis will also be listed by subject. In addition, the worst-case results 


 
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post baseline relative to baseline relative to normal range will be reported for 
haematology, and clinical chemistry. The details of the planned displays are in Appendix 
10 
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10 
For worst-case results post baseline relative to baseline for vital signs, the average of any 
triplicate measurement, if taken, will be considered.  
 


 
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8. 
PHARMACOKINETIC ANALYSES 
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
As an overview, individual, mean and median plasma VH3739937 concentration-time 
profiles will be plotted by treatment and day (for MAD) (linear and semi-log profiles). 
PK sampling times will be related to the start of the dosing date/time. Actual sampling 
times will be used to calculate all non-compartmental pharmacokinetic parameters. 
Individual concentrations of VH3739937 in plasma will be listed and summarised by 
treatment and nominal time.   
 
8.1. 
Primary Pharmacokinetic Analyses 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma 
concentration-time data, as data permits. 
Parameter 
Parameter Description 
AUC(0-inf) 
Area under the concentration-time curve extrapolated to infinity will be calculated as:  
AUC = AUC(0-t) + C(t) / lambda_z 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-24) 
Area under the plasma concentration time curve from zero to 24 hrs 
AUC(0-168) 
Area under the plasma concentration time curve from zero to 168 hrs 
AUC(0-) 
Area under the curve (Area under the plasma drug concentration-time curve 
from pre-dose to the end of the dosing interval at steady state) 
%AUCex 
The percentage of AUC (0-inf) obtained by extrapolation (%AUCex) will be calculated as: 
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
C24 
Concentration at 24 hours post-dose 
C168 
Concentration at 168 hours post-dose 
Clast 
Last quantifiable concentration 


 
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Parameter 
Parameter Description 
C 
Pre-dose (trough) concentration at the end of the dosing interval 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
t½ 
Apparent terminal half-life will be calculated as: t½ = ln2 / lambda_z 
tlag 
Absorption lag time 
tlast 
Time of last quantifiable concentration 
CL/F  
Apparent oral clearance 
NOTES:  
• 
Additional parameters may be included as required. 
 
All the derived parameters described above will be listed.  For each of these 
parameters, except tmax and tlag, the following summary statistics will be calculated 
for each treatment group:  n, arithmetic mean, standard deviation (SD), median, 
minimum, maximum, geometric mean with associated 95% CI, standard deviation of 
logarithmically transformed data, and the between-participant CV (%CVb) (where 
%CVb = 100*√ (exp(SD2)-1) based on the geometric mean for the log-transformed PK 
parameters. For tmax and tlag, median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
 
8.1.2. 
Summary Measure 
The following PK parameters will be derived and summarized as data permits: 
• Part 1 (single dose): AUC(0-24), AUC(0-t) , AUC(0-inf) , Cmax, C24, tmax, tlag, t1/2, Clast, tlast, 
CL/F 
 
• Part 2 (repeated once daily [QD] dose): 
o Day 1: AUC (0-24), Cmax, C24, tmax, tlag 
o Day 14 (Cohorts 3 and 4): AUC(0-t), Cmax, C, tmax, t1/2, and CL/F 
o Day 14 (Cohort 5): AUC(0-), Cmax, C, tmax 
o Day 18 (Cohort 5): AUC(0-t), Cmax, C, tmax, t1/2, and CL/F 
• Part 2 (repeated once weekly [QW] dose, as data permits: 
o Day 1 (Cohort 6): AUC (0-168), Cmax, C168, tmax, tlag 
o Day 8 (Cohort 6): AUC (0-168), Cmax, C168, tmax 
o Day 15 (Cohort 6): AUC(0-t), Cmax, C, tmax, t1/2, and CL/F 
 
• Part 3 (single dose): AUC (0-24), AUC(0-inf), Cmax, C24, tmax, tlag, t1/2, Clast, tlast, CL/F 
 
Additionally, in Part 3 the parameters used for the treatment comparison of relative 
bioavailability of the single dose PiB formulation relative to the single dose tablet 
formulation, and the food effect of the tablet fed relative to tablet fasted state will be 
AUC(0-24), AUC(0-inf), and Cmax.  
 


 
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8.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Missing data will not be imputed, regardless of the reason. 
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10 and will be based on GSK 
Data Standards and statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.   
8.1.5.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
8.1.5.1.1. Dose Proportionality (Power Model) 
Part 1 and 2 
In Part 1 where participants may participate in multiple cohorts the power model will be 
used to estimate the dose proportionality constant as follows: 
𝑦𝑖𝑗= 𝜃1 + 𝜃2 𝑑𝑖𝑗+ 𝑠𝑖+ 𝜖𝑖𝑗 
Where yij is log-PK of i-th participant to j-th dose, dij is j-th log-dose administered to i-th 
participant. θ1 and θ2 are population intercept and slope, respectively, si is random effect 
of i -th participant and 𝜖𝑖𝑗 is random error of i -th participant in j-th dose.  
The posterior distribution of the mean value 𝜇𝑖𝑗 of the log-PK parameter is then described 
as: 
𝜇𝑖𝑗~𝑁(𝑦𝑖𝑗, 𝜎2) 
 
In Part 2 where participants will only participate in one cohort and intra-participant 
variability cannot be estimated the following power model will be used to estimate the 
dose proportionality constant. 
𝑦𝑖= 𝜃1 + 𝜃2 𝑑𝑖+ 𝜖𝑖 
 
[2] 


 
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Where yi is log-PK of i-th participant, di is the log-dose administered to i-th participant. θ1 
and θ2 are population intercept and slope respectively and i is random error of i-th 
participant. 
The posterior distribution of the mean value 𝜇𝑖 of the log-PK parameter is then described 
as: 
𝜇𝑖~𝑁(𝑦𝑖, 𝜎2) 
In both models 𝜃2 represents the dose proportionality constant. The point estimate and 
95% credible interval for this parameter will be estimated and reported using separate 
models for Part 1 and Part 2.  
Non-informative prior distributions for the estimated parameters are defined below:  
𝜃1~𝑁(0,102) 
𝜃2~𝑁(0,102) 
𝑠𝑖~𝑁(0, 𝜏𝑖) 
𝜏𝑖~𝐺𝑎𝑚𝑚𝑎(0.01,0.01) 
𝜎2 ~𝐺𝑎𝑚𝑚𝑎(0.01,0.01) 
 
8.1.5.1.2. Accumulation Ratio 
Part 1 
Predidicted daily dose accumulation from single dose data (Part 1) for AUC will be as 
follows:  
 
𝑅𝑝(𝐴𝑈𝐶) = 𝐴𝑈𝐶(0 −∞)
𝐴𝑈𝐶(0 −24) 
 
Point estimates of the mean ratio and associated 90% confidence intervals will be 
displayed by treatment. 
 
Part 2  
Accumulation will also be evaluated for each treatment by determining the ratio of Day 
14 (Part 2 cohort 3 and 4) or Day 18 (Part 2 cohort 5) to Day 1 AUC(0-) (R(AUC(0-)), 
Cmax (R(Cmax)), and C (R(C)).  Day 1 C will be defined as the 24-hr post day 1 
dosing concentration (C24 for Day 1). For part 2 cohort 3,4, and 5 the dosing interval is 
24-hrs. Therefore, =hrs. 
For Cohort 6 accumulation will be evaluated by determining the ratio of third dose 
(occurring on Day 15) to first dose (Day 1) for AUC(0-) (R(AUC(0-)), Cmax 


 
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(R(Cmax)), and C (R(C)). For part 2 cohort 6 the dosing interval is 7 days (168 hrs). 
Therefore, = hrs. In Cohort 6, since sampling at 168 hrs post 3rd dose was not 
collected, it will be predicted using linear model based on the other collected timepoints 
post dose.  
 Point estimates of the mean ratios and associated 90% confidence intervals will be 
displayed by treatment. 
 
Endpoint / Variables 
• Rp(AUC) for Part 1 
Where  
𝑅𝑝(𝐴𝑈𝐶) = 𝐴𝑈𝐶(0 −∞)
𝐴𝑈𝐶(0 −24) 
• R(AUC(0-)), R(Cmax), R(C) on Days 1 and 14 for Part 2 Cohort 3 and 4 where, = hrs 
• R(AUC(0-)), R(Cmax), R(C) on Days 1 and 18 for Part 2 Cohort 5 where, = hrs 
• R(AUC(0-)), R(Cmax), R(C) on Days 1 and 15 for Part 2 Cohort 6 where, = hrs 
 
Where  
𝑅(𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟 ) = 
(𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟 𝑉𝑎𝑙𝑢𝑒  𝑜𝑛 𝐷𝑎𝑦 𝑋𝑋 )
(𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟 𝑉𝑎𝑙𝑢𝑒  𝑜𝑛 𝐷𝑎𝑦 1 )   
 
Model Specification 
• In Part 1 the mean of the raw mean of the ratio of AUC(0-inf) to AUC(0-24) will be reported. 
There is no formal modeling.  
• In the model for Part 2 Cohort 3,4,5,6 the ratio of the specific parameter will be the dependent 
variable, day will be included as a fixed effect categorical variable with the reference as Day 
1, and participant will be included as a random effect. 
Model Checking & Diagnostics 
• A compound symmetry covariance structure for the R matrix will be used by specifying 
“type=CS” on the RANDOM line 
• In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH. 
• The Kenward and Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will be 
used.  
• Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are 
reasonable. 
• If there are any departures from the distributional assumptions, alternative models will 
be explored using appropriate transformed data. 


 
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Model Results Presentation 
• For Part 1, point estimates of the means of AUC(0-inf) and AUC(0-24), the point 
estimate of the predicted accumulation ratio, and the associated 90% confidence 
interval will be presented in tabular format by treatment group. 
• For Part 2, point estimates of the Geometric least squares means and 90% confidence 
intervals for the accumulation ratio will be presented in tabular format by treatment 
group.  
Subgroup Analyses 
• Not Applicable. 
Sensitivity and Supportive Analyses 
• Not Applicable. 
 
8.1.5.1.3. Assessment of Steady State 
For Part 2 cohorts 3 and 4, steady-state VH3739937 concentrations will be assessed by 
estimating the slope of concentrations on pre-dose assessments on Days 2-14 (Part 2 
cohort 3 and 4) and the day 15 24-hr post-dose (relative to dosing on day 14). For Part 2 
cohort 5, steady state VH37339937 concentrations will be assessed by estimating the slop 
eof the concentrations of pre-dose assessments on Days 2-18 and the day 19 24-hr post-
dose (relative to dosing on day 18).  
To determine when steady state is achieved the separate mixed effects linear regression 
models will be estimated for each treatment and each subset of days. The first subset of 
days will include all C values for days 2-15. Then the value from the earliest timepoint 
will dropped and the analysis re-run. Earlier days will be iteratively dropped (e.g. Days 2-
15, then Days 3-15, then Days 4-15, etc.) until only 3 dosing days, and the 24-hr post 
final dose assessment, remain. The final assessment of the slope will be determined by at 
least the last 3 pre-dose concentrations and the concentration 24 hours post last dose. 
Endpoint / Variables 
• 
C Day (2-15) for Part 2 Cohort 3 and 4 
• 
C Day (2-19) for Part 2 Cohort 5 
 
Model Specification 
• In the model for Part 2 Cohort 3 and 4, C Day (2-15) will be the dependent variable, day will 
be included as a fixed effect, and participant will be included as a random effect 
• In the model for Part 2 Cohort 5, C Day (2-19) will be the dependent variable, day will be 
included as a fixed effect, and participant will be included as a random effect 
Model Checking & Diagnostics 
• Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption 


 
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of the model respectively) to gain confidence that the model assumptions are 
reasonable. 
• If there are any departures from the distributional assumptions, alternative models will 
be explored using appropriate transformed data. 
Model Results Presentation 
• Point estimates and 90% confidence intervals for the slope will be presented in tabular 
format by treatment group. The analysis will be conducted for all days (2-15 for Cohort 3 
and 4 and 2-19 for Cohort 5) and repeated by dropping one earlier day at a time until the 
final 3 days of dosing remain (that is days 12-14 and day 15 for cohort 3 and 4 and days 
16-18 and day 19 for cohort 5) .  
• 
Individual values of C  Day (2-15) for Part 2 Cohort 3 and 4 will be plotted graphically 
by treatment group 
• 
Individual values of C  Day (2-19) for Part 2 Cohort 5 will be plotted graphically by 
treatment group 
Subgroup Analyses 
• Not Applicable. 
Sensitivity and Supportive Analyses 
• Not Applicable. 
 
8.1.5.1.4. Relative Bioavailability and Food Effect 
Part 3 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
Endpoint / Variables 
• Log-transformed AUC(0-24), AUC(0-inf) (or AUC(0-tlast) if AUC(0-∞) cannot be derived), 
and Cmax 
Model Specification 
• AUC(0-24), AUC(0-inf) and Cmax will be separately analysed using a mixed effects models. 
In each model the dependent variable will be the log-transformed PK parameter of interest 
(AUC(0-inf) or Cmax).  
• For the RBA model the primary comparison will be Tablet vs. PiB (B vs. A), the independent 
variables will include a fixed effect for treatment (PiB or Tablet) and period, and a random 
effect for participant.  
• For the Food effect model the primary comparison will be Tablet Fed vs. Tablet Fasted (B 
vs. C), the independent variables will include a fixed effect for fasting status (fed vs. fasted) 
and period, and a random effect for participant 
log(𝑃𝑘 𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟) = 𝛽0 + 𝛽1Treatment + 𝛽2𝑃𝑒𝑟𝑖𝑜𝑑+ 𝛾𝑖𝑆𝑢𝑏𝑗𝑒𝑐𝑡 
 


 
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Model Checking & Diagnostics 
• 
A compound symmetry covariance structure for the R matrix will be used by specifying “type=CS” on the 
RANDOM line 
• 
In the event that this model fails to converge, alternative correlation structures may be considered such as 
CSH. 
• The Kenward and Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will be 
used.  
• Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are 
reasonable. 
• If there are any departures from the distributional assumptions, alternative models will 
be explored using appropriate transformed data. 
Model Results Presentation 
• 
The estimated difference and CI obtained on the log scale will be exponentiated to provide an estimate of 
the fed to fasted or tablet to PiB ratio and its associated 90% CI. Estimates of within-subject variability 
(%CVw) will also be provided (%CVw=SQRT(exp(MSE) – 1)×100).  %CVw represents a pooled measure 
of within-subject variability across all treatments. 
• Comparative plots of individual PK parameters will be generated by treatment on linear 
and semi-logarithmic scales. 
• Plots of adjusted geometric mean ratio of test to reference treatment together with 90% 
confidence intervals will be produced. 
• Listing of individual PK parameter ratios will be generated. 
• Supportive SAS output from statistical analysis will be generated. 
Subgroup Analyses 
• Not Applicable. 
Sensitivity and Supportive Analyses 
• Not Applicable. 
 
8.2. 
Exploratory Pharmacokinetic Analyses 
Exploratory analyses to assess the exposure response relationship between VH3739937 
and  QTcF following single and repeated administration (Part 1 & 2) will be conducted. 
Linear regression models using exposure as the independent variable and change from 
baseline in QTcF as the outcome variable will be run separately for Part 1 and 2.  
 𝑦𝛿𝑄𝑇𝑐𝐹= 𝛽0 + 𝛽1𝑋𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 
The model estimates  𝛽̂0 and  𝛽̂1  and their 95% confidence intervals will be reported, and 
the regression line will be overlayed on the plot of the comparison of change in QTcF and 
concentration. 


 
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9. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
The population PK analysis and pharmacodynamic analyses are exploratory endpoints 
that will be performed under a separate RAP and reported separately from the main 
clinical study report (CSR). 
 


 
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10. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Any exploratory pharmacokinetic/pharmacodynamic analyses only consider exploratory 
endpoints and will be analyzed and reported separately. 
 


 
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11. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
11.1. 
Study Population 
11.1.1. 
Subject Disposition 
The ‘Summary of Subject Status and Subject Disposition for the Study Conclusion 
Record’ and the ‘Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment’ will be repeated, with the reason for withdrawal/discontinuation categorized 
as due to the COVID-19 pandemic, or non-due to the COVID-19 pandemic based on 
information collected on the COVID-19 Pandemic Study Impact form. The summaries 
will be based on GSK Core Data Standards, and details are provided in Appendix 10. 
11.1.2. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced of important protocol deviations related to COVID-19, and important 
protocol deviations not related to COVID-19. A listing of non-important protocol 
deviations related to COVID-19 will also be produced.  
Visits and assessments missed due to the COVID-19 pandemic, together with visits 
conducted remotely, will be listed by subject. The summaries will be based on GSK Core 
Data Standards, and details are provided in Appendix 10 
11.1.3. 
Additional Displays for Participants with a COVID-19 Infection 
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. 
A listing of the participants with a suspected, probable or confirmed COVID-19 
infection, and of COVID-19 test results will be based on GSK Core Data Standards. The 
details of the planned displays are provided in Appendix 10 
11.2. 
Safety 
11.2.1. 
Assessment of COVID-19 AEs 
A Standardised MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The incidence of AEs and SAEs (Fatal and Non-Fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation, and COVID-19 AEs leading to study withdrawal, 
and COVID-19 AEs by severity, will be obtained from standard AE and SAE summaries.  
11.2.2. 
Impact of COVID-19 Pandemic on Safety Results  
Since this single-site, United States-based, study began enrolment after the COVID-19 
pandemic began, the beginning of pandemic measures in the United States had no effect 
on the safety results. Therefore, separate AE summaries and listings before and after the 
pandemic start are not produced.  


 
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12. 
REFERENCES 
GlaxoSmithKline Document Number 2019N400726_01: A Double-Blind (Sponsor 
Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation 
Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3739937 in 
Healthy Participants. Effective Date: 11-June-2020 
Whitehead J. et al., Easy-to-implement Bayesian methods for dose-escalation studies in 
healthy participants, Biostatistics, 2, 47cs, 2, 47v 2001 
 


 
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13. 
APPENDICES 
13.1. 
Appendix 1: Exclusions from Analysis Populations 
Any analysis population exclusions, due to protocol deviations, will be discussed by the 
study team and documented.  


 
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13.2. 
Appendix 2: Schedule of Activities 
13.2.1. 
Protocol Defined Schedule of Events 
Please refer to Protocol Section 1.2. 
 


 
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13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
All acceptable assessment windows are defined in Section 4.1 (dosing), Section 8.1.4 
(ECG), of the protocol and the study reference manual. No assessment windows are 
redefined in the RAP.  
 


 
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13.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
13.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
treatment administration(s). 
Study Phase 
Definition 
Pre-Treatment  
Date <Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date≤ Date ≤ Study Treatment Stop Date + 22 days 
Post-Treatment 
Date > Study Treatment Stop Date + 22 days 
13.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
13.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date & on or before treatment stop 
date. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.). 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date [+ 22 
days]. 
• 
For studies with greater than one treatment period (e.g., crossover study) and 
the dates of changes in grade are collected, if AE onset is during one period 
and worsens during a later period it would be counted in both periods. For the 
initial period the logic would be as above. For the later period the logic would 
use the treatment dates associated with the later period: 
• 
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date [+ 22 days]. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 


 
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13.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
13.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software 9.4 or higher will be used. 
Reporting Area 
HARP Server 
:\\us1salx00259.corpnet2.com 
HARP Compound 
:\arwork\gsk3739937\mid212548\final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
ADaM IG Version 1.1].   
Generation of RTF Files 
• 
RTF files will be generated for Tables, one RTF file per item. Listings will be generated in L10 
format, and Figures will be generated in PDF format. 
Generation of xlm Files 
• 
xlm files will not be generated for the current reporting efforts 
Dictionaries 
• The current dictionary version in effect at the time of reporting will be used 
Adverse Events MedDRA 24.0 
• Concomitant Medications GSKDRUG v 1.9 and WHODrug GLOBAL C3 March 1, 2020 
13.5.2. 
Reporting Standards 
General 
• 
The current GSK Statistical Display Standards in the GSK Standards Library (IDSL) will be applied 
for reporting, unless otherwise stated (Library Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings 
Formats 
• 
GSK Statistical Display Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the GSK Standard Statistical Display 
Principles but may be adjusted to a clinically interpretable number of DP’s. 
  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to GSK 
Standard Statistical Display Principle 5.05.1). 


 
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• 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and/or figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to GSK Standard Statistical Display Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to GSK Standard Statistical Display Principals 7.01 to 7.13. 
13.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
Standards for the Transfer and Reporting of PK Data document. Note: 
Concentration values will be imputed as per GUI_51487 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to the GSK Standard PK Display Standard. 
Refer to the GSK Standard Statistical Display Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Programmer:  
• 
Relative bioavailability (Treatment B / Treatment A) of AUC(0-24), 
AUC(0-inf), and Cmax 
• 
Food Effect (Treatment B / Treatment C) of AUC(0-24), AUC(0-inf), and 
Cmax 
• 
Predicted Dose accumulation of AUC single dose AUC 
𝑅𝑝 = 𝐴𝑈𝐶(0 −∞)
𝐴𝑈𝐶(0 −24) 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to Standards for Handling NQ Impacted PK Parameters. 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to GSK Standard PK Display Standard. 
Untransformed PK 
parameter 
tmax (TMAX), tlast (TLST), tlag (TLAG). 
PK parameter listed 
only 
lambda_z (LAMZ), lambda_z_lower (LAMZL), lambda_x_upper (LAMZU), 
No_points_lambda_z (LAMZNPT). 
 
 


 
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13.6. 
Appendix 6: Derived and Transformed Data 
13.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
13.6.2. 
Study Population 
Treatment Compliance 
Extent of Exposure 
• 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
• 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
 
13.6.3. 
Safety 
Adverse Events 
AEs of Special Interest 
• 
While VH3739937 does not have a defined list of AESI, the AESI for the similar compound 
GSK3640254 will be used for this study (apart from “HIV-1 resistance to GSK3640254” which is not 
applicable to this study of healthy volunteers).  Details of specific SOCs and SMQs for AESI of 
GS3640254 are maintained by that compound’s SRT. The list broadly includes the following items: 
o QT prolongation 
o GI intolerability/toxicity 
o Psychiatric events 
▪ 
Suicidal ideation/behaviour 
▪ 
Depression 
▪ 
Bipolar disorder Psychosis 
▪ 
Anxiety 
▪ 
Sleep disorders 
o Nervous system disorders 
 


 
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ECG Parameters 
RR Interval 
• IF RR interval (msec) is not provided directly, then RR can be derived as : 
[1] If QTcB is machine read & QTcF is not provided, then : 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive. 
Corrected QT Intervals 
• When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements. 
• IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as :  
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
13.6.4. 
Pharmacokinetic 
Derived pharmacokinetic data is described in Section 8.1.1.2. Additionally, daily dose 
accumulation from single dose data (Part 1) for AUC will be predicted as follows:  
 
𝑅𝑝 = 𝐴𝑈𝐶(0 −∞)
𝐴𝑈𝐶(0 −24) 
 
13.6.5. 
Pharmacodynamic  
No pharmacodynamic endpoints will be derived or transformed.  
13.6.6. 
Laboratory 
If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is missing, 
but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or 
greater than x in the comment field) is present, the number of significant digits in the 
observed values will be used to determine how much to add or subtract in order to impute 
the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
 


 
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13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion was defined as complete if he/she has completed all 
phases of the study including the last visit and the last scheduled procedure shown 
in the schedule of activities  
• 
Withdrawn participants may be replaced in the study depending on study part and 
whether adequate sample size for a cohort as already been reached. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
13.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
13.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.  
• 
Where necessary, display macros may impute dates as temporary variables 
for sorting data in listings only. In addition, partial dates may be imputed for 
‘slotting’ data to study phases (see Section 13.4.1) or for specific analysis 
purposes as outlined below. 
• 
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), or elapsed time 
variables (e.g., time since diagnosis). In addition, imputed dates are not used 
for deriving the last contact date in overall survival analysis dataset. 
Adverse Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = 1st of 
month. 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of 
study treatment start date then 


 
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Element 
Reporting Detail 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date then set 
start date= 1st of month. 
▪ 
Else set start date = study treatment start date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start date 
then 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date then set 
start date = January 1. 
▪ 
Else set start date = study treatment start 
date.       
o 
Else set start date = January 1. 
Missing stop day  
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied.  
Concomitant 
Medications/Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = 1st of 
month. 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of 
study treatment start date then 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date then set start 
date= 1st of month. 
▪ 
Else set start date = study treatment start date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start 
date then 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date then set start 
date = January 1. 
▪ 
Else set start date = study treatment 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 the 
month. 
Completely missing 
start/end date 
No imputation 
• 
The recorded partial date will be displayed in listings. 


 
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13.8. 
Appendix 8: Values of Potential Clinical Importance 
13.8.1. 
Laboratory Values 
Element 
Reporting Detail 
Laboratory 
Values and 
Adverse 
Events 
• The Division of AIDS (DAIDS) grading for severity of laboratory toxicities 
and clinical adverse events, version 2.1, July 2017 will be used to assign 
grades to laboratory values. 
• When deriving the Grading for severity of laboratory toxicity only numeric 
criteria are considered. The following note will be included in the listing 
including laboratory severity output: “Grades were derived based on 
numeric criteria as defined in DAIDS Version 2.1 and did not take into 
consideration of clinical signs or symptoms which is needed for the final 
grade associated with the adverse event.” 
• Reference ranges for all laboratory parameters collected throughout the 
study are provided by the laboratory. A laboratory value that is outside the 
reference range is considered either high abnormal (value above the upper 
limit of the reference range) or low abnormal (value below the lower limit of 
the reference range). Note: a high abnormal or low abnormal laboratory 
value is not necessarily of clinical concern. The laboratory reference 
ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings. 
 
13.8.2. 
Urinalysis Values 
A participant is considered to have urinalysis results of PCI, if there is an increase in 
Protein or an increase in Occult Blood results during the study, or if microscopy is 
performed.   
13.8.3. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
                 < 320 
> 450  
Absolute PR Interval 
msec 
< 120  
> 200  
Absolute QRS Interval 
msec 
< 75  
> 110 
Heart Rate 
bpm 
< 40 
> 110 
Change from Baseline 
Increase from Baseline QTcF 
msec 
 
>60 
 
 


 
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13.8.4. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern Range 
Decrease 
Increase 
Systolic Blood Pressure 
mmHg 
≥ 40 
≥ 40 
Diastolic Blood Pressure 
mmHg 
≥ 20 
≥ 20 
Heart Rate 
bpm 
≥ 30 
≥ 30 
 
 


 
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13.9. 
Appendix 9: Abbreviations & Trade Marks 
13.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library (GSK Standards Library) 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 


 
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Abbreviation 
Description 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
 
 
 
 
13.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
[NONMEM] 
 
 
[SAS] 
 
 
[WinNonlin] 
 
 


 
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13.10. 
Appendix 10: List of Data Displays 
All data displays will use the term “subject” rather than “participant” in accordance with 
CDSIC and GSK Statistical Display Standards. 
13.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.44 
NA 
Safety 
3.1 to 3.35 
NA 
Pharmacokinetic 
4.1 to 4.10 
4.1 to 4.20 
Section 
Listings 
ICH Listings 
1 to 16 
Other Listings 
17 to 34 
 
13.10.2. 
Mock Example Shell Referencing 
Nonstandard specifications will be referenced as indicated and if required example mock-
up displays provided in Appendix 11: Example Mock Shells for Data Displays. 
 
Section 
Figure 
Table 
Listing 
Pharmacokinetic (PK) 
PK_F1 
PK_T1 
PK_T2 
PK_T3 
PK_T4 
PK_T5 
NA 
Safety 
NA 
NA 
SAFE_L1 
 
13.10.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
HL  
Headline Data Delivery 
SAC [1] 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


 
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13.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
GSK Standard  
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Safety 
ES1xo 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record – Part 1 
ICH E3, FDAAA, EudraCT 
SAC [1], HL 
1.2. 
Safety 
ES1 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record – Part 2 
ICH E3, FDAAA, EudraCT 
SAC [1], HL 
1.3. 
Safety 
ES1xo 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record – Part 3 
ICH E3, FDAAA, EudraCT 
SAC [1], HL 
1.4. 
Safety 
ES1xo 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record Related to COVID-19 Pandemic – 
Part 1 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.5. 
Safety 
ES1 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record Related to COVID-19 Pandemic – 
Part 2 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.6. 
Safety 
ES1xo 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record Related to COVID-19 Pandemic – 
Part 3 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.7. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment– Part 1 
ICH E3, Treatment group column will 
indicate treatment sequence to which 
the subject was assigned. 
 
Add Footnote: Since Part 1 only has a 
single dose per period, a participant’s 
treatment status is complete if they take 
any dose within any period.  
SAC [1] 


 
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Study Population Tables 
No. 
Population 
GSK Standard  
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.8. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – Part 2 
ICH E3, Treatment group column will 
indicate the treatment that the subject 
was taking at the time of 
discontinuation 
SAC [1] 
1.9. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – Part 3 
ICH E3, Treatment group column will 
indicate the treatment that the subject 
was taking at the time of 
discontinuation 
 
Add Footnote: Since Part 3 only has a 
single dose per period, a participant’s 
treatment status is complete if they take 
any dose within any period. 
SAC [1] 
1.10. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment Related to COVID-19 Pandemic– Part 1 
ICH E3, Treatment group column will 
indicate the treatment that the subject 
was taking at the time of 
discontinuation 
 
Add Footnote: Since Part 1 only has a 
single dose per period, a participant’s 
treatment status is complete if they take 
any dose within any period. 
SAC [1] 
1.11. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment Related to COVID-19 Pandemic – Part 2 
ICH E3, Treatment group column will 
indicate the treatment that the subject 
was taking at the time of 
discontinuation 
SAC [1] 


 
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Study Population Tables 
No. 
Population 
GSK Standard  
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.12. 
Safety 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment Related to COVID-19 Pandemic – Part 3 
ICH E3, Treatment group column will 
indicate the treatment that the subject 
was taking at the time of 
discontinuation 
 
Add Footnote: Since Part 3 only has a 
single dose per period, a participant’s 
treatment status is complete if they take 
any dose within any period. 
SAC [1] 
1.13. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Period– Part 1 
ICH E3 
 
SAC [1] 
1.14. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Period– Part 2 
ICH E3 
 
SAC [1] 
1.15. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Period– Part 3 
ICH E3 
 
SAC [1] 
1.16. 
Safety 
ES5 
Summary of Reason for Withdrawal at Each Period – Part 1 
FDAAA, EudraCT 
SAC [1] 
1.17. 
Safety 
ES5 
Summary of Reason for Withdrawal at Each Period – Part 2 
FDAAA, EudraCT 
SAC [1] 
1.18. 
Safety 
ES5 
Summary of Reason for Withdrawal at Each Period – Part 3 
FDAAA, EudraCT 
SAC [1] 
1.19. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements.  
 
SAC [1] 
1.20. 
Safety 
ES11 
Summary of Outcome of Adverse Events Which Led to Study 
Withdrawal at Each Study Period – Part 1 
EudraCT 
 
SAC [1] 
1.21. 
Safety 
ES11 
Summary of Outcome of Adverse Events Which Led to Study 
Withdrawal at Each Study Period – Part 2 
EudraCT 
 
SAC [1] 


 
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Study Population Tables 
No. 
Population 
GSK Standard  
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.22. 
Safety 
ES11 
Summary of Outcome of Adverse Events Which Led to Study 
Withdrawal at Each Study Period – Part 3 
EudraCT 
 
SAC [1] 
1.23. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID – Part 1 
EudraCT/Clinical Operations 
SAC [1] 
1.24. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID – Part 2 
EudraCT/Clinical Operations 
SAC [1] 
1.25. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID – Part 3 
EudraCT/Clinical Operations 
SAC [1] 
1.26. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
Relative to COVID-19 Pandemic Measures – Part 1 
 
SAC [1] 
1.27. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
Relative to COVID-19 Pandemic Measures – Part 2 
 
SAC [1] 
1.28. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
Relative to COVID-19 Pandemic Measures – Part 3 
 
SAC [1] 
Protocol Deviation 
1.29. 
Safety 
DV1 
Summary of Important Protocol Deviations – Part 1 
ICH E3 
SAC [1] 
1.30. 
Safety 
DV1 
Summary of Important Protocol Deviations – Part 2 
ICH E3 
SAC [1] 
1.31. 
Safety 
DV1 
Summary of Important Protocol Deviations – Part 3 
ICH E3 
SAC [1] 
1.32. 
Safety 
DV1 
Summary of Important Protocol Deviations and Relation with 
COVID-19 -Part 1 
ICH E3 
SAC [1] 
1.33. 
Safety 
DV1 
Summary of Important Protocol Deviations and Relation with 
COVID-19 -Part 2 
ICH E3 
SAC [1] 
1.34. 
Safety 
DV1 
Summary of Important Protocol Deviations and Relation with 
COVID-19  -Part 3 
ICH E3 
SAC [1] 


 
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Study Population Tables 
No. 
Population 
GSK Standard  
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Population Analysed 
1.35. 
Screened 
SP1 
 
Summary of Study Populations 
GSK Statistical Display Standard.  
SAC [1] 
Demographic and Baseline Characteristics 
1.36. 
Safety 
DM1xo 
Summary of Demographic Characteristics – Part 1 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.37. 
Safety 
DM1 
Summary of Demographic Characteristics – Part 2 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.38. 
Safety 
DM1xo 
Summary of Demographic Characteristics – Part 3 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.39. 
Enrolled 
DM11xo 
Summary of Age Ranges – Part 1 
EudraCT 
SAC [1] 
1.40. 
Enrolled 
DM11 
Summary of Age Ranges – Part 2 
EudraCT 
SAC [1] 
1.41. 
Enrolled 
DM11xo 
Summary of Age Ranges – Part 3 
EudraCT 
SAC [1] 
1.42. 
 Safety 
DM6xo 
Summary of Race and Racial Combination Details – Part 1 
ICH E3, FDA, FDAAA, EudraCT 
SAC [1] 
1.43. 
Safety 
DM6 
Summary of Race and Racial Combination Details – Part 2 
ICH E3, FDA, FDAAA, EudraCT 
SAC [1] 
1.44. 
Safety 
DM6xo 
Summary of Race and Racial Combination Details – Part 3 
ICH E3, FDA, FDAAA, EudraCT 
SAC [1] 
13.10.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE5B 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part 1 
ICH E3 
 
SAC [1], HL 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.2.  
Safety 
AE5B 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part 2 
ICH E3 
 
SAC [1], HL 
3.3.  
Safety 
AE5B 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part 3 
ICH E3 
 
SAC [1], HL 
3.4.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 1 
ICH E 
 
 SAC [1] 
3.5.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 2 
ICH E 
 
 SAC [1] 
3.6.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 3 
ICH E 
 
 SAC [1] 
3.7.  
Safety 
AE5B 
Summary of All Drug-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term – Part 1 
ICH E3 
 
SAC [1], HL 
3.8.  
Safety 
AE5B 
Summary of All Drug-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term – Part 2 
ICH E3 
 
SAC [1], HL 
3.9.  
Safety 
AE5B 
Summary of All Drug-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term – Part 3 
ICH E3 
 
SAC [1], HL 
3.10. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) – Part 1 
FDAAA, EudraCT 
 
IA [1], SAC [1] 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.11. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) – Part 2 
FDAAA, EudraCT 
 
IA [1], SAC [1] 
3.12. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) – Part 3 
FDAAA, EudraCT 
 
IA [1], SAC [1] 
3.13. 
Safety 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by System Organ Class and Preferred Term – Part 1 
Use GSK3640254 SRT spreadsheet at 
time of reporting to identify AESI 
 
SAC [1] 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.14. 
Safety 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by System Organ Class and Preferred Term – Part 2 
Use GSK3640254 SRT spreadsheet at 
time of reporting to identify AESI 
 
SAC [1] 
3.15. 
Safety 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by System Organ Class and Preferred Term – Part 3 
Use GSK3640254 SRT spreadsheet at 
time of reporting to identify AESI 
 
SAC [1] 
Serious and Other Significant Adverse Events 
3.16. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) – 
Part 1 
FDAAA, EudraCT 
 
SAC [1], HL 
3.17. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) – 
Part 2 
FDAAA, EudraCT 
 
SAC [1], HL 
3.18. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) – 
Part 3 
FDAAA, EudraCT 
 
SAC [1], HL 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.19. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term – Part 1 
GSK Statistical Display Standard 
 
SAC [1], HL 
3.20. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term – Part 2 
GSK Statistical Display Standard 
 
SAC [1], HL 
3.21. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term – Part 3 
GSK Statistical Display Standard 
 
SAC [1], HL 
Laboratory: Chemistry  
3.22. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline 
ICH E3, Page by Part 
 
SAC [1] ,HL 
3.23. 
Safety 
LB15A 
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline  
ICH E3 
 
SAC [1] 
Laboratory: Hematology 
3.24. 
Safety 
LB1 
Summary of Haematology Changes from Baseline  
ICH E3, Page by Part 
 
SAC [1] ,HL 
3.25. 
Safety 
LB15A 
Summary of Worst Case Haematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline  
ICH E3, Page by Part 
 
SAC [1] 
Laboratory: Urinalysis 
3.26. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline – Part 1 
ICH E3,For discrete or character values 
only 
 
SAC [1], HL 
3.27. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline – Part 2 
ICH E3,For discrete or character values 
only 
 
SAC [1], HL 


 
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Safety: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.28. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline – Part 3 
ICH E3,For discrete or character values 
only 
SAC [1], HL 
ECG 
3.29. 
 Safety 
EG1 
Summary of ECG Findings  - Part 1 
GSK Statistical Display Standard  
SAC [1] 
3.30. 
 Safety 
EG1 
Summary of ECG Findings – Part 2 
GSK Statistical Display Standard  
SAC [1] 
3.31. 
 Safety 
EG1 
Summary of ECG Findings – Part 3 
GSK Statistical Display Standard  
SAC [1] 
3.32. 
Safety 
EG10A 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
GSK Statistical Display Standard, ICH 
E14, page by part 
SAC [1], HL 
3.33. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
GSK Statistical Display Standard, page  
by part 
 
SAC [1] 
3.34. 
Safety 
EG11A 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
GSK Statistical Display Standard, page 
by part 
SAC [1], HL 
Vital Signs 
3.35. 
Safety 
VS3A 
 
Summary of Vital Sign Shifts from Baseline Relative to Potential 
Clinical Importance (PCI) Criteria 
GSK Statistical Display Standard, page 
by part 
 
SAC [1], HL 


 
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13.10.6. 
Pharmacokinetic Tables 
 Pharmacokinetic: Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK  
PK01 
Summary of VH3739937 Plasma Pharmacokinetic 
Concentration (ng/mL) -Time Data by Treatment 
Page by part 
SAC [1] 
4.2.  
PK 
PK03 
Summary of Derived VH3739937 Plasma Pharmacokinetic 
Parameters by Treatment  
 
SAC [1],HL 
4.3.  
PK  
PK05 
Summary of Log-Transformed Derived VH3739937 Plasma PK 
Parameters by Treatment 
 
SAC [1] ,HL 
Dose Proportionality, Accumulation, and Steady State 
4.4.  
PK 
PK_T1 
Summary Results of Single Dose Proportionality Assessment 
Using Power Model – Part 1 
Stats output,  
 
Non-Standard Shell PK_T1  
 
PK parameters: AUC(0-inf), 
AUC(0-t), Cmax 
SAC 
4.5.  
PK 
PK_T1 
Summary Results of Multiple Dose Proportionality Assessment 
Using Power Model – Part 2 
Stats output 
Non-standard shell PK_T1 
PK parameters: AUC(0-inf), 
AUC(0- 𝜏), Cmax 
SAC 
4.6.  
PK 
PK_T2 
Summary Results of Steady State VH3739937 Concentrations 
Assessment – Part 2 
Stats output 
Non-standard shell PK_T2 
 
Use up to day 14 for cohort 3 and 4 
and day 18 for cohort 5.  
SAC 


 
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 Pharmacokinetic: Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 Add footnote: Ctrough was collected 
on days 2,3,4,6,8, 10,11,12,13,14,15 
for cohort 3 and 4 and days 2,3,4,6,8, 
10,11,12,13,14,15, 16, 17,18 for 
cohort 5. 
Use 𝐶𝜏 to determine steady state for 
daily dosing MAD. See example from 
Table 4.13 from study 207187 
4.7.  
PK 
PK_T3 
Summary Results of VH3739937 PK Parameter Treatment 
Comparisons Predicted Accumulation Ratio- Part 1 
Stats output, Non-Standard Shell 
at end of RAP 
 
Non-standard shell PK_T3 
 
 
SAC 
4.8.  
PK 
PK_T4 
Summary Results of VH3739937 PK Parameter Treatment 
Comparisons Accumulation Ratio- Part 2  
Stats output,  
 
Non-standard shell PK_T4  
 
Add footnote: In Cohort 6, since 
sampling at 168 hrs (7 days) post 
3rd dose was not collected, it will be 
approximated by 192 hrs post 
dose.  
SAC 
Relative Bioavailability/Food Effect 
4.9.  
PK  
PK_T5 
Summary of Result of Plasma VH3739937 Pharmacokinetic 
Parameter Treatment Comparisons for Relative Bioavailability 
Stats output 
SAC [1], HL 


 
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 Pharmacokinetic: Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Parameters: AUC (0-24), 
AUC(0-inf), and Cmax 
Ratio: Test/Reference (Tablet/PiB) 
See study mid208131 Table 4.4 for 
reference 
Non-standard shell PK_T5 
4.10. 
PK  
PK_T5 
Summary of Result of Plasma VH3739937 Pharmacokinetic 
Parameter Treatment Comparisons for Food Effect 
Stats output 
PK Parameters: AUC (0-24), 
AUC(0-inf), and Cmax Ratio: 
Test/Reference (Fed Tablet/Fasted 
Tablet). See study mid208131 
Table 4.4 for reference 
 
Non-standard shell PK_T5 
SAC [1], HL 


 
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13.10.7. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK 
 
PK24 
Individual VH3739937 Plasma Concentration-Time Plots 
(Linear and Semi-log) – Part 1 
Paged by Dose, overlay all 
participants for each dose. Include 
LOQ line in plot. See Fig 4.1 from 
mid207187 
SAC [1] 
4.2.  
PK 
 
PK24 
Individual VH3739937 Plasma Concentration-Time Plots 
(Linear and Semi-log) – Part 2 
Paged by Dose and Day, overlay 
all participants for each dose. 
Include Day 1 and 14 for Cohort 3 
and 4. Include Day 1, 14, and 18 
for Cohort 5 
See fig 4.6 from mid207187 
Include LOQ line in plot. 
SAC [1] 
4.3.  
PK 
 
PK16B 
Individual VH3739937 Plasma Concentration-Time Plots 
(Linear and Semi-log) – Part 3 
Paged by participant, overlay all 
treatments for each participant. 
Include LOQ line in plot. 
SAC [1] 
4.4.  
PK 
 
PK17 
Mean VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 1 
By treatment. Use nominal times in 
X axis. 
SAC [1] 
4.5.  
PK 
 
PK17 
Mean VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 2 
By treatment. Use nominal times in 
X axis. 
SAC [1] 
4.6.  
PK 
 
PK17 
Mean VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 3 
By treatment. Use nominal times in 
X axis. 
SAC [1] 
4.7.  
PK 
 
PK18 
Median VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 1 
By treatment. Use nominal times in 
X axis. 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.8.  
PK 
 
PK18 
Median VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 2 
By treatment. Use nominal times in 
X axis.  
SAC [1] 
4.9.  
PK 
 
PK18 
Median VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Part 3 
By treatment. Use nominal times in 
X axis. 
SAC [1] 
4.10. 
PK 
PK24 
Individual VH3739937 Plasma Concentration-Time Plots 
(Linear and Semi-log) – Part 3 
Paged by treatment, overlay all 
participants for each treatment. 
Show all timepoints. Include LOQ 
line in plot. See Fig 4.1 from 
mid207187 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.11. 
PK 
PK24 
Plasma VH3739937 Trough Concentration-Time Plots (Linear 
and Semi-Log) by Cohort by Day - Part 2 
 
All Subjects Overlay - Days 1 
Through 14 for Cohort (3 and 4) 
Days 1-18 for Cohort 5. All points 
for Cohort 6 
 
Trough Concentrations Only 
 
Add footnote: For Cohort 3 and 4 
Pre-dose (trough) 
concentrations shown for days 
1-14. Last dose taken on Day 
14. Days 15-19 are follow-up 
visits. 
 
For Cohort 5: 
Pre-dose (trough) 
concentrations shown for days 
1-18. Last dose taken on Day 
18. Days 19-23 are follow-up 
visits. 
 
See fig 4.62 from mid207187 
 


 
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Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Relative Bioavailability/Food Effect 
4.12. 
PK  
PK28 
Geometric Mean Treatment Ratio and 90% Confidence Interval 
of VH3739937 PK Parameters for Relative Bioavailability  
Stats output: use mean from Table 
4.12 
See Reference Figure 4.4 from 
mid208131 
 
PK Parameters: AUC (0-24), AUC(0-
inf), and Cmax 
Ratio: Test/Reference (Tablet/PiB) 
SAC [1] 
4.13. 
PK  
PK28 
Geometric Mean Treatment Ratio and 90% Confidence Interval 
of VH3739937 PK Parameters for Food Effect  
Stats output: use mean from Table 
4.13 
 
See Reference Figure 4.4 from 
mid208131 
 
PK Parameters: AUC (0-24), AUC(0-
inf), and Cmax  
Ratio: Test/Reference (Tablet 
Fed/Tablet Fasted) 
SAC [1] 
4.14. 
PK  
PK25 
Comparative Plot of Individual Plasma VH3739937 PK 
Parameters for Relative Bioavailability by Treatment (Linear 
and Semi-log) 
PK Parameters: AUC (0-24), AUC(0-
inf), and Cmax  
 
Treatments and positioning: PiB 
Fed on left, Tablet Fed on right. 
 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.15. 
PK  
PK25 
Comparative Plot of Individual Plasma VH3739937 PK 
Parameters for Food Effect by Treatment (Linear and Semi-
log) 
PK Parameters: AUC (0-24), AUC(0-
inf), and Cmax  
 
Treatments and positioning: 
Tablet Fasted on left, Tablet 
Fed on Right side 
 
SAC [1] 
4.16. 
PK 
PK_F1 
Scatter Plot of Individual QTcF Change from Baseline vs Time 
Matched VH3739937 PK Concentration – Part 1 
Stats Output (for regression) 
Non-Standard Figure 
See shell at end of RAP, 
Reference study mid207187 Figure 
5.1,  
Overlay regression line and 95% 
CI, print Beta regression line on 
plot. 
SAC [1] 
4.17. 
PK 
PK_F1  
Scatter Plot of Individual QTcF Change from Baseline vs Time 
Matched VH3739937 PK Concentration – Part 2 
Non-Standard Figure see shell at 
end of RAP, Reference study 
mid207187 Figure 5.2 
SAC [1] 
4.18. 
PK 
 
PK24 
Individual VH3739937 Plasma Concentration-Time Plots 
(Linear and Semi-log) – Weekly Dosing Cohort 6 
Include all timepoints, with time 
relative to first dose. Keep dots 
small or remove to reduce clutter.  
 
See Figure 4.6 from mid207187 
Include LOQ line in plot. 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.19. 
PK 
 
PK17 
Mean VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Weekly Dosing Cohort 6 
Include all timepoints, with time 
relative to first dose.  
Use nominal times in X axis. 
SAC [1] 
4.20. 
PK 
 
PK17 
Median VH3739937 Plasma Concentration-Time Plots (Linear 
and Semi-log) – Weekly Dosing Cohort 6 
Include all timepoints, with time 
relative to first dose.  
Use nominal times in X axis. 
SAC [1] 
 


 
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13.10.8. 
ICH Listings 
ICH: Listings 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Safety  
ES2xo 
Listing of Reasons for Study Withdrawal  
ICH E3 
SAC [1] 
2.  
Safety 
SD2xo 
Listing of Reasons for Study Treatment Discontinuation  
ICH E3 
 
SAC [1] 
3.  
Safety 
BL1xo 
Listing of Subjects for Whom the Treatment Blind was Broken 
ICH E3 
 
SAC [1] 
Protocol Deviations 
4.  
Safety 
DV2xo 
Listing of Important Protocol Deviations 
ICH E3 
 
SAC [1] 
5.  
Safety 
IE3xo 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations  
ICH E3 
SAC [1] 
Populations Analysed 
6.  
Safety 
SP3xo  
Listing of Subjects Excluded from Any Population  
ICH E3 
 
SAC [1] 
Demographic and Baseline Characteristics 
7.  
Safety  
DM2xo 
Listing of Demographic Characteristics 
ICH E3 
SAC [1] 
8.  
Safety 
DM9xo 
Listing of Race 
ICH E3 
SAC [1] 
Exposure and Treatment Compliance 
9.  
Safety 
EX3xo 
Listing of Exposure Data  
ICH E3 
SAC [1] 
10.  
Safety 
SAFE_L1 
Listing of Meal Data 
Non-standard shell. Reference Study 
mid208131 Listing 12 
SAC [1] 
Adverse Events 


 
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ICH: Listings 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
11.  
Safety 
AE8CPxo 
Listing of All Adverse Events 
ICH E3. Page by Part 
SAC [1],HL 
12.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3, Page by part 
SAC [1] 
Serious and Other Significant Adverse Events 
13.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3, Page by part 
SAC [1] 
14.  
Safety 
AECP8xo 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment  
ICH E3, Page by Part 
SAC [1] 
All Laboratory 
15.  
Safety 
LB5Axo 
Listing of All Laboratory Data for Subjects with Any Toxicity 
ICH E3 
 
SAC [1] 
16.  
Safety 
UR2xo 
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance  
ICH E3 
 
SAC [1] 
 
 
 


 
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13.10.9. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition  
17.  
Screened 
ES7 
Listing of Reasons for Screen Failure  
Journal Guidelines 
 
SAC [1] 
18.  
Safety 
TA1xo 
Listing of Planned and Actual Treatments 
GSK Statistical Display Standard 
SAC [1] 
19.  
Enrolled 
PAN5  
Country Level Listing of Start Dates of COVID-19 Pandemic 
Measures   
 
 
 
SAC [1] 
Protocol Deviation 
20.  
Safety 
 
DV2xo 
Listing of All Non-Important COVID-19 Related Protocol 
Deviations  
 
SAC [1] 
21.  
Safety 
PAN7 
Listing of All Subjects with Visits and Assessments 
Impacted by COVID-19 Pandemic 
 
SAC [1] 
Prior and Concomitant Medications and Medical History 
22.  
Safety 
CM10xo  
Listing of Concomitant Medications  
GSK Statistical Display Standard, 
page by part 
SAC [1] 
23.  
Safety 
MH2xo 
Listing of Medical Conditions 
Page by Part 
SAC [1] 
Adverse Events 
24.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments for Subjects with COVID-19 Adverse Events 
 
SAC [1] 


 
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Non-ICH: Listings 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
25.  
Safety 
EG3xo 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance  
 
SAC [1] 
Vital Signs 
26.  
Safety 
VS4xo 
Listing of All Vital Signs for Subjects with any Value of 
Potential Clinical Importance  
 
SAC [1] 
Laboratory 
27.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
 
SAC [1] 
CSSRS 
28.  
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation and Behaviour Data 
Include only subjects with at least 
one positive (Yes) response 
SAC [1] 
PK Endpoints 
29.  
PK  
PK07xo 
Listing of VH3739937 Plasma Pharmacokinetic 
Concentration-Time Data Treatment  
 
SAC [1] 
30.  
PK 
PK13xo 
Listing of Derived VH3739937 Plasma Pharmacokinetic 
Parameters by Treatment  
 
SAC [1] 
Hepatobiliary (Liver):  
31.   
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting  
GSK Hepatic Safety Panel  
SAC [1] 
32.  
Safety 
LIVER15 
Liver Stopping Event Profile 
GSK Hepatic Safety Panel 
SAC [1] 
33.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline 
 
SAC [1] 
34.  
Safety 
MH2xo 
Listing of Medical Conditions for Subjects with Liver 
Stopping Events 
Optional listing 
SAC [1] 


 
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13.11. 
Appendix 11: Example Mock Shells for Data Displays 
Data Displays available on Request