Conditions: HIV Infections
Keywords: Healthy participants GSK3640254 Human immunodeficiency virus (HIV) Safety
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This is an open-label, single-dose, four-period, four sequential, and crossover study conducted to assess the relative bioavailability of GSK3640254 mesylate tablets and GSK3640254 mesylate capsules (in the presence of a moderate fat meal). This study will also evaluate the effect of food (fasted, moderate fat meal, and high fat meal) on the pharmacokinetics of GSK3640254 mesylate tablet formulation. Participants will be randomized to receive a single dose of GSK3640254 200 milligram (mg) capsules under moderate fat conditions and GSK3640254 200 mg tablets under moderate fat, fasted and high fat conditions in each treatment period. Approximately 16 participants will be enrolled and the duration of the study will be approximately 54 days.

Detailed description:

Arms:
arm 1: Participants will receive a single dose of GSK3640254 200 mg (Treatment A- Reference), capsules, orally under moderate fat conditions on Day 1 in first intervention period; followed by GSK3640254 200 mg (Treatment B- Test), tablets, orally under moderate fat conditions on Day 1 in second intervention period; followed by GSK3640254 200 mg (Treatment C- Reference), tablets, orally under fasted conditions on Day 1 in third intervention period; further followed by GSK3640254 200 mg (Treatment D- Test), tablets, orally under high fat conditions on Day 1 in fourth intervention period. There will be at least 7 days wash out period between each dose of study intervention. arm 2: Participants will receive a single dose of GSK3640254 200 mg (Treatment B- Test), tablets, orally under moderate fat conditions on Day 1 in first intervention period; followed by GSK3640254 200 mg (Treatment A- Reference), capsules, orally under moderate fat conditions on Day 1 in second intervention period; followed by GSK3640254 200 mg (Treatment D- Test), tablets, orally under high fat conditions on Day 1 in third intervention period; further followed by GSK3640254 200 mg (Treatment C- Reference), tablets, orally under fasted conditions on Day 1 in fourth intervention period. There will be at least 7 days wash out period between each dose of study intervention. arm 3: Participants will receive a single dose of GSK3640254 200 mg (Treatment C- Reference), tablets, orally under fasted conditions on Day 1 in first intervention period; followed by GSK3640254 200 mg (Treatment D- Test), tablets, orally under high fat conditions on Day 1 in second intervention period; followed by GSK3640254 200 mg (Treatment A- Reference), capsules, orally under moderate fat conditions on Day 1 in third intervention period; further followed by GSK3640254 200 mg (Treatment B- Test), tablets, orally under moderate fat conditions on Day 1 in first intervention period. There will be at least 7 days wash out period between each dose of study intervention. arm 4: Participants will receive a single dose of GSK3640254 200 mg (Treatment D- Test), tablets, orally under high fat conditions on Day 1 in first intervention period; followed by GSK3640254 200 mg (Treatment C- Reference), tablets, orally under fasted conditions on Day 1 in second intervention period; followed by GSK3640254 200 mg (Treatment B- Test), tablets, orally under moderate fat conditions on Day 1 in third intervention period; further followed by GSK3640254 200 mg (Treatment A- Reference), capsules, orally under moderate fat conditions on Day 1 in first intervention period. There will be at least 7 days wash out period between each dose of study intervention.

Interventions: intervention 1: GSK3640254 Tablet intervention 2: GSK3640254 Capsule
Intervention descriptions: intervention 1: GSK3640254 tablets will contain mesylate salt with a unit dose of 100 mg (2x100 mg) and will be administered orally. intervention 2: GSK3640254 capsules will contain mesylate salt with a unit dose of 100 mg (2x100 mg) and will be administered orally.

Protocol document:
Prot_000.pdf: 
2018N383392_00
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TITLE PAGE
Protocol Title: A Randomized, Open-Label, Single Dose, Four-Period 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: 209713
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
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: 30-AUG-2019
Copyright 2019 the ViiV Healthcare group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited.
PPD


PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Background ................................................................................................13
2.2.1.
Background and Key Safety Data With a Prior Maturation 
Inhibitor........................................................................................13
2.2.2.
Preliminary Safety and Pharmacokinetic Data in 
Study 207187 ..............................................................................14
2.2.3.
Preliminary Safety and Pharmacokinetic Data in 
Study 208131 ..............................................................................15
2.3.
Benefit/Risk Assessment ............................................................................16
2.3.1.
Risk Assessment .........................................................................17
2.3.2.
Benefit Assessment.....................................................................20
2.3.3.
Overall Benefit: Risk Conclusion..................................................20
3.
OBJECTIVES AND ENDPOINTS...........................................................................20
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Scientific Rationale for Study Design ..........................................................21
4.3.
Justification for Dose ..................................................................................22
4.4.
End-of-Study Definition...............................................................................22
5.
STUDY POPULATION...........................................................................................22
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................24
5.3.
Lifestyle Considerations..............................................................................26
5.3.1.
Meals and Dietary Restrictions ....................................................26
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................27
5.3.3.
Activity .........................................................................................27
5.4.
Screen Failures...........................................................................................27
6.
STUDY INTERVENTION........................................................................................27
6.1.
Study Interventions Administered ...............................................................28
6.2.
Preparation/Handling/Storage/Accountability..............................................28
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................29
6.4.
Study Intervention Compliance ...................................................................29
6.5.
Concomitant Therapy..................................................................................29
6.6.
Dose Modification .......................................................................................29
6.7.
Intervention After the End of the Study .......................................................29
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................29
7.1.
Discontinuation of Study Intervention..........................................................29
7.1.1.
Liver Chemistry Stopping Criteria ................................................30


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7.1.1.1.
Study Intervention Restart or Rechallenge After 
Liver Stopping Criteria Met .........................................30
7.1.2.
QTc Stopping Criteria ..................................................................30
7.1.3.
Columbia Suicide Severity Rating Scale Criteria..........................30
7.1.4.
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria................................................................31
7.2.
Participant Discontinuation/Withdrawal From the Study..............................31
7.3.
Lost to Follow-Up........................................................................................32
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................32
8.1.
Efficacy Assessments.................................................................................33
8.2.
Safety Assessments ...................................................................................33
8.2.1.
Physical Examinations.................................................................33
8.2.2.
Vital Signs....................................................................................33
8.2.3.
Electrocardiograms......................................................................33
8.2.4.
Clinical Safety Laboratory Assessments ......................................34
8.2.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms..................................................................34
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan.............35
8.3.
Adverse Events and Serious Adverse Events.............................................37
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................37
8.3.2.
Method of Detecting AEs and SAEs.............................................37
8.3.3.
Follow-up of AEs and SAEs.........................................................38
8.3.4.
Regulatory Reporting Requirements for SAEs .............................38
8.3.5.
Pregnancy ...................................................................................38
8.4.
Treatment of Overdose...............................................................................38
8.5.
Pharmacokinetics .......................................................................................39
8.6.
Pharmacodynamics ....................................................................................39
8.7.
Genetics .....................................................................................................39
8.8.
Biomarkers .................................................................................................40
8.9.
Medical Resource Utilization and Health Economics ..................................40
9.
STATISTICAL CONSIDERATIONS........................................................................40
9.1.
Statistical Hypotheses.................................................................................40
9.2.
Sample Size Determination ........................................................................40
9.2.1.
Sample Size Assumptions ...........................................................40
9.2.2.
Sample Size Sensitivity................................................................41
9.3.
Populations for Analyses ............................................................................42
9.4.
Statistical Analyses.....................................................................................42
9.4.1.
Pharmacokinetic Analyses...........................................................42
9.4.2.
Safety Analyses...........................................................................44
9.4.3.
Other Analyses ............................................................................44
9.5.
Interim Analyses .........................................................................................44
9.5.1.
Data Monitoring Committee (DMC)..............................................44
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................45
10.1.
Appendix 1: Abbreviations and Trademarks................................................45
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................48
10.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................50


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10.3.1.
Definitions....................................................................................50
10.3.1.
Collection of Pregnancy Information ............................................51
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................53
10.4.1.
Regulatory and Ethical Considerations ........................................53
10.4.2.
Financial Disclosure.....................................................................53
10.4.3.
Informed Consent Process ..........................................................53
10.4.4.
Data Protection............................................................................54
10.4.5.
Publication Policy.........................................................................54
10.4.6.
Dissemination of Clinical Study Data ...........................................55
10.4.7.
Data Quality Assurance ...............................................................55
10.4.8.
Source Documents ......................................................................56
10.4.9.
Study and Site Closure ................................................................56
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................57
10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................59
10.6.1.
Definition of AE............................................................................59
10.6.2.
Definition of SAE..........................................................................60
10.6.3.
Recording and Follow-Up of AE and SAE....................................61
10.6.4.
Reporting of SAE to VH/GSK.......................................................63
10.7.
Appendix 7: Genetics..................................................................................64
11. REFERENCES.......................................................................................................65


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Randomized, Open-Label, Single Dose, Four-Period 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 an open-label, single-dose, 4-period 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 clinical studies to date, 
including a Phase 2a 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, as compared to administration under fasting conditions. 
Objectives and Endpoints:
Objectives
Endpoints
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

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, randomized, open-label, single-dose, 4-period crossover study to 
compare the relative BA of a tablet formulation of GSK3640254 with the capsule 
formulation and to assess the effect of food on the PK of the tablet formulation in healthy 
participants.
The study will consist of a Screening period and 4 sequential treatment periods with a 
single dose of study intervention per treatment period.
For treatments administered in the fed state, participants will fast overnight for at least 
10 hours prior to dosing and will receive a moderate fat or high 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. For 
treatments administered in the fasted state, participants will fast overnight for at least 
10 hours prior to dosing and until 4 hours after dosing.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be collected prior to 
dosing (0 hour) on Day 1 and up to 96 hours postdose in Periods 1, 2, 3, and 4.
Safety and tolerability will be assessed by monitoring and recording of adverse events, 
clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram
results, and physical examination findings.
Study assessments will be performed as indicated in the Schedule of Activities
(Section 1.3). Study participants will be confined to the clinic from Day −1 until 
discharge on Day 5 of Period 4. 
Disclosure Statement: This is a crossover treatment study with 1 arm that has no 
masking.


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Number of Participants: Approximately 16 participants will be treated to ensure that 
12 evaluable participants complete the study. If participants prematurely discontinue the 
study, additional participants may be randomized after consultation with the sponsor to 
ensure that 12 evaluable participants complete the study.
Intervention Groups and Duration: Prior to dosing on Day 1 of Period 1, participants 
will be randomly assigned to 1 of 4 treatment sequences (ABCD, BADC, CDAB, or 
DCBA). Participants will receive each of the following treatments administered as 
1 treatment per period:

Treatment A: GSK3640254 200 mg (single dose given as 2 × 100-mg capsules) 
administered under moderate fat conditions (reference).

Treatment B: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under moderate fat conditions (test).

Treatment C: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under fasted conditions (reference).

Treatment D: GSK3640254 200 mg (single dose given as 2 × 100-mg 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. The duration of the study, 
including Screening, is approximately 54 days.
Data Monitoring Committee: No
1.2.
Schema
A summary of the overall study design is presented in Figure 1.
Figure 1
Study Design Schematic
Treatment A = GSK3640254 200 mg (capsules) administered under moderate fat conditions; 
Treatment B = GSK3640254 200 mg (tablets) administered under moderate fat conditions; 
Treatment C = GSK3640254 200 mg (tablets) administered under fasted conditions; 
Treatment D = GSK3640254 200 mg (tablets) administered under high fat conditions. 
1
Washout will be at least 7 days minus 4 hours.


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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
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
1
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
Procedure
Check-in
Periods 1, 2, and 3
Period 4 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 4.
Brief physical 
examination
X
D7 
(Period 2 
only)
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 predose on Day 1 
in Periods 1-4. Single blood pressure and 
pulse will be measured predose on other 
study days.
12-lead ECG
X
X
X
X
All ECGs on Day 1 in Periods 1-4 will be 
predose, postdose at 2 hours, and 
postdose at 4 hours. The predose ECGs 
in Periods 1-4 will be taken in triplicate. 
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.


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Procedure
Check-in
Periods 1, 2, and 3
Period 4 only
Notes
Day 
–1
Day
1
Washout
Day
1
Day
2
Days
3-4
Day
51
Day
2
Days 
3-5
Days 
6-7
Pregnancy test
X
X
Serum testing at Day -1
Columbia-Suicide 
Severity
Rating Scale 
X
D7
X
Genetic sample 
(optional)
X
Study intervention: 
GSK3640254 200 mg 
(capsule or tablet)
X
X
Participants will fast overnight for at least 
10 hours prior to dosing; be provided a 
moderate fat meal, a high fat meal, or no 
meal 30 minutes prior to dosing; and be 
provided standardized meals ≥4 hours 
postdose. See Section 4.1. 
Serial PK sampling
X
X
X
X
X
X
X
Blood collection 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 postdose 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 4 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 an open-label, single-dose, 4-period 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 clinical studies to date, 
including a Phase 2a 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, as compared to 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; (4) it has potential for improved 
gastrointestinal (GI) tolerability; and (5) it has a projected lower once-daily human dose. 
Summaries of the pre-clinical and clinical studies are included in the Clinical 
Investigator's Brochure (CIB) [GlaxoSmithKline (GSK) Document 
Number 2018N379610_00].
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 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 I 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 once daily (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.
Preliminary 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_00] 
and the Study Synopsis [GSK Document Number 2018N375461_00]. A concise 
summary of the data is presented below.
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 
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_00] and the Study 
Synopsis [GSK Document Number 2018N375461_00].
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, and diarrhea. There was no dose/AE relationship.


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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) 
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, a QTc using the Fridericia formula (QTcF) effect above 
10 ms could be excluded up to GSK3640254 plasma concentrations of approximately 
2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, the dose used in 
this study is 200 mg QD). Finally, there were no laboratory abnormality trends across 
doses that were clinically significant or associated with any symptoms.
Preliminary 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 a median time of maximum 
observed concentration (Tmax) observed between 3 to 4.5 hours after dosing with a 
moderate fat breakfast and slowly eliminated with a mean half-life ranging from 22 to 
26 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 preliminary 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 mean half-life ranged from approximately 22 to 
29 hours. Overall, there was a trend of a slightly less than dose-proportional increase in 
Cmax and AUC from time 0 to 24 hours after dosing (AUC[0-24]) from 50 to 320 mg. 
The exposure on Day 14 was, on average, 1.9- to 2.3-fold higher than that of Day 1 for 
Cmax and 2.2- to 2.6-fold higher than Day 1 for AUC(0-24). Detailed summary statistics 
are available in the Study Synopsis [GSK Document Number 2018N375461_00].
2.2.3.
Preliminary 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 
blinded preliminary 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.
Preliminary PK 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 
110% and 116% based on AUC from time zero extrapolated to infinity and Cmax, 
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, 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 
up to GSK3640254 plasma concentrations of approximately 2000 ng/mL (corresponding 
to doses approximately ≤200 mg QD; note, 200 mg QD is 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 (at Tmax once 
GSK3640254 attains steady state concentration), 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.
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_00).


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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 2.3, in the concentration-QTc analysis, a 
QTcF effect above 10 ms could be excluded up to 
GSK3640254 plasma concentrations of 
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 
Screening: Protocol exclusion criterion based on 
pre-existing GI pathology or Baseline GI 
signs/symptoms.
On-Treatment: Participants will undergo 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 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 subjects. The greatest 
incidences were in the GSK3640254 200 mg arms 
(Cohorts 5 and 7) but ultimately, no dose/AE 
relationship was apparent. One subject each in the 
GSK3640254 200 mg arm and blinded 320 mg arm 
reported nausea (mild in intensity), considered by 
the investigator in each case to be related to study 
drug.
continuous evaluation for AEs during their 
participation in the study; there will be individual 
clinical stopping criteria based upon intensity of 
treatment-emergent AEs. 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 
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 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 5 subjects (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 
subjects 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 subject 
from the blinded 320 mg arm who experienced 
lethargy which was considered related to study 
drug
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 
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 Studies 207187 and 208131, 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

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

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, randomized, open-label, single-dose, 4-period crossover study to 
compare the relative BA of a tablet formulation of GSK3640254 with the capsule


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formulation and to assess the effect of food on the PK of the tablet formulation in healthy 
participants.
The study will consist of a Screening period and 4 sequential treatment periods with a 
single dose of study intervention per treatment period. Prior to dosing on Day 1 of 
Period 1, participants will be randomly assigned to 1 of 4 treatment sequences (ABCD, 
BADC, CDAB, or DCBA). Participants will receive each of the following treatments 
administered as 1 treatment per period:

Treatment A: GSK3640254 200 mg (single dose given as 2 × 100-mg capsules) 
administered under moderate fat conditions (reference).

Treatment B: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under moderate fat conditions (test).

Treatment C: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under fasted conditions (reference).

Treatment D: GSK3640254 200 mg (single dose given as 2 × 100-mg 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. Treatments A, B, and D 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 (Treatments A and B) or high fat (Treatment D) 
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 C 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.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be collected prior to 
dosing (0 hour) on Day 1 and up to 96 hours postdose in Periods 1, 2, 3, and 4.
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). Study 
participants will be confined to the clinic from Day −1 until discharge on Day 5 of 
Period 4. The total duration of the study, including Screening, is approximately 54 days.
4.2.
Scientific Rationale for Study Design
This is an open-label, single-dose, 4-period 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. In addition, this study will investigate the effect of food on 
the PK of the GSK3640254 mesylate tablet formulation.


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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 clinical studies to date, including a 
Phase 2a 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, as compared to 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.
4.3.
Justification for Dose
The dose of 200 mg GSK3640254 was selected for this study as the maximum projected 
clinically therapeutic dose of GSK3640254 is 200 mg QD. 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.


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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.
4.
Male or female
a.
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.


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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), 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.
3.
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.
4.
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.
5.
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.
6.
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
7.
Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study intervention.
8.
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).
9.
Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.


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10. ALT >1.5 × upper limit of normal (ULN). A single repeat of ALT is allowed within 
a single Screening period to determine eligibility.
11. 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.
12. Any acute laboratory abnormality at Screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound.
13. 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.
14. 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
15. 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.)
16. Treatment with any vaccine within 30 days prior to receiving study intervention.
17. 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
18. 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).
19. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
Diagnostic Assessments
20. Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS.


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21. 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.
22. Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate 1
<45 or >100 bpm
<50 or >100 bpm
QTcF interval 2 (Fridericia’s)
>450 ms
>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.
Other Exclusions
23. 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.
24. Unable to refrain from tobacco or nicotine-containing products within 3 months prior 
to Screening.
25. 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 juice or 
one of these fruits per day, in combination.

Treatments A, B, and D will be administered in the fed state. The participants 
will fast overnight for at least 10 hours prior to dosing and will receive a 
moderate fat (Treatments A and B) or high fat (Treatment D) meal 30 minutes 
prior to dosing. Participants will eat this meal in 30 minutes or less. Dose 
administration will occur within 5 minutes of completion of meal consumption. 
Participants will not receive any further food until 4 hours after dosing on serial 
PK sampling days (e.g., Day 1 of Periods 1, 2, 3, and 4). The moderate fat meal 
will contain about 600 calories with approximately 30% of the calories coming 


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from fat. The high fat meal will contain about 800 to 1000 calories with 
approximately 50% of the calories coming from fat (DHHS, 2002).

Treatment C will be administered in the fasted state. The participants will fast 
overnight for at least 10 hours prior to dosing 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 Periods 1, 2, 3, and 4).
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, 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 labelled as required per 
country requirement.
Provided in high-density 
polyethylene bottles. Each bottle 
will be labelled 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 1 of
4 treatment sequences (ABCD, BADC, CDAB, or DCBA) 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 Baseline QTcF should be based on averaged QTcF values of triplicate 
ECGs obtained over a brief (e.g., 5-10 minute) recording period from the Day 
−1 ECG.

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.
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.


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7.1.4.
Individual Participant Laboratory Abnormality and Adverse Event 
Stopping Criteria
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 or both drugs

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, triglyceride, or CPK increase) 
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.

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.


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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.

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.


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
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.

Twelve-lead ECGs will be performed with the participant in a supine or 
semi-supine position after a rest of at least 10 minutes.


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
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.

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.
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 


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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 4.0). 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.
8.4.
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.


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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
Not applicable.
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 
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.


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See Appendix 7 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.
8.8.
Biomarkers
Not applicable.
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.
9.2.
Sample Size Determination
9.2.1.
Sample Size Assumptions
Based on the results from previous PK studies for GSK3640254 (GSK Study 207187 and 
208131) the intra-subject coefficient of variability (CVw) ranged from 17%-38% and 
13%-31%, respectively for AUC from time 0 to the end of the dosing interval (AUC0-τ) 
and Cmax. For recent PK study GSK 209712 the CVw were 7.8% and 11.5%, 
respectively for AUC(0-τ) and Cmax. 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 
estimate of 0.9, 1.0, and 1.1 were explored.
Administration of GSK3640254 with a high-fat meal compared to fasting is expected to 
increase the exposure to GSK3640254; therefore, a range for point estimate of 1.0, 1.1, 
and 1.2 were explored.
For GSK3640254, with a sample size of 12 evaluable participants, 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 point estimate will be:
Comparison
CVw 
(%)
Half-Width 
(log scale)
Half-Width 
(original 
scale)
Point 
Estimate
90% CI
GSK3640254 
tablet to 
capsule
38
0.269
0.309
0.9
(0.688, 1.178)
1.0
(0.764, 1.309)
1.1
(0.841, 1.440)


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Comparison
CVw 
(%)
Half-Width 
(log scale)
Half-Width 
(original 
scale)
Point 
Estimate
90% CI
GSK3640254 
high fat meal 
to fasting
38
0.269
0.309
1.0
(0.764, 1.309)
1.1
(0.841, 1.440)
1.2
(0.917, 1.570)
9.2.2.
Sample Size Sensitivity 
For a sensitivity analysis, assuming a range of within-participant variability, a sample 
size of 12 evaluable participants, 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 point estimate
will be:  
Comparison
CVw (%)
Half-Width 
(log scale)
Half-Width 
(original scale)
Point 
Estimate
90% CI
Tablet to 
capsule
or
high fat meal 
to fasting
10
0.073
0.076
0.9
(0.837, 0.968)
1.0
(0.930, 1.076)
1.1
(1.023, 1.183)
1.2
(1.116, 1.291)
20
0.145
0.156
0.9
(0.779, 1.040)
1.0
(0.865, 1.156)
1.1
(0.952, 1.272)
1.2
(1.038, 1.387)
30
0.215
0.240
0.9
(0.726, 1.116)
1.0
(0.807, 1.240)
1.1
(0.887, 1.364)
1.2
(0.968, 1.488)
40
0.283
0.327
0.9
(0.678, 1.194)
1.0
(0.754, 1.327)
1.1
(0.829, 1.460)
1.2
(0.904, 1.593)
Approximately 16 participants (4 per treatment sequence) will be treated to ensure that 
12 evaluable participants complete the study. If participants prematurely discontinue the 


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study, additional participants may be randomized after consultation with the sponsor to 
ensure that 12 evaluable participants complete the study.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants who sign the ICF.
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, summary tables, and plotting of 
concentration-time data.
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, summary tables, and statistical analysis 
tables.
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 6.4 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.
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:
AUC(0-∞), AUC(0-t), Cmax, and Tmax 


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Endpoint
Statistical Analysis Methods

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:
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:
Treatment B (test) versus Treatment C (reference)
Treatment D (test) versus Treatment C (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:
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:
Treatment B (test) versus Treatment C (reference)
Treatment D (test) versus Treatment C (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.
Secondary

Based on the individual concentration-actual time data the following 
secondary plasma PK parameters will be estimated:
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. 


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Endpoint
Statistical Analysis Methods

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
No interim analysis is planned.
9.5.1.
Data Monitoring Committee (DMC)
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
AUC
Area under the plasma concentration-time curve
AUC(0-24)
Area under the plasma concentration-time curve from time 0 to 24 hours 
after dosing
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
AST
Aspartate transaminase
BA
Bioavailability
BMS
Bristol-Myers Squibb
bpm
Beats per minute
CL/F
Apparent oral clearance
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
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


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GCP
Good Clinical Practice
GI
Gastrointestinal
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
IU/L
International units per liter
IRB
Institutional Review Board 
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
PK
Pharmacokinetic(s)
QD
Once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using the Fridericia formula
RNA
Ribonucleic acid


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SAD
Single-ascending dose
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
Refer to Section 5.1 Inclusion Criteria for Screening pregnancy criteria.
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the time points indicated in the SoA (Section 1.3).
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, nitrite, 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
Serum testing will be performed on Screening and on Day -1. At all other timepoints, local urine testing will be 
standard for the protocol unless serum testing is required by local regulation or IRB/IEC.


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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-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.


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CONTRACEPTIVESa ALLOWED DURING AND AFTER 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. The documentation on male sterility can come from the 
site personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner. 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.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) 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.
10.3.1.
Collection of Pregnancy Information
Female participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK 
within 24 hours of learning of a participant's pregnancy. 


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
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which 
will be forwarded to GSK. Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy 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:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

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:

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

Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.4.4.
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. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.4.5.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.


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
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.4.6.
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 intends to make anonymized patient-level data from this study 
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 study 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), 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. 


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
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 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 Closure
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

Discontinuation of further study intervention development


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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 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 


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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
microsomal antibodies, and quantitative 
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 signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 


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leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.6.2.
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 AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
Baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (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


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Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
1 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 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 


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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
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 1 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 


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postmortem 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.
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 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’s last visit or other period as per local requirements.


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11.
REFERENCES
Bristol-Myers Squibb Company Document Control Number 930109388. A randomized, 
double-blind, double-dummy, positive-controlled, crossover study to determine 
electrocardiographic effects of BMS-955176 in healthy subjects. Report Date: 
13 January 2017.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research (US). Guidance for Industry: Food-Effect 
Bioavailability and Fed Bioequivalence Studies. December 2002 [12 screens]. Available 
from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070241.pdf
GlaxoSmithKline Document Number 2016N302783_00. Clinical Study Report: A Phase 
2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy 
and Dose-response of BMS-955176/GSK3532795, Given on a Backbone of 
Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults – Week 24 Interim 
Analysis, 21 Jun 2017.
GlaxoSmithKline Document Number 2017N322200_00. A Phase 2b Randomized, 
Active-Controlled, Staged, Open-Label Trial to Investigate Safety and Efficacy of 
BMS-955176/GSK3532795 in Combination with Dolutegravir and Atazanavir (with or 
without Ritonavir) in Treatment-Experienced HIV-1 Infected Adults. 25 September 2018.
GlaxoSmithKline Document Number 2018N375461_00. Clinical Pharmacology 
Synopsis. A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in Healthy Participants. September 2018.
GlaxoSmithKline Document Number 2018N379610_00. GSK3640254 Investigator’s 
Brochure, Version 01. Effective Date: 04 Oct 2018.
Hasler WL. Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen - protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Disp. 2009;37(8):1779-84.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164(7):1035-43.
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal 
Disorders. Available: 
http://www.theromefoundation.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
18 Feb 2019.


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Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of 
Gastroenterology. 5th edition. 2009. Blackwell Publishing.

SAP_001.pdf: 
 
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Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for A Randomized, Open-Label, 
Single Dose, Four-Period 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 
Compound Number  : GSK3640254 
Effective Date  
: 15-Jan-2020 
 
Description: 
 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 209713. 
 
This RAP is intended to describe the full analyses required for the study.  
 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 4 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 4 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 4 
2.3. 
Study Design ................................................................................................ 6 
2.4. 
Statistical Hypotheses................................................................................... 6 
3. 
PLANNED ANALYSES ............................................................................................ 7 
3.1. 
Final Analyses .............................................................................................. 7 
4. 
ANALYSIS POPULATIONS ..................................................................................... 7 
4.1. 
Protocol Deviations ....................................................................................... 7 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ....................................................................................................... 9 
5.1. 
Study Treatment & Sub-group Display Descriptors ....................................... 9 
5.2. 
Baseline Definitions ...................................................................................... 9 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 10 
6. 
STUDY POPULATION ANALYSES ....................................................................... 11 
6.1. 
Overview of Planned Study Population Analyses ........................................ 11 
7. 
PHARMACOKINETIC ANALYSES ......................................................................... 12 
7.1. 
Primary Pharmacokinetic Analyses ............................................................. 12 
7.1.1. 
Endpoint / Variables ..................................................................... 12 
7.1.1.1. 
Drug Concentration Measures .................................... 12 
7.1.1.2. 
Derived Pharmacokinetic Parameters......................... 12 
7.1.2. 
Summary Measure ...................................................................... 12 
7.1.3. 
Population of Interest ................................................................... 12 
7.1.4. 
Statistical Analyses / Methods ..................................................... 13 
7.1.4.1. 
Statistical Methodology Specification .......................... 13 
7.2. 
Secondary Pharmacokinetic Analyses ........................................................ 14 
7.2.1. 
Endpoint / Variables ..................................................................... 14 
7.2.1.1. 
Drug Concentration Measures .................................... 14 
7.2.1.2. 
Derived Pharmacokinetic Parameters......................... 14 
7.2.2. 
Summary Measure ...................................................................... 15 
7.2.3. 
Population of Interest ................................................................... 15 
7.2.4. 
Statistical Analyses / Methods ..................................................... 15 
8. 
SAFETY ANALYSES ............................................................................................. 16 
8.1. 
Adverse Events Analyses ........................................................................... 16 
8.2. 
Clinical Laboratory Analyses ....................................................................... 16 
8.3. 
Adverse Events of Special Interest ............................................................. 16 
8.4. 
Other Safety Analyses ................................................................................ 17 
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9. 
REFERENCES ....................................................................................................... 18 
10. APPENDICES ........................................................................................................ 19 
10.1. 
Appendix 1: Schedule of Activities .............................................................. 19 
10.1.1. 
Protocol Defined Schedule of Events ........................................... 19 
10.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 22 
10.2.1. 
Study States for Lab, Electrocardiograms, and Vital Signs .......... 22 
10.2.1.1. Study Phases for Concomitant Medication ................. 22 
10.2.2. 
Treatment Emergent Flag for Adverse Events ............................. 23 
10.3. 
Appendix 3: Data Display Standards & Handling Conventions .................... 24 
10.3.1. 
Reporting Process ....................................................................... 24 
10.3.2. 
Reporting Standards .................................................................... 24 
10.3.3. 
Reporting Standards for Pharmacokinetics .................................. 25 
10.4. 
Appendix 4: Derived and Transformed Data ............................................... 27 
10.4.1. 
General ........................................................................................ 27 
10.4.2. 
Study Population .......................................................................... 27 
10.4.3. 
Safety .......................................................................................... 28 
10.5. 
Appendix 5: Reporting Standards for Missing Data ..................................... 29 
10.5.1. 
Premature Withdrawals ................................................................ 29 
10.5.2. 
Handling of Missing Data ............................................................. 29 
10.5.2.1. Handling of Missing and Partial Dates ........................ 29 
10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events .......................................... 30 
10.6.1. 
Laboratory Values ........................................................................ 30 
10.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 33 
10.7.1. 
ECG ............................................................................................. 33 
10.7.2. 
Vital Signs .................................................................................... 33 
10.8. 
Appendix 8: Abbreviations & Trade Marks .................................................. 34 
10.8.1. 
Abbreviations ............................................................................... 34 
10.8.2. 
Trademarks ................................................................................. 35 
10.9. 
Appendix 9: List of Data Displays ............................................................... 36 
10.9.1. 
Data Display Numbering .............................................................. 36 
10.9.2. 
Mock Example Shell Referencing ................................................ 36 
10.9.3. 
Deliverables ................................................................................. 36 
10.9.4. 
Study Population Tables .............................................................. 37 
10.9.5. 
Safety Tables ............................................................................... 38 
10.9.6. 
Safety Figures ............................................................................. 40 
10.9.7. 
Pharmacokinetic Tables ............................................................... 41 
10.9.8. 
ICH Listings ................................................................................. 42 
10.9.9. 
Non-ICH Listings .......................................................................... 45 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 209713. 
Due to a potential contamination issue in the study drug, the study was early terminated. 
Only an abbreviated set of outputs will be generated to support the clinical study report. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
This is a Phase 1, randomized, open-label, single-dose, 4-period crossover study to 
compare the relative bioavailability (BA) of a tablet formulation of GSK3640254 with 
the capsule formulation and to assess the effect of food on the pharmacokinetics (PK) of 
the tablet formulation in healthy participants. 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
 
None 
 
Randomized population is 
defined as all participants 
who were randomly 
assigned to a treatment 
sequence 
 
This is a randomized study 
and listing of randomization 
schedule will be produced 
based on randomized 
population. 
 
Pharmacokinetic concentration 
population will be used for the 
PK concentration listings, 
summary tables, and plotting of 
concentration-time data. 
 
Pharmacokinetic 
concentration population 
will be used for the PK 
concentration listings and 
summary tables. 
 
Study terminated earlier 
due to potential 
contamination issue. An 
abbreviated clinical study 
report will be reported, and 
PK figures are not needed. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
 
To assess the relative BA 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 Objectives 
Secondary Endpoints 
 
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 
 
Safety and tolerability parameters for 
AEs/SAEs, observed and change from 
baseline clinical laboratory assessments, 
ECGs, and vital sign measurements 
 
To characterize the PK of GSK3640254 
 
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; BA = bioavailability; 
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. 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Figure 1 Study Design Schematic 
 
Treatment A = GSK3640254 200 mg (capsules) administered under moderate fat conditions;  
Treatment B = GSK3640254 200 mg (tablets) administered under moderate fat conditions;  
Treatment C = GSK3640254 200 mg (tablets) administered under fasted conditions;  
Treatment D = GSK3640254 200 mg (tablets) administered under high fat conditions.  
1 Washout will be at least 7 days minus 4 hours. 
Design 
Features 
 
A phase 1, randomized, open-label, single-dose, 4-period crossover study. 
 
The study will consist of a screening period and 4 sequential treatment periods. 
 
There will be a single dose of study intervention per treatment period. 
 
There will be at least 7 days (minus 4 hours) between each dose of study intervention. 
 
Participants will be randomly assigned to 1 of 4 treatment sequences in 1:1:1:1 ratio. 
 
Approximately 16 participants will be treated to ensure that 12 evaluable participants 
complete the study. 
Dosing 
 
Treatment A: GSK3640254 200 mg (single dose given as 2 × 100-mg capsules) 
administered under moderate fat condition (reference) 
 
Treatment B: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under moderate fat conditions (test) 
 
Treatment C: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under fasted conditions (reference) 
 
Treatment D: GSK3640254 200 mg (single dose given as 2 × 100-mg tablets) 
administered under high fat condition (test). 
Time & 
Events 
 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
 
This is an open-label study and randomized study. 
 
Participants will be randomly assigned to 1 of 4 treatment sequences (ABCD, BADC, 
CDAB, or DCBA) in 1:1:1:1 ratio. 
 
Site pharmacy group will use a computer-generated randomization schedule for 
treatment assignments. 
 
The computer-generated randomization schedule will be produced by SAS software 
(9.4). 
Interim 
Analysis 
 
No interim analysis is planned for this study 
2.4. 
Statistical Hypotheses 
There is no formal research hypothesis that will be statistically tested in this study. 
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3. 
PLANNED ANALYSES 
3.1. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) have been declared by Data Management. 
The study early terminated due to potential contamination issue in study drug. All 
participants completed Treatment Period 2 before the study was terminated. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
 
All participants who signed the informed consent form 
 
This population will be used for screen failure listing 
and summary. 
 
Study Population 
Randomized 
 
All participants who were randomly assigned to a 
treatment sequence. 
 
This population will be used for listing of randomization 
schedule. 
 
Study Population 
Safety 
 
All participants who received at least 1 dose of study 
medication. 
 
This population will be used for all demographic, 
disposition (exclude screen failure), and safety listings, 
summaries, and figures 
 
Study Population 
 
Safety 
Pharmacokinetic 
Concentration 
 
All participants who underwent plasma PK sampling 
and had evaluable PK assay results. 
 
This population will be used for the PK concentration 
listings and summary tables. 
 
PK Concentration 
Pharmacokinetic 
Parameter 
 
All participants who underwent plasma PK sampling 
and had evaluable PK parameters estimated. 
 
This population will be used for PK parameter listings, 
summary tables, and statistical analysis tables. 
 
PK Parameter 
 
PK statistical 
analysis 
Refer to Appendix 9: List of Data Displays which details the population used for each display. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. The “significant” protocol 
deviation in the Protocol Deviation Management Plan is equivalent to “important” 
protocol deviations. 
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o Data will be reviewed prior to freezing the database to ensure all significant 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the electronic 
case report form (eCRF). 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
Data Displays for Reporting  
Description 
Code 
Order in TLF  
GSK3640254 200 mg (single dose given as 2 × 100-mg 
capsules) administered under moderate fat condition 
Treatment A 
1 
GSK3640254 200 mg (single dose given as 2 × 100-mg 
tablets) administered under moderate fat conditions 
Treatment B 
2 
GSK3640254 200 mg (single dose given as 2 × 100-mg 
tablets) administered under fasted conditions 
Treatment C 
3 
GSK3640254 200 mg (single dose given as 2 × 100-mg 
tablets) administered under high fat condition 
Treatment D 
4 
5.2. 
Baseline Definitions 
For vital signs and 12-lead ECGs, the baseline value will be the average (for quantitative 
assessments) or the worst case (for interpretation) of the triplicate predose assessments 
within each period. For clinical laboratory parameters, the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits, before the first dose of study drug administration. If time is not collected, Day 1 
assessments within each period are assumed to be taken prior to the dose and used as 
baseline. 
Parameter 
Study Assessments Considered as 
Baseline 
Baseline Used in Data Display 
 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Safety 
 
Vital Sign 
X 
X 
X 
Day 1 (Pre-Dose)[1] for each period 
12-Lead ECG 
X 
X 
X 
Day 1 (Pre-Dose)[1] for each period 
Hematology 
X 
X 
 
Day -1 
Clinical 
Chemistry 
X 
X 
 
Day -1 
Urinalysis 
X 
X 
 
Day -1 
ECG = Electrocardiogram. 
[1] The average (for quantitative assessments) or the worst case (for interpretation) of the predose triplicate 
assessments will be used as the baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
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5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
10.1 
Appendix 1: Schedule of Activities  
10.2 
Appendix 2: Study Phases and Treatment Emergent Adverse Events 
10.3 
Appendix 3: Data Display Standards & Handling Conventions 
10.4 
Appendix 4: Derived and Transformed Data 
10.5 
Appendix 5: Reporting Standards for Missing Data 
10.6 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
10.7 
Appendix 7: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety or Screened or Randomized 
population, unless otherwise specified. 
Study population analyses including analyses of randomization schedule, participant 
disposition, protocol deviations (including inclusion/exclusion criteria deviations), 
demographic and baseline characteristics, prior and concomitant medications, and 
exposure will be based on GSK Core Data Standards. Details of the planned displays are 
presented in Appendix 9: List of Data Displays. 
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7. 
PHARMACOKINETIC ANALYSES 
7.1. 
Primary Pharmacokinetic Analyses 
7.1.1. 
Endpoint / Variables 
7.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3 
Reporting Standards for Pharmacokinetics). Plasma concentrations of GSK3640254 will 
be measured and presented in tabular form and will be summarized descriptively. Plasma 
GSK3640254 concentration-time data will be listed by participant, treatment group and 
sampling time and summarized by treatment group and sampling time for each period of 
the study.  
7.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher). All calculations of non-compartmental parameters will be 
based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits. Subjects who experience 
emesis at or before 2 times median Tmax will be excluded from the calculation of 
summary statistics and statistical analysis for the respective treatment. 
Parameter 
Parameter Description 
AUC(0- 
Area under the plasma concentration-time curve from time 0 extrapolated to infinity, to be 
calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the last quantifiable 
concentration, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
Tmax 
Time of maximum observed concentration 
NOTES: 
 
Additional parameters may be included as required. 
7.1.2. 
Summary Measure 
Pharmacokinetic parameters AUC(0-), AUC(0-t), Cmax, and Tmax following single 
dose administration of GSK3640254 to healthy participants. 
7.1.3. 
Population of Interest  
The primary PK analyses will be based on the PK concentration population for plasma 
PK concentrations and the PK parameter population for plasma PK parameters and 
statistical analysis. 
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7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics and listed. 
Primary plasma PK parameters (AUC[0-], AUC[0-t], Cmax, and Tmax) will be 
estimated for GSK3640254. Summary statistics (arithmetic mean, geometric mean, 
median, standard deviation (SD), coefficient of variation (CV), minimum, maximum, 
between-subject coefficient of variation (CVb), and 90% confidence interval (CI) for 
plasma GSK3640254 PK parameter values will be summarized by treatment. 
7.1.4.1. 
Statistical Methodology Specification 
The following PK statistical analyses will only be performed if sufficient data are 
available (i.e. if participants have well defined plasma profiles). 
Endpoint / Variables 
 Plasma primary PK endpoints include AUC(0-), AUC(0-t), Cmax, and Tmax for GSK3640254 
as data permit 
Model Specification 
 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 comparisons: 
o Treatment B (test) versus Treatment A (reference) 
o 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 B (test) versus Treatment C (reference) 
o Treatment D (test) versus Treatment C (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 treatment 
comparison: 
o Treatment B (test) versus Treatment A (reference) 
o 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 treatment comparisons: 
o Treatment B (test) versus Treatment C (reference) 
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o Treatment D (test) versus Treatment C (reference) 
Model Checking & Diagnostics 
 Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
Model Results Presentation 
 Statistical analysis for comparison of relative BA by analysis of variance (ANOVA) will be 
presented in tabular format with geometric mean ratios for the following treatment comparison: 
o Treatment B (test) versus Treatment A (reference) 
 Statistical analysis for the effect of food (moderate or high fat meal) by ANOVA will be 
presented in tabular format with geometric mean ratios for the following treatment 
comparisons: 
o Treatment B (test) versus Treatment C (reference) 
o Treatment D (test) versus Treatment C (reference) 
 Statistical analysis for comparison of Tmax of a tablet formulation with a capsule formulation by 
non-parametric analysis will be presented in tabular format with the median, median difference, 
and 90% CIs along with a p-value generated by the Wilcoxon signed-rank test for the following 
treatment comparison: 
o Treatment B (test) versus Treatment A (reference) 
 Statistical analysis for comparison of the effect of food (moderate or high fat meal) on the 
Tmax by non-parametric analysis will be presented in tabular format with the median, median 
difference, and 90% CIs along with a p-value generated by the Wilcoxon signed-rank test for 
the following treatment comparisons: 
o Treatment B (test) versus Treatment C (reference) 
o Treatment D (test) versus Treatment C (reference) 
7.2. 
Secondary Pharmacokinetic Analyses 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Drug Concentration Measures  
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3 
Reporting Standards for Pharmacokinetic). 
7.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher). All calculations of non-compartmental parameters will be 
based on actual sampling times.  
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Plasma pharmacokinetic parameters listed below will be determined from the plasma 
concentration-time data, as data permits: 
Parameter 
Parameter Description 
tlag 
Lag time for absorption 
t1/2 
Apparent terminal phase half-life 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent volume of distribution 
NOTES: 
 
Additional parameters may be included as required. 
7.2.2. 
Summary Measure 
Pharmacokinetic parameters tlag, t1/2, CL/F, and Vz/F following single dose 
administration of GSK3640254 to healthy participants. 
7.2.3. 
Population of Interest  
The secondary PK analyses will be based on the PK concentration population for plasma 
PK concentrations, and the PK parameter population for plasma PK parameters, unless 
otherwise specified. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.2.1 will be 
summarized using descriptive statistics and listed. 
Secondary plasma PK parameters (tlag, t1/2, CL/F, and Vz/F) will be estimated for 
GSK3640254. Summary statistics (arithmetic mean, geometric mean, median, CV, SD, 
minimum, maximum, CVb, and 90% CI) for secondary plasma PK parameters of 
GSK3640254 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. 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population unless otherwise specified. 
8.1. 
Adverse Events Analyses 
Adverse event analyses including the analysis of AEs, SAEs, and other significant AEs 
will be based on GSK Core Data Standards. The details of the planned displays are 
provided in Appendix 9: List of Data Displays. 
8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards and will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017). The details of 
the planned displays are in Appendix 9: List of Data Displays. 
8.3. 
Adverse Events of Special Interest 
At the end of the study, QT prolongation, gastrointestinal intolerability/toxicity, 
psychiatric events, and nervous system disorders will be summarized by treatment. A 
listing will also be provided accordingly. 
QT prolongation AE of special interest will be defined as cardiac disorders system organ 
class (SOC) plus preferred terms (PTs) using the Medical Dictionary for Regulatory 
Activities (MedDRA) Standardized MedDRA Query (SMQ) “Torsade de pointes/QT 
Prolongation” (narrow and broad terms) plus seizure. 
Gastrointestinal intolerability/toxicity AEs of special interest will be defined within three 
narrow sub-SMQs [Gastrointestinal nonspecific symptoms and therapeutic procedures 
SMQ; Gastrointestinal nonspecific dysfunction SMQ; Gastrointestinal nonspecific 
inflammation (SMQ)] plus a selection of relevant broad PTs from the Gastrointestinal 
non-specific symptoms and therapeutic procedures SMQ.  
Psychiatric AEs of special interest will be defined within the following:  
 Sub-SMQ “Suicide/self-injury” (SMQ) from parent SMQ of “Depression and 
Suicide/Self Injury”. Only narrow terms from the sub-SMQ selected. 
 Sub-SMQ “Depression (excluding suicide and self-injury)” (SMQ) from parent SMQ 
of “Depression and Suicide/Self Injury”. Only narrow terms from the sub-SMQ 
selected. 
 All preferred terms from high level group term (HLGT) “Manic and Bipolar mood 
disorders and disturbances” under SOC “Psychiatric disorders”. 
 Narrow terms from SMQ “Psychosis and psychotic disorders” selected. 
 All preferred terms from HLGT “Anxiety disorders and symptoms”, under SOC 
'Psychiatric disorders'. 
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 All preferred terms from HLGT “Sleep Disorders and Disturbances” and HLGT 
“Sleep disturbances (incl subtypes)”. 
Nervous system disorders AEs of special interest will be defined within the following:  
 Four HLGTs under Nervous System Disorders SOC: “Headaches”; “Mental 
impairment disorders”; “Neurological disorders” and “Seizures” 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including electrocardiograms (ECGs), 
and vital signs will be based on GSK Core Data Standards, unless otherwise specified. A 
figure of mean change from baseline in QTc using the Fridericia formula (QTcF) interval 
along with the 2-sided 95% CI using Student’s t distribution will be presented by 
treatment and visit. The details of the planned displays are presented in Appendix 9: List 
of Data Displays. 
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9. 
REFERENCES 
ViiV Healthcare group of companies Document Number 2018N383392_00 
(30-AUG-2019): A Randomized, Open-Label, Single Dose, Four-Period 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. 
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10. 
APPENDICES 
10.1. 
Appendix 1: Schedule of Activities 
10.1.1. 
Protocol Defined Schedule of Events 
Screening Visit 
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 
1. A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal (GI), and neurological systems. 
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Time and Events Table 
Procedure 
Check-in 
Periods 1, 2, and 3 
Period 4 only 
Notes 
 
Day  
–1 
Day 
1 
Washout 
Day 
1 
Day 
2 
Days 
3-4 
Day 
50 
 
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 4. 
Brief physical 
examination 
X 
 
 
 
D7 
(Period 2 
only) 
 
 
 
X 
Interim or symptom targeted physical 
examination will be performed at the 
discretion of the investigator. See 
Protocol 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 predose on Day 1 
in Periods 1-4. Single blood pressure and 
pulse will be measured predose on other 
study days. 
12-lead ECG 
X 
X 
 
 
 
X 
 
 
X 
All ECGs on Day 1 in Periods 1-4 will be 
predose, postdose at 2 hours, and 
postdose at 4 hours. The predose ECGs 
in Periods 1-4 will be taken in triplicate.  
Drug, alcohol, and  
cotinine screen 
X 
 
 
 
 
 
 
 
 
See Protocol Appendix 2 for specific tests 
to be performed. 
Laboratory 
assessments  
(hematology, chemistry, 
urinalysis) 
X 
 
X 
 
 
 
X 
 
X 
See Protocol 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 
Serum testing at Day -1 
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Procedure 
Check-in 
Periods 1, 2, and 3 
Period 4 only 
Notes 
 
Day  
–1 
Day 
1 
Washout 
Day 
1 
Day 
2 
Days 
3-4 
Day 
50 
 
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  
(capsule or tablet) 
 
X 
 
 
 
X 
 
 
 
Participants will fast overnight for at least 
10 hours prior to dosing; be provided a 
moderate fat meal, a high fat meal, or no 
meal 30 minutes prior to dosing; and be 
provided standardized meals ≥4 hours 
postdose. See Protocol Section 4.1.  
Serial PK sampling 
 
X 
X 
X 
 
X 
X 
X 
X 
Blood collection 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 postdose 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 4 will also be performed for participants who discontinue early. 
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10.2. 
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events 
10.2.1. 
Study States for Lab, Electrocardiograms, and Vital Signs 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date(/time) and stop date(/time). 
Study Phase 
Definition 
Pre-Treatment  
Date and Time ≤ Study Treatment Start Date and Time 
On-Treatment 
Study Treatment Start Date and Time < Date and Time ≤ Study Treatment Stop Date 
and Time + 5 days the Date and Time of Early Withdrawal Visit whichever is later. 
Post-Treatment  
Date and Time > Study Treatment Stop Date and Time + 5 days or the Date and Time 
of Early Withdrawal Visit whichever is later 
10.2.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before Day -1 
Concomitant 
Any medication that is not a prior 
NOTES:  
 
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
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10.2.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
 
If AE onset date and time is on or after treatment start date and time & on or 
before treatment stop date and time + 5 days.  
 
Study Treatment Start Date and Time ≤ AE Start Date and Time ≤ Study 
Treatment Stop Date and Time + 5 days. 
 
If the AE onset date is completely missing, the AE is considered as treatment 
emergent. 
NOTES:  
 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
 
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
adverse events. Use the rules in this table if the adverse event onset date is completely missing. 
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10.3. 
Appendix 3: Data Display Standards & Handling 
Conventions 
10.3.1. 
Reporting Process 
Software 
 
The currently supported versions of SAS software (9.4) will be used. 
Reporting Area 
HARP Server 
\\us1salx00259.corpnet2.com 
HARP Compound 
GSK3640254 
Analysis Datasets  
 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).  
 
For creation of ADaM datasets (ADC1/ADCM/ADAE), the same version of dictionary datasets will be 
implemented as those being used for conversion from SI to SDTM. 
Generation of RTF Files 
 
RTF files will be generated for all reporting efforts described in the RAP. 
10.3.2. 
Reporting Standards 
General 
 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
 
4.03 to 4.23: General Principles 
 
5.01 to 5.08: Principles Related to Data Listings 
 
6.01 to 6.11: Principles Related to Summary Tables 
 
7.01 to 7.13: Principles Related to Graphics  
 
Do not include participant level listings in the main body of the GSK CSR. All participant level listings 
should be located in the modular appendices as ICH or non-ICH listings. 
Formats 
 All data will be reported according to the actual treatment the participant received unless 
otherwise stated. 
 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated. 
 
Numeric data will be reported at the precision collected on the eCRF. 
 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
 
Reporting for tables, figures, and formal statistical analyses: 
 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
 
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
 
Reporting for Data Listings:  
 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
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 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures (mean figures only for PK concentrations), summaries, 
and statistical analyses (excluding statistical analyses of PK parameters). 
Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables except for determining the worst-case values. 
 
Unscheduled visits will not be included in figures. 
 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
10.3.3. 
Reporting Standards for Pharmacokinetics 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
For continuous data: 
 
NQs at the beginning of a participant profile (i.e. before the first incidence of a 
measurable concentration) are deemed to be zero as it is assumed that in this 
circumstance no drug is yet measurable in the blood. 
 
For NQs at the end of the participant profile (i.e. after the last incidence of a 
measurable concentration); 
 
for individual plots and pharmacokinetic analyses these are dropped (set 
to missing) as they do not provide any useful information (and can 
erroneously indicate that absolutely no drug is present) 
 
for summary statistics, these are set to 0 (to avoid skewing of the 
summary statistics) 
 
Individual NQs which fall between two measurable concentrations are set to 
missing (individual values of this nature are assumed to be an anomaly) 
If two or more NQ values occur in succession between measurable concentrations, 
the profile will be deemed to have terminated at the last measurable concentration 
prior to these NQs. For the purpose of individual participant plots, these NQs will be 
set to 0, and the subsequent measurable concentrations will be retained. For the 
derivation of pharmacokinetic parameters, these NQs and any subsequent 
measurable concentrations will be omitted (set to missing). 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
N, n, arithmetic mean, 90% CI of arithmetic mean, geometric mean, 95% CI of 
geometric mean, SD, SD of logged data CV (%), and between-subject geometric 
coefficient of variation (CVb (%)) will be reported. 
CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of Ln-Transformed data) 
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Parameters Not 
Being Ln-
Transformed 
Tmax, tlag, λz, λz lower, λz upper, and λz no. of points. 
Parameters Not 
Being Summarized 
λz, λz lower, λz upper, and λz no. of points. 
Listings 
Include the first point, last point and number of points used in the determination of 
λz and Rsq_adjusted for listings. 
 
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10.4. 
Appendix 4: Derived and Transformed Data 
10.4.1. 
General 
Multiple Measurements at One Analysis Time Point 
 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
 
The worst finding/interpretation associated with multiple measurements as the finding/interpretation for 
that time point. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
 
Calculated as the number of days from Dose Date on Period 1 Day 1: 
 
Assessment Date = Missing  
  → Study Day = Missing  
 
Assessment Date < Dose Date on Period 1 Day 1  
  → Study Day = Assessment Date –Dose Date on Period 1 Day 1 
 
Assessment Date >= Dose Date on Period 1 Day 1  
  → Study Day = Assessment Date – Dose Date on Period 1 Day 1 + 1 
Period Day 
 
Calculated as the number of days from First Dose Date for the respective period: 
 
Assessment Date = Missing  
  → Period Day = Missing  
 
Assessment Date < Dose Date on Period 1 Day 1 
  → Period Day = Assessment Date – Dose Date on Period 1 Day 1 
 
Dose Date on Period 1 Day 1 <= Assessment Date < Dose Date on Period 2 Day 1 
  → Period Day = Assessment Date – Dose Date on Period 1 Day 1 + 1 
 
Dose Date on Period 2 Day 1 <= Assessment Date < Dose Date on Period 3 Day 1 
  → Period Day = Assessment Date – Dose Date on Period 2 Day 1 + 1 
 
Dose Date on Period 3 Day 1 <= Assessment Date < Dose Date on Period 4 Day 1 
  → Period Day = Assessment Date – Dose Date on Period 3 Day 1 + 1 
 
Assessment Date >= Dose Date on Period 4 Day 1  
  → Period Day = Assessment Date – Dose Date on Period 4 Day 1 + 1 
 
10.4.2. 
Study Population 
Age 
 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows: 
o Any participant with a missing day will have this imputed as day ‘15’. 
o Any participant with a missing day and month will have this imputed as ‘30th June’. 
 
Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
 
Calculated as Weight (kg) / [Height (m)2] 
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10.4.3. 
Safety 
Adverse Events 
AEs of Special Interest 
 QT prolongation 
 Gastrointestinal intolerability/toxicity 
 Psychiatric events 
 Nervous system disorders 
 
12-Lead Electrocardiograms 
QTcB Interval 
 QTc using the Bazett formula (QTcB) interval in msec will be calculated using QT interval 
(msec) and RR (msec) as 
 
 
where RR interval in msec is calculated using QT interval (msec) and QTcF interval (msec) as 
 
 
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10.5. 
Appendix 5: Reporting Standards for Missing Data 
10.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 
Participant study completion (i.e. as specified in the protocol) was defined as the 
participant had completed all phases of the study including the final date on which data 
were or are expected to be collected.  
 
Withdrawn participants were not replaced in the study. 
 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
10.5.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the CSR. 
10.5.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 2: Study Phases and 
Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications 
 
Partial dates for any concomitant medications recorded in the eCRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
 
The recorded partial date will be displayed in listings. 
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10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
10.6.1. 
Laboratory Values 
Laboratory abnormalities will be graded according to the DAIDS grading table Version 2.1, July 2017. Laboratory results are converted to 
use SI units; only the numeric part of the criteria will be used. If for a laboratory parameter there are multiple grades sharing the same 
criteria, the maximum grade will be used. 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute Lymphocyte Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not HIV infected) 
600 to < 650 
0.600 × 109 to < 0.650 × 109 
500 to < 600 
0.500 × 109 to < 0.600 × 
109 
350 to < 500 
0.350 × 109 to < 0.500 × 109 
< 350 
< 0.350 × 109 
Absolute Neutrophil Count, Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 × 109 to 1.000 × 109 
600 to 799 
0.600 × 109 to 0.799 × 
109 
400 to 599 
0.400 × 109 to 0.599 × 109 
< 400 
< 0.400 × 109 
Hemoglobin, Low (g/dL; mmol/L) 
≥ 13 years of age (male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
<4.34 
Hemoglobin, Low (g/dL; mmol/L) 
≥ 13 years of age (female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
Platelets, Decreased (cells/mm3; cells/L) 
100,000 to < 125,000 
100.000 × 109 to < 125.000 
× 109 
50,000 to < 100,000 
50.000 × 109 to < 
100.000 × 109 
25,000 to < 50,000 
25.000 × 109 to < 50.000 × 
109 
< 25,000 
< 25.000 × 109 
White Blood Cell, Decreased (cells/mm3; 
cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 × 109 to 2.499 × 109 
1,500 to 1,999 
1.500 × 109 to 1.999 × 
109 
1,000 to 1,499 
1.000 × 109 to 1.499 × 109 
< 1,000 
< 1.000 × 109 
 
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Clinical Chemistry 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin, Low (g/dL; g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0 
≥ 20 to < 30 
< 2.0 
< 20 
NA 
Alkaline Phosphatase, High 
1.25 to < 2.5 × ULN 
2.5 to < 5.0 × ULN 
5.0 to < 10.0 × ULN 
≥ 10.0 × ULN 
Alanine Aminotransferase, High 
1.25 to < 2.5 × ULN 
2.5 to < 5.0 × ULN 
5.0 to < 10.0 × ULN 
≥ 10.0 ULN 
Amylase (Total), High 
1.1 to < 1.5 × ULN 
1.5 to < 3.0 × ULN 
3.0 to < 5.0 × ULN 
≥ 5.0 × ULN 
Aspartate Aminotransferase, High 
1.25 to < 2.5 × ULN 
2.5 to < 5.0 × ULN 
5.0 to < 10.0 × ULN 
≥ 10.0 × ULN 
Bicarbonate, Low (mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 110. 
< 8.0 
< 8.0 
Direct Bilirubin, High 
> 28 days of age 
NA 
NA 
> ULN with other signs and 
symptoms of hepatotoxicity 
> ULN with life-threatening consequences 
(e.g., signs and symptoms of liver failure) 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 × ULN 
1.6 to < 2.6 × ULN 
2.6 to < 5.0 × ULN 
≥ 5.0 × ULN 
Calcium, High (mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium, Low (mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
Creatine Kinase, High 
3 to < 6 × ULN 
6 to < 10 × ULN 
10 to < 20 × ULN 
≥ 20 × ULN 
Creatinine, High 
Choose the method that selects for the 
higher grade 
1.1 to 1.3 × ULN 
> 1.3 to 1.8 × ULN OR 
Increase to 1.3 to < 1.5 × 
participant’s baseline 
> 1.8 to < 3.5 ULN OR 
Increase to 1.5 to < 2.0 × 
participant’s baseline 
≥ 3.5 × ULN OR Increase of ≥ 2.0 × 
participant’s baseline 
Glucose Fasting, High (mg/dL; mmol/L) 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
≥ 500 
≥ 27.75 
Glucose, Low (mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to < 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lipase, High 
1.1 to < 1.5 × ULN 
1.5 to < 3.0 × ULN 
3.0 to < 5.0 × ULN 
≥ 5.0 × ULN 
Cholesterol, Fasting, High (mg/dL; 
mmol/L) 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
Triglycerides, Fasting, High (mg/dL; 
mmol/L) 
150 to 300 
1.71 to 3.42 
> 300 to 500 
> 3.42 to 5.7 
> 500 to < 1.000 
> 5.7 to 11.4 
> 1,000 
> 11.4 
Phosphate, Low (mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65 
1.0 to < 1.4 
0.32 to < 0.45 
< 1.0 
< 0.32 
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Clinical Chemistry 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium, High (mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low (mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High (mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low (mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 130 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High (mEq/L; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
NA=not applicable; LLN = lower limit of normal; ULN=upper limit of normal. 
 
Urinalysis 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Glucose/Glycosuria (random collection 
tested by dipstick) 
Trace to 1+ or ≤ 250 mg 
2+ or > 250 to ≤ 500 mg 
> 2+ or > 500 mg 
NA 
Protein/Proteinuria (random collection 
tested by dipstick) 
1+ 
2+ 
3+ or higher 
NA 
Red Blood Cells (RBCs)/Hematuria (not 
to be reported based on dipstick findings 
or on blood believed to be of menstrual 
origin) 
6 to < 10 RBCs per high 
power field 
≥ 10 RBCs per high 
power field 
Gross, with or without clots 
OR with RBC casts OR 
intervention indicated 
Life-threatening consequences 
NA=not applicable 
 
 
 
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10.7. 
Appendix 7: Values of Potential Clinical Importance 
10.7.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
<320 
>450 
Absolute PR Interval 
msec 
< 120 
> 200 
Absolute QRS Interval 
msec 
< 60 
> 120 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
> 60 
 
 
10.7.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 140 
Diastolic Blood Pressure 
mmHg 
< 45 
> 90 
Heart Rate 
bpm 
< 40 
> 100 
 
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10.8. 
Appendix 8: Abbreviations & Trade Marks 
10.8.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area under the Plasma Concentration-Time Curve 
AUC(0-) 
AUC from Time 0 Extrapolated to Infinity 
AUC(0-t) 
AUC from Time 0 to Time t 
BA 
Bioavailability 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CL/F 
Apparent Oral Clearance 
Cmax 
Maximum Observed Concentration 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
CVb  
Coefficient of Variation (Between)  
DAIDS 
Division of AIDS 
DBF 
Database Freeze 
DBR 
Database Release 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
GSK 
GlaxoSmithKline 
HLGT 
High Level Group Term 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QTcB 
QTc using the Bazett formula 
QTcF 
QTc using the Fridericia formula 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
t1/2 
Apparent Terminal Phase Half-life 
tlag 
Lag Time for Absorption 
Tmax 
Time of Maximum Observed Concentration 
ULN 
Upper Limit of Normal 
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Abbreviation 
Description 
Vz/F 
Apparent Volume of Distribution 
10.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 
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10.9. 
Appendix 9: List of Data Displays 
10.9.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.4 
 
Safety 
2.1 to 2.15 
2.1 
Pharmacokinetic 
3.1 to 3.7 
 
Section 
Listings 
ICH Listings 
1 to 32 
Other Listings 
33 to 34 
 
10.9.2. 
Mock Example Shell Referencing 
Non-IDSL specifications will be referenced as indicated and if required example 
mock-up displays provided in the Table/Listing/Figure Shells. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
10.9.3. 
Deliverables 
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 
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10.9.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
 
SAC 
1.2. 
Screened 
SD1 
Summary of Screening Status and Reasons for Screen Failures 
 
SAC 
Demographic and Baseline Characteristics 
1.3. 
Safety 
DM1 
Summary of Demographic Characteristics 
 
SAC 
1.4. 
Safety 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
 
 
 
 
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10.9.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.1.  
Safety 
AE1CP 
Summary of Adverse Events by System Organ Class and 
Preferred Term 
 
SAC 
2.2.  
Safety 
AE1CP 
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
 
SAC 
2.3.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
2.4.  
Safety 
AE1CP 
Summary of Adverse Events of Special Interest by System 
Organ Class and Preferred Term 
 
SAC 
Laboratory: Chemistry  
2.5.  
Safety 
LB1 
Summary of Clinical Chemistry Data 
 
SAC 
2.6.  
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline 
 
SAC 
Laboratory: Hematology 
2.7.  
Safety 
LB1 
Summary of Hematology Data 
 
SAC 
2.8.  
Safety 
LB1 
Summary of Hematology Changes from Baseline 
 
SAC 
Laboratory: Urinalysis 
2.9.  
Safety 
LB1 
Summary of Urine Concentration 
 
SAC 
2.10. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline 
 
SAC 
ECG 
2.11. 
Safety 
EG2 
Summary of ECG Values 
 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.12. 
Safety 
EG2 
Summary of ECG Changes from Baseline 
 
SAC 
Vital Signs 
2.13. 
Safety 
VS1 
Summary of Vital Signs 
 
SAC 
2.14. 
Safety 
VS1 
Summary of Vital Sign Changes from Baseline 
 
SAC 
C-SSRS 
2.15. 
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation and Behavior Data 
Only include participants who have 
suicidal ideation or behavior 
SAC 
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10.9.6. 
 Safety Figures 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
2.1.  
Safety 
EG9 
Mean (95% CI) Change from Baseline in QTcF Interval by 
Timepoint and Treatment 
 
SAC 
 
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10.9.7. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
3.1.  
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (ng/mL) by Treatment 
 
SAC 
PK Derived Parameters 
3.2.  
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment 
Parameters with units; present PK 
parameters in ug/mL or ug.h/mL 
SAC 
3.3.  
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment 
Parameters with units; present PK 
parameters in ug/mL or ug.h/mL 
SAC 
PK Analysis Tables 
3.4.  
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA)- Relative 
Bioavailability 
AUC(0-), AUC(0-t) and Cmax, 
SAC 
3.5.  
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA)- Food Effect 
AUC(0-), AUC(0-t) and Cmax, 
SAC 
3.6.  
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Non-parametric analysis- Relative Bioavailability 
Tmax 
SAC 
3.7.  
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Non-parametric analysis-Food Effect 
Tmax 
SAC 
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10.9.8. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Randomized 
POP_L1 
Listing of Randomization Schedule 
 
SAC 
2.  
Safety 
ES3 
Listing of Reasons for Study Withdrawal 
 
SAC 
3.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
Protocol Deviations 
4.  
Safety 
DV2 
Listing of Important Protocol Deviations 
 
SAC 
5.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Populations Analyzed 
6.  
Safety 
SP3A 
Listing of Subjects Excluded from Any Population 
 
SAC 
Demographic and Baseline Characteristics 
7.  
Safety 
DM2 
Listing of Demographic Characteristics 
 
SAC 
8.  
Safety 
DM9 
Listing of Race 
 
SAC 
Prior and Concomitant Medications 
9.  
Safety 
CM5 
Listing of Concomitant Medications  
Based on GSK Drug Dictionary 
SAC 
Exposure and Treatment Compliance 
10.  
Safety 
EX4 
Listing of Exposure Data 
 
SAC 
11.  
Safety 
POP_L2 
Listing of Meal Data 
 
SAC 
Adverse Events 
12.  
Safety 
AE2 
Listing of Relationship Between System Organ Class and 
Verbatim Text 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
14.  
Safety 
AE9CP 
Listing of All Adverse Events 
 
SAC 
Serious and Other Significant Adverse Events 
15.  
Safety 
AE9CP 
Listing of Study Drug Related Adverse Events 
 
SAC 
16.  
Safety 
AE9CP 
Listing of Serious Adverse Events (Fatal & Non-Fatal) 
 
SAC 
17.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC 
18.  
Safety 
AE9CP 
Listing of Adverse Events Leading to Withdrawal from Study 
 
SAC 
19.  
Safety 
AE9CP 
Listing of Adverse Events of Special Interest 
 
SAC 
Hepatobiliary (Liver) 
20.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
 
SAC 
21.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
 
SAC 
All Laboratory 
22.  
Safety 
LB5A 
Listing of Clinical Chemistry with any Toxicities  
 
SAC 
23.  
Safety 
LB5A 
Listing of All Clinical Chemistry Data for Subjects with any 
Toxicities  
 
SAC 
24.  
Safety 
LB5A 
Listing of Hematology with any Toxicities  
 
SAC 
25.  
Safety 
LB5A 
Listing of All Hematology Data for Subjects with any Toxicities  
 
SAC 
26.  
Safety 
LB5A 
Listing of Urinalysis with any Toxicities  
 
SAC 
27.  
Safety 
LB5A 
Listing of All Urinalysis Data for Subjects with any Toxicities  
 
SAC 
ECG 
28.  
Safety 
EG6 
Listing of All ECG Findings 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
29.  
Safety 
EG6 
Listing of All Abnormal ECG Findings 
 
SAC 
30.  
Safety 
EG4 
Listing of All ECG Values 
 
SAC 
Vital Signs 
31.  
Safety 
VS5 
Listing of All Vital Signs of Potential Clinical Importance 
 
SAC 
32.  
Safety 
VS5 
Listing of All Vital Signs for Subjects with any Value of Potential 
Clinical Importance 
 
SAC 
 
 
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10.9.9. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetics 
33.  
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentration-Time Data by 
Treatment 
 
SAC 
34.  
PK 
Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters 
Based on Actual Time by Treatment 
 
SAC 
 
 
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