A Two-Part, Randomized, Open-Label, Single Dose, Crossover Clinical Trial to Assess the Relative Bioavailability of a Tablet Compared to a Capsule of GSK3640254 and to Assess the Effect of Food on the GSK3640254 Tablet in Healthy Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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ViiV Healthcare group of companies
213567
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TITLE PAGE
Protocol Title: A Two-Part, Randomized, Open-Label, Single Dose, Crossover Clinical 
Trial to Assess the Relative Bioavailability of a Tablet Compared to a Capsule of 
GSK3640254 and to Assess the Effect of Food on the GSK3640254 Tablet in Healthy
Participants
Protocol Number: 213567/ Amendment 01
Compound Number
GSK3640254
Study Phase: Phase 1
Short Title: A Relative Bioavailability and Food-Effect Study of GSK3640254 Tablet 
and Capsule Formulations in Healthy Participants
Sponsor Name and Legal Registered Address:
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
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: 
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.  PPD with GlaxoSmithKline are supporting 
ViiV Healthcare in the conduct of this study.  
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND: 139,838
Approval Date: 20-FEB-2020
Copyright 2020 ViiV Healthcare group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited.
 
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PPD

 
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PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1
20-Feb-2020
2019N425126_01
Original Protocol
27-Dec-2019
2019N425126_00
Amendment 1 20-Feb-2020
Overall Rationale for the Amendment: Update study conduct information.
Section # 
and Name
Description of Change
Brief Rationale
1.1 Overall 
Design
Removed eligibility of subject who 
enter part 1 from entering into part 
2. 
Study decision not to include same 
subjects in part 2. 
9.5 Interim 
Analyses
Added details of a planned 
preliminary PK interim analyses 
following completion of Part 1. 
Study decision to inform on future Phase 
II clinical trials. 
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................7
1.1.
Synopsis.......................................................................................................7
1.2.
Schema ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................11
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Background ................................................................................................17
2.2.1.
Background and Key Safety Data With a Prior Maturation 
Inhibitor........................................................................................17
2.2.2.
Safety and Pharmacokinetic Data in Study 207187 .....................18
2.2.3.
Safety and Pharmacokinetic Data in Study 208131 .....................19
2.2.4.
Safety Data in Study 209712 .......................................................20
2.2.5.
Safety Data in Study 208134 .......................................................20
2.2.6.
Preliminary Safety and Pharmacokinetic Data in 
Study 208132 ..............................................................................20
2.3.
Benefit/Risk Assessment ............................................................................21
2.3.1.
Risk Assessment .........................................................................23
2.3.2.
Benefit Assessment.....................................................................26
2.3.3.
Overall Benefit: Risk Conclusion..................................................26
3.
OBJECTIVES AND ENDPOINTS...........................................................................26
4.
STUDY DESIGN ....................................................................................................26
4.1.
Overall Design ............................................................................................26
4.2.
Scientific Rationale for Study Design ..........................................................28
4.3.
Justification for Dose ..................................................................................29
4.4.
End of Study Definition ...............................................................................29
5.
STUDY POPULATION...........................................................................................29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................30
5.3.
Lifestyle Considerations..............................................................................33
5.3.1.
Meals and Dietary Restrictions ....................................................33
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................34
5.3.3.
Activity .........................................................................................34
5.4.
Screen Failures...........................................................................................34
6.
STUDY INTERVENTION........................................................................................34
6.1.
Study Interventions Administered ...............................................................35
6.2.
Preparation/Handling/Storage/Accountability..............................................35
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................36
6.4.
Study Intervention Compliance ...................................................................36
6.5.
Concomitant Therapy..................................................................................36
6.6.
Dose Modification .......................................................................................36
6.7.
Intervention after the End of the Study........................................................36
 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................36
7.1.
Discontinuation of Study Intervention..........................................................36
7.1.1.
Liver Chemistry Stopping Criteria ................................................37
7.1.1.1.
Study Intervention Restart or Rechallenge After 
Liver Stopping Criteria Met .........................................37
7.1.2.
QTc Stopping Criteria ..................................................................37
7.1.3.
Columbia-Suicide Severity Rating Scale Criteria..........................37
7.1.4.
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria Participant 
Discontinuation/Withdrawal from the Study..................................38
7.2.
Participant Discontinuation/Withdrawal From the Study..............................38
7.3.
Lost to Follow Up........................................................................................39
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
8.1.
Efficacy Assessments.................................................................................40
8.2.
Safety Assessments ...................................................................................40
8.2.1.
Physical Examinations.................................................................40
8.2.2.
Vital Signs....................................................................................40
8.2.3.
Electrocardiograms......................................................................40
8.2.4.
Clinical Safety Laboratory Assessments ......................................41
8.2.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms..................................................................41
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan.............42
8.3.
Adverse Events and Serious Adverse Events.............................................44
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................44
8.3.2.
Method of Detecting AEs and SAEs.............................................44
8.3.3.
Follow-up of AEs and SAEs.........................................................45
8.3.4.
Regulatory Reporting Requirements for SAEs .............................45
8.3.5.
Pregnancy ...................................................................................45
8.3.6.
Adverse Events of Special Interest ..............................................45
8.4.
Treatment of Overdose...............................................................................46
8.5.
Pharmacokinetics .......................................................................................46
8.6.
Pharmacodynamics ....................................................................................46
8.7.
Genetics .....................................................................................................46
8.8.
Biomarkers .................................................................................................47
8.9.
Medical Resource Utilization and Health Economics ..................................47
9.
STATISTICAL CONSIDERATIONS........................................................................47
9.1.
Statistical Hypotheses.................................................................................47
9.2.
Sample Size Determination ........................................................................47
9.2.1.
Sample Size Assumptions ...........................................................47
9.2.2.
Sample Size Sensitivity................................................................48
9.3.
Populations for Analyses ............................................................................49
9.4.
Statistical Analyses.....................................................................................50
9.4.1.
Pharmacokinetic Analyses...........................................................50
9.4.2.
Safety Analyses...........................................................................52
9.4.3.
Other Analyses ............................................................................52
9.5.
Interim Analyses .........................................................................................52
9.6.
Data Monitoring Committee ........................................................................52
 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................53
10.1.
Appendix 1: Abbreviations and Trademarks................................................53
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................56
10.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................58
10.3.1.
Definitions....................................................................................58
10.3.2.
Collection of Pregnancy Information ............................................59
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................61
10.4.1.
Regulatory and Ethical Considerations ........................................61
10.4.2.
Financial Disclosure.....................................................................61
10.4.3.
Informed Consent Process ..........................................................61
10.4.4.
Data Protection............................................................................62
10.4.5.
Committees Structure ..................................................................63
10.4.6.
Dissemination of Clinical Study Data ...........................................63
10.4.7.
Data Quality Assurance ...............................................................63
10.4.8.
Source Documents ......................................................................64
10.4.9.
Study and Site Start and Closure.................................................64
10.4.10. Publication Policy.........................................................................65
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................66
10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................68
10.6.1.
Definition of AE............................................................................68
10.6.2.
Definition of SAE..........................................................................69
10.6.3.
Recording and Follow-Up of AE and SAE....................................70
10.6.4.
Reporting of SAE to VH/GSK.......................................................72
10.7.
Appendix 7: Genetics..................................................................................73
10.8.
Appendix 8: Protocol Amendment History...................................................74
11. REFERENCES.......................................................................................................75
 
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Two-Part, Randomized, Open-Label, Single Dose, Crossover Clinical 
Trial to Assess the Relative Bioavailability of a Tablet Compared to a Capsule of 
GSK3640254 and to Assess the Effect of Food on the GSK3640254 Tablet in Healthy 
Participants
Short Title: A Relative Bioavailability and Food-Effect Study of GSK3640254 Tablet 
and Capsule Formulations in Healthy Participants
Rationale:
This is a Phase 1, 2-part, randomized, open-label, single-dose, crossover study to 
compare the relative bioavailability (BA) of the GSK3640254 formulation planned for 
Phase 2b (mesylate salt in a tablet) with the Phase 2a formulation (mesylate salt in a 
capsule) when administered following a moderate calorie and fat meal. Data from this 
study will determine whether dose adjustments are required due to formulation changes 
when transitioning from Phase 2a to Phase 2b clinical studies.
In addition, this study will investigate the effect of food on the pharmacokinetics (PK) of 
the GSK3640254 mesylate tablet formulation. All GSK3640254 completed clinical 
studies to date, including a Phase 2a (Part 1) proof of concept study, have been conducted 
with moderate calorie and fat meals. It is intended that this will be the only food-effect 
BA clinical study for GSK3640254; therefore, this study will investigate the effect of 
moderate and high calorie and fat meals on the PK, safety, and tolerability of the 
GSK3640254 mesylate tablet formulation, in comparison with administration under 
fasting conditions.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary

To assess the relative bioavailability of 
GSK3640254 mesylate tablets and 
GSK3640254 mesylate capsules (in the 
presence of a moderate fat meal)

To assess the effect of food (fasted, 
moderate fat meal, and high fat meal) on 
the PK of the GSK3640254 mesylate tablet 
formulation

AUC(0-), AUC(0-t), Cmax, and Tmax for 
GSK3640254
 
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Objectives
Endpoints
Secondary
Secondary

To assess the safety and tolerability of 
GSK3640254 following single oral 
administration to healthy participants under 
fasted or fed (moderate fat or high fat) 
conditions 

To characterize the PK of GSK3640254

Safety and tolerability parameters for 
AEs/SAEs, observed and change from 
Baseline clinical laboratory assessments, 
ECGs, and vital sign measurements

tlag, t1/2, CL/F, and Vz/F for GSK3640254

GSK3640254 PK concentrations in plasma
AE = adverse event; AUC(0-) = area under the plasma concentration-time curve from time zero extrapolated to 
infinity; AUC(0-t) = area under the plasma concentration-time curve from time zero to time t; CL/F = apparent oral 
clearance; Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetics; 
SAE = serious adverse event; t1/2 = apparent terminal phase half-life; tlag = lag time for absorption; Tmax = time of 
maximum observed concentration; Vz/F = apparent volume of distribution.
Overall Design:
This is a Phase 1, 2-part (1 cohort each part), randomized, open-label, single-dose, 
crossover study to compare the relative BA of a tablet formulation of GSK3640254 with 
the capsule formulation (Part 1) and to assess the effect of food on the PK of the tablet 
formulation in healthy participants (Part 2).
Part 1 will consist of a Screening period and 2 sequential treatment periods with a single 
dose of study intervention per treatment period. This will be followed by an interim 
analysis.
Part 2 will consist of a Screening period and 3 sequential treatment periods with a single 
dose of study intervention per treatment period. This will be followed by an End of Study 
analysis.
In Part 1, Treatments A and B will be administered in the fed state. Participants will fast 
overnight for at least 10 hours prior to dosing and will receive a moderate fat meal 
30 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.
In Part 2, Treatments C and E will be administered in the fed state. Participants will fast 
overnight for at least 10 hours prior to dosing and will receive a moderate fat 
(Treatment C) or high fat (Treatment E) meal 30 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 D will 
be administered in the fasted state. Participants will fast overnight for at least 10 hours 
prior to dosing and until 4 hours after dosing.
In both Part 1 and Part 2, PK blood samples for the analysis of GSK3640254 will be 
collected prior to dosing (0 hour) on Day 1 and up to 96 hours post-dose in each period.
 
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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.
Study assessments will be performed as indicated in the Schedule of Activities (SoA; 
Section 1.3). For Part 1, study participants will be confined to the clinic from Day –1 of
Period 1 until discharge on Day 5 of Period 2. For Part 2, study participants will be 
confined to the clinic from Day –1 of Period 1 until discharge on Day 5 of Period 3.
Disclosure Statement: This is a crossover treatment study with 2 treatments that has no 
masking.
Number of Participants: In Part 1, approximately 18 participants will be treated to 
ensure that 14 evaluable participants complete Part 1. In Part 2, approximately 
21 participants will be treated to ensure that 16 evaluable participants complete Part 2. If 
participants prematurely discontinue the study, additional participants may be 
randomized after consultation with the sponsor to ensure that the required number of 
evaluable participants complete the study.
Intervention Groups and Duration: Participants in Part 1 and Part 2 will be randomly 
assigned to a treatment sequence prior to dosing on Day 1 of Period 1. Participants will 
receive each of the following treatments administered as 1 treatment per period:
Part 1 (treatment sequence AB or BA):

Treatment A: GSK3640254 200 mg (as 2x 100mg capsules) administered under 
moderate fat conditions (reference) 

Treatment B: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
moderate fat conditions (test)
Part 2 (treatment sequence CDE, DEC, or ECD):

Treatment C: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
moderate fat conditions (test)

Treatment D: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
fasted conditions (reference)

Treatment E: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
high fat conditions (test) 
To ensure adequate washout, there will be at least 7 days between each dose of study 
intervention, with an allowance window of 4 hours (i.e., 7 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic. For Part 1, the total duration 
of the study, including Screening, is approximately 40 days. For Part 2, the total duration 
of the study, including Screening, is approximately 47 days.
Data Monitoring or Other Committee: No
 
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1.2.
Schema
A summary of the overall study design schema for Part 1 is presented in Figure 1 and for 
Part 2 in Figure 2.
Figure 1
Study Design Schematic - Part 1
Treatment A = GSK3640254 200 mg (as 2x 100mg capsules) administered under moderate fat conditions (reference) 
Treatment B = GSK3640254 200 mg (as 2x 100mg tablets) administered under moderate fat conditions (test) 
Figure 2
Study Design Schematic - Part 2
Treatment C = GSK3640254 200 mg (as 2x 100mg tablets) administered under moderate fat conditions (test)
Treatment D = GSK3640254 200 mg (as 2x 100mg tablets) administered under fasted conditions (reference)
Treatment E = GSK3640254 200 mg (as 2x 100mg tablets) administered under high fat conditions (test) 
 
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1.3.
Schedule of Activities (SoA)

Screening procedures may be done over more than 1 visit but must all be 
completed within 28 days prior to the first dose of study intervention.

The following demographic parameters will be captured: year of birth, sex, race, 
and ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria.
Screening Visit (Part 1 and Part 2)
Procedure
Screening (up to 28 days before 
Day 1)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight 1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
12-lead electrocardiogram 
X
Vital sign measurements
X
Medication/drug/alcohol history
X
Past and current medical conditions
X
Columbia-Suicide Severity Rating Scale 
X
Serum pregnancy test
X
Follicle-stimulating hormone (as needed, to confirm postmenopausal status)
X
Drug, alcohol, and cotinine screen
X
Human immunodeficiency virus, hepatitis B and C Screening 
X
A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
 
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Time and Events Table - Part 1
Procedure
Check-in
Period 1
Period 2
Notes
Day 
–1
Day
1
Washout
Day
1
Day
2
Days
3-4
Day
51
Day
2
Days 
3-5
Days 
6-7
Admit to clinic
X
Discharge from clinic
X
Discharge from clinic following completion of 
the last study procedure on Day 5 of 
Period 2.
Brief physical examination
X
D7
X
Interim or symptom-targeted physical 
examination will be performed at the 
discretion of the investigator. See 
Section 8.2.1 for description of brief physical 
examination. 
Vital signs
X
X
X
D3-5
X
X
X
X
Blood pressure and pulse will be measured 
in triplicate pre-dose on Day 1 in both 
periods. Single blood pressure and pulse 
will be measured on other study days.
12-lead ECG
X
X
X
X
The ECGs on Day 1 in both periods will be 
taken at pre-dose, and post-dose at 2 and
4 hours. The pre-dose ECGs in both periods
will be taken in triplicate. The post-dose 
ECGs are single ECGs.
Drug, alcohol, and cotinine screen
X
See Appendix 2 for specific tests to be 
performed.
Laboratory assessments 
(hematology, chemistry, 
urinalysis)
X
X
X
X
See Appendix 2 for specific tests to be 
performed. Day 2 samples in each period to 
be collected 24 hours after dosing.
Pregnancy test
X
X
 
 
 
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Procedure
Check-in
Period 1
Period 2
Notes
Day 
–1
Day
1
Washout
Day
1
Day
2
Days
3-4
Day
51
Day
2
Days 
3-5
Days 
6-7
Columbia-Suicide Severity
Rating Scale 
X
D7
X
Genetic sample (optional)
X
Study intervention: 
GSK3640254 200 mg 
(as 2x 100mg capsule or tablet)
X
X
Participants will fast overnight for at least 
10 hours prior to dosing; will be provided a 
moderate fat meal 30 minutes prior to 
dosing; and will be provided standardized 
meals ≥4 hours post-dose. See Section 4.1. 
Serial PK sampling
X
X
X
X
X
X
X
Blood for PK analysis of GSK3640254 will 
be collected within 40 minutes prior to 
dosing and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 
8, 12, 24, 48, 72, and 96 hours post-dose in 
both periods.
AE review
=============================X============================
SAE review
==================================X===================================
Concomitant medications
==================================X===================================
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 
1
Evaluations scheduled for Day 5 in Period 2 will also be performed for participants who discontinue early.
 
 
 
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Time and Events Table - Part 2
Procedure
Check-in
Periods 1 and 2
Period 3 only
Notes
Day 
–1
Day
1
Washout
Day
1
Day
2
Days
3-4
Day
51
Day
2
Days 
3-5
Days 
6-7
Admit to clinic
X
Discharge from clinic
X
Discharge from clinic following completion 
of the last study procedure on Day 5 of 
Period 3.
Brief physical examination
X
D7 
(Period 1 
and 2)
X
Interim or symptom-targeted physical 
examination will be performed at the 
discretion of the investigator. See 
Section 8.2.1 for description of brief 
physical examination. 
Vital signs
X
X
X
D3-5
X
X
X
X
Blood pressure and pulse will be 
measured in triplicate pre-dose on Day 1 
in Periods 1 to 3. Single blood pressure 
and pulse will be measured on other 
study days.
12-lead ECG
X
X
X
X
The ECGs on Day 1 in Periods 1 to 3 will 
be taken at pre-dose and post-dose at 
2 and 4 hours. The pre-dose ECGs in 
Periods 1 to 3 will be taken in triplicate. 
The post-dose ECGs are single ECGs.
Drug, alcohol, and 
cotinine screen
X
See Appendix 2 for specific tests to be 
performed.
Laboratory assessments 
(hematology, chemistry, urinalysis)
X
X
X
X
See Appendix 2 for specific tests to be 
performed. Day 2 samples in each period 
to be collected 24 hours after dosing.
Pregnancy test
X
X
 
 
 
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Procedure
Check-in
Periods 1 and 2
Period 3 only
Notes
Day 
–1
Day
1
Washout
Day
1
Day
2
Days
3-4
Day
51
Day
2
Days 
3-5
Days 
6-7
Columbia-Suicide Severity Rating 
Scale 
X
D7
X
Genetic sample (optional)
X
Study intervention: 
GSK3640254 200 mg tablet
X
X
Participants will fast overnight for at least 
10 hours prior to dosing; will be provided 
no meal, a moderate fat meal, or a high 
fat meal 30 minutes prior to dosing; and 
will be provided standardized meals 
≥4 hours post-dose. See Section 4.1. 
Serial PK sampling
X
X
X
X
X
X
X
Blood for PK analysis of GSK3640254 will 
be collected within 40 minutes prior to 
dosing and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 
6, 8, 12, 24, 48, 72, and 96 hours 
post-dose in each period.
AE review
=============================X============================
SAE review
==================================X===================================
Concomitant medications
==================================X===================================
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 
1
Evaluations scheduled for Day 5 in Period 3 will also be performed for participants who discontinue early.
 
 
 
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
The timing and number of planned study assessments, including safety, 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. 

Any changes in the timing or addition of time points for any planned study assessments 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. The Institutional Review Board/Independent Ethics Committee 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. The changes will be approved by the competent authorities and the ethics committee 
before implementation.
 
 
 
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2.
INTRODUCTION
2.1.
Study Rationale
This is a Phase 1, 2-part, randomized, open-label, single-dose, crossover study to 
compare the relative bioavailability (BA) of the GSK3640254 formulation planned for 
Phase 2b (mesylate salt in a tablet) with the Phase 2a formulation (mesylate salt in a 
capsule) when administered following a moderate calorie and fat meal. Data from this 
study will determine whether dose adjustments are required due to formulation changes 
when transitioning from Phase 2a to Phase 2b clinical studies.
In addition, this study will investigate the effect of food on the pharmacokinetics (PK) of 
the GSK3640254 mesylate tablet formulation. All GSK3640254 completed clinical 
studies to date, including a Phase 2a (Part 1) proof of concept study, have been conducted 
with moderate calorie and fat meals. It is intended that this will be the only food-effect 
BA clinical study for GSK3640254; therefore, this study will investigate the effect of 
moderate and high calorie and fat meals on the PK, safety, and tolerability of the 
GSK3640254 mesylate tablet formulation, in comparison with administration under 
fasting conditions.
2.2.
Background
GSK3640254 is a human immunodeficiency virus (HIV) maturation inhibitor (MI) which 
is improved over prior developmental MIs in the following ways: (1) it exhibits 
significantly improved pan-genotypic coverage and potency against polymorphic 
variants; (2) in vitro data suggest that GSK3640254 exhibits a higher barrier to 
emergence of resistant viruses (except for A364V); (3) GSK3640254 has 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 and clinical studies are included in the 
Clinical Investigator's Brochure (CIB) [GSK Document Number 2018N379610_01].
2.2.1.
Background and Key Safety Data With a Prior Maturation 
Inhibitor
Bristol-Myers Squibb (BMS), and later ViiV Healthcare (VH), developed a structurally 
similar HIV-1 MI (BMS-955176/GSK3532795), which was studied through Phase 2b 
studies in both treatment-naïve (AI468038/205891) and experienced (AI468048/205892) 
HIV-1 infected adults. In study AI468038/205891, a greater number of participants who 
received GSK3532795 experienced gastrointestinal (GI) intolerability (most frequently 
Grade 1 to 2 diarrhea and abdominal pain). A detailed examination of all GI adverse 
events (AEs) (regardless of grade/relationship) revealed a relationship with dose [GSK 
Document Number 2016N302783_00]. Ultimately, the rate of GI intolerability in the 
GSK3532795 dose groups in the Phase 2b Study 205891 led to VH’s decision to end all 
trials and not progress to Phase 3 studies. Gastrointestinal AEs were also previously 
observed in healthy participants in Phase 1 studies with varying doses, durations, and 
formulations of GSK3532795. In all 3 studies, the most common GI AEs were abdominal 
pain and diarrhea.
 
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Aside from mild to moderate GI intolerability, 2 serious adverse events (SAEs) occurred 
in the Phase 1 thorough QT Study AI468044/206220 [BMS Document Control 
Number 930109388] at supra-therapeutic doses: 1 healthy participant had an episode of 
acute psychosis and another had suicidal ideation/homicidal ideation as diagnosed 
through an interview by a psychiatrist. The 2 participants received GSK3532795 240 mg 
twice daily and 240 mg QD with food, respectively. These events were assessed as 
related to study intervention but 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).
2.2.2.
Safety and Pharmacokinetic Data in Study 207187
The primary objective of the first time in human (FTIH) clinical trial (207187) was to 
investigate the safety and tolerability of GSK3640254 following single and repeated daily 
administration. A total of 78 healthy men were ultimately randomized: 20 in the 
single-ascending dose ([SAD], doses ranging from 1 to 700 mg) and 58 in the 
multiple-ascending dose ([MAD], 50 to 320 mg QD for 14 days). A comprehensive 
summary of results is described in the CIB [GSK Document Number 2018N379610_01].
No deaths or SAEs were reported. There were 4 AEs leading to discontinuation. Only 
1 of these AEs was related to study medication. A participant who received GSK3640254 
200 mg QD developed a maculopapular rash after 8 days of study medication. The rash 
lasted for 6 days and there were no laboratory abnormalities. A dermatology consultant 
concluded this was a drug rash and the participant later received fexofenadine 180 mg 
QD and a topical steroid cream with resolution of the rash. The other 3 AEs occurred in 
the SAD portion of the study (depression in a participant who received placebo and 
2 participants with viral infection).
There were 9 participants with 12 AEs assessed as related to study medication by the 
principal investigator (11 Grade 1; 1 Grade 2). The most clinically notable was a 
participant who developed elevated transaminases while receiving GSK3640254 50 mg 
QD for 14 days. Specifically, there was a progressive rise in alanine aminotransferase 
(ALT) during treatment with a peak ALT of 83 IU/L on Day 16. The remaining liver 
chemistries were normal throughout. An ultrasound showed a subcapsular area of 
heterogenous echogenicity within segment 7, measuring approximately 35 × 23 × 36 mm. 
Follow-up magnetic resonance imaging and liver chemistries were normal. This 
participant also had 3 unrelated AEs during the course of an isolated increased ALT: 
musculoskeletal stiffness, contact dermatitis, and headache. All other related AEs are 
described in the CIB [GSK Document Number 2018N379610_01].
In the SAD portion of the study, 17 participants experienced 60 individual AEs 
(58 Grade 1; 2 Grade 2). The 2 Grade 2 AEs were headache and depression (both 
unrelated). The most frequent AEs were headache, contact dermatitis primarily due to 
electrocardiogram (ECG) electrodes, diarrhea, and dizziness. There was no dose/AE 
relationship.
In the MAD portion of the study, 44 participants experienced 130 individual AEs 
(126 Grade 1; 4 Grade 2). The 4 Grade 2 AEs were headache (1 related and 1 unrelated) 
 
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and back pain (2 unrelated). The most frequent AEs were headache, contact dermatitis, 
dizziness, contusion, fatigue, and back pain.
There were no clinically significant abnormal fluctuations or trends in vital signs in the 
SAD or MAD cohorts. There were no abnormal clinically significant arrhythmias or QT 
prolongations (values >500 ms or increases >60 ms from baseline) observed for any 
participant in the SAD or MAD. A cardiodynamic evaluation of healthy participants in 
the MAD portion of Study 207187 (placebo or GSK3640254 dose range 50 to 320 mg 
daily for 14 days) was performed. Serial ECGs were extracted from continuous Holter 
monitors at time-matched baseline on Day –1 and for approximately 24 hours post-dose 
on Days 1 and 14. In the concentration-corrected QT interval (QTc) analysis, a final 
model with a treatment effect-specific intercept reasonably represented the data. The 
slope of the concentration-QTc relationship was 0.004 ms per ng/mL (90% confidence 
interval [CI]: 0.0023 to 0.0048) with a small treatment effect-specific intercept of -0.9 ms 
(90% CI: -4.47 to 2.69). The QT effect (∆ΔQTcF) of GSK3640254 could be predicted to 
be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms (90% CI: 2.79 to 10.61) for the 200 mg 
(1779 ng/mL) and 320 mg (2154 ng/mL) doses, respectively, on Day 14. Based on this 
concentration-QTc analysis, corrected QT interval using the Fridericia formula (QTcF) 
effect above 10 ms could be excluded for GSK3640254 plasma concentrations of up to 
approximately 2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, 
the dose used in the current study will be 200 mg QD). Finally, there were no laboratory 
abnormality trends that were clinically significant or associated with any symptoms
across doses. 
GSK3640254 PK parameters derived based on nominal sampling times following single 
doses of 1 to 700 mg administered after a moderate calorie and fat breakfast showed 
GSK3640254 was slowly absorbed with an average time of maximum observed 
concentration (Tmax) of 3.5 hours after dosing and slowly eliminated with an average 
half-life of 24 hours. In general, exposure (maximum observed concentration [Cmax] and 
area under the plasma concentration-time curve [AUC]) increased in a 
close-to-dose-proportional manner from 1 to 400 mg with no further increase in exposure 
at 700 mg.
Repeat dose PK parameters following administration of GSK3640254 50 to 320 mg QD 
for 14 days were determined on Day 1 and Day 14 and showed a median Tmax ranging 
from 3.8 to 4.3 hours. The estimated half-life ranged from 22.1 to 28.4 hours. Dose 
proportionality assessment of AUC from time 0 to the end of the dosing interval at steady 
state (AUC[0-τ]), plasma concentration at the end of the dosing interval (Cτ), and Cmax 
following repeat dose administration of doses 50 to 320 mg showed a trend towards
less-than-dose-proportional increase with increase in doses. The exposures on Day 14 
were, on an average, 1.9- to 2.6-fold higher than on Day 1 for AUC, Cmax, and Cτ [GSK 
Document Number 2018N379610_01].
2.2.3.
Safety and Pharmacokinetic Data in Study 208131
The FTIH Study 207187 used a bis-hydrochloride salt capsule formulation of 
GSK3640254, which is not suitable for long-term clinical development.
 
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Study 208131 was a single-center, open-label, 2-period, 2-sequence crossover design, 
conducted in 14 healthy participants in the United Kingdom. This study was designed to 
assess the relative BA of the formulation planned for Phase 2a (mesylate salt in a 
capsule) to the FTIH formulation (bis-hydrochloride salt in a capsule) administered 
following a moderate calorie and fat meal. All participants completed dosing and the 
safety data showed a total of 11 AEs (all Grade 1). Two AEs of headache were related to 
study drug. The most common AE was headache (3 instances). There were 3 GI AEs 
(abdominal pain, bleeding gums, and flatulence). There were no cardiac or psychiatric 
AEs. There were no clinically significant changes in vital signs, ECG parameters, or 
safety laboratory parameters.
Pharmacokinetic results from Study 208131 showed that in the presence of a moderate fat 
meal, the relative BA of GSK3640254 following 200 mg GSK3640254 mesylate salt 
administration relative to 200 mg GSK3640254 bis-hydrochloride salt administration was 
112% and 116% based on AUC(0-t) and Cmax, respectively.
2.2.4.
Safety Data in Study 209712
Study 209712 was a Phase 1, open-label, single-sequence, 2-way drug interaction study 
to investigate the effect of dolutegravir (DTG) on the steady-state PK of GSK3640254, 
and the effect of GSK3640254 on the steady-state PK of DTG. Sixteen participants were 
treated. All doses were administered with a moderate fat meal. A total of 5 participants 
reported 10 AEs during the study. Medical device site dermatitis (contact dermatitis at the 
ECG electrode site) was reported by 2 participants overall; all other AEs were reported 
by only 1 participant each. No AEs leading to withdrawal were reported during the study. 
All AEs were considered Grade 1 (mild) in intensity, and none of the AEs were 
considered related to the study treatment. There were no clinically relevant mean changes 
from baseline in vital signs, ECGs, or in clinical laboratory results during the study and 
no apparent treatment-related trends were observed.
2.2.5.
Safety Data in Study 208134
This was a Phase 1, open-label, fixed-sequence, 2-period, 1-way drug interaction study 
designed to assess the PK, safety, and tolerability of GSK3640254 and tenofovir 
alafenamide/emtricitabine (TAF/FTC) when administered alone and in combination to 
healthy participants. Sixteen participants were treated. There were no deaths or SAEs 
reported, and a total of 9 participants reported 21 AEs during the study. The most 
commonly reported AEs were upper respiratory tract infection, rash pustular, and nausea; 
all were reported after the participants received TAF/FTC alone. Two participants 
reported 3 AEs (nausea, somnolence, and urticaria) that were considered drug-related by 
the investigator. One participant was discontinued due to the AE of urticaria. There were 
no clinically relevant mean changes from baseline in vital signs, ECGs, or clinical 
laboratory results during the study and no apparent treatment-related trends were 
observed.
2.2.6.
Preliminary Safety and Pharmacokinetic Data in Study 208132
This is a Phase 2a, global, multicenter, randomized, double-blind (Sponsor-unblinded), 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
 
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tolerability, and PK/PD of GSK3640254 over 7 to 10 days in antiretroviral therapy-naïve 
HIV-1 infected adults. This study is being conducted in 2 parts, separated to allow for an 
unblinded interim analysis performed after Part 1, based upon preliminary datasets. Part 1 
evaluated 2 active doses (10 mg and 200 mg) of GSK3640254 in cohorts of 6 participants 
each. In addition, Part 1 included 2 participants who received placebo. No data from 
Part 2 are available at the time of this protocol submission.
There were no deaths and there was 1 SAE in Part 1 of the study. The SAE was severe 
dilated cardiomyopathy and was considered unrelated to study treatment. A 
comprehensive summary of this case is described in the CIB [GSK Document Number 
2018N379610_01]. A total of 9 participants reported 25 AEs during the study. The most 
commonly reported AEs were nasopharyngitis, headache, and oropharyngeal pain. All 
AEs related to study medication were Grade 1, except 1 instance of nausea (Grade 2). No 
AEs led to withdrawal of a participant from the study. There were no clinically relevant 
mean changes from baseline in vital signs, ECGs, or clinical laboratory results during the 
study and no apparent treatment-related trends were observed.
Preliminary GSK3640254 PK parameters derived based on nominal times following 
once-daily administration of 10 mg and 200 mg QD for 10 days were determined on 
Day 1 and Day 10. Following multiple dose administration of 10 mg and 200 mg QD 
with a moderate fat meal, Day 1 median Tmax was 3.00 and 6.00 hours, respectively.
2.3.
Benefit/Risk Assessment
Based upon preclinical and clinical studies, the major risks for GSK3640254 are GI 
intolerability (e.g., abdominal pain and diarrhea) and toxicity (e.g., single-cell parietal 
cell necrosis), prolongation of the QTc interval, and neuropsychiatric safety. 
Reproduction of preclinical GI toxicity findings would be unlikely during the limited 
dosing of GSK3640254 in this study. One preclinical study showed 1 dog with an 
increased QTc interval when given a single dose of GSK3640254. As described in 
Section 2.2.2, a cardiodynamic analysis of healthy participants in Study 207187 was 
conducted. A final model from the MAD data showed a QT effect (∆ΔQTcF) of 
GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms 
(90% CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) doses, 
respectively, on Day 14. Based on this concentration-QTc analysis, a QTcF effect above 
10 ms could be excluded for GSK3640254 plasma concentrations of up to approximately 
2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, 200 mg QD will 
be the dose used in this study). Importantly, there were no abnormal clinically significant 
arrhythmias or QTc prolongations (values >500 ms or increases >60 ms from Baseline) in 
Study 207187. This study contains specific cardiac exclusion criteria, has ECG 
monitoring, and has QTcF-based stopping criteria.
Finally, the protocol will exclude potential participants with any significant pre-existing 
psychiatric condition or positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee)-administered Columbia-Suicide Severity Rating Scale 
(C-SSRS). The C-SSRS assessment will also be administered by a clinician (or qualified 
designee) during the on-treatment portion of the study.
 
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To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability, QTc prolongation, and neuropsychiatric safety), this clinical study will 
include healthy adults who will receive clinical, ECG, and laboratory evaluations during 
their participation. More detailed information about the known and expected benefits and 
risks and reasonably expected AEs of GSK3640254 may be found in the CIB [GSK 
Document Number 2018N379610_01).
 
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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) GSK3640254
Cardiovascular (QT prolongation) 
Preclinically, GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and L-type calcium 
channel currents recorded from HEK 293 cells stably 
transfected with complementary Deoxyribonucleic acid (DNA) 
from the ion channels. In a single-dose safety pharmacology 
study in telemeterized dogs, increases in QT interval (up to 
20 ms) occurred primarily in 1 dog given 17 mg/kg. Later, 
there were no GSK3640254-related effects on ECG 
parameters in dogs given up to 25 mg/kg/day for 4 weeks.
In the first time in human Study 207187, no participant 
exhibited QTc change from Baseline >60 ms or QTc >500 ms. 
As described in Section 2.2.2, in the concentration-QTc 
analysis, a QTcF effect above 10 ms could be excluded for 
GSK3640254 plasma concentrations of up to approximately 
2000 ng/mL (corresponding to doses approximately ≤200 mg 
QD).
Screening: Protocol exclusion criteria 
based on screening ECG parameters and 
cardiac medical history.
On-Treatment: Participants will have ECG 
monitoring (at a clinically reasonable 
frequency) during the course of the study 
(see SoA, Section 1.3) with QTc stopping 
criteria (see Section 7.1.2).
GI intolerability and toxicity
Clinical signs indicative of GI intolerability (sporadic vomiting 
and abnormal feces beginning on Day 1 and continuing 
throughout the dosing periods) occurred mainly in dogs at 
1 mg/kg/day. Additionally, toxicity findings of single-cell 
necrosis of parietal cells and/or chief cells were present in 
preclinical species. These findings were reversible. 
Gastrointestinal intolerability (predominantly abdominal pain 
and diarrhea) was seen with a structurally related compound 
Screening: Protocol exclusion criterion 
based on pre-existing GI pathology or 
baseline GI signs/symptoms.
On-Treatment: Participants will undergo 
continuous evaluation for AEs during their 
participation in the study; there will be 
individual clinical stopping criteria based 
upon intensity of treatment-emergent AEs. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK3532795, which was evaluated through Phase 2b dosing.
In the multiple ascending dose part of the first time in human 
Study 207187, clinically relevant GI AEs (abdominal pain 
lower, diarrhoea, feces soft, gastro-esophageal reflux disease, 
nausea, abdominal distention, and abdominal pain) were 
experienced by 9 participants. The greatest incidences were in 
the GSK3640254 200 mg arms (Cohorts 5 and 7) but 
ultimately, no dose/AE relationship was apparent. One 
participant each in the GSK3640254 200 mg arm and 320 mg 
arm reported nausea (mild in intensity), considered by the 
investigator in each case to be related to study drug.
A GI toxicity evaluation and monitoring plan 
will be available to guide investigators 
should GI AEs emerge (see Section 8.2.6).
Neurologic/psychiatric safety
Two psychiatric SAEs in previous maturation inhibitor 
GSK3532795 clinical program (acute psychosis, 
homicidal/suicidal ideation) were seen at supratherapeutic 
doses in healthy participants in the thorough QT (TQT) study.
From a neurologic and psychiatric AE summary and 
PK/pharmacodynamic analysis for GSK3532795 across all 
studies, Grade 1 headache and Grade 1 sleep abnormalities 
were the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing dose (based 
on TQT and Phase 2b studies). No exposure-response 
relationship was seen for select neurologic and psychiatric 
AEs (based on TQT and Phase 2b studies). Central nervous 
system penetration data for GSK3532795 and GSK3640254 in 
rats demonstrate a similarly low brain distribution/penetration.
In the multiple ascending dose part of first time in human 
Study 207187, clinically relevant preferred terms from the 
system organ class nervous system were experienced by 
Screening: Protocol exclusion criterion 
based on any pre-existing psychiatric 
condition (including results of psychological 
assessment) for participants. Participants 
will have a clinician (or qualified designee) 
administered C-SSRS and will be included 
given no positive (abnormal) response.
On-Treatment: Participants will undergo 
physical examinations and laboratory 
testing. In addition, participants will undergo 
continuous evaluation for AEs during their 
participation in the study; there are 
individual clinical stopping criteria and 
monitoring based upon incidence and 
intensity of treatment-emergent psychiatric 
AEs (Section 7.1.4 and Section 8.2.5). 
Participants will be housed throughout study 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
5 participants (somnolence, disturbance in attention, and 
lethargy) and showed that the greatest incidence arose in the 
GSK3640254 200 mg arms (Cohorts 5 and 7), but no dose/AE 
relationship was apparent. Seven participants experienced 
five psychiatric AEs: agitation, abnormal dreams, insomnia, 
depressed mood, and nightmare. All events were mild in 
intensity and considered by the investigator to be unrelated to 
study drug, apart from one participant from the 320 mg arm 
who experienced lethargy which was considered related to 
study drug.
conduct to ensure rapid diagnosis and 
management of any potential event.
The C-SSRS will be administered during 
and after the treatment phase of the study. 
In the event of a positive (abnormal) 
response confirmed by the investigator, the 
participant will discontinue from the trial and 
the investigator will arrange for urgent 
specialist psychiatric evaluation and 
management. Guidance for the investigator 
on the management of emergent psychiatric 
symptoms will be available.
 
 
 
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2.3.2.
Benefit Assessment
This is a study in healthy participants; no medical benefit will be derived by participants’ 
participation.
2.3.3.
Overall Benefit: Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the clinical data gathered from Phase 1-2a studies, and the planned 
clinical procedures and evaluations in this study, the potential risks to participants 
receiving GSK3640254 are low, evaluable, and manageable.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Primary

To assess the relative bioavailability of 
GSK3640254 mesylate tablets and 
GSK3640254 mesylate capsules (in the 
presence of a moderate fat meal)

To assess the effect of food (fasted, 
moderate fat meal, and high fat meal) on 
the PK of the GSK3640254 mesylate tablet 
formulation

AUC(0-), AUC(0-t), Cmax, and Tmax for 
GSK3640254
Secondary
Secondary

To assess the safety and tolerability of 
GSK3640254 following single oral 
administration to healthy participants under 
fasted or fed (moderate fat or high fat) 
conditions 

To characterize the PK of GSK3640254

Safety and tolerability parameters for 
AEs/SAEs, observed and change from 
Baseline clinical laboratory assessments, 
ECGs, and vital sign measurements

tlag, t1/2, CL/F, and Vz/F for GSK3640254

GSK3640254 PK concentrations in plasma
AE = adverse event; AUC(0-) = area under the plasma concentration-time curve from time zero extrapolated to 
infinity; AUC(0-t) = area under the plasma concentration-time curve from time zero to time t; CL/F = apparent oral 
clearance; Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetics; 
SAE = serious adverse event; t1/2 = apparent terminal phase half-life; tlag = lag time for absorption; Tmax = time of 
maximum observed concentration; Vz/F = apparent volume of distribution.
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase 1, 2-part, randomized, open-label, single-dose, crossover study to 
compare the relative BA of a tablet formulation of GSK3640254 with the capsule 
 
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formulation (Part 1) and to assess the effect of food on the PK of the tablet formulation in 
healthy participants (Part 2).
Part 1 will consist of a Screening period and 2 sequential treatment periods with a single 
dose of study intervention per treatment period. Participants will be randomly assigned to 
1 of 2 treatment sequences (AB or BA) prior to dosing on Day 1 of Period 1. This will be 
followed by an interim analysis.
Part 2 will consist of a Screening period and 3 sequential treatment periods with a single 
dose of study intervention per treatment period. Participants will be randomly assigned to 
1 of 3 treatment sequences (CDE, DEC, or ECD) prior to dosing on Day 1 of Period 1.
This will be followed by an End of Study analysis.
Participants will receive each of the following treatments administered as 1 treatment per 
period:
Part 1:

Treatment A: GSK3640254 200 mg (as 2x 100mg capsules) administered under 
moderate fat conditions (reference) 

Treatment B: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
moderate fat conditions (test)
Part 2:

Treatment C: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
moderate fat conditions (test)

Treatment D: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
fasted conditions (reference)

Treatment E: GSK3640254 200 mg (as 2x 100mg tablets) administered under 
high fat conditions (test) 
To ensure adequate washout, there will be at least 7 days between each dose of study 
intervention, with an allowance window of 4 hours (i.e., 7 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic. 
In Part 1, Treatments A and B will be administered in the fed state. Participants will fast 
overnight for at least 10 hours prior to dosing and will receive a moderate fat meal 
30 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.
In Part 2, Treatments C and E will be administered in the fed state. Participants will fast 
overnight for at least 10 hours prior to dosing and will receive a moderate fat 
(Treatment C) or high fat (Treatment E) meal 30 minutes prior to dosing. Dose 
administration will occur within 5 minutes of completion of meal consumption. 
 
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Participants will not receive any further food until 4 hours after dosing. Treatment D will 
be administered in the fasted state. Participants will fast overnight for at least 10 hours 
prior to dosing and until 4 hours after dosing.
In both Part 1 and Part 2, PK blood samples for the analysis of GSK3640254 will be 
collected prior to dosing (0 hour) on Day 1 and up to 96 hours post-dose in each period.
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.
Study assessments will be performed as indicated in the SoA (Section 1.3). For Part 1, 
study participants will be confined to the clinic from Day –1 of Period 1 until discharge 
on Day 5 of Period 2; the total duration of the study, including Screening, is 
approximately 40 days. For Part 2, study participants will be confined to the clinic from 
Day –1 of Period 1 until discharge on Day 5 of Period 3; the total duration of the study, 
including Screening, is approximately 47 days.
4.2.
Scientific Rationale for Study Design
This is a Phase 1, 2-part, randomized, open-label, single-dose, crossover study to 
compare the relative BA of the GSK3640254 formulation planned for Phase 2b (mesylate 
salt in a tablet) with the Phase 2a formulation (mesylate salt in a capsule) when 
administered following a moderate calorie and fat meal (Part 1). In addition, this study 
will investigate the effect of food on the PK of the GSK3640254 mesylate tablet 
formulation (Part 2).
The effect of food on the PK of a structurally similar HIV-1 MI (GSK3532795) was 
previously evaluated: AUC increased 1.8-, 2.1-, and 2.5-fold when a single dose of 
180 mg GSK3532795 was given with a light, moderate, or high fat meal, respectively, as 
compared to administration under fasting conditions [GSK Document Number 
2017N322200_00]. All GSK3640254 completed clinical studies to date, including a 
Phase 2a (Part 1) proof of concept study, have been conducted with moderate calorie and 
fat meals. It is intended that this will be the only food-effect BA clinical study for 
GSK3640254; therefore, Part 2 of this study will investigate the effect of moderate and 
high calorie and fat meals on the PK, safety, and tolerability of the GSK3640254 
mesylate tablet formulation, as compared with administration under fasting conditions.
The open-label crossover design of this study is well-established for evaluation of the 
relative BA of different oral dosage forms and for studying the effect of food on BA. 
Random assignment to treatment sequences is an attempt to prevent bias. The washout of 
at least 7 days between each dose of study intervention should eliminate the possibility of 
carryover of drug exposure from the previous dose. There are appropriately named “test” 
and “reference” study treatments, which will be evaluated for the relative BA 
comparisons. 
This study is participant to the appropriate regulatory and ethics committee approval and 
will be listed on the website ClinicalTrials.gov. No blinding or placebo control will be 
used, as these are not necessary for the purposes of this study.
 
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4.3.
Justification for Dose
The dose of 200 mg GSK3640254 was selected for this study as this is the maximum 
projected clinically therapeutic dose of GSK3640254. The t1/2 of GSK3640254 was 
approximately 22 hours in the MAD portion of Study 207187 at the 200-mg dose. To 
ensure adequate washout, there will be at least 7 days between each dose of study 
intervention, with an allowance window of 4 hours (i.e., 7 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic.
4.4.
End of Study Definition
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the final date on which data were or are expected to be 
collected.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA (Section 1.3) for the last participant 
in the study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1.
Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are 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). 
Weight
3.
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 31.0 kg/m2 (inclusive).
Sex
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
 
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4.
Male or female
a.
Male participants:
1. Males shall not engage in intercourse while confined in the clinic. There is no 
need for an extended period of double barrier use or prolonged abstinence 
after study discharge.
b. Female participants:
1. A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least 1 of the following conditions applies:

Is not a woman of childbearing potential (WOCBP) as defined in 
Appendix 3.
OR

Is a WOCBP and using a nonhormonal contraceptive method that is 
highly effective, with a failure rate of <1%, as described in 
Appendix 3, for 28 days before intervention, during the intervention 
period, and for at least 28 days after the last dose of study intervention. 
The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
2. A WOCBP must have a negative highly sensitive serum pregnancy test 
(Appendix 2) at Screening and Day –1.
3. Additional requirements for pregnancy testing during and after study 
intervention are outlined 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
5.
Capable of giving signed informed consent as described in Appendix 4, 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 History
1.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
2.
A pre-existing condition interfering with normal GI anatomy or motility 
(e.g., gastroesophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or renal 
function that could interfere with the absorption, metabolism, and/or excretion of the 
study intervention or render the participant unable to take oral study intervention.
 
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3.
Prior cholecystectomy surgery (prior appendectomy is acceptable).
4.
Any history of significant underlying psychiatric disorder, including, but not limited 
to, schizophrenia, bipolar disorder with or without psychotic symptoms, other 
psychotic disorders, or schizotypal (personality) disorder.
5.
Any history of major depressive disorder with or without suicidal features, or anxiety 
disorders that required medical intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient 
treatment. Participants with other conditions such as adjustment disorder or 
dysthymia that have required shorter term medical therapy (<6 months) without 
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the VH/GSK Medical 
Monitor.
6.
Any pre-existing physical or other psychiatric condition (including alcohol or drug 
abuse), which, in the opinion of the investigator (with or without psychiatric 
evaluation), could interfere with the participant’s ability to comply with the dosing 
schedule and protocol evaluations or which might compromise the safety of the 
participant.
7.
Medical history of cardiac arrhythmias, prior myocardial infarction in the past 
3 months, or cardiac disease or a family or personal history of long QT syndrome.
Laboratory Assessments
8.
Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study intervention.
9.
Positive hepatitis C antibody test result at Screening or within 3 months prior to 
starting study intervention AND positive on reflex to hepatitis C ribonucleic acid 
(RNA).
10. Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
11. ALT >1.5 × upper limit of normal (ULN). A single repeat of ALT is allowed within 
a single Screening period to determine eligibility.
12. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). A single repeat of any laboratory 
abnormality is allowed within a single Screening period to determine eligibility.
13. Any acute laboratory abnormality at Screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound.
14. Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine 
phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides), 
and ALT (described above), will exclude a participant from the study unless the 
investigator can provide a compelling explanation for the laboratory result(s) and has 
the assent of the sponsor. A single repeat of any laboratory abnormality is allowed 
within a single Screening period to determine eligibility.
 
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15. A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine 
(indicating active current smoking) at Screening or before the first dose of study 
intervention.
Prior/Concomitant Therapy
16. Unable to refrain from the use of prescription or nonprescription drugs including 
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 the first dose of study intervention and for the duration of the study. 
(Note: acetaminophen/paracetamol at doses of 2 grams/day and topical 
hydrocortisone cream 1% are permitted for use any time during the study.)
17. Treatment with any vaccine within 30 days prior to receiving study intervention.
18. Unwillingness to abstain from excessive consumption of any food or drink 
containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or 
pomelos or their fruit juices within 7 days prior to the first dose of study 
intervention(s) until the end of the study.
Prior/Concurrent Clinical Study Experience
19. Participation in another concurrent clinical study or prior clinical study (with the 
exception of imaging trials) prior to the first dosing day in the current study: 30 days, 
5 half-lives, or twice the duration of the biological effect of the study intervention 
(whichever is longer).
20. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
Diagnostic Assessments
21. Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS.
22. Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the 
past 3 months, symptomatic bradycardia, non-sustained or sustained atrial 
arrhythmias, non-sustained or sustained ventricular tachycardia, second-degree 
atrioventricular block Mobitz Type II, third-degree atrioventricular block, complete 
heart block, or conduction abnormality) which, in the opinion of the investigator or 
VH/GSK Medical Monitor, will interfere with the safety for the individual 
participant.
23. Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility 
determination):
Heart rate 1
<50 or >100 beats per minute (bpm)
QTcF interval 2 (Fridericia’s)
>450 ms
1
A heart rate from 100 to 110 bpm can be rechecked by electrocardiogram or vital signs within 30 minutes to verify 
eligibility.
2
The QTc is the QT interval corrected for heart rate using Fridericia’s formula (QTcF). It is either machine read or 
manually over-read. The specific formula used to determine eligibility and discontinuation for an individual 
participant will be Fridericia’s formula.
 
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Other Exclusions
24. History of regular alcohol consumption within 6 months of the study, defined as an 
average weekly intake of >14 units. 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.
25. Unable to refrain from tobacco or nicotine-containing products within 3 months prior 
to Screening.
26. History of sensitivity to any of the study medications, or components thereof, or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Refrain from excessive consumption of red wine, grapefruit and grapefruit juice, 
Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days 
prior to the first dose of study intervention(s) until the end of the study. 
Excessive consumption is defined as more than one glass of wine or 8 oz juice 
or one of these fruits per day, in combination.

In Part 1, Treatments A and B will be administered in the fed state. Participants 
will fast overnight for at least 10 hours prior to dosing and will receive a 
moderate fat meal 30 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.

In Part 2, Treatments C and E will be administered in the fed state. Participants 
will fast overnight for at least 10 hours prior to dosing and will receive a 
moderate fat (Treatment C) or high fat (Treatment E) meal 30 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 D will be administered in the fasted state. Participants will 
fast overnight for at least 10 hours prior to dosing and until 4 hours after dosing.

No water is allowed from 1 hour prior to dosing until 1 hour after dosing except 
for the glass of water needed to administer the study intervention (e.g., 240 mL). 
Water is allowed ad libitum at all other times.

A standard lunch will be provided 4 hours after dosing. A standard dinner will 
be served approximately 10 hours after dosing. The food content of meals must 
be identical on serial PK sampling days (e.g., Day 1 of each period).

The moderate fat meal will contain about 600 calories with approximately 30% 
of the calories coming from fat. The high fat meal will contain about 800 to 
1000 calories with approximately 50% of the calories coming from fat (DHHS, 
2002).
 
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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 sample.

Participants will abstain from alcohol for 48 hours before the start of dosing
until after collection of the final PK sample. 

Use of tobacco- and nicotine-containing products will not be allowed from 
3 months prior to Screening until after the final visit.

Participants must have a negative drug test at Screening and Day –1 and must
abstain from recreational drug use from Screening until after the final 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, any protocol deviations, and any 
SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
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.
 
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6.1.
Study Interventions Administered
Intervention Name
GSK3640254
GSK3640254
Type 
drug
drug
Dose Formulation
tablet 
capsule 
Unit Dose Strength(s)
100 mg
100 mg 
Dosage Level(s)
200 mg, single dose
200 mg, single dose
Route of 
Administration
oral
oral
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
Labeling
Provided in high-density 
polyethylene bottles. Each bottle 
will be labeled as required per 
country requirement.
Provided in high-density 
polyethylene bottles. Each bottle 
will be labeled as required per 
country requirement.
IMP = investigational medicinal product; NIMP = non-investigational medicinal product
6.2.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM).
5.
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.
6.
A Material Safety Data Sheet/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 VH/GSK.
 
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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. Study participants will be randomly assigned to a treatment 
sequence in accordance with the randomization schedule generated by PPD prior to the 
start of the study and using validated software.
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site 
staff. 

When participants are dosed at the site, they will receive study intervention 
directly from the investigator or designee, under medical supervision. The date 
and time of each dose administered in the clinic will be recorded in the source 
documents. The dose of study intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. Study site personnel will 
examine each participant’s mouth to ensure that the study intervention was 
ingested.
6.5.
Concomitant Therapy
Acetaminophen/paracetamol at doses of 2 grams/day and topical hydrocortisone cream 
1% are permitted for use any time during the study and their use should be documented in 
the case report form (CRF). Other medications are not permitted without prior discussion 
with the VH/GSK medical monitor.
6.6.
Dose Modification
Not applicable.
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment from VH/GSK, or with 
GSK3640254, after the completion of the study because only healthy participants are 
eligible for study participation.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety. See the SoA (Section 1.3) for data to be 
collected at the time of discontinuation of study intervention.
 
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7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the Food and Drug 
Administration premarketing clinical liver safety guidance: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf).
Discontinuation of study intervention for abnormal liver tests is required when a 
participant has an ALT ≥3 × ULN or if the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Details of liver safety follow-up procedures are described 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 same correction formula (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 ECG taken on Day –1 will be a single reading to confirm eligibility. In each 
study period, the Day 1 pre-dose timepoint will have triplicate averaged QTcF
(over a brief approximately 5 to 10 minute recording period). This pre-dose 
triplicate averaged QTcF value will serve as the baseline for the applicable study 
period.

A randomized participant that develops an on-treatment QTcF >500 ms or an 
increase from Baseline QTcF >60 ms should have two repeat unscheduled ECGs 
within 10 minutes. Using these triplicate ECGs, if the average QTcF >500 ms or 
an increase from Baseline QTcF >60 ms, the participant will be withdrawn from 
the study. Finally, this participant should have repeated unscheduled ECGs until 
their QTcF measurement returns to their original averaged QTcF value at 
Day --1.
See the SoA (Section 1.3) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.1.3.
Columbia-Suicide Severity Rating Scale Criteria
Emergence of any positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered C-SSRS during the treatment phase of the 
study will be cause for discontinuation of study intervention and the investigator will 
arrange for urgent specialist psychiatric evaluation and management.
 
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Refer to the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.4.
Individual Participant Laboratory Abnormality and Adverse Event 
Stopping Criteria Participant Discontinuation/Withdrawal from 
the Study
Investigators should make every effort to have a discussion with the medical monitor 
before the next dose to help assess if the study intervention should be stopped. 

Any clinically significant AE deemed to require discontinuation of study 
intervention

Any Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement 

Any allergic or hypersensitivity reactions to either formulation

Any Grade 3 or higher psychiatric AE

New onset suicidal ideation

Any Grade 3 or higher AE related to study intervention

Any Grade 4 AE or laboratory abnormalities (with the exception of an 
asymptomatic Grade 4 cholesterol or triglyceride)

Grade 4 CPK increase in the absence of a clinically reasonable explanation
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, 
behavioral, compliance, or administrative reasons. This is expected to be 
uncommon.

A participant who is withdrawn from the study for any reason related to safety 
(listed in Section 7.1.4 or otherwise) will be continued to be followed to assess 
the outcome of the safety event that triggered discontinuation of study 
intervention.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.
 
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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
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 4.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All Screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
Screening log to record details of all participants screened and to confirm 
eligibility or record reasons for Screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be 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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
The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, GI, and neurological systems. Height and weight 
will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed in the semi-recumbent 
position with a completely automated device. Manual techniques will be used 
only if an automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions 
(e.g., television, cell phones).

At each time point at which triplicate measurements are required, 3 consecutive 
blood pressure and pulse readings will be recorded at intervals of at least 
1 minute. Each measurement will be recorded in the CRF.

When vital signs are scheduled at the same time as blood collections for 
laboratory tests, vital signs are to be taken first.
8.2.3.
Electrocardiograms

Twelve-lead ECGs will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. Refer 
to Section 7.1.2 for QTcF withdrawal criteria and additional QTcF readings that 
may be necessary.
 
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
Twelve-lead ECGs will be performed with the participant in a supine position 
after a rest of at least 10 minutes.

At each time point at which triplicate ECGs are required, 3 individual ECG
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed over a brief 
(e.g., 5 to 10 minutes) recording period. Each measurement will be recorded in 
the CRF.
8.2.4.
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 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
intervention should be repeated until the values return to normal or Baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor.

If such values do not return to normal/Baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms
GSK3640254 is not a central nervous system active drug nor is it being developed for a 
neurologic or psychiatric condition. However, given the risk of suicidal ideation 
identified with previous MI GSK3532795, all participants will undergo screening using 
the C-SSRS administered by a clinician (or qualified designee); any positive (abnormal) 
response confirmed by the investigator, will exclude them from participating. A repeat 
assessment will be done during the treatment phase of the study. In case of positive 
(abnormal) response confirmed by the investigator, the participant will discontinue from 
the trial and the investigator will arrange for urgent specialist psychiatric evaluation and 
management.
As described in Section 7.1.4, new onset suicidal ideation at any time will result in 
immediate discontinuation from the trial and the investigator will arrange for urgent 
specialist psychiatric evaluation and management.
 
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The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia-Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behavior, 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.
Emergent non-suicidal psychiatric AE evaluation and management:

Any Grade 1 or 2 psychiatric AE: A Grade 1 or 2 psychiatric AE may result in 
additional unscheduled visits (in-clinic or at home) as clinically indicated. This 
may include a more in-depth assessment of AE through interview, additional 
unscheduled clinical labs, and/or imaging. Psychiatric consultation may be 
required at the discretion of the investigator. Any pharmacotherapy should be 
discussed with the medical monitor.

Any Grade 3 or 4 psychiatric AE: As described in Section 7.1.4, a Grade 3 or 4 
psychiatric AE will result in discontinuation from the trial and emergency 
psychiatric evaluation (including potential hospitalization and pharmacotherapy 
as indicated).
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan
Preclinical toxicology studies in rats and dogs have suggested a potential for GI-related 
toxicity with GSK3640254. This section provides general guidance to the investigator on 
the evaluation and management of primarily upper GI symptoms (Table 1). The 
investigator may contact the VH/GSK Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the study.
Table 1
Gastrointestinal Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of 
proper evaluation and management. The following are potential 
manifestations of some GI clinical syndromes that may occur (possibly in 
combination) during the clinical study. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and 
whether it is intraperitoneal, extraperitoneal, medication related, infection related, 
or due to a metabolic disorder (Hasler, 2012). Medications can cause nausea 
and vomiting acutely. 
Dyspepsia
The investigator should identify the presence of red flags (odynophagia, 
unexplained weight loss, recurrent vomiting, GI bleeding, jaundice, palpable 
mass or adenopathy, or family history of GI malignancy). Symptoms of 
dyspepsia could include early satiety, bloating, or belching. Additionally, atypical 
symptoms of dyspepsia could include: pharyngitis, asthma, bronchitis, 
hoarseness, chest pain, or abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the 
clinical study are available elsewhere (Rome Foundation, 2019).
 
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PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the 
history (Hasler, 2012). Acutely, the investigator may assess for signs of 
intravascular volume depletion (e.g., orthostasis) and/or aspiration of 
vomitus as appropriate. Abdominal tenderness and guarding may indicate 
inflammation. The presence of fecal blood can indicate mucosal damage 
(e.g., from an ulcer). Complete evaluation of dyspepsia should include an 
oral examination (poor dentition or pharyngeal erythema) and lungs for 
wheezing. 
DIAGNOSTIC 
EVALUATION AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a participant with upper GI 
symptoms is to quickly arrive at a final diagnosis without exposing the 
participant to unnecessary (invasive) testing; investigators should 
exercise good clinical judgment in this regard (Soll, 2009). A major goal of 
therapy is directed at correcting the underlying identifiable medical or 
surgical abnormalities. Consultation (e.g., gastroenterologist) is 
recommended as clinically indicated.
Grade 1 symptoms
Participants may be treated symptomatically. If participants develop dyspepsia 
alone, generally only limited and direct diagnostic testing should be performed. If 
the participant has dyspepsia they should limit alcohol, caffeine, chocolate, 
tobacco, and eating directly before bedtime. 
Grade 2 symptoms
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

Serum chemistries and assessment of hemoglobin if not recently performed 

Testing for Helicobacter pylori

Polymerase chain reaction for viruses (e.g., cytomegalovirus)
For participants who are infected with H. pylori, discontinuation from the study is 
necessary. Management should be targeted at addressing the underlying 
pathology.
Grade 3 symptoms 1
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2

A barium swallow 

Computed tomography scan to identify GI inflammation 

Upper endoscopy with biopsy as indicated (e.g., mucosal injury or the 
presence of red flags)
Management should be targeted at addressing the underlying pathology.
Grade 4 symptoms 1
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series
Initial management can include correction of hemodynamic and electrolyte 
abnormalities as clinically indicated. After stabilization, management should be 
targeted at addressing the underlying pathology.
GI = gastrointestinal. 
1
A Grade 4 or related Grade 3 AE: The Investigator will discontinue the participant from the study and perform an 
evaluation/management plan incorporating element above.
 
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8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 6. As described in 
Appendix 6, intensity of AEs (and laboratory abnormalities) will be graded using the 
most recent version of the Division of AIDS (DAIDS) grading table at the time of the last 
participant last visit. While the study population will consist of HIV-1 seronegative 
healthy participants, the DAIDS criteria will be used in later phase clinical studies 
(Phase 2a and beyond); additionally, the DAIDS criteria have a more conservative 
grading scale relative to other scales (e.g., Common Terminology Criteria
for Adverse Events [CTCAE] v 5.0). 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 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the end of the study 
at the time points specified in the SoA (Section 1.3).

All AEs will be collected from the start of intervention until the end of the study 
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be considered medical history, not an AE, and 
will be recorded in the source documents.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 6. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6.

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.
 
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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 6.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the CIB and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start 
of study intervention and through the end of pregnancy (termination or 
delivery).

If a pregnancy is reported, the investigator should inform VH/GSK within 
24 hours of learning of the pregnancy.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Adverse Events of Special Interest
Adverse events of special interest include all AEs classified in the cardiovascular (per 
MedDRA) system organ class, seizure, and syncope. Additional AEs of special interest
within other SOC (e.g., GI, Neurologic, and Psychiatric) may be defined in the Reporting 
and Analysis Plan.
 
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8.4.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than the planned dose within a 24-hour 
time period (±2 hours) will be considered an overdose.
VH/GSK does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat an 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 
GSK3640254 can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis immediately and through 7 days after 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 or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3640254 as specified in the SoA (Section 1.3). 

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 and handling of biological samples will be 
provided by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the PK of GSK3640254. Samples collected for 
analyses of GSK3640254 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.

Once the plasma has been analyzed for GSK3640254, any remaining plasma 
may be analyzed for other compound-related metabolites and the results 
reported under a separate protocol.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
A 6-mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
 
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optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 7 for information regarding genetic research. Details on processes for 
collection, shipment, and destruction of these samples can be found in the SRM.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There is no formal hypothesis that will be statistically tested in this study, the sample size 
is not selected based on statistical considerations but was determined using feasibility.  
For Part 1, a total of approximately 18 participants will be enrolled to ensure that 
14 evaluable subjects complete Part 1. For Part 2, a total of approximately 21 participants
will be enrolled to ensure that 16 evaluable subjects complete Part 2.
9.2.
Sample Size Determination
9.2.1.
Sample Size Assumptions
Based on the results from previous PK studies for GSK3640254 (GSK Studies 207187 
and 208131) the intra-subject coefficient of variability (CVw) ranged from 17% to 38% 
and 13% to 31%, respectively for AUC(0-τ) and Cmax, respectively. For recent PK 
Study 209712 the CVw was 7.8% and 11.5%, for AUC(0-τ) and Cmax, respectively. 
Therefore, it is decided that 38% would be a conservative estimate on which the sample 
size calculation is based.  
Administration of GSK3640254 mesylate salt tablet formulation may change the 
exposure to GSK3640254 from the capsule formulation; therefore, a range for point 
estimates (PEs) of 0.9, 1.0, and 1.1 was explored.
Administration of GSK3640254 with a high fat meal compared to fasting is expected to 
increase the exposure to GSK3640254; therefore, a range for PE of 1.0, 1.1, and 1.2 was
explored.
 
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For GSK3640254, with a sample size of 14 evaluable subjects in Part 1 and a sample size 
of 16 evaluable subjects in Part 2, it is estimated that the precision (i.e. half-width of the 
90% CI on the log and ratio scales), and CI on the original scale for each PE will be:
Comparison
CVw (%)
Half-Width 
(log scale)
Half-Width 
(original 
scale)
Point Estimate
90% CI
GSK3640254 
tablet to capsule
38
0.246
0.279
0.9
(0.704, 1.151)
1.0
(0.782, 1.279)
1.1
(0.860, 1.407)
GSK3640254 
high fat to 
fasted
38
0.236
0.266
1.0
(0.797, 1.255)
1.1
(0.877, 1.380)
1.2
(0.956, 1.506)
9.2.2.
Sample Size Sensitivity
For a sensitivity analysis, assuming a range of within-subject variability, a sample size of 
14 evaluable subjects for Part 1 and a sample size of 16 evaluable subjects for Part 2, it is 
estimated that the precision (i.e. half-width of the 90% CI on the log and ratio scale), and 
CI on the original scale for each PE will be:
Comparison
CVw (%)
Half-Width 
(log scale)
Half-Width 
(original 
scale)
Point Estimate
90% CI
Tablet to 
capsule
10
0.067
0.069
0.9
(0.842, 0.962)
1.0
(0.935, 1.069)
1.1
(1.029, 1.176)
20
0.133
0.142
0.9
(0.788, 1.028)
1.0
(0.875, 1.142)
1.1
(0.963, 1.256)
30
0.196
0.217
0.9
(0.740, 1.095)
1.0
(0.822, 1.217)
1.1
(0.904, 1.338)
40
0.258
0.294
0.9
(0.695, 1.165)
1.0
(0.773, 1.294)
1.1
(0.850, 1.424)
 
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Comparison
CVw (%)
Half-Width 
(log scale)
Half-Width 
(original 
scale)
Point Estimate
90% CI
Fasted to fed
10
0.064
0.066
1.0
(0.940, 1.064)
1.1
(1.034, 1.170)
1.2
(1.128, 1.277)
20
0.127
0.135
1.0
(0.884, 1.131)
1.1
(0.973, 1.244)
1.2
(1.061, 1.357)
30
0.189
0.208
1.0
(0.834, 1.200)
1.1
(0.917, 1.320)
1.2
(1.000, 1.440)
40
0.248
0.281
1.0
(0.787, 1.270)
1.1
(0.866, 1.397)
1.2
(0.945, 1.524)
In Part 1, approximately 18 participants will be treated to ensure that 14 evaluable 
participants complete the study. In Part 2, approximately 21 participants will be treated to 
ensure that 16 evaluable participants complete the study. If participants prematurely 
discontinue the study, additional participants may be randomized after consultation with 
the sponsor to ensure that the required number of evaluable participants complete the 
study.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
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Population
Description
Screened
All participants who sign the ICF.
Randomized
All participants who are randomly assigned to a treatment 
sequence.
Safety
All participants who receive at least 1 dose of study medication. 
This population will be used for all demographic and safety 
summaries.
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 PK 
concentration listings.
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 listings, PK concentration and parameter summary 
tables, statistical analysis tables, and plotting of the PK 
concentration-time data.
9.4.
Statistical Analyses
9.4.1.
Pharmacokinetic Analyses
Plasma GSK3640254 concentration-time data will be analyzed by PPD, under the 
oversight of Clinical Pharmacology Modeling & Simulation department within GSK, 
using noncompartmental methods with Phoenix WinNonlin Version 8.0 or higher. 
Statistical analysis will be performed by PPD, under the oversight of Clinical Statistics, 
GSK. Calculations will be based on the actual sampling times recorded during the study.
 
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Endpoint
Statistical Analysis Methods
Primary

The primary endpoints of this study are PK-related. The analysis for the 
primary PK endpoints will be performed for the PK Parameter 
Population. Plasma concentrations of GSK3640254 will be subjected to 
PK analyses using noncompartmental methods.

Based on the individual concentration-time data the following primary 
plasma PK parameters will be estimated:
o
AUC(0-), AUC(0-t), Cmax, and Tmax 

Analysis will be performed to compare the relative BA of a tablet 
formulation of GSK3640254 with the capsule formulation, as appropriate. 
Analyses will be performed on the natural logarithms of AUC(0-), 
AUC(0-t), and Cmax using linear mixed-effect models with treatment, 
period, and sequence as fixed effects and participant as a random effect. 
Effects will be estimated, and CIs will be constructed for the following 
treatment comparison:
o
Treatment B (test) versus Treatment A (reference)
Point estimates and 90% CIs for treatment differences on the log scale 
derived from the model will be exponentiated to obtain estimates for 
geometric mean ratios and CIs on the original scale.

The effect of food (moderate or high fat meal) on the PK of the tablet 
formulation of GSK3640254 will be similarly analyzed for the following 
treatment comparisons:
o
Treatment C (test) versus Treatment D (reference)
o
Treatment E (test) versus Treatment D (reference)

Non-parametric analysis will be performed to compare the Tmax of a 
tablet formulation of GSK3640254 with the capsule formulation, as 
appropriate. The Hodges-Lehmann estimate will be used to produce the 
median, median difference, and 90% CIs for the following comparison:
o
Treatment B (test) versus Treatment A (reference)
A p-value will be generated by the Wilcoxon signed-rank test.

The effect of food (moderate or high fat meal) on the Tmax of the tablet 
formulation of GSK3640254 will be similarly analyzed for the following 
comparisons:
o
Treatment C (test) versus Treatment D (reference)
o
Treatment E (test) versus Treatment D (reference)

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma 
GSK3640254 primary PK parameter values will be summarized by 
treatment.
 
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Endpoint
Statistical Analysis Methods
Secondary

Based on the individual concentration-actual time data the following 
secondary plasma PK parameters will be estimated:
o
tlag, t1/2, CL/F, and Vz/F

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma 
GSK3640254 secondary PK parameter values will be summarized by 
treatment. 

Summary statistics (arithmetic mean, median, standard deviation, 
minimum, maximum, and coefficient of variation) for plasma 
GSK3640254 PK concentrations will be summarized by treatment using 
the PK Concentration Population.
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. No formal statistical analysis 
of the safety data will be conducted.
The details of the statistical analyses of safety data will be provided in the reporting and 
analysis plan.
9.4.3.
Other Analyses
Not applicable.
9.5.
Interim Analyses
After completion of the study Part 1, preliminary PK data based on nominal time will be 
analyzed by PPD pharmacokinetics as soon as PK data are available, the decision will be 
used for the selection of formulations to proceed with in future Phase II clinical trials. 
9.6.
Data Monitoring Committee
Not applicable.
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate transaminase
AUC
Area under the plasma concentration-time curve
AUC(0-)
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity
AUC(0-t)
Area under the plasma concentration-time curve from time zero to time t
AUC(0-τ)
AUC from time 0 to the end of the dosing interval
BA
Bioavailability
BMS
Bristol-Myers Squibb
bpm
Beats per minute
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
CL/F
Apparent oral clearance
Cmax
Maximum observed concentration 
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase
CRF
Case report form
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CVw
Intra-subject coefficient of variability
DAIDS
Division of AIDS
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram 
FSH
Follicle-stimulating hormone
FTIH
First time in human
g
Grams
GCP
Good Clinical Practice
GI
Gastrointestinal
 
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GSK
GlaxoSmithKline 
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HRT
Hormonal replacement therapy
ICF
Informed consent form 
ICH
International Council for Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee 
IMP
Investigational medicinal product
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board 
IU/L
International units per liter
kg
Kilograms
kg/m2
Kilograms per square meter
lbs
Pounds
MAD
Multiple-ascending dose
mg
Milligrams
mg/kg/day
Milligrams per kilogram per day
MI
Maturation inhibitor
mL
Milliliter
mm
Millimeter
ms
Milliseconds
ng/mL
Nanograms per milliliter
NIMP
Non-investigational medicinal product
PE
Point estimate
PK
Pharmacokinetic(s)
QD
Once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using the Fridericia formula
RNA
Ribonucleic acid
SAD
Single-ascending dose
 
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SAE
Serious adverse event 
SoA
Schedule of activities
SRM
Study Reference Manual 
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Apparent terminal phase half-life
tlag
Lag time for absorption
Tmax
Time of maximum observed concentration 
TQT
Thorough QT
ULN
Upper limit of normal 
VH
ViiV Healthcare
Vz/F
Apparent volume of distribution
WOCBP
Woman of childbearing potential 
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
NONE
DAIDS
Phoenix WinNonlin
 
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 2 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.

Pregnancy Testing
o
Refer to Section 5.1 Inclusion Criteria for Screening pregnancy criteria.
o
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the time points indicated in the SoA (Section 1.3).
o
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study.
Table 2
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Red blood cell indices:
White blood cell count with 
differential:
Red Blood Cell Count
Mean corpuscular volume
Neutrophils
Hemoglobin
Mean corpuscular hemoglobin 
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Absolute neutrophil count
Clinical Chemistry 1
Blood urea nitrogen
Carbon dioxide
Total protein
Creatinine
Aspartate aminotransferase
Albumin
Glucose (fasting)
Alanine aminotransferase
Globulin
Potassium
Gamma-glutamyl transferase
Anion gap
Sodium
Total and direct bilirubin
Alkaline phosphatase
Calcium
Lactate dehydrogenase
Uric acid
Chloride
Total cholesterol
Creatine phosphokinase
Phosphorus
Triglycerides
Serum lipase
Serum amylase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrites, and 
leukocyte esterase by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is abnormal)
 
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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serology: HIV-1 and -2 antigen/antibody immunoassay, hepatitis B surface 
antigen, hepatitis C antibody

Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Pregnancy 2
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 ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).
2
Local serum testing will be standard for the protocol.
 
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10.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
10.3.1.
Definitions
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
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

Documented bilateral tubal ligation
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Müllerian 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 1 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-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 enrollment.
 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE THE FOLLOWING:

Highly Effective Methodsb That Have Low User Dependency: Failure rate of <1% per year 
when used consistently and correctly.

Non hormonal Intrauterine device

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.

For the 28 days after study exit, women may resume oral hormonal contraceptives but 
double barrier methods (a combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide) must be used in addition.

Highly Effective Methodsb That Are User Dependent: Failure rate of <1% per year when 
used consistently and correctly.

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.
Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception.
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.
10.3.2.
Collection of Pregnancy Information
Female participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to VH/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 VH/GSK. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. 
 
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
Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
VH/GSK as described in Appendix 6. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
intervention or be withdrawn from the study.
 
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10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations
10.4.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:
o
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, CIB, 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 IRB/IEC 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:
o
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/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations
10.4.2.
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.
10.4.3.
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. 
 
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
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 Code of Federal Regulations 
Part 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.
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK3640254 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have the GSK3640254 approved 
for medical use or approved for payment coverage.
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box.
10.4.4.
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 who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
 
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10.4.5.
Committees Structure
Not applicable.
10.4.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
VH/GSK site or other mutually-agreeable location.

VH/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.

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 VH/GSK Policy.

VH/GSK intend to make anonymized patient-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.
10.4.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).
 
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
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 25 years from the issue of the final 
clinical study report/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the 
sponsor. 
10.4.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic CRF that are transcribed 
from source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
10.4.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first participant screened and will be the study start 
date.
VH/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 VH/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
 
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
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up.
10.4.10.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Liver Chemistry Stopping Criteria
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubin1,2 2 × ULN (>35% direct bilirubin) or 
international normalized ratio (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 VH/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, stabilize, or return to within Baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN 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 twice weekly until liver 
chemistries resolve, stabilize or return to 
within Baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminase values show downward trend

Obtain blood sample for PK analysis, 
obtained within 48 hours of last dose4 

Serum CPK and lactate dehydrogenase.

Fractionate bilirubin, if total bilirubin 
≥2 × ULN

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
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
 
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Liver Chemistry Stopping Criteria
perform liver event follow-up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within Baseline
total immunoglobulin G or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]. NOTE: 
not required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3 × ULN and bilirubin 2 × ULN. 
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 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN 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 (IgM) antibody, hepatitis B surface antigen, and hepatitis B core antibody; 
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.
Pharmacokinetic 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: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.6.1.
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 sign 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.

Situations in which an untoward medical occurrence did not occur (social and/or 
 
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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.
10.6.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AE. If 
a complication prolongs hospitalization or 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 or significant 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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
 
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reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.6.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to VH/GSK in lieu of completion of the VH/GSK AE/SAE CRF 
page.

There may be instances when copies of medical records for certain cases are 
requested by VH/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 VH/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 using the DAIDS grading table Version 2.1, July 2017 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) and assign it to 
1 of the following categories: 

Mild: no or minimal interference with usual social and functional activities 

Moderate: greater than minimal interference with usual social and functional 
activities

Severe: inability to perform usual social and functional 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.

Life Threatening: inability to perform basic self-care functions
 
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An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the CIB 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 VH/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 VH/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 VH/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 VH/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 VH/GSK within 24 hours of 
receipt of the information.
 
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10.6.4.
Reporting of SAE to VH/GSK
SAE Reporting to VH/GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to VH/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 electronic CRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to study intervention/study participation (causality) 
within 72 hours of SAE entry into the electronic CRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to VH/GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.
 
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10.7.
Appendix 7: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis.

DNA samples will be used for research related to GSK3640254 or HIV and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to GSK3640254 or HIV MIs and HIV. Genetic research 
may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as 
appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to GSK3640254 or study interventions of this 
class. The results of genetic analyses may be reported in the clinical study report 
or in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3640254 (or study 
interventions of this class) or HIV continues but no longer than 15 years after 
the last participant last visit or other period as per local requirements.
 
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10.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
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11.
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