Conditions: HIV Infections
Keywords: Darunavir Ritonavir Etravirine GSK3640254 Pharmacokinetics
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 54
Healthy volunteers: yes

Brief summary:
This is an open-label, single-sequence, multiple-dose, 3 cohort study to investigate the effects of DRV/RTV and/or ETR on the pharmacokinetics (PK) of GSK3640254 and the effects of GSK3640254 on the PK of DRV/RTV and/or ETR. This study will aid in understanding these interactions and resulting changes in exposure (if any) when given in combination with GSK3640254.

Detailed description:

Arms:
arm 1: Cohort 1 will include 3 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 DRV/RTV will be administered (Treatment B). In Period 3 GSK3640254 (Treatment A) and DRV/RTV (Treatment B) will be administered. arm 2: Cohort 2 will include 3 periods. In Period 1 GSK3640254 will be given (Treatment A). In Period 2 ETR will be given (Treatment C). In Period 3 GSK3640254 (Treatment A) and ETR (Treatment C) will be administered. arm 3: Cohort 3 will include 2 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 GSK3640254 (Treatment A), DRV/RTV (Treatment B), and ETR (Treatment C) will be administered.

Interventions: intervention 1: GSK3640254 intervention 2: Darunavir/Ritonavir (DRV/RTV) intervention 3: Etravirine (ETR)
Intervention descriptions: intervention 1: GSK3640254 will be available as oral tablets. intervention 2: DRV/RTV will be available as oral tablets. intervention 3: ETR will be available as oral tablets.

Protocol document:
Prot_000.pdf: 
2020N432810_00
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TITLE PAGE
Protocol Title: Open-Label, Single-Sequence Study to Evaluate the Effects of 
Darunavir/Ritonavir and/or Etravirine on the Pharmacokinetics of GSK3640254 and the 
Effects of GSK3640254 on the Pharmacokinetics of Darunavir/Ritonavir and/or 
Etravirine in Heathy Adults
Protocol Number: 213054
Compound Number 
or Name:
GSK3640254
Brief Title: Evaluation of the Effects of Darunavir/Ritonavir and/or Etravirine on the 
Pharmacokinetics of GSK3640254 and the Effect of GSK3640254 on the 
Pharmacokinetics of Darunavir/Ritonavir and/or Etravirine in Heathy Adults
Study Phase: Phase 1
Sponsor Name and Legal Registered Address: 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
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.
Regulatory Agency Identifying Number(s): IND: 139,838
Approval Date: 29-SEP-2020
Copyright 2020 ViiV Healthcare group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited.


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................9
1.3.
Schedule of Activities (SoA)..........................................................................9
2.
INTRODUCTION....................................................................................................23
2.1.
Study Rationale ..........................................................................................23
2.2.
Background ................................................................................................23
2.2.1.
Key Safety Data with a Prior Maturation Inhibitor 
(GSK3532795).............................................................................23
2.2.2.
Summary of GSK3640254 Clinical Pharmacokinetics..................24
2.2.3.
Summary of GSK3640254 Metabolism ........................................24
2.2.4.
Preclinical Summary with GSK3640254.......................................25
2.2.5.
Summary of GSK3640254 Safety................................................26
2.2.5.1.
Cardiac Safety............................................................27
2.2.6.
Drug Interaction Potential with Darunavir/Ritonavir and
Etravirine .....................................................................................27
2.3.
Benefit/Risk Assessment ............................................................................30
2.3.1.
Risk Assessment .........................................................................32
2.3.2.
Benefit Assessment.....................................................................35
2.3.3.
Overall Benefit: Risk Conclusion..................................................35
3.
OBJECTIVES AND ENDPOINTS...........................................................................35
4.
STUDY DESIGN ....................................................................................................36
4.1.
Overall Design ............................................................................................36
4.2.
Scientific Rationale for Study Design ..........................................................38
4.3.
Justification for Dose ..................................................................................38
4.4.
End of Study Definition ...............................................................................39
5.
STUDY POPULATION...........................................................................................39
5.1.
Inclusion Criteria.........................................................................................39
5.2.
Exclusion Criteria........................................................................................40
5.3.
Lifestyle Considerations..............................................................................43
5.3.1.
Meals and Dietary Restrictions ....................................................43
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................44
5.3.3.
Activity .........................................................................................44
5.4.
Screen Failures...........................................................................................44
5.5.
Criteria for Temporarily Delaying ................................................................44
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY ..................................44
6.1.
Study Interventions Administered ...............................................................45
6.2.
Preparation/Handling/Storage/Accountability..............................................45
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................46
6.4.
Study Intervention Compliance ...................................................................46
6.5.
Dose Modification .......................................................................................46
6.6.
Continued Access to Study Intervention after the End of the Study ............46
6.7.
Treatment of Overdose...............................................................................46
6.8.
Concomitant Therapy..................................................................................47


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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................47
7.1.
Discontinuation of Study Intervention..........................................................47
7.1.1.
Liver Chemistry Stopping Criteria ................................................47
7.1.2.
QTc Stopping Criteria ..................................................................48
7.1.3.
Rash/Hypersensitivity Evaluation Criteria.....................................48
7.1.4.
Columbia-Suicide Severity Rating Scale Criteria..........................48
7.1.5.
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria................................................................49
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................49
7.3.
Lost to Follow-up ........................................................................................50
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
8.1.
Efficacy Assessments.................................................................................51
8.2.
Safety Assessments ...................................................................................51
8.2.1.
Physical Examinations.................................................................51
8.2.2.
Vital Signs....................................................................................51
8.2.3.
Electrocardiograms......................................................................51
8.2.4.
Clinical Safety Laboratory Assessments ......................................52
8.2.5.
Pregnancy Testing.......................................................................52
8.2.6.
Suicidal Ideation and Behavior Risk Monitoring ...........................53
8.2.7.
Gastrointestinal Intolerability Evaluation and Monitoring 
Plan (with Stopping Criteria) ........................................................53
8.2.8.
COVID-19 Measures ...................................................................55
8.3.
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting....................................................................................................55
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................56
8.3.2.
Method of Detecting AEs and SAEs.............................................56
8.3.3.
Follow-up of AEs and SAEs.........................................................56
8.3.4.
Regulatory Reporting Requirements for SAEs .............................57
8.3.5.
Pregnancy ...................................................................................57
8.3.6.
Adverse Events of Special Interest ..............................................58
8.4.
Pharmacokinetics .......................................................................................58
8.5.
Genetics and/or Pharmacogenomics ..........................................................58
8.6.
Biomarkers .................................................................................................58
8.7.
Immunogenicity Assessments.....................................................................58
8.8.
Medical Resource Utilization and Health Economics ..................................58
9.
STATISTICAL CONSIDERATIONS........................................................................59
9.1.
Statistical Hypotheses.................................................................................59
9.2.
Sample Size Determination ........................................................................59
9.2.1.
Sample Size Assumptions ...........................................................59
9.2.2.
Sample Size Sensitivity................................................................60
9.3.
Analysis Sets..............................................................................................62
9.4.
Statistical Analyses.....................................................................................62
9.4.1.
Pharmacokinetic Analyses...........................................................62
9.4.2.
Safety Analyses...........................................................................63
9.4.3.
Other Analysis .............................................................................64
9.5.
Interim Analysis ..........................................................................................64


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................65
10.1.
Appendix 1: Abbreviations and Trademarks................................................65
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................67
10.3.
Appendix 3: Contraceptive and Barrier Guidance .......................................69
10.3.1.
Definitions:...................................................................................69
10.3.2.
Contraception Guidance: .............................................................70
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight
Considerations............................................................................................71
10.4.1.
Regulatory and Ethical Considerations ........................................71
10.4.2.
Financial Disclosure.....................................................................71
10.4.3.
Informed Consent Process ..........................................................71
10.4.4.
Data Protection............................................................................72
10.4.5.
Committees Structure ..................................................................73
10.4.6.
Dissemination of Clinical Study Data ...........................................73
10.4.7.
Data Quality Assurance ...............................................................73
10.4.8.
Source Documents ......................................................................74
10.4.9.
Study and Site Start and Closure.................................................74
10.4.10. Publication Policy.........................................................................75
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................76
10.6.
Appendix 6: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting .............................................................................................78
10.6.1.
Definition of AE............................................................................78
10.6.2.
Definition of SAE..........................................................................79
10.6.3.
Recording and Follow-Up of AE and SAE....................................80
10.6.4.
Reporting of SAE to VH/GSK.......................................................82
10.7.
Appendix 7: COVID-19 Pandemic and Clinical Trial Continuity...................83
10.7.1.
Changes to Study Visits and Study Procedures...........................83
10.7.2.
COVID-19 Specific Data Capture.................................................83
10.7.2.1.
Capturing COVID-19 Specific Protocol 
Deviations ..................................................................83
10.7.2.2.
Capturing COVID-19 Specific Adverse Events 
and Serious Adverse Events ......................................84
10.7.2.2.1.
World Health Organization Case 
Definition (March 20, 2020 
Version)..................................................84
10.8.
Appendix 8: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Corrected Version 2.1, July 2017.................86
11. REFERENCES.......................................................................................................87


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: Open-Label, Single-Sequence Study to Evaluate the Effects of 
Darunavir/Ritonavir and/or Etravirine on the Pharmacokinetics of GSK3640254 and the 
Effects of GSK3640254 on the Pharmacokinetics of Darunavir/Ritonavir and/or 
Etravirine in Heathy Adults
Brief Title: Evaluation of the Effects of Darunavir (DRV)/Ritonavir (RTV) and/or 
Etravirine (ETR) on the Pharmacokinetics (PK) of GSK3640254 and the Effect of 
GSK3640254 on the PK of DRV/RTV and/or ETR in Heathy Adults
Rationale: The current study is being conducted to investigate the effects of DRV/RTV
600/100 mg and/or ETR 200 mg on the PK of GSK3640254 200 mg and the effects of 
GSK3640254 on the PK of DRV/RTV 600/100 mg and/or ETR 200 mg. This study will 
aid in understanding these interactions and resulting changes in exposure (if any) when 
given in combination with GSK3640254.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Cohort 1

To assess the effect of co-administration of 
DRV/RTV 600/100 mg BID with GSK3640254 
200 mg QD on the PK of GSK3640254 in 
healthy participants 

To assess the effect of co-administration of 
DRV/RTV 600/100 mg BID with GSK3640254 
200 mg QD on the PK of DRV/RTV in healthy 
participants.

AUC(0-tau), and Cmax for 
GSK3640254

AUC(0-tau), and Cmax for 
DRV/RTV
Cohort 2

To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of GSK3640254 in healthy 
participants.

To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of ETR in healthy participants. 

AUC(0-tau), and Cmax for 
GSK3640254

AUC(0-tau), and Cmax for ETR
Cohort 3

To assess the effect of co-administration of 
ETR 200 mg BID and DRV/RTV 600/100 mg 
BID with GSK3640254 200 mg QD on the PK of 
GSK3640254 in healthy participants.

AUC(0-tau), and Cmax for 
GSK3640254


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Objectives
Endpoints
Secondary
Cohort 1

To assess the effect of co-administration of 
GSK3640254 200 mg QD with DRV/RTV 
600/100 mg BID on the secondary PK 
parameters of DRV and RTV in healthy 
participants.

Ctau, and Tmax for DRV, RTV, and 
GSK3640254
Cohort 2

To assess the effect of co-administration of 
GSK3640254 200 mg QD with ETR 200 mg 
BID on the secondary PK parameters of ETR in 
healthy participants.

Ctau, and Tmax for ETR, and 
GSK3640254
Cohort 
1, 2 & 3

To assess the safety and tolerability of 
GSK3640254 administered alone and in 
combination with DRV/RTV and/or ETR.

Safety and tolerability endpoints 
include incidence of AEs, SAEs, 
AEs leading to discontinuation, 
deaths, marked laboratory 
abnormalities, and abnormalities in 
vital signs and 12-lead ECGs.
AE = adverse event; AUC(0-tau) = area under the plasma concentration-time curve from time zero to the end of the 
dosing interval at steady state; BID = twice daily; DRV = darunavir; Cmax = maximum observed concentration, 
Ctau = plasma concentration at the end of the dosing interval; ECG = electrocardiogram; ETR = etravirine; 
PK = pharmacokinetics; QD = once daily; RTV = ritonavir; SAE = serious adverse event; Tmax = time of maximum 
observed concentration.
Overall Design: This is an open-label, single-sequence, multiple-dose, 3 cohort study to 
investigate the effects of DRV/RTV 600 mg/100 mg and/or ETR 200 mg on the PK of 
GSK3640254 200 mg and the effects of GSK3640254 200 mg on the PK of DRV/RTV
600/100 mg and/or ETR 200 mg.
The study will consist of a screening period and a treatment period. Participants will be 
screened within 28 days before the first dose of study intervention.
All doses, of all study interventions will be administered under fed conditions. The 
participants will fast overnight for at least 8 hours prior to breakfast and before the AM 
dose and for at least 2 hours prior to dinner and before the PM dose. A moderate fat meal 
(defined as approximately 600 calories, 30% from fat) will be consumed 30 minutes prior 
to dosing. Participants will eat this meal in 25 minutes or less. Dose administration will 
occur within 5 minutes of completion of meal consumption.
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.
Participants will be confined to the study site from Day -1 until study discharge on 
Day 35 for Cohort 1, Day 36 for Cohort 2, and Day 26 for Cohort 3. The duration of the 
study, including screening, is approximately 63 days for Cohort 1, 64 days for Cohort 2, 
and 54 days for Cohort 3.


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Brief Summary: Evaluation of the Effects of DRV/RTV and/or ETR on the PK of 
GSK3640254 and the Effect of GSK3640254 on the PK of DRV/RTV and/or ETR in 
Heathy Adults. Study details include:

Study Duration: 35 days for Cohort 1, 36 days for Cohort 2, and 26 days for 
Cohort 3

Treatment Duration: 27 days for Cohort 1 and 2 and 21 days for Cohort 3
Number of Participants: Per cohort, approximately 16 participants will be treated to 
ensure that 14 evaluable participants complete the study.
Intervention Groups and Duration:
Cohort 1: 

Period 1: GSK3640254 200 mg tablets once daily (QD) (Treatment A) on Days 1 
through 7.

Period 2: DRV/RTV 600/100 mg tablets twice daily (BID) (Treatment B) on 
Days 12 through 21.

Period 3: GSK3640254 200 mg tablets QD (Treatment A) and DRV/RTV 
600/100 mg tablets BID (Treatment B) on Days 22 through 31.
Cohort 2: 

Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 through 7.

Period 2: ETR 200 mg tablets BID (Treatment C) on Days 12 through 21.

Period 3: GSK3640254 200 mg tablets QD (Treatment A) and ETR 200 mg 
tablets BID (Treatment C) on Days 22 through 31.
Cohort 3: 

Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 through 7.

Period 2: GSK3640254 200 mg tablets QD (Treatment A), DRV/RTV 
600/100 mg tablets BID (Treatment B), and ETR 200 mg tablets BID (Treatment 
C) on Days 8 through 21.
All doses of all study interventions will be administered under fed conditions.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be obtained at the 
following time points:

Cohorts 1 and 2:
o
Pre-dose on Days 5, 6, and 7 and up to 24 hours following dosing on 
Day 7 (Period 1)
o
Pre-dose on Days 29, 30, and 31 and up to 24 hours following dosing on 
Day 31 (Period 3) 

Cohort 3:
o
Pre-dose on Days 5, 6, and 7 and up to 24 hours following dosing on 
Day 7 (Period 1)


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o
Pre-dose and up to 24 hours following dosing on Day 21 (Period 2) 
Pharmacokinetic blood samples for the analysis of DRV/RTV and/or ETR will be 
obtained at the following time points:

Cohorts 1 and 2:
o
Pre-dose on Days 19, 20, and 21 and up to 12 hours following dosing on 
Day 21 (Period 2)
o
Pre-dose and up to 12 hours following dosing on Day 31 (Period 3)

Cohort 3:
o
Pre-dose on Days 19, 20, and 21 and up to 12 hours following dosing on 
Day 21 (Period 3)
The duration of the study, including screening, is approximately 63 days for Cohort 1, 
64 days for Cohort 2, and 54 days for Cohort 3.
Data Monitoring/Other Committee: No
1.2.
Schema
BID = twice daily; N = number of participants; QD = once daily.
1.3.
Schedule of Activities (SoA)

Screening procedures may be completed 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.


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
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, clinical 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
Molecular test for SARS-CoV-22
X
1.
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.
2.
Two consecutive approved molecular tests (polymerase chain reaction or antigen test). The first test should be 
performed ≥7 days prior to admission. 


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Time and Events Table - Cohort 1
Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
B
(Days 12-
21)
Period 3
Treatment A +Treatment B (Days 22-31)
Notes
Day -2
D -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
34
Day 
35
Admit to clinic
X
Discharge from 
clinic
X
Brief physical 
examination
X
X
X
X
X
X
Includes, at a minimum, 
assessments of the skin, 
lungs, cardiovascular 
system, and abdomen 
(liver and spleen).
Vital sign 
measurements
X
X
X
D2
X
X
D12, 
D13, 
D17
X
X
X
X
Blood pressure and pulse 
measured in triplicate at 
pre-dose on Days 1, 12, 
and 22. Single blood 
pressure and pulse will be 
measured on other study 
days.
Temperature 
Check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
B
(Days 12-
21)
Period 3
Treatment A +Treatment B (Days 22-31)
Notes
Day -2
D -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
34
Day 
35
12-lead ECG
X
X
X
X
X
D12
X
X
X
X
ECGs on Days 1, 12, and 
22, will be taken pre-dose, 
and at 2 and 4 and 6 hours 
post-dose. Pre-dose ECGs 
on Days 1, 12, and 22 will 
be taken in triplicate. The 
post-dose ECGs are single 
ECGs.
Drug, alcohol, 
and cotinine 
screen
X
See Appendix 2 for tests.
Laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis)
X
X
X
X
X
X
See Appendix 2 for tests.


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
B
(Days 12-
21)
Period 3
Treatment A +Treatment B (Days 22-31)
Notes
Day -2
D -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
34
Day 
35
Molecular test for 
SARS-CoV-2
X1
D6
D13, 
D20
D27
X
Test to be obtained every 
7 days from Check-in 
(regardless of period or 
washout) while in-house.
1The second test should 
be performed 24 hours 
prior to admission to the 
unit. Participants should be 
quarantined within the unit 
until the second test result 
is negative. Once the 
second test result is 
confirmed to be negative, 
they can be released into 
the unit and follow
infection control practices.
Pregnancy test 
X
X
Urine pregnancy test to 
confirm status.
Columbia-
Suicide Severity 
Rating Scale
X
X
X
X
See Section 8.2.6 for 
details.
Study 
intervention: 
DRV/RTV (BID)
X
X
X
X
X
X
X
X
See Section 6.1 for study 
intervention details.


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
B
(Days 12-
21)
Period 3
Treatment A +Treatment B (Days 22-31)
Notes
Day -2
D -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
34
Day 
35
Study 
intervention: 
GSK3640254 
200 mg (QD)
X
X
X
X
X
X`
X
X
X
See Section 6.1 for study 
intervention details.
DRV/RTV PK 
sampling
D19, 
D20
X
X
Pre-dose Days 19, 20 and 
21. Post Day 21 dose at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 
and 12 hours post-dose.
Pre-dose Day 31. Post 
Day 31 dose at 0.5, 1, 1.5, 
2, 3, 4, 6, 8, and 12 hours.
GSK3640254 PK 
sampling
D5, 
D6
X
D8
D29, 
D30
X
X
Pre-dose Days 5, 6, and 7. 
Post Day 7 dose at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 16, 
and 24 hours. 
Pre-dose Days 29, 30, and 
31. Post Day 31 dose at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 
16, and 24 hours.
AE review
===================================================================================
SAE review
============================================================================================
Concomitant 
medication 
review
============================================================================================
Abbreviations: AE = adverse event; BID = twice daily; D = day; DRV = darunavir; ECG = electrocardiogram; PK = pharmacokinetic; QD = once daily; RTV = ritonavir; SAE = serious 
adverse event.


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Time and Events Table - Cohort 2
Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
C
(Days 12-
21)
Period 3
Treatment A +Treatment C (Days 22-31)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
35
Day 
36
Admit to clinic
X
Discharge from 
clinic
X
Brief physical 
examination
X
X
X
X
X
X
Includes, at a minimum, 
assessments of the skin, 
lungs, cardiovascular 
system, and abdomen 
(liver and spleen).
Vital sign 
measurements
X
X
X
D2
X
X
D12, 
D13, 
D17
X
X
X
X
Blood pressure and pulse 
measured in triplicate at 
pre-dose on Days 1, 12, 
and 22. Single blood 
pressure and pulse will be 
measured on other study 
days.
Temperature 
Check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
C
(Days 12-
21)
Period 3
Treatment A +Treatment C (Days 22-31)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
35
Day 
36
12-lead ECG
X
X
X
X
X
D12
X
X
X
X
ECGs on Days 1, 12, and 
22, will be taken pre--dose, 
and at 2, 4, and 6 hours 
post-dose. Pre-dose ECGs 
on Days 1, 12, and 22 will 
be taken in triplicate. The 
post-dose ECGs are single 
ECGs.
Drug, alcohol, 
and cotinine 
screen
X
See Appendix 2 for tests.
Laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis)
X
X
X
X
X
X
See Appendix 2 for tests.


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
C
(Days 12-
21)
Period 3
Treatment A +Treatment C (Days 22-31)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
35
Day 
36
Molecular test for 
SARS-CoV-2
X1
D6
D13, 
D20
D27
X
Test to be obtained every 
7 days from Check-in 
(regardless of period or 
washout) while in-house.
1The second test should 
be performed 24 hours 
prior to admission to the 
unit. Participants should be 
quarantined within the unit 
until the second test result 
is negative. Once the 
second test result is 
confirmed to be negative, 
they can be released into 
the unit and follow
infection control practices.
Pregnancy test 
X
X
Urine pregnancy test to 
confirm status.
Columbia-
Suicide Severity 
Rating Scale
X
X
X
X
See Section 8.2.6 for 
details.
Study 
intervention: 
ETR (BID)
X
X
X
X
X
X
X
X
See Section 6.1 for study 
intervention details.


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Procedure
Check-
In
Baseline
Period 1
Treatment A (Days 1-7)
Washout (Days 8-11)
Period 2
Treatment 
C
(Days 12-
21)
Period 3
Treatment A +Treatment C (Days 22-31)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day 
8-
10
Day
11
Days
12-20
Day
21
Day
22
Day
23
Days
24-
25
Day
26
Days 
27-
30
Day 
31
Day 
32
Days 
33-
35
Day 
36
Study 
intervention: 
GSK3640254 
200 mg (QD)
X
X
X
X
X
X`
X
X
X
See Section 6.1 for study 
intervention details.
ETR PK 
sampling
D19, 
D20
X
X
Pre-dose Days 19, 20 and 
21. Post Day 21 dose at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 
and 12 hours post-dose. 
Pre-dose Day 31. Post 
Day 31 dose at 0.5, 1, 1.5, 
2, 3, 4, 6, 8, and 12 hours.
GSK3640254 PK 
sampling
D5, 
D6
X
D8
D29, 
D30
X
X
Pre-dose Days 5, 6, and 7. 
Post Day 7 dose at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 16, 
and 24 hours.
Pre-dose Days 29, 30, and 
31. Post Day 31 dose at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 
16, and 24 hours.
AE review
====================================================================================
SAE review
===========================================================================================
Concomitant 
medication 
review
===========================================================================================
Abbreviations: AE = adverse event; BID = twice daily; D = day; ECG = electrocardiogram; ETR = etravirine; PK = pharmacokinetic; QD = once daily; SAE = serious adverse event.


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Time and Events Table - Cohort 3
Procedure
Check-
in
Baseline
Period 1
Treatment A 
(Days 1-7)
Period 2
Treatment A + Treatment B + Treatment C (Days 8-21)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day
8
Day
9
Days
10-
12
Day
13
Day
14
Days
15-
16
Day
17
Days 
18-20
Day 
21
Day 
22
Days 
23-25
Day 
26
Admit to clinic
X
Discharge from 
clinic
X
Brief physical 
examination
X
X
X
X
Includes, at a minimum, 
assessments of the skin, lungs, 
cardiovascular system, and 
abdomen (liver and spleen).
Vital sign 
measurements
X
X
X
D2
X
X
X
X
X
Blood pressure and pulse 
measured in triplicate at pre-
dose on Days 1 and 8. Single 
blood pressure and pulse will be 
measured on other study days.
Temperature 
Check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
ECGs on Day 1 will be taken 
pre-dose, and at 2, 4, and 
6 hours post-dose. ECGs on 
Days 8 and 9 will be taken at 2, 
4 and 6 hours post dose. 
Pre-dose ECGs on Day 1 will be 
taken in triplicate. The post-dose 
ECGs are single ECGs.
Drug, alcohol, and 
cotinine screen
X
See Appendix 2 for tests.


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Procedure
Check-
in
Baseline
Period 1
Treatment A 
(Days 1-7)
Period 2
Treatment A + Treatment B + Treatment C (Days 8-21)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day
8
Day
9
Days
10-
12
Day
13
Day
14
Days
15-
16
Day
17
Days 
18-20
Day 
21
Day 
22
Days 
23-25
Day 
26
Laboratory 
assessments 
(hematology, 
clinical chemistry, 
urinalysis)
X
X
X
X
See Appendix 2 for tests.
Molecular Test for 
SARS-CoV-2
X1
D6
X
D20
X
Test to be obtained every 
7 days from Check-in 
(regardless of period or 
washout) while in-house.
1The second test should be 
performed 24 hours prior to 
admission to the unit. 
Participants should be 
quarantined within the unit until 
the second test result is 
negative. Once the second test 
result is confirmed to be 
negative, they can be released 
into the unit and follow infection
control practices.
Pregnancy test 
X
X
Urine pregnancy test to confirm 
status.
Columbia-Suicide 
Severity Rating 
Scale
X
X
X
X
X
See Section 8.2.6 for details.


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Procedure
Check-
in
Baseline
Period 1
Treatment A 
(Days 1-7)
Period 2
Treatment A + Treatment B + Treatment C (Days 8-21)
Notes
Day -2
Day -1
Day
1
Days
2-6
Day 
7
Day
8
Day
9
Days
10-
12
Day
13
Day
14
Days
15-
16
Day
17
Days 
18-20
Day 
21
Day 
22
Days 
23-25
Day 
26
Study 
intervention: 
DRV/RTV and 
ETR (BID)
X
X
X
X
X
X
X
X
X
See Section 6.1 for study 
intervention details.
Study 
intervention: 
GSK3640254 
200 mg (QD)
X
X
X
X
X
X
X
X
X`
X
X
X
See Section 6.1 for study 
intervention details.
DRV/RTV and 
ETR PK sampling
D19, 
D20
X
Pre-dose Days 19, 20, and 21. 
Post Day 21 dose at 0.5, 1, 1.5, 
2, 3, 4, 6, 8, and 12 hours.
GSK3640254 PK 
sampling
D5, 
D6
X
X
X
X
Pre-dose Days 5, 6, and 7. Post 
Day 7 dose at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 12, 16, and 24 hours.
Pre-dose Day 21. Post Day 21
dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12, 16, and 24 hours.
AE review
================================================================================
SAE review
=======================================================================================
Concomitant 
medication review
=======================================================================================
AE = adverse event; BID = twice daily; D = day; DRV = darunavir; ECG = electrocardiogram; ETR = etravirine; PK = pharmacokinetic; QD = once daily; RTV = ritonavir; SAE = serious 
adverse event.

Participants will fast overnight for at least 8 hours prior to breakfast and before the AM dose and for at least 2 hours prior to dinner 
and before the PM dose. Participants will receive the moderate fat meal 30 minutes prior to dosing. Participants will eat this meal 


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in 25 minutes or less. Dose administration will occur within 5 minutes of completion of meal consumption. Refer to Section 5.3.1
for meal timings.

Serial PK blood samples will be collected before (at 0 hour) and after the AM study drug administration at the time points listed. 
For the study interventions that are administered twice daily (BID) (DRV/RTV and ETR), the 12-hour sample will be collected 
before the PM dose.

Day 35 for Cohort 1, Day 36 for Cohort 2, and Day 26 for Cohort 3 is study discharge. Evaluations scheduled for study discharge 
will also be performed for participants who discontinue prior to completing.

The timing of planned study assessments may change during the course of the study based on emerging data/in-stream data review
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing 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 (IRB)/Independent Ethics Committee (IEC) will be informed of 
any safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of 
the informed consent form (ICF). The changes will be approved by the health authority and the ethics committee before 
implementation.


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2.
INTRODUCTION
2.1.
Study Rationale
This is a randomized, open-label, single-sequence, multi-dose study to investigate the 
effects of GSK3640254 200 mg on the pharmacokinetics (PK) of darunavir
(DRV)/ritonavir (RTV) 600/100 mg and/or etravirine (ETR) 200 mg and the effects of 
DRV/RTV 600/100 mg and/or ETR 200 mg on the PK of GSK3640254. This study will 
aid in understanding these interactions and resulting changes in exposure (if any) when 
given in combination with GSK3640254.
2.2.
Background
GSK3640254 is a next generation human immunodeficiency virus (HIV)-1 maturation 
inhibitor (MI) which binds near a key structural element within the group-specific antigen 
(Gag) polyprotein that is required for virion maturation and assembly. Maturation 
inhibitors block the last protease cleavage event between Gag protein segments 
designated as 24-kilodalton HIV capsid protein p24 and spacer peptide 1. Blockage at 
this step results in the release of immature non-infectious virus particles. Other small 
molecules within this class have demonstrated a PK/pharmacodynamic relationship and 
longer-term efficacy through Phase 2a and 2b studies.
At the time of this protocol submission, GSK has completed a Phase 2a study (short-term,
monotherapy, proof of concept) on GSK3640254. Additionally, the safety, tolerability,
and PK have been evaluated in 7 other completed Phase 1 studies in healthy volunteers
up to a maximum dose of 320 mg daily for 14 days. The totality of the clinical data
shows: 1) GSK3640254 is generally well-tolerated in short-term studies, and 2)
GSK3640254 has a short-term PK/PD (decline in HIV-1 RNA) relationship. Summaries
of the preclinical and clinical studies are included in the Clinical Investigator's Brochure
(CIB) [GlaxoSmithKline (GSK) Document Number 2018N379610_01, 2019].
2.2.1.
Key Safety Data with a Prior Maturation Inhibitor (GSK3532795)
Previously, ViiV Healthcare (VH) studied a structurally similar MI, GSK3532795, in the
Phase 2b Study 205891. The Week 24 primary endpoint analysis showed GSK3532795
was not optimal for Phase 3 development due to gastrointestinal (GI) intolerability and
treatment-emergent resistance. Specifically, a relatively higher rate of GI intolerability
(predominately Grade 1 and 2 diarrhea in 38 to 61% of participants and abdominal pain 
in 8 to 22% of participants, respectively) and a higher rate of nucleoside reverse 
transcriptase inhibitor resistance (6.5%) with clinically significant changes in 
GSK3532795 susceptibility which was observed across all 3 GSK3532795 treatment 
arms [Morales-Ramirez, 2018]. Given these clinical and tolerability issues, the sponsor 
terminated Study 205891 and did not advance GSK3532795 into Phase 3 studies.
Aside from mild to moderate GI intolerability, 2 serious adverse events (SAEs) occurred 
in the Phase I thorough QT study AI468044/206220 [Bristol-Myers Squibb Document 
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


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twice daily and 240 mg once daily (QD) with food, respectively. These events were
assessed as related to study drug but were not observed in any other clinical trial with
GSK3532795. The most frequent neuropsychiatric adverse events (AEs) in studies with
GSK3532795 were headache, dizziness, and sleep abnormalities (e.g., insomnia and 
abnormal dreams).
Importantly, neither of these GI or psychiatric safety findings have been reproduced in
the completed or ongoing clinical trials of GSK3640254 in healthy participants or HIV-1
infected treatment-naïve participants.
2.2.2.
Summary of GSK3640254 Clinical Pharmacokinetics
Pharmacokinetic data for clinical studies performed to date are summarized as follows:

Following multiple-dose administration over 50 to 320 mg dose range for 14 days 
with a moderate fat meal in the single ascending dose (SAD)/multiple ascending 
dose (MAD) first time in human (FTIH) Study 207187:
o
Median time of maximum observed concentration (Tmax) ranged between 
3.8 to 4.3 hours.
o
The mean half-life ranged from approximately 22 to 29 hours.
o
There was a slightly less than dose-proportional increase in maximum 
observed concentration (Cmax) and area under the plasma concentration-time 
curve (AUC) from time zero to the end of the dosing interval at steady state 
(AUC[0-tau]) from 50 to 320 mg QD.
o
The exposure on Day 14 was, on average, 1.9- to 2.3-fold higher for Cmax 
and 2.2- to 2.6-fold higher for AUC(0-tau) compared to those on Day 1, which 
is an agreement with half-life estimates.
o
PK variability (between-subject variability) was modest, ranged from 8% to 
50%.

Coadministration with food increases overall GSK3640254 exposure 2- to 4-fold; 
therefore, GSK3640254 is recommended to be taken with food.

There was no clinically meaningful drug interaction between GSK3640254 and 
either tenofovir alafenamide/emtricitabine (Study 208134) or dolutegravir 
(Study 209712).
Additional information regarding clinical PK data can be found in the CIB [GSK 
Document Number 2018N379610_01].
2.2.3.
Summary of GSK3640254 Metabolism
GSK3640254 had low oxidative intrinsic clearance in mouse, rat, dog, monkey, and
human liver microsomes and hepatocytes. Metabolic pathways observed in vitro across 


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species mainly included mono-oxidation, N-dealkylation, and direct glucuronidation, 
with no unique metabolites generated in human liver microsomes or hepatocytes and no 
evidence of metabolic activation. An acyl glucuronide metabolite was formed via direct 
glucuronidation of GSK3640254 and the acyl glucuronide of GSK3640254 was found to 
be stable under conditions of physiological pH and temperature. With recombinant 
cytochrome P450 (CYP) enzymes, GSK3640254 was mainly metabolized by 
CYP3A4/3A5, CYP2C9, CYP1A2 and CYP2C8. GSK3640254 was stable in 
recombinant uridine diphosphate glucuronosyltransferase enzymes.
In rat and dog plasma, GSK3640254 was either the only or the predominant drug-related
component with minor oxidative metabolites (e.g., hydroxylation and N-dealkylation). 
Preliminary analysis of bile samples of bile duct cannulated rats dosed with unlabeled 
GSK3640254 suggested that GSK3640254 was eliminated mainly by direct 
glucuronidation followed by biliary excretion in rats. In human plasma, GSK3640254 
was the predominant drug-related component with low levels of oxidative metabolites as 
shown by preliminary human metabolism study following repeat oral doses of 
320 mg/day. None of the circulating metabolites in human plasma were quantifiable by 
nuclear magnetic resonance analysis. Additional information regarding GSK3640254 
metabolism can be found in the CIB [GSK Document Number 2018N379610_01].
2.2.4.
Preclinical Summary with GSK3640254
Pharmacokinetics and product metabolism in animals
Following intravenous administration, GSK3640254 exhibited low systemic clearance, 
high volume distribution, and elimination half-life of 5.06, 4.0, 18.7 and 5.3 hours in 
mouse, rats, dogs and monkeys, respectively. GSK3640254 was eliminated mainly by
direct glucuronidation followed by biliary excretion in bile-duct-cannulated rats.
Following repeat oral administration in the rat and dog, increases in systemic exposure to
GSK3640254 was generally sub-proportional with dose. There was no or minimal
accumulation of GSK3640254 after repeat dosing, and no consistent indication of a
difference in exposure between genders.
Metabolic pathways observed in vitro included mono-oxidation, N-dealkylation, and
direct glucuronidation with no unique metabolites generated in human liver microsomes
or hepatocytes. In rat and dog plasma, GSK3640254 was either the only or the
predominant drug-related component with minor oxidative metabolites. Based on the 
predicted systemic exposures in human, there is a potential risk for GSK3640254 to act 
as a perpetrator of drug-drug interactions (DDIs) of substrates of OATP1B3 and MRP2. 
GSK3640254 was an inhibitor of UGT1A1 and clinical DDIs via this mechanism could 
be possible.
Toxicology
The primary target organ of toxicity in non-clinical studies with GSK3640254 was 
stomach, with microscopic changes affecting parietal and chief cells in mice, rats and 
dogs.  Following four weeks of dosing in rats, the no observed adverse effect level 
(NOAEL) for microscopic findings in the stomach was 10 mg/kg/day (AUC = 22.4 
ug.hr/mL).  In the 4-week studies in rats and dogs, microscopic findings in the stomach 


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CCI


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
Across studies, low grade GI intolerability has been observed: the majority were 
mild. Both Studies 207187 (MAD) and 208312 (proof of concept) are relevant to 
this study given dosing of 7 to 14 days; most AEs in 207187 were unrelated and 
most AEs in 208132 were related.

Across studies, there were generally no clinically significant changes in vital sign 
measurements, ECG results, or safety laboratory parameters (other than the 
elevated transaminases due to Portia, noted above). Specifically, no participant 
has demonstrated QT prolongation: absolute value >500 msec or an increase from 
baseline >60 msec.

With the exception of elevated transaminases as noted above, across studies there 
were generally no clinically significant changes in vital sign measurements, ECG 
results, or safety laboratory parameters.
The full safety profile for GSK3640254 can be found in the CIB [GSK Document 
Number 2018N379610_01].
2.2.5.1.
Cardiac Safety
A cardiodynamic evaluation of healthy participants in the MAD portion of Study 207187 
[GSK Document Number 2020N430256_00] (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. 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 cohorts. In the concentration-corrected QT interval 
(C-QTc) analysis, a final model with a treatment effect-specific intercept reasonably 
represented the data. The slope of the C-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 C-QTc analysis, a QTc using the Fridericia formula (QTcF) effect 
above 10 ms could be excluded in GSK3640254 plasma concentrations of up to 
approximately 2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, 
the dose used in the current study will be 200 mg QD).
2.2.6.
Drug Interaction Potential with Darunavir/Ritonavir and Etravirine
This study is being conducted to investigate any potential DDIs when GSK3640254 is 
co-administered with DRV/RTV and ETR. Darunavir/RTV and ETR are commonly used 
in HIV-infected treatment-experienced (HTE) patients. GSK3640254 is primarily
metabolized by CYP3A4/3A5, CYP2C9, CYP1A2, and CYP2C8. Co-administration of 
GSK3640254 with DRV/RTV may increase GSK3640254 exposure due to inhibition of 
CYP3A4 by DRV/RTV. Etravirine is a substrate and moderate inducer of CYP3A4 and a 
weak inhibitor of CYP2C9, CYP2C19, and P-glycoprotein (P-gp). Thus, 
co-administration of GSK3640254 with ETR may decrease or increase GSK3640254


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exposure. Co-administration of GSK3640254 with both DRV/RTV and ETR may result
in no net effect.
The mean systemic exposure (AUC) of ETR was reduced when ETR was 
co-administered with DRV/RTV. Because all participants in the Phase 3 studies received 
DRV/RTV as part of the background regimen and ETR exposures from these studies 
were determined to be safe and effective, ETR and DRV/RTV can be co-administered 
without dose adjustments [Intelence Product Information, 2019].
Ritonavir (Norvir)
Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. 
Inhibition of HIV protease renders the enzyme incapable of processing the Gag-pol 
polyprotein precursor, which leads to production of noninfectious immature HIV 
particles. The PK behavior of RTV has been studied in healthy participants and 
HIV-infected patients. After a 600-mg dose of oral solution, peak concentrations of RTV
were achieved approximately 2 and 4 hours after dosing under fasting and non-fasting 
conditions, respectively. In vitro studies utilizing human liver microsomes have 
demonstrated that CYP3A is the major isoform involved in RTV metabolism, although 
CYP2D6 also contributes. Ritonavir inhibits CYP3A in vitro and in vivo. Agents that are 
extensively metabolized by CYP3A and have high first-pass metabolism appear to be the 
most susceptible to large increases in AUC (>3-fold) when co-administered with RTV. 
Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of 
CYP2D6 with RTV could result in increases (up to 2-fold) in the AUC of the other agent, 
possibly requiring a proportional dosage reduction. Ritonavir also appears to induce 
CYP3A as well as other enzymes, including glucuronosyl transferase, CYP1A2, and 
possibly CYP2C9 and CYP2C19.
Ritonavir is rarely used as monotherapy at the original therapeutic dose of 600 mg 
administered BID because of the high incidence of a variety of side effects. The fact that 
RTV is a potent inhibitor of CYP-based metabolism has been employed to increase the 
exposure of other co-administered HIV protease inhibitors, which are better tolerated
[Aarnoutse, 2004; Piliero, 2001]. Ritonavir achieves its metabolic inhibition at doses, 
which are much lower than therapeutic; for example, 100 mg QD when combined with 
atazanavir will boost the Cmax and AUC of atazanavir [Norvir Product Information, 
2019]. The most frequent AEs reported in participants receiving RTV as monotherapy or 
in combination with nucleoside analogues include asthenia, nausea, vomiting, abdominal 
pain, diarrhea, anorexia, taste perversion, circumoral paresthesia, peripheral neuropathy, 
dizziness, and insomnia. Laboratory abnormalities reported with the use of RTV include 
elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
levels, nonfasting triglyceride, cholesterol, creatine phosphokinase, and uric acid. The 
frequency of AEs following administration of low-dose RTV is not well known, as it 
would not be administered alone, in such low doses. However, it is expected that the 
incidence of AEs would be reduced at low doses.


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Darunavir (Prezista)
Darunavir is an inhibitor of HIV-1 protease. Darunavir is primarily metabolized by 
CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of 
DRV. When a single dose of DRV 600 mg was given orally in combination with 100 mg 
RTV BID, there was an approximate 14-fold increase in the systemic exposure of DRV. 
Therefore, DRV is used in combination with 100 mg of RTV to achieve sufficient 
exposures of DRV. 
The PK behavior of DRV co-administered with low dose RTV (100 mg) has been studied 
in healthy participants and HIV-infected patients (Prezista Product Information, 2019). 
Following 600 mg DRV co-administered with 100 mg RTV BID orally, a Tmax of 
approximately 2.5 to 4 hours was established. The terminal elimination half-life of DRV
was approximately 15 hours when co-administered with RTV. The absolute oral 
bioavailability of a single 600-mg dose of DRV alone and after co-administration with 
100 mg RTV BID was 37% and 82%, respectively. When DRV was administered with 
food, the Cmax and AUC of DRV, co-administered with RTV, are approximately 40% 
higher relative to the fasting state. Therefore, DRV, co-administered with RTV, should 
always be taken with food. Within the range of meals studied, DRV exposure is similar.
In vivo data suggest that DRV/RTV is an inhibitor of the P-gp transporters. Additionally, 
DRV is extensively metabolized by CYP enzymes, primarily by CYP3A.
In clinical studies of HIV treatment-naïve participants receiving DRV 800 mg and RTV
100 mg QD, the majority of AEs reported were mild in severity. The most common AEs 
were diarrhea, headache, abdominal pain, and rash. Less common AEs included acute 
pancreatitis, dyspepsia, flatulence, asthenia, acute hepatitis, hypersensitivity, diabetes 
mellitus, myalgia, abnormal dreams, angioedema, pruritus, Stevens-Johnson syndrome, 
and urticaria.
Etravirine (IntelenceTM)
Etravirine in combination with other antiretroviral agents is indicated for the treatment of 
HIV-1 infection in antiretroviral-treatment-experienced adult patients who have evidence 
of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase 
inhibitor and other antiretroviral agents. The PK behavior of ETR has been studied in 
healthy participants and treatment-experienced HIV-infected patients. Following oral 
administration, ETR was absorbed with a Tmax of approximately 2.5 to 4 hours. The 
absolute oral bioavailability is unknown [Intelence Product Information, 2019]. The 
systemic exposure (AUC) to ETR was decreased by approximately 50% when 
administered under fasting conditions compared with when administered after a meal. 
Within the range of meals studied, the systemic exposures to ETR were similar.
In vitro experiments with human liver microsomes indicate that ETR primarily undergoes 
metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. Etravirine is an inducer of 
CYP3A and inhibitor of CYP2C9, CYP2C19, and P-gp. Therefore, co-administration of 
drugs that are inhibitors, inducers, or substrates of CYP3A, CYP2C9, and CP2C19 or are 
transported by P-gp with ETR may alter the therapeutic effect or adverse reaction profile 
of ETR and/or the co-administered drug(s). The most common AEs reported after 
administration of ETR include rash, Stevens-Johnson syndrome, hypersensitivity 


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reaction, and erythema multiforme. Some of the AEs reported in HIV-infected 
participants are not expected in healthy participants. Darunavir co-administered with low 
dose RTV and ETR 200 mg twice daily can be used without dose adjustments.
Given the complexity of the drug-drug interaction mechanism, an estimation of the extent 
of the expected interaction is difficult. However, data from a similar DDI study 
conducted with the structurally-similar prior MI GSK3532795, showed a maximum 
increase in GSK3532795 Cmax and AUC(0-) of approximately two-fold, following 
coadministration with DRV/RTV (600/100 mg BID) and ETR (200 mg BID).   A similar 
fold increase in exposure for GSK3640254 would result in a Cmax and AUC at steady 
state of approximately 4.4 ug/mL and 60 ug.hr/mL, respectively.
2.3.
Benefit/Risk Assessment
Based upon preclinical and clinical studies (including the prior MI GSK3532795), the 
potential risks for GSK3640254 are GI intolerability (e.g., abdominal pain and diarrhea) 
and gastric toxicity (effects on parietal cell and chief cells), prolongation of the QTc, 
neuropsychiatric safety, and rash.
First, GI intolerability will be assessed using clinical monitoring as outlined in 
Section 8.2.7.
Second, prolongation of the QTc interval is a risk. One preclinical trial showed 1 dog 
with an increased QTc interval when given a single dose of GSK3640254. A 
cardiodynamic analysis of healthy participants in Study 207187 was conducted and is 
summarized above (Phase 2b study). Importantly, in GSK3640254 clinical studies to 
date, there have been no abnormal clinically significant arrhythmias, and no participants 
met the trial based QTc stopping criteria for QTcF prolongations: values >500 ms or 
increases >60 ms from baseline. This study contains specific cardiac exclusion criteria, 
has ECG monitoring (at Tmax once GSK3640254 attains steady state concentration), and 
has QTcF based stopping criteria (See Section 7.1.2).
Third, given the risk of psychiatric risks seen with GSK3532795 (see Section 2.2.1) the 
protocol will exclude potential participants with any significant pre-existing psychiatric 
condition or positive (abnormal) response on the Columbia-Suicide Severity Rating Scale 
(C-SSRS). Participants will also be required to provide response to the C-SSRS during 
the on-treatment portion of the study – and will be clinically evaluated for suicidality as 
indicated (See Section 7.1.4 and Section 8.2.6).
Across clinical trials, AEs leading to discontinuation have included urticaria and 
maculopapular rash. This study includes individual participant stopping criteria for any 
Grade 3 or higher rash or Grade 2 rash with evidence of systemic involvement or any 
allergic or hypersensitivity reactions.
To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability, QTc prolongation, neuropsychiatric safety, and rash), this clinical study 
will include healthy adults who will receive clinical, ECG, and laboratory evaluations 
during their participation while confined to the clinic. More detailed information about 


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the known and expected benefits and risks and reasonably expected AEs of GSK3640254 
may be found in the CIB [GSK Document Number 2018N379610_01].


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2.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3640254
Cardiovascular (QT 
prolongation) 
Preclinically, GSK3640254 inhibited cardiac hERG/IKr potassium, cardiac 
SCN5A sodium and L-type calcium channel currents recorded from HEK 
293 cells stably transfected with complementary deoxyribonucleic acid 
(DNA) from the ion channels. In a single-dose safety pharmacology study in 
telemeterized dogs, increases in QT interval (up to 20 ms) occurred 
primarily in 1 dog given 17 mg/kg. The no observed adverse effect level in 
the study was 12.5 mg/kg, which produced similar systemic exposures 
(8.79 μg/mL, 2 × the mean Cmax associated with the highest anticipated 
exposure (4.4 μg/mL) in the this study. Later, there were no 
GSK3640254-related effects on ECG parameters in dogs given up to 
25 mg/kg/day for 4 weeks.
In the FTIH study 207187 (doses up to 700 mg in SAD and 320 mg QD for 
14 days in MAD), no participant exhibited QTc change from Baseline 
>60 ms or QTc >500 ms. As described in Section 2.2.5.1, in the 
concentration-QTc analysis, a QTcF effect above 10 ms could be excluded 
for GSK3640254 plasma concentrations of up to approximately 2000 ng/mL 
(corresponding to doses approximately 200 mg QD).
Screening: Protocol exclusion criteria based on 
screening ECG parameters and cardiac medical history.
On-Treatment: Participants will have ECG monitoring (at 
a clinically reasonable frequency) during the course of the 
study (see SoA, Section 1.3) with QTc stopping criteria 
(see Section 7.1.2).
GI intolerability and 
toxicity
Observations indicative of GI intolerability (sporadic vomiting and abnormal 
feces beginning on Day 1 and continuing throughout the dosing periods) 
occurred mainly in dogs at 1 mg/kg/day Additionally, toxicity findings of 
single-cell necrosis of parietal cells and/or chief cells were present in 
preclinical species. In a 4-week oral toxicity study in rats, at the lowest 
affected dose of 30 mg/kg/day (AUC=61.1 ug.hr/mL, approximately equal to 
the highest anticipated exposure in this study), these findings were minimal 
and reversible. 
Gastrointestinal intolerability (predominantly abdominal pain and diarrhea) 
was seen with a structurally related compound GSK3532795 which was 
Screening: Protocol exclusion criterion based on pre-
existing GI pathology or baseline GI signs/symptoms.
On-Treatment: Participants will undergo continuous 
evaluation for AEs during their participation in the study; 
there will be individual clinical stopping criteria based 
upon intensity of treatment-emergent AEs. A GI 
intolerability evaluation and monitoring plan is available to 
guide investigators should GI AEs emerge (see 
Section 8.2.7).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
evaluated through Phase 2b dosing. (Note: in the FTIH study 207187, 
AUC = 46.4 to 73.3 μg*h/mL; 2.6 to 4.2 × the mean AUC associated with 
the 200 mg multiple dose [17.5 μg*h/mL]). No clinical trends in the system 
organ class of GI AEs have been seen across Phase 1 to 2a GSK3640254 
clinical trials.
Neurologic/psychiatric 
safety
Two psychiatric SAEs in previous maturation inhibitor GSK3532795 clinical 
program (acute psychosis, homicidal/suicidal ideation) were seen at 
supratherapeutic doses in healthy participants in the thorough QT (TQT) 
study.
From a neurologic and psychiatric AE summary and PK/pharmacodynamic 
analysis for GSK3532795 across all studies, Grade 1 headache and Grade 
1 sleep abnormalities were the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing dose (based on TQT and 
Phase 2b studies). No exposure-response relationship was seen for select 
neurologic and psychiatric AEs (based on TQT and Phase 2b studies). 
Central nervous system penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low brain 
distribution/penetration.
No clinical trends in the system organ class of neurologic or psychiatric AEs 
have been observed across the Phase 1 to 2a clinical trials.
Screening: Protocol exclusion criterion based on any 
pre-existing psychiatric condition (including results of 
psychological assessment) for participants. Participants 
will have a clinician (or qualified designee) administered 
C-SSRS and will be included given no positive (abnormal) 
response.
On-Treatment: Participants will undergo physical 
examinations and laboratory testing. In addition, 
participants will undergo continuous evaluation for AEs 
during their participation in the study; there are individual 
clinical stopping criteria and monitoring based upon 
incidence and intensity of treatment-emergent psychiatric 
AEs (Section 7.1.5 and Section 8.2.6). 
Participants will be housed throughout study conduct to 
ensure rapid diagnosis and management of any potential 
event.
Participants will also provide responses to the C-SSRS 
throughout the study. Ultimately, in the event of a new 
onset suicidality ideation or behavior, as determined by 
the investigator (in consultation with psychiatry, as 
needed), the participant will discontinue from the study 
and the investigator will arrange for urgent specialist 
psychiatric evaluation and management. Guidance for the 
investigator on the management of emergent psychiatric 
symptoms is available (Section 8.2.6).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Rash
Across clinical trials, AEs leading to discontinuation have included urticaria 
and maculopapular rash.
Screening: A physical examination, including skin 
assessment, will be performed at screening.
On-Treatment: Participants will undergo continuous 
evaluation for AEs during their participation in the trial 
supplemented by the use of physical exams.
Protocol includes individual participant stopping criteria, 
including: 

Any Grade 3 or higher rash or Grade 2 rash with 
evidence of systemic involvement

Any allergic or hypersensitivity reactions (Section 
7.1.3)
Darunavir/Ritonavir
Drug-induced 
hepatitis
Drug-induced hepatitis has been reported with DRV/RTV.
Screening: Protocol exclusion criteria based on 
screening liver function tests.
On-Treatment: Participants will be monitored by clinical 
laboratory testing for liver function tests (see SoA, 
Section 1.3) with protocol defined stopping criteria (see 
Section 7.1.5.
Etravirine
Skin reactions
Severe, potentially life-threatening, and fatal skin reactions have been 
reported. These include cases of Stevens-Johnson syndrome, toxic 
epidermal necrolysis and erythema multiforme. Hypersensitivity reactions 
including drug rash with eosinophilia and symptoms have also been reported 
and were characterized by rash, constitutional findings, and sometimes 
organ dysfunction, including hepatic failure.
Screening: A physical examination of the skin will be 
performed at screening.
On Treatment: Participants will have brief physical 
examinations that will include assessment of the skin at
specific time points throughout the study (See SoA, 
Section 1.3). Participants presenting with a Grade 3 or 
higher rash or a Grade 2 rash with evidence of systemic 
involvement will be followed until AE resolution per 
Section 7.1.3. Skin stopping criteria can be found in 
Section 7.1.3.


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2.3.2.
Benefit Assessment
This is a study in healthy participants; no medical benefit will be derived by participants’ 
participation.
2.3.3.
Overall Benefit: Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the clinical data gathered from Phase 1 and 2a studies, and the 
planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 and co-administered multiple doses of the potential 
interaction drugs are low, evaluable, and manageable.
The drugs with the potential for a drug interaction in this study are commonly used in 
clinical practice for HIV-1 infected patients and have a well-characterized and acceptable 
safety profile. Given that only healthy participants will be enrolled and that participants 
will be confined to a clinical facility after dosing with the drugs of potential interaction, 
the safety risk of participation in this study is expected to be low. To minimize risk 
further, the protocol contains exclusions relevant to the study intervention and prohibits 
the concurrent intake of potentially interacting drugs or foods that might increase the 
concentrations of study intervention.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Cohort 1

To assess the effect of co-administration of 
DRV/RTV 600/100 mg BID with GSK3640254 
200 mg QD on the PK of GSK3640254 in 
healthy participants 

To assess the effect of co-administration of 
DRV/RTV 600/100 mg BID with GSK3640254 
200 mg QD on the PK of DRV/RTV in healthy 
participants.

AUC(0-tau), and Cmax for 
GSK3640254

AUC(0-tau), and Cmax for 
DRV/RTV
Cohort 2

To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of GSK3640254 in healthy 
participants.

To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of ETR in healthy participants. 

AUC(0-tau), and Cmax for 
GSK3640254

AUC(0-tau), and Cmax for ETR
Cohort 3

To assess the effect of co-administration of 
ETR 200 mg BID and DRV/RTV 600/100 mg 

AUC(0-tau), and Cmax for 
GSK3640254


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Objectives
Endpoints
BID with GSK3640254 200 mg QD on the PK of 
GSK3640254 in healthy participants.
Secondary
Cohort 1

To assess the effect of co-administration of 
GSK3640254 200 mg QD with DRV/RTV 
600/100 mg BID on the secondary PK 
parameters of DRV and RTV in healthy 
participants.

Ctau, and Tmax for DRV, RTV, and 
GSK3640254
Cohort 2

To assess the effect of co-administration of 
GSK3640254 200 mg QD with ETR 200 mg 
BID on the secondary PK parameters of ETR in 
healthy participants.

Ctau, and Tmax for ETR, and 
GSK3640254
Cohort 
1, 2 & 3

To assess the safety and tolerability of 
GSK3640254 administered alone and in 
combination with DRV/RTV and ETR.

Safety and tolerability endpoints 
include incidence of AEs, SAEs, 
AEs leading to discontinuation, 
deaths, marked laboratory 
abnormalities, and abnormalities in 
vital signs and 12-lead ECGs.
AE = adverse event; AUC(0-tau) = area under the plasma concentration-time curve from time zero to the end of the 
dosing interval at steady state; BID = twice daily; DRV = darunavir; Cmax = maximum observed concentration, 
Ctau = plasma concentration at the end of the dosing interval; ECG = electrocardiogram; ETR = etravirine; 
PK = pharmacokinetics; QD = once daily; RTV = ritonavir; SAE = serious adverse event; Tmax = time of maximum 
observed concentration.
4.
STUDY DESIGN
4.1.
Overall Design
This is an open-label, single-sequence, multiple-dose, 3 cohort study to investigate the 
effects of DRV/RTV 600 mg/100 mg and/or ETR 200 mg on the PK of GSK3640254 
200 mg and the effects of GSK3640254 200 mg on the PK of DRV/RTV 600/100 mg 
and/or ETR 200 mg.
The study will consist of a screening period and a treatment period. Participants will be 
screened within 28 days before the first dose of study intervention.
Participants will be randomly assigned to a cohort and will receive the following 
treatments in each cohort:
Cohort 1: 

Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 to 7.

Period 2: DRV/RTV 600/100 mg tablets BID (Treatment B) on Days 12 
through 21.


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
Period 3: GSK3640254 200 mg tablets QD (Treatment A) and DRV/RTV
600/100 mg tablets BID (Treatment B) on Days 22 through 31.
Cohort 2: 

Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 to 7.

Period 2: ETR 200 mg tablets BID (Treatment C) on Days 12 through 21.

Period 3: GSK3640254 200 mg tablets QD (Treatment A) and ETR 200 mg 
tablets BID (Treatment C) on Days 22 through 31.
Cohort 3: 

Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 to 7

Period 2: GSK3640254 200 mg tablets QD (Treatment A), DRV/RTV
600/100 mg tablets BID (Treatment B), and ETR 200 mg tablets BID
(Treatment C) on Days 8 through 21
All doses of all study interventions will be administered under fed conditions. The 
participants will fast overnight for at least 8 hours prior to breakfast and before the AM 
dose and for at least 2 hours prior to dinner and before the PM dose. A moderate fat meal
(defined as approximately 600 calories, 30% from fat) will be consumed 30 minutes prior 
to dosing. Participants will eat this meal in 25 minutes or less. Dose administration will 
occur within 5 minutes of completion of meal consumption.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be obtained at the 
following time points:

Cohorts 1 and 2:
o
Pre-dose on Days 5, 6, and 7 and up to 24 hours following dosing on 
Day 7 (Period 1)
o
Pre-dose on Days 29, 30, and 31 and up to 24 hours following dosing on 
Day 31 (Period 3)

Cohort 3: 
o
Pre-dose on Days 5, 6, and 7 and up to 24 hours following dosing on 
Day 7 (Period 1)
o
Pre-dose and up to 24 hours following dosing on Day 21 (Period 2)
Pharmacokinetic blood samples for the analysis of DRV/RTV and/or ETR will be 
obtained at the following time points:

Cohorts 1 and 2:
o
Pre-dose on Days 19, 20, and 21 and up to 12 hours following dosing on 
Day 21 (Period 2)
o
Pre-dose and up to 12 hours following dosing on Day 31 (Period 3)

Cohort 3:
o
Pre-dose on Days 19, 20, and 21 and up to 12 hours following dosing on 
Day 21 (Period 3).


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Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings.
Study assessments will be performed as indicated in the Schedule of Activities (SoA)
(Section 1.3). Participants will be confined to the study site from Day -1 until study 
discharge on Day 35 for Cohort 1, Day 36 for Cohort 2, and Day 26 for Cohort 3. The 
duration of the study, including screening, is approximately 63 days for Cohort 1, 64 days 
for Cohort 2, and 54 days for Cohort 3.
4.2.
Scientific Rationale for Study Design
This study is being conducted to investigate any potential DDIs when GSK3640254 is 
co-administered with DRV/RTV and/or ETR. Darunavir/RTV and ETR are commonly 
used in treatment experienced (including Heavily Ttreatment Experienced) HIV-1 
infected patients.
GSK3640254 is primarily metabolized by CYP3A4/3A5, CYP2C9, CYP1A2, and
CYP2C8. The co-administration of DRV/RTV with GSK3640254 may increase 
GSK3640254 exposure due to inhibition of CYP3A4 by DRV/RTV. The 
co-administration of ETR with GSK3640254 may decrease GSK3640254 exposure due 
to induction of CYP3A4 by ETR. Co-administration of GSK3640254 with DRV/RTV
and ETR may result in no net effect on any of the PK parameters.
This study is designed in accordance with the US Food and Drug Administration 
Guidance for Industry, Clinical Drug Interaction Studies - Study Design, Data Analysis, 
and Clinical Implications [DHHS, 2017] to assess the PK, safety, and tolerability of 
GSK3640254 and the drugs of potential interaction when administered alone and in 
combination. The drugs with potential for a DDI used in this study are DRV/RTV
600/100 mg and ETR 200 mg.
4.3.
Justification for Dose
A dose of 200 mg GSK3640254 was selected for this study as it is the maximum 
projected clinical dose. The apparent terminal phase half-life of GSK3640254 was 
approximately 22 hours in the MAD portion of Study 207187 [GSK Document Number
2020N430256_00] at the 200-mg dose and predicted time to steady state is approximately 
5 days. The 200 mg dose is the top dose to be evaluated in a longitudinal Phase 2b dose 
range finding study of GSK3640254 (Study 208379).
Dosing of GSK3640254 QD from Days 1 to 7 (Period 1) and Days 22 to 31 (Period 3) in 
Cohorts 1 and 2 will be sufficient to bring plasma concentrations to steady state. For 
Cohort 3, there is no subsequent need for a washout of GSK3640254 following Period 1 
since the primary remaining evaluation is for the co-administered DRV/RTV and ETR
and GSK3640254 at steady state.
Doses of DRV/RTV 600/100 mg BID and ETR 200 mg BID are commonly used for 
HIV-1 infected patients . Further information on DRV/RTV and ETR is provided in 
Section 2.2.4. 


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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 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 the last scheduled procedure shown in the SoA (Section 1.3) for the last 
participant in the study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by investigator or medically 
qualified designee based on a medical evaluation including medical history, physical 
examination, laboratory tests, and cardiac monitoring (history and screening 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
Sex and Contraceptive/Barrier Requirements
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.
Male participants:
1. Males participants should not engage in intercourse while confined in the 
study site. There is no need for an extended period of double barrier use or 
prolonged abstinence after study discharge.


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b. Female participants:
1. A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one 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 or urine pregnancy 
test (Appendix 2) at screening and check-in (Day -1).
3. Additional requirements for pregnancy testing during and after study 
intervention are outlined in Appendix 2.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 4, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
2.
A pre-existing condition interfering with normal GI anatomy or motility 
(e.g., gastroesophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or renal 
function that could interfere with the absorption, metabolism, and/or excretion of the 
study intervention or render the participant unable to take oral study intervention.
3.
Prior cholecystectomy surgery (prior appendectomy is acceptable).
4.
Clinically significant illness, including viral syndromes within 3 weeks of dosing.
5.
A participant with known or suspected active COVID-19 infection OR contact with 
an individual with known COVID-19, within 14 days of study enrollment (World 
Health Organization [WHO] definitions in Appendix 7).


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6.
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.
7.
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.
8.
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.
9.
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
10. Presence of hepatitis B surface antigen at screening or within 3 months prior to 
starting study intervention.
11. Positive hepatitis C antibody test result at screening or within 3 months prior to 
starting study intervention.
12. Positive HIV-1 and -2 antigen/antibody immunoassay at screening.
13. ALT >1.5 × upper limit of normal (ULN). A single repeat of ALT is allowed within 
a single screening period to determine eligibility.
14. 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.
15. Any acute laboratory abnormality at screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound.
16. Any Grade 2 to 4 laboratory abnormality at screening, with the exception of creatine 
phosphokinase (CPK), 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.
17. Urine drug screen positive (showing presence of): amphetamines, barbiturates, 
cannabinoids, cocaine, or phencyclidine, or nonprescribed opiates, oxycodone, 
benzodiazepines, methadone, MDMA, methamphetamines, or tricyclic 
antidepressants at screening or before the first dose of study intervention


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Prior/Concomitant Therapy
18. 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.)
19. Treatment with any vaccine within 30 days prior to receiving study intervention.
20. Unwillingness to abstain from excessive consumption (defined in Section 5.3.1) 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
21. 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).
22. Prior intolerance to GSK3640254, DRV/RTV or ETR in this or another clinical 
study.
23. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
Diagnostic assessments
24. Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS.
25. A sustained supine systolic blood pressure >140 mm Hg or <90 mm Hg or a supine 
diastolic blood pressure >95 mm Hg or <50 mm Hg at Screening or Check-in . Up to 
2 repeats are allowed for confirmation.
26. 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, any degree of 
atrioventricular 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.


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27. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Heart rate 1
<50 or >100 bpm
PR interval
>200 ms
QTc2
>450 ms
1
A heart rate from 100 to 110 bpm can be rechecked by ECG 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. The investigator’s or ViiV medical monitor’s over-read can supersede that 
of the machine at any time.
Other Exclusions
28. 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.
29. Unable to refrain from tobacco or nicotine-containing products within 3 months prior 
to screening.
30. 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

Abstain 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 1 glass of wine or 8 oz juice or one of these 
fruits per day, in combination.

All doses of GSK3640254 and DRV/RTV and ETR in this study will be 
administered in the fed state. Participants will fast overnight for at least 8 hours 
before breakfast and prior to the AM dose and for at least 2 hours before dinner 
and prior to the PM dose. Participants will receive a moderate fat meal 30 minutes 
prior to dosing. Participants will eat this meal in 25 minutes or less. Dose 
administration will occur within 5 minutes of the completion of meal 
consumption. Participants will not receive any further food until 4 hours post-dose 
on serial PK sampling days (Days 7, 21, and 31 for Cohorts 1 and 2 and Days 7 
and 21 for Cohort 3). The moderate fat meal will contain about 600 calories with 
approximately 30% of the calories coming from fat.

A standard lunch will be provided approximately 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.

No water is allowed from 1 hour prior to dosing until 1 hour after dosing with 
GSK3640254 and/or DRV/RTV and ETR drugs (both AM and PM dose) except 


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for the glass of water needed to administer the study intervention (e.g., 240 mL). 
Water is allowed ad libitum at all other times. If necessary, additional water may 
be administered to allow dosing of all medications, but the additional volume of 
water must be kept to a minimum. The amount of additional water should be 
documented in the source documents.
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 on 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 publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, any protocol deviations, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
5.5.
Criteria for Temporarily Delaying
Not applicable.
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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6.1.
Study Interventions Administered
Intervention Name
GSK3640254
Darunavir
Ritonavir
Etravirine
Type 
Drug
Drug
Drug
Drug
Dose Formulation
Tablet
Tablet
Tablet
Tablet
Unit Dose Strengths
100 mg
600 mg
100 mg
200 mg
Dosage Levels
200 mg
600 mg
100 mg
200 mg
Route of Administration
oral
oral
oral
oral
IMP and NIMP
IMP
IMP
IMP
IMP
Sourcing
Sourced by Sponsor
Sourced by PPD
Packaging and Labeling
Provided in bulk by GSK. 
The investigator will 
package in high-density 
polyethylene bottles. 
Each bottle will be 
labeled as required per 
country requirement.
In accordance with product label
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. In the case of unintentional 
occupational exposure notify the monitor, medical monitor, and/or VH/GSK study 
contact.
6.
A Material Safety Data Sheet/equivalent document describing occupational hazards 
and recommended handling precautions will either be provided to the investigator, 
where this is required by local laws, or is available upon request from VH/GSK.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. Study participants in each cohort will receive the same 
treatments in the same sequence.
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 staff will examine 
each participant’s mouth to ensure that the study intervention was ingested.
6.5.
Dose Modification
Not applicable.
6.6.
Continued Access to Study Intervention after the End of the 
Study
Participants will not receive any additional treatment from VH/GSK or with 
GSK3640254, DRV/RTV or ETR after the completion of the study because only healthy 
participants are eligible for study participation.
6.7.
Treatment of Overdose
For this study, any dose of GSK3640254, DRV/RTV, or ETR 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 of GSK3640254. The 
investigator will use clinical judgment to treat an overdose.
Human experience of acute overdose with ETR or DRV co-administered with low dose 
RTV is limited. There is no specific antidote for an overdose with either DRV/RTV or 
ETR. Treatment of an overdose consists of general supportive measures including 
monitoring of vital signs and observation of the clinical status of the participant. Since 
DRV and ETR are highly protein bound, dialysis is unlikely to be beneficial in significant 
removal of the active substances.
In the event of an overdose, the investigator should:
1.
Contact the medical monitor immediately.


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2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254, DRV/RTV, or ETR 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 
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 case report form (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.
6.8.
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 CRF. Other medications are not permitted without prior discussion with the VH/GSK 
medical monitor.
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.
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 value ≥3 × ULN or if the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Note, if ALT ≥3 × ULN AND bilirubin 2 × ULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, the event will be reported as an SAE.
Details of liver safety follow-up procedures are described in Appendix 5.


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7.1.2.
QTc Stopping Criteria
The same correction formula (QTcF) must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.

The ECG taken on Day -1 will be a single reading to confirm eligibility. The
intra-period pre-dose time point ECGs on Days 1, 12, and 22 for Cohorts 1 and 2 
and Day 1 for Cohort 3 will generate a triplicate averaged QTcF (over a brief 
approximately 5- to 10-minute recording period). This pre-dose triplicate 
averaged QTcF value will serve as the baseline for the applicable study period.
For example, in Cohorts 1 and 2, the pre-dose triplicate ECGs on Days 1, 12, and 
22 will serve as the basis for the Baseline QTcF for Periods 1, 2, and 3, 
respectively. In contrast, in Cohort 3, pre-dose triplicate ECG will only be taken 
on Day 1. 

An enrolled participant that develops an on-treatment QTcF >500 ms or an 
increase from Baseline QTcF >60 ms should have 2 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 1) a complete, unscheduled chemistry panel, 
2) an unscheduled GSK3640254 PK sample, and 3) repeated unscheduled ECGs 
until their QTc measurement returns to their original averaged QTcF value at 
Day 1 pre-dose.
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.
Rash/Hypersensitivity Evaluation Criteria
A participant presenting with a Grade 3 AE or higher rash (diffuse macular, 
maculopapular, OR morbilliform rash with vesicles or limited number of bullae; OR 
superficial ulcerations of mucous membrane limited to 1 site) or a Grade 2 rash (diffuse 
macular, maculopapular, or morbilliform rash; OR target lesions) with evidence of 
systemic involvement will be followed as appropriate until resolution of the AE(s).
7.1.4.
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 immediate clinical assessment of suicidality (by the investigator 
or a consulting psychiatrist). Emergence of new onset suicidal ideation or a Grade 3 or 
higher psychiatric AE will result in immediate discontinuation and urgent specialist 
psychiatric evaluation and management.
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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7.1.5.
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 or abnormalities in vital sign measurements, 
laboratory results or ECGs deemed to require discontinuation of study 
intervention; however, participants will continue to be clinically evaluated as 
necessary to ensure their safety

Any Division of AIDS (DAIDS) (Appendix 8) Grade 3 or higher rash or Grade 2 
rash with evidence of systemic involvement

Any allergic or hypersensitivity reactions to study intervention

Any DAIDS Grade 3 or higher psychiatric AE

New onset suicidal ideation

Any DAIDS Grade 3 or higher AE related to study intervention

Any DAIDS Grade 4 AE

DAIDS Grade 3 or higher laboratory abnormalities
A participant must permanently discontinue study intervention and be
discontinued from the study if they have COVID-19 infection as clinically
determined by the investigator (suspected, probable, or confirmed using the
most recent version of the WHO case definition. Note: if this occurs, all other
participants within the same cohort as the participant who developed COVID-19
infection will be discharged from the site regardless of whether or not they are
symptomatic.
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, or compliance reasons. This is expected to be uncommon.

A participant who is withdrawn from the study for any reason related to safety 
(listed in Section 7.1.5 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.


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
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, 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 


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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.

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 a supine position with 
a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements 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 assessments, vital signs are to be taken first.
8.2.3.
Electrocardiograms

Twelve-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using
an ECG machine that automatically calculates the heart rate and measures PR, 




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
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 involvement in the 
study.
8.2.6.
Suicidal Ideation and Behavior Risk Monitoring
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 a previous MI compound, 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 
undergo immediate clinical assessment of suicidality (by the investigator or a consulting 
psychiatrist). Emergence of new onset suicidal ideation or a Grade 3 or higher psychiatric 
AE will result in immediate discontinuation and 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 
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 DAIDS 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 the AE through 
interview, additional unscheduled clinical laboratory tests, and/or imaging. 
Psychiatric consultation may be required at the discretion of the investigator. 
Any pharmacotherapy should be discussed with the medical monitor.

Any DAIDS Grade 3 or 4 psychiatric AE: As described in Section 7.1.5, a 
Grade 3 or 4 psychiatric AE will result in discontinuation from the study and 
emergency psychiatric evaluation (including potential hospitalization and 
pharmacotherapy as indicated).
8.2.7.
Gastrointestinal Intolerability Evaluation and Monitoring Plan
(with Stopping Criteria)
Preclinical toxicology studies in rats and dogs have suggested a potential for GI-related 
toxicity with GSK3640254. Prior clinical studies have not evaluated for the presence of
gastric toxicity in humans. Thus, it is unclear if any of the GI AEs observed in any
clinical studies were representative of, associated with, or resulted from gastric toxicity 
(if present). Thus, in a clinically conservative fashion 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


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discuss evaluation and management (including discontinuation of a participant) of any GI 
symptoms throughout the study.
For any DAIDS Grade 4 or related Grade 3 AE, the investigator will discontinue the 
participant from the study and may perform an evaluation/management plan 
incorporating the elements in Table 1.
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. 
Abdominal Pain
The investigator should obtain information on chronology, location, 
intensity/character, aggravating and alleviating factors, and associated 
symptoms in the context of the participants relevant past medical history 
[Millham, 2016]. With chronic symptoms, factors suggestive of an organic 
process include: fever, night sweats, loss of appetite, weight loss, and 
nocturnal awakening [Yarze, 2016]. The historical and physical examination 
should be efficient and lead to an accurate diagnosis soon after presentation.
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. 
Diarrhea
Similar to other GI symptoms, important historical assessment includes 
duration, onset, pattern, epidemiology (e.g. travel and diet), aggravating or 
iatrogenic factors, alleviating factors, stool appearance, presence of other 
symptoms (e.g. abdominal pain), or weight loss. The differential can be 
narrowed if there are clear watery, inflammatory, or fatty manifestations 
[Schiller, 2016].
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in 
the clinical study are available elsewhere [Rome Foundation, 2019].
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the 
history [Hasler, 2012]. The examination elements may include: 
auscultation for bowel sounds (up to 2 minutes if necessary) and 
palpation (including assessment for rebound, guarding, and muscular
rigidity) [Millham, 2016]. 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 


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which are protected by third party copyright laws and therefore have been excluded.


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(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). While the 
study population will consist of HIV-1 seronegative healthy participants, the DAIDS 
criteria is being used in later phase clinical studies (e.g., Phase 2); additionally, the 
DAIDS criteria have a more conservative grading scale relative to other scales (e.g., 
Common Terminology Criteria for Adverse Events [CTCAE] Version 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 on 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 or 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 for 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 an AE and/or SAE. 
Open-ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest 
(as defined in Section 8.3.6) will be followed until the event is resolved, stabilized, 


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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 an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/ IECs, 
and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the CIB and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and 
through the end of pregnancy (termination or delivery).

If a pregnancy is reported, the investigator will record pregnancy information on 
the appropriate form and submit it to VH/GSK within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the 
necessary signed informed consent from the female partner) pregnancy. While
pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be
reported as an AE or SAE.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported as such.

The participant/pregnant female partner will be followed to determine the 
outcome of the pregnancy. The investigator will collect follow-up information on 
the participant /pregnant female partner, and the neonate and the information will 
be forwarded to the sponsor.

Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants/pregnant female partner, he or she may 
learn of an SAE through spontaneous reporting.


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
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study.
8.3.6.
Adverse Events of Special Interest 
Adverse events of special interest include all AEs classified in the cardiovascular (per the 
Medical Dictionary for Regulatory Activities) system organ class, seizure, and syncope.
Additional AEs of special interest within other system organ classes (e.g., GI, neurologic, 
or psychiatric) may be defined in the reporting and analysis plan.
8.4.
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).

Separate whole blood samples of approximately 4 mL will be collected for 
measurement of plasma concentrations of DRV, RTV, and ETR as specified in 
the SoA (Section 1.3). 

A maximum of 10 samples (approximately 20 mL) 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 and DRV, RTV, and 
ETR. Samples collected for analyses of plasma concentrations 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 and DRV, RTV, and ETR,
any remaining plasma may be analyzed for other compound-related metabolites 
and the results provided in a separate report.
8.5.
Genetics and/or Pharmacogenomics
Genetics are not evaluated in this study.
8.6.
Biomarkers
Biomarkers are not evaluated in this study.
8.7.
Immunogenicity Assessments
Immunogenicity is not evaluated in this study.
8.8.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this 
study.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There is no formal hypothesis that will be statistically tested in this study.
Administration of GSK3640254 may change the exposure to DRV/RT and ETR, and 
administration of DRV/RTV and ETR may change the exposure to GSK3640254.
9.2.
Sample Size Determination
9.2.1.
Sample Size Assumptions
As there is no formal research hypothesis being statistically tested in this study, the 
sample size was not selected based on statistical considerations but determined using 
feasibility. Per cohort, approximately 16 participants will be enrolled to ensure that 
14 evaluable participants complete the study. If participants prematurely discontinue the 
study, additional participants may be enrolled after consultation with the sponsor to 
ensure that the required number of evaluable participants complete the study.
Based on the results from previous PK studies for GSK3640254 (GSK Study 207187 and 
208131) the coefficient of variability (CVw) ranged from 17 to 38% and 13 to 31%, 
respectively for AUC0-tau and Cmax. Therefore, it is decided that for GSK3640254 38% 
would be a conservative estimate on which the sample size calculation is based.
Historical references were used to calculate the CVw for PK parameters of DRV, RTV, 
and ETR and are provided in Table 2.
Table 2
Historical References for the Sample Size (n) and Intrasubject 
Coefficient of Variability for Pharmacokinetic Parameters of 
Darunavir, Ritonavir, and Etravirine
Historical Reference
Analyte
Parameter
n
CVw (%)
Sekar (2010)
Darunavir
AUC(0-tau)
11
34.7
Cmax
11
40.8
Cmin
11
54.2
Ritonavir
AUC(0-tau)
11
26.4
Cmax
11
20.4
Cmin
11
40.8
Schöller-Gyüre (2007)
Etravirine (Study C168)
AUC(0-tau)
23
16.3
Cmax
23
12.1
Cmin
23
15.4
Etravirine (Study 178)
AUC(0-tau)
37
9.7
Cmax
37
10.4


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Historical Reference
Analyte
Parameter
n
CVw (%)
Cmin
37
13.3
CVw = coefficient of variability.
Based upon the historical references [Sekar, 2010; Schöller-Gyüre, 2007] the
conservative estimates of CVw chosen for the analytes DRV, RTV, ETR are 54.2%, 
40.8%, and 16.3%, respectively.
Administration of GSK3640254 may change the exposure to DRV/RTV and ETR, and 
administration of DRV/RTV and ETR may change the exposure to GSK3640254; 
therefore, a range for point estimates (0.9, 1.0, and 1.1) was explored for the treatment 
differences in terms of geometric mean ratios of PK parameters.
With a sample size of 14 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:
Drug
CVw (%)
Half-Width 
(Log Scale)
Half-Width 
(Original Scale)
Point Estimate
90% CI
GSK3640254 
38
0.246
0.279
0.9
(0.704, 1.151)
1.0
(0.782, 1.279)
1.1
(0.860, 1.407)
Darunavir
54.2
0.340
0.405
0.9
(0.641, 1.264)
1.0
(0.712, 1.405)
1.1
(0.783, 1.545)
Ritonavir
40.8
0.263
0.301
0.9
(0.692, 1.171)
1.0
(0.769, 1.301)
1.1
(0.846, 1.431)
Etravirine
16.3
0.108
0.114
0.9
(0.808, 1.003)
1.0
(0.898, 1.114)
1.1
(0.987, 1.225)
Abbreviation: CVw = coefficient of variability.
9.2.2.
Sample Size Sensitivity
For a sensitivity analysis, assuming a range of within-subject variability and a sample 
size of 12, 14, and 16 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:


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Evaluable 
Participants
CVw (%)
Half-Width (Log Scale)
Half-Width (Original 
Scale)
Point 
Estimate
90% CI
12
30
0.215
0.240
0.9
(0.726, 1.116)
1.0
(0.807, 1.240)
1.1
(0.887, 1.364)
40
0.283
0.327
0.9
(0.678, 1.194)
1.0
(0.754, 1.327)
1.1
(0.829, 1.460)
50
0.346
0.413
0.9
(0.637, 1.272)
1.0
(0.708, 1.413)
1.1
(0.778, 1.555)
14
30
0.196
0.217
0.9
(0.740 , 1.095)
1.0
(0.822 , 1.217)
1.1
(0.904 , 1.338)
40
0.258
0.294
0.9
(0.695 , 1.165)
1.0
(0.773 , 1.294)
1.1
0.850 , 1.424)
50
0.316
0.372
0.9
(0.656 , 1.234)
1.0
(0.729 , 1.372)
1.1
(0.802 , 1.509)
16
30
0.182
0.200
0.9
(0.750, 1.080)
1.0
(0.834, 1.200)
1.1
(0.917, 1.320)
40
0.239
0.270
0.9
(0.709, 1.143)
1.0
(0.787, 1.270)
1.1
(0.866, 1.397)
50
0.293
0.340
0.9
(0.671, 1.206)
1.0
(0.746, 1.340)
1.1
(0.821, 1.474)
CI = confidence interval; CVw = coefficient of variability.
For each cohort, approximately 16 participants will be treated to ensure that 14 evaluable 
participants complete the study.


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9.3.
Analysis Sets
For the purposes of analysis, the following analysis sets are defined:
Population
Description
Screened
The Screened Population will include all participants who sign the ICF.
Safety
The Safety Population will include 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 at least 1 evaluable PK parameter 
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 and DRV, RTV, and ETR concentration-time data will be analyzed 
by PPD, under the oversight of the Clinical Pharmacology Modeling & Simulation 
Department within GSK, using noncompartmental methods with Phoenix WinNonlin 
Version 8.0 or higher. Statistical analysis will be performed by PPD, under the oversight 
of Clinical Statistics, GSK. Calculations will be based on the actual sampling times 
recorded during the study.


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Endpoint
Statistical Analysis Methods
Primary

The primary endpoints of this study are PK-related. The analysis for the primary PK 
endpoints will be performed for the PK Parameter Population. Plasma concentrations 
of GSK3640254 will be subjected to PK analyses using noncompartmental methods.

Based on the individual concentration-time data the following primary plasma PK 
parameters for GSK3640254 will be estimated:
AUC(0-tau) and Cmax

Analysis will be performed to compare the PK exposure of GSK3640254 with and 
without DRV/RTV (Cohort 1), ETR (Cohort 2), or DRV/RTV/ETR (Cohort 3). Analyses 
will be performed on the natural logarithms of AUC(0-tau) and Cmax using linear 
mixed-effect models with treatment as a fixed effect and measurements within 
participant as repeated measures, and subject as a random effect. Effects will be 
estimated, and 90% CIs will be constructed for the following treatment comparisons:

Treatment A+B versus Treatment A (Cohort 1)

Treatment A+C versus Treatment A (Cohort 2)

Treatment A+B+C versus Treatment A (Cohort 3)
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.

Plasma concentrations of DRV, RTV, and ETR will be subjected to PK analyses as
described above for GSK3640254. Based on the individual concentration-time data 
the following plasma PK parameters for DRV, RTV, and ETR will be estimated:
AUC(0-tau) and Ctau

Analysis will be performed to compare the PK exposure of DRV (Cohort 1), RTV 
(Cohort 1), and ETR (Cohort 2) with and without GSK3640254 as described above. 
Effects will be estimated, and 90% CIs will be constructed for the following treatment 
comparisons:

Treatment A+B versus Treatment B (Cohort 1)

Treatment A+C versus Treatment C (Cohort 2)
Summary statistics (arithmetic mean, geometric mean, median, standard deviation, 
minimum, maximum, and coefficient of variation) for plasma GSK3640254, DRV, RTV, and 
ETR primary PK parameter (AUC[0-tau] and Cmax) values will be summarized by treatment.
Secondary
Summary statistics (arithmetic mean, geometric mean, median, standard deviation, 
minimum, maximum, and coefficient of variation) for plasma GSK3640254, DRV, RTV, and 
ETR secondary PK parameters (Tmax and Ctau) values will be presented. 
Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 (Treatment A),
DRV/RTV (Treatment B), and ETR (Treatment C) will be summarized and used to assess 
achievement of steady state.
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 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.


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9.4.3.
Other Analysis
Additionally, special statistical and data analysis considerations may be warranted in the 
event that COVID-19 or related epidemics or natural disasters may affect the study and 
data integrity. To the extent possible, these will be described in the main study reporting 
and analysis plan; alternatively, a separate reporting and analysis plan focusing on 
modified data handling rules (e.g., changes to analysis populations, visit windows and 
endpoints) and analyses (e.g., sensitivity analyses to assess impact of and account for 
missing data) may be prepared, taking into account applicable regulatory guidance and 
industry best practices for handling such situations [DHHS, 2020; EMA, 2020a; EMA
2020b].
9.5.
Interim Analysis
No interim analysis is planned.


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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-tau)
Area under the plasma concentration-time curve from 
time zero to the end of the dosing interval at steady 
state
BID
Twice daily
bpm
Beats per minute
CIB
Clinical Investigator’s Brochure 
Cmax
Maximum observed concentration 
C-QTc
Concentration-corrected QT interval
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctau
Plasma concentration at the end of the dosing interval
CVw
Coefficient of variability
CYP
Cytochrome P450
DAIDS
Division of AIDS
DDI
Drug-drug interaction
DRV
Darunavir
ECG
Electrocardiogram 
ETR
Etravirine
FSH
Follicle-stimulating hormone
FTIH
First time in human
Gag
Group-specific antigen
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline 
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HRT
Hormonal replacement therapy
HTE
HIV-infected treatment-experienced
ICF
Informed consent form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee 


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IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional Review Board 
MAD
Multiple ascending dose
MI
Maturation inhibitor
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
QD
Once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using the Fridericia formula
QTL
Quality tolerance limits
RTV
Ritonavir
SAD
Single ascending dose
SAE
Serious adverse event 
SoA
Schedule of activities
SRM
Study Reference Manual 
Tmax
Time of maximum observed concentration
TQT
Thorough QT
ULN
Upper limit of normal 
VH
ViiV Healthcare
WOCBP
Woman of childbearing potential 

Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
NONE
DAIDS
Intelence
Norvir
Phoenix WinNonlin
Prezista
Reyataz


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 3
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 Chemistry1
Blood urea nitrogen
Carbon dioxide
Total protein
Creatinine
AST
Albumin
Glucose (fasting)
ALT
Globulin
Potassium
Gamma-glutamyl transferase
Anion gap
Sodium
Total and direct bilirubin
Alkaline phosphatase2
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, nitrite, and leukocyte esterase 
by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is abnormal)
Pregnancy testing

Highly sensitive human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)3
Other Screening 
Tests

FSH (as needed in women of non-childbearing potential only)

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, cannabinoids, cocaine, or phencyclidine, or nonprescribed 
opiates, oxycodone, benzodiazepines, methadone, or tricyclic 
antidepressants)


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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 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.
If alkaline phosphatase is elevated, consider fractionating.
3.
Local urine pregnancy 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 and Barrier Guidance
10.3.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
Women in the following categories are considered WOCBP (fertile):
1. Following menarche
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below)
Notes:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (>40 IU/L or mIU/mL) is required. 
o
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.

Permanent sterilization methods (for the purpose of this study) include:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
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.


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10.3.2.
Contraception Guidance:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Azoospermic partner (vasectomized or due to a to medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 
days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview..
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Male condom 
and female condom should not be used together (due to risk of failure from friction)


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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 and 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 or her representative will explain the nature of the study 
to the participant or his or her legally authorized representative and answer all 
questions regarding the study.

Participants must be informed that their participation is voluntary. Participants or 
his or her legally authorized representative will be required to sign a statement of 


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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 his or her legally 
authorized representative.

Participants who are rescreened are required to sign a new ICF
VH/GSK (alone or working with others) may use participant’s coded study data and 
samples and other information to carry out this study; understand the results of this study; 
learn more about GSK3640254 or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the GSK3640254 
approved for medical use or approved for payment coverage.
The ICF may contain a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the
corresponding “No” box.
10.4.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his or her personal study-related data will 
be used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his or her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities.


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10.4.5.
Committees Structure
Not applicable.
10.4.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
VH/GSK site or other mutually-agreeable location.

VH/GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participant, 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 trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.4.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.

Guidance on completion of CRFs will be provided in the electronic CRF 
Completion Guidelines.

Quality tolerance limits (QTLs) will be pre-defined in the QTL report to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during the study, and 
deviations from the QTLs and remedial actions taken will be summarized in the 
clinical study report.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 


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handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).

Records and documents, including signed ICFs, 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.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by 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. 
10.4.9.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first participant screened and will be the study start 
date.


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Study/Site Termination
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:
For study termination:

Discontinuation of further study intervention development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination 
or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up
10.4.10.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be designated 
by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubin1,2 2 × ULN (>35% direct bilirubin) or international 
normalized ratio (INR) >1.5, report as an SAE.
See additional Actions and Follow-up Assessments listed below
Required Actions and Follow-up Assessments 
Actions
Follow-up Assessments

Immediately discontinue study intervention

Report the event to VH/GSK within 24 hours

Complete the liver event CRF, and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow-up assessments

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within Baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or INR 
>1.5

Repeat liver chemistries (include ALT, 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 
perform liver event follow-up assessments 
within 24-72 hours

Monitor participant weekly until liver chemistries 
resolve, stabilize or return to within Baseline

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 creatine phosphokinase 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 CRF
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative 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 


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Liver Chemistry Stopping Criteria 
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.
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 and Serious 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 DDI.

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.


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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.6.2.
Definition of SAE
A SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. 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.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Possible Hy’s Law case: ALT ≥3 × ULN AND total bilirubin ≥2 × ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as a SAE.


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
Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.
o
Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention
abuse.
10.6.3.
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.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to VH/GSK in lieu of completion of the VH/GSK required form.

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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe.

Life-Threatening: Inability to perform basic self-care functions.


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An event is defined as “serious” when it meets at least 1 of the pre-defined 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 or her assessment.

For each AE/SAE, the investigator must document in the medical notes that he or 
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 or her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
VH/GSK to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide VH/GSK with a copy of any postmortem 
findings including histopathology.

New or updated information will be recorded in the originally submitted 
documents.


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
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 an 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) 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 Data Collection Tool

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 tool within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the SRM.


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10.7.
Appendix 7: COVID-19 Pandemic and Clinical Trial 
Continuity
The COVID-19 pandemic may impact the conduct of clinical studies. Significant 
logistical challenges may arise from quarantines, variable restrictions on site resources
and operations, site closures, travel limitations and the inability of an individual 
participant to attend clinic visits, interruptions to the supply chain for the investigational 
product, or other considerations if site personnel or study participants become infected 
with COVID-19. These challenges may lead to difficulties in meeting protocol-specified 
procedures, including dispensation of the investigational product to the participant or
adhering to protocol-mandated visits and laboratory/diagnostic testing.
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in study
treatment for participants enrolled in this clinical study.
In order to maintain the scientific integrity of the study and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database.
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect participant safety, welfare, and rights, and to ensure data integrity 
and the integrity of the clinical trial, as a result of COVID-19 only. These measures may 
be implemented in accordance with any requirements and expectations set out by local 
IRBs/IECs and National Competent Authorities, as necessary.
This appendix does not apply to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19. 
10.7.1.
Changes to Study Visits and Study Procedures

There may be cases where the current principal investigator of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g., to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in principal investigator
should be communicated to the sponsor.

There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority/IRB/IEC regulations.
10.7.2.
COVID-19 Specific Data Capture
10.7.2.1.
Capturing COVID-19 Specific Protocol Deviations
Please refer to the SRM for specific details on capturing protocol deviations as a result of 
COVID-19.


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10.7.2.2.
Capturing COVID-19 Specific Adverse Events and Serious Adverse 
Events
ViiV Healthcare is monitoring the evolving situation with respect to COVID-19 carefully 
and the impact this may have on ongoing or planned clinical trials.  It is important for the 
study team to describe COVID-19 related AEs/SAEs and their impact on study data and 
outcomes. Standardization of case definitions will facilitate future data analyses. 
Please use the following guidance: 
1.
Adverse events should continue to be evaluated as to whether they meet SAE criteria 
as defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. Serious AEs and AEs should be submitted following usual 
study procedures and timelines. 
2.
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for standardized 
collection. We recognize definitions are likely to continue to evolve; the most recent 
definitions should be consulted for each case (WHO). When reporting both serious 
and non-serious AEs (related to COVID-19 infection), investigators should use the 
following verbatim terms: 
a.
Suspected COVID-19 infection; or 
b. Probable COVID-19 infection; or 
c.
Confirmed COVID-19 infection 
3.
Sites should contact the study medical monitor for questions related to definitions,
reporting, and decisions around the impact to study drug continuation in the setting 
of clinically defined mild COVID-19 infection. 
4.
A new COVID-19 infection CRF will be included in the electronic CRF to collect 
additional details about the reported COVID-19 AE or SAE data. It is important that 
the correct information is collected from each participant reporting a COVID-19 AE 
or SAE. Therefore, please use the CRF templates to help you collect this 
information for all COVID-19 related AEs/SAEs.
10.7.2.2.1. World Health Organization Case Definition (March 20, 2020 Version)
Suspected case: 
A. A participant with acute respiratory illness (fever and at least one sign/symptom 
of respiratory disease, e.g., cough, shortness of breath) AND a history of travel to 
or residence in a location reporting community transmission of COVID-19 
disease during the 14 days prior to symptom onset; 
OR 
B. A participant with any acute respiratory illness AND having been in contact (see 
definition of “COVID-19 contact” below) with a confirmed or probable 
COVID-19 case (see definition of “contact”) in the last 14 days prior to symptom
onset; 
OR 


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C. A participant with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation. 
Probable case: 
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason. 
Confirmed case: 
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical 
signs and symptoms. 
COVID-19 Contact:
A contact is a person who experienced any one of the following exposures during the 
2 days before and the 14 days after the onset of symptoms of a probable or confirmed 
case: 
1.
Face-to-face contact with a probable or confirmed case within 1 meter and for more 
than 15 minutes; 
2.
Direct physical contact with a probable or confirmed case; 
3.
Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; OR 
4.
Other situations as indicated by local risk assessments. 
Note: For confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation.


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11.
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
 
 
213054 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Open-Label, Single-Sequence Study to Evaluate the Effects 
of Darunavir/Ritonavir and/or Etravirine on the 
Pharmacokinetics of GSK3640254 and the Effects of 
GSK3640254 on the Pharmacokinetics of 
Darunavir/Ritonavir and/or Etravirine in Heathy Adults 
Compound Number  : GSK3640254 
Effective Date  
: 15/10/2021 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 213054. 
• 
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. 
 
 
 


 
CONFIDENTIAL 
 
 
 
213054 
 
2 
 
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................................................................................... 7 
2.5. 
Sample Size Determination .......................................................................... 7 
3. 
PLANNED ANALYSES ............................................................................................ 8 
3.1. 
Final Analyses .............................................................................................. 8 
4. 
ANALYSIS POPULATIONS ..................................................................................... 9 
4.1. 
Protocol Deviations ....................................................................................... 9 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 10 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 10 
5.2. 
Baseline Definitions .................................................................................... 10 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 11 
6. 
STUDY POPULATION ANALYSES ....................................................................... 12 
6.1. 
Overview of Planned Study Population Analyses ........................................ 12 
7. 
PHARMACOKINETIC ANALYSES ......................................................................... 13 
7.1. 
Primary Pharmacokinetic Analyses ............................................................. 13 
7.1.1. 
Endpoint / Variables ..................................................................... 13 
7.1.1.1. 
Drug Concentration Measures .................................... 13 
7.1.1.2. 
Derived Pharmacokinetic Parameters......................... 13 
7.1.2. 
Summary Measure ...................................................................... 13 
7.1.3. 
Population of Interest ................................................................... 13 
7.1.4. 
Statistical Analyses / Methods ..................................................... 13 
7.1.4.1. 
Statistical Methodology Specification .......................... 14 
7.2. 
Secondary Pharmacokinetic Analyses ........................................................ 15 
7.2.1. 
Endpoint / Variables ..................................................................... 15 
7.2.1.1. 
Drug Concentration Measures .................................... 15 
7.2.2. 
Summary Measure ...................................................................... 15 
7.2.3. 
Population of Interest ................................................................... 15 
7.2.4. 
Statistical Analyses / Methods ..................................................... 16 
8. 
SAFETY ANALYSES ............................................................................................. 17 
8.1. 
Adverse Events Analyses ........................................................................... 17 
8.2. 
Clinical Laboratory Analyses ....................................................................... 17 
8.3. 
Adverse Events of Special Interest ............................................................. 17 
8.4. 
Other Safety Analyses ................................................................................ 18 
8.5. 
COVID 19 Related Analyses ....................................................................... 18 
9. 
REFERENCES ....................................................................................................... 19 


 
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10. APPENDICES ........................................................................................................ 20 
10.1. 
Appendix 1: Schedule of Activities .............................................................. 20 
10.1.1. 
Protocol Defined Schedule of Events ........................................... 20 
10.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 35 
10.2.1. 
Study Phases .............................................................................. 35 
10.2.1.1. Study Phases for Lab, Electrocardiograms, and 
Vital Signs .................................................................. 35 
10.2.1.2. Study Phases for Concomitant Medication ................. 35 
10.2.2. 
Treatment Emergent Flag for Adverse Events ............................. 35 
10.3. 
Appendix 3: Data Display Standards & Handling Conventions .................... 36 
10.3.1. 
Reporting Process ....................................................................... 36 
10.3.2. 
Reporting Standards .................................................................... 36 
10.3.3. 
Reporting Standards for Pharmacokinetics .................................. 37 
10.4. 
Appendix 4: Derived and Transformed Data ............................................... 39 
10.4.1. 
General ........................................................................................ 39 
10.4.2. 
Study Population .......................................................................... 39 
10.4.3. 
Safety .......................................................................................... 39 
10.5. 
Appendix 5: Reporting Standards for Missing Data ..................................... 41 
10.5.1. 
Premature Withdrawals ................................................................ 41 
10.5.2. 
Handling of Missing Data ............................................................. 41 
10.5.2.1. Handling of Missing and Partial Dates ........................ 41 
10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events .......................................... 42 
10.6.1. 
Laboratory Values ........................................................................ 42 
10.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 45 
10.7.1. 
ECG ............................................................................................. 45 
10.7.2. 
Vital Signs .................................................................................... 45 
10.8. 
Appendix 8: Abbreviations & Trademarks ................................................... 46 
10.8.1. 
Abbreviations ............................................................................... 46 
10.8.2. 
Trademarks ................................................................................. 47 
10.9. 
Appendix 9: List of Data Displays ............................................................... 48 
10.9.1. 
Data Display Numbering .............................................................. 48 
10.9.2. 
Mock Example Shell Referencing ................................................ 48 
10.9.3. 
Deliverables ................................................................................. 48 
10.9.4. 
Study Population Tables .............................................................. 49 
10.9.5. 
Safety Tables ............................................................................... 50 
10.9.6. 
Safety Figures ............................................................................. 53 
10.9.7. 
Pharmacokinetic Tables ............................................................... 54 
10.9.9. 
ICH Listings ................................................................................. 64 
10.9.10. Non-ICH Listings .......................................................................... 67 
 


 
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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 CSR for Protocol: 213054. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
This is an open-label, single-sequence, multiple-dose, 3 cohort study. 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
 
2.2. 
Study Objective(s) and Endpoint(s) 
 
Objectives 
Endpoints 
 
Primary 
Cohort 1 
• 
To assess the effect of co-administration of 
DRV/ RTV 600/100 mg BID with GSK3640254 
200 mg QD on the PK of GSK3640254 in 
healthy participants. 
• 
To assess the effect of co-administration of 
GSK3640254 200 mg QD with DRV/RTV 
600/100 mg BID on the PK of DRV/RTV in 
healthy participants. 
• 
AUC(0-tau) and Cmax for 
GSK3640254 
 
 
• 
AUC(0-tau), and Cmax for 
DRV/RTV 
Cohort 2 
• 
To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of GSK3640254 in healthy 
participants. 
• 
To assess the effect of co-administration of 
ETR 200 mg BID with GSK3640254 200 mg 
QD on the PK of ETR in healthy participants. 
• 
AUC(0-tau) and Cmax for 
GSK3640254 
 
• 
AUC(0-tau), and Cmax for ETR 
Cohort 3 
• 
To assess the effect of co-administration of 
ETR 200 mg BID and DRV/RTV 600/100 mg 
BID with GSK3640254 200 mg QD on the PK 
of GSK3640254 in healthy participants. 
• 
AUC(0-tau) and Cmax for 
GSK3640254 
 
 
 
Version / Release Date 
Summary of Changes 
Final 1.0 / 2021-02-24 
 
Final 2.0 / 2021-10-15 
• 
Add Enrolled population as “ All participants who 
passed screening and entered the study “ for the 
presentation of .disposition analysis (Data 
display 1.1). 
• In Section 5.2, change baseline for Cohort 3 
Period 2 to Day 1 (Pre-Dose). 


 
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Secondary 
Cohort 1 
• 
To assess the effect of co-administration of 
GSK3640254 200 mg QD with DRV/RTV 
600/100 mg BID on the secondary PK 
parameters of DRV and RTV in healthy 
participants. 
• 
Ctau, and Tmax for DRV, RTV, and 
GSK3640254 
Cohort 2 
• 
To assess the effect of co-administration of 
GSK3640254 200 mg QD with ETR 200 mg 
BID on the secondary PK parameters of 
ETR in healthy participants. 
• 
Ctau, and Tmax for ETR, and 
GSK3640254 
 
Cohort  
1, 2 & 3 
• 
To assess the safety and tolerability of 
GSK3640254 administered alone and in 
combination with DRV/RTV and/or ETR. 
• 
Safety and tolerability endpoints 
include incidence of AEs, SAEs, 
AEs leading to discontinuation, 
deaths, marked laboratory 
abnormalities, and abnormalities in 
vital signs and 12-lead ECGs. 
AE = adverse event; AUC(0-tau) = area under the plasma concentration-time curve from time zero to the end of the 
dosing interval at steady state; BID = twice daily; DRV = darunavir; Cmax = maximum observed concentration, 
Ctau = plasma concentration at the end of the dosing interval; ECG = electrocardiogram; ETR = etravirine; 
PK = pharmacokinetics; QD = once daily; RTV = ritonavir; SAE = serious adverse event; Tmax = time of maximum 
observed concentration. 
 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
BID = twice daily; N = number of participants; QD = once daily. 
Design 
Features 
A Phase 1, single-sequence, multiple-dose, 3 cohort study. 
The study will consist of a screening period and a treatment period. 
• 
Screening Period: within 28 days before the first dose of study intervention 
• 
Treatment Period – Cohort 1 
▪ 
Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 through 
7. 
▪ 
Period 2: Darunavir (DRV)/ Ritonavir (RTV) 600/100 mg tablets twice daily 
(BID) (Treatment B) on Days 12 through 21. 
▪ 
Period 3: GSK3640254 200 mg tablets once daily (QD) (Treatment A) and 
DRV/RTV 600/100 mg tablets BID (Treatment B) on Days 22 through 31. 
• 
Treatment Period – Cohort 2 
▪ 
Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 through 
7. 
▪ 
Period 2: Etravirine (ETR) 200 mg tablets BID (Treatment C) on Days 12 
through 21. 
▪ 
Period 3: GSK3640254 200 mg tablets QD (Treatment A) and ETR 200 mg 
tablets BID (Treatment C) on Days 22 through 31. 
• 
Treatment Period – Cohort 3 
▪ 
Period 1: GSK3640254 200 mg tablets QD (Treatment A) on Days 1 through 
7. 
▪ 
Period 2: GSK3640254 200 mg tablets QD (Treatment A), DRV/RTV 
600/100 mg tablets BID (Treatment B), and ETR 200 mg tablets BID 


 
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Overview of Study Design and Key Features 
(Treatment C) on Days 8 through 21. 
Per cohort, approximately 16 participants will be treated to ensure that 14 
evaluable participants complete the study. 
Dosing 
• 
Treatment A: GSK3640254 200 mg tablets QD 
• 
Treatment B: DRV/RTV 600/100 mg tablets BID 
• 
Treatment C: ETR 200 mg tablets BID 
Time & 
Events 
• 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
• 
PPD Clinical Pharmacology will remain open—label throughout the study.First 16 
participants will be assigned to Cohort 3, and remaining 32 participants will be 
randomly assigned to Cohort 1 or 2. 
Interim 
Analysis 
• 
No interim analysis is planned for this study 
 
2.4. 
Statistical Hypotheses 
There is no formal hypothesis that will be statistically tested in this study. 
Administration of GSK3640254 may change the exposure to DRV/RT and ETR, and 
administration of DRV/RTV and ETR may change the exposure to GSK3640254. 
2.5. 
Sample Size Determination 
As there is no formal research hypothesis being statistically tested in this study, the 
sample size was not selected based on statistical considerations but determined using 
feasibility. Per cohort, approximately 16 participants will be enrolled to ensure that 
14 evaluable participants complete the study. If participants prematurely discontinue the 
study, additional participants may be enrolled after consultation with the sponsor to 
ensure that the required number of evaluable participants complete the 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. 
 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who signed the informed consent 
form. 
• 
Study Population 
Enrolled 
• 
All participants who passed screening and entered 
the study 
• 
Disposition 
Randomized 
• 
All participants who are randomly assigned to a 
cohort. 
• 
Disposition  
Safety 
• 
The Safety Population will include all participants who 
receive at least 1 dose of study medication. 
Participants will be analyzed according to the 
intervention they actually received.  
• 
Demographic 
• 
Safety 
Pharmacokinetic 
Concentration 
• 
The PK Concentration Population will include all 
participants who undergo plasma PK sampling and 
have evaluable PK assay results. 
• 
PK Concentration 
Pharmacokinetic 
Parameter 
• 
The PK Parameter Population will include all 
participants who undergo plasma PK sampling and 
have at least 1 evaluable PK parameter estimated. 
• 
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 Study Deviation Tool and Rules. The “significant” protocol 
deviation in the Study Deviation Tool and Rules is equivalent to “important” protocol 
deviations. 
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 categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the electronic 
case record 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  
Cohort Used 
GSK3640254 200 mg tablets QD on Days 1 through 7. 
Treatment A 
1 
Cohorts 1, 2, 3 
DRV/RTV 600/100 mg tablets twice daily (BID) 
(Treatment B) on Days 12 through 21. 
Treatment B 
2 
Cohort 1 
GSK3640254 200 mg tablets QD and DRV/RTV 
600/100 mg tablets BID on Days 22 through 31. 
Treatment A + 
Treatment B 
3 
Cohort 1 
ETR 200 mg tablets BID on Days 12 through 21. 
Treatment C 
4 
Cohort 2 
GSK3640254 200 mg tablets QD and ETR 200 mg 
tablets BID on Days 22 through 31. 
Treatment A + 
Treatment C 
5 
Cohort 2 
GSK3640254 200 mg tablets QD, DRV/RTV 
600/100 mg tablets BID, and ETR 200 mg tablets BID 
on Days 8 through 21. 
Treatment A + 
Treatment B 
+Treatment C 
6 
Cohort 3 
 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions), baseline is defined as the latest 
pre-dose assessment with a non-missing value, including those from unscheduled visits. 
Cohorts 1 and 2: 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data Display 
 
Check-in 
(Day -2) 
Baseline 
(Day -1) 
Day 1 
(Pre-dose) 
Day 12 
(Pre-dose) 
Day 22 
(Pre-dose) 
Period 1 
Period 2 
Period 3 & 
Follow-up 
Vital Sign 
X 
X 
X 
X 
X 
Day 1 
(Pre-Dose)[1] 
Day 12 
(Pre-Dose)[1] 
Day 22 
(Pre-Dose)[1] 
12-Lead 
ECG 
X 
X 
X 
X 
X 
Day 1 
(Pre-Dose)[1] 
Day 12 
(Pre-Dose)[1] 
Day 22 
(Pre-Dose)[1] 
[1] The average (for blood pressure, pulse, and ECG numeric assessment) or the worst case (for ECG interpretation - 
Normal> Abnormal, Not Clinical Significant> Abnormal, Clinically Significant) of the pre-dose triplicate assessments will 
be used as the baseline. 
 


 
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Cohort 3: 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
 
Check-in 
(Day -2) 
Baseline 
(Day -1) 
Day 1  
(Pre-dose) 
Day 8 
(Pre-dose) 
Period 1 
Period 2 and 
follow-up 
Vital Sign 
X 
X 
X 
X 
Day 1 
(Pre-Dose)[1] 
Day 8 
(Pre-Dose)[1] 
12-Lead 
ECG 
X 
X 
X 
X 
Day 1 
(Pre-Dose)[1] 
Day 1 
(Pre-Dose)[1] 
[1] The average (for blood pressure, pulse, and ECG numeric assessment) or the worst case (for ECG interpretation - 
Normal> Abnormal, Not Clinical Significant> Abnormal, Clinically Significant)) of the pre-dose 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. 
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 Phase and Treatment Emergent Adverse Event 
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”, “Randomized” or 
“Screened”, population, unless otherwise specified. 
Study population analyses including analyses of participant’s 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 PK). Plasma concentrations of GSK3640254, DRV, RTV, and 
ETR will be measured and presented in tabular form and will be summarized 
descriptively. Plasma GSK3640254, DRV, RTV, and ETR concentration-time data will 
be listed by participant, treatment group, and sampling time and summarized by treatment 
group and sampling time.  
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 for the given treatment will be excluded from the 
calculation of summary statistics and statistical analysis for the respective treatment. 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
AUC(0-tau) 
Area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
NOTES: 
• 
Additional parameters may be included as required. 
7.1.2. 
Summary Measure 
Pharmacokinetic parameters AUC(0-tau) and Cmax following administration of 
GSK3640254 with or without administration of DRV/RTV and/or ETR 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. 
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. 


 
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Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate), and 
listed. 
Primary plasma PK parameters (AUC[0-tau] and Cmax) will be estimated for 
GSK3640254, DRV, RTV, and ETR. Summary statistics (arithmetic mean, geometric 
mean, median, standard deviation [SD], minimum, maximum, between-subject 
coefficient of variation [CVb], and 95% CI for plasma 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-tau) and Cmax, as data permit 
Model Specification 
• 
Analysis will be performed to compare the PK exposure of GSK3640254 with and 
without DRV/RTV (Cohort 1), ETR (Cohort 2), or DRV/RTV/ETR (Cohort 3). Analyses will be performed 
on the natural logarithms of AUC(0-tau) and Cmax using linear mixed-effect models with treatment as a 
fixed effect, and measurements within participant as repeated measures, and subject as a random 
effect.  
• 
Effects will be estimated, and CIs will be constructed for the following treatment comparisons: 
Treatment A+B versus Treatment A (Cohort 1) 
Treatment A+C versus Treatment A (Cohort 2) 
Treatment A+B+C versus Treatment A (Cohort 3) 
• 
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. 
• 
Analysis will be performed to compare the PK exposure of DRV (Cohort 1), RTV (Cohort 1), and ETR 
(Cohort 2) with and without GSK3640254. Analyses will be performed on the natural logarithms of 
AUC(0-tau) and Cmax using linear mixed-effect models with treatment as a fixed effect, and 
measurements within participant as repeated measures, and subject as a random effect.  
• 
Effects will be estimated, and CIs will be constructed for the following treatment comparisons: 
Treatment A+B versus Treatment B (Cohort 1) 
Treatment A+C versus Treatment C (Cohort 2) 
• 
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. 
 
Model Checking & Diagnostics 
• 
• Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
• 
Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with geometric 
mean ratios and 90% CIs for: 
Treatment A+B versus Treatment A (Cohort 1) 
Treatment A+C versus Treatment A (Cohort 2) 


 
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Treatment A+B+C versus Treatment A (Cohort 3) 
• 
Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with geometric 
mean ratios and 90% CIs for: 
Treatment A+B versus Treatment B (Cohort 1) 
Treatment A+C versus Treatment C (Cohort 2) 
 
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 PK) 
7.2.1.2. 
Derived Pharmacokinetic Parameters 
Plasma PK parameters listed below will be determined from the plasma 
concentration-time data, as data permits. 
Parameter 
Parameter Description 
Tmax 
Time of maximum observed concentration 
Ctau 
Plasma concentration at the end of the dosing interval 
NOTES: 
• 
Additional parameters may be included as required. 
 
If additional pharmacokinetic parameters are needed they 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. Subjects who 
experience emesis at or before 2 times median Tmax for the given treatment will be 
excluded from the calculation of summary statistics and statistical analysis for the 
respective treatment. 
7.2.2. 
Summary Measure 
Pharmacokinetic parameters Tmax and Ctau of GSK3640254, DRV, RTV, and ETR 
following administration of GSK3640254 with or without administration of DRV/RTV 
and/or ETR 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 and statistical analysis, 
unless otherwise specified. 


 
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7.2.4. 
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, graphically presented (where appropriate), and 
listed. 
Secondary plasma PK parameters (Tmax and Ctau) will be estimated for GSK3640254, 
DRV, RTV and ETR. Summary statistics (arithmetic mean, geometric mean, median, SD, 
minimum, maximum, and coefficient of variation) for plasma PK parameter values will 
be summarized by treatment. 
Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254, DRV, RTV, 
and ETR will be summarized and used to assess achievement of steady state. 


 
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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 events (AEs) analyses including the analysis of AEs, serious AEs (SAEs), AEs 
of special interest (AESI), 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. 
For studies with greater than one treatment period (e.g., crossover study), if AE onset is 
during one period and worsens during a later period, it will be counted in both periods. 
For the later period the onset date of AE with the elevated grade will be the first dose date 
of the later treatment period. 
8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, liver function tests, and pregnancy test 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, gastric toxicity, 
psychiatric events, nervous system disorders, and skin and subcutaneous tissue disorders 
will be summarized by treatment. A listing will also be provided accordingly. 
The AESI of QT prolongation 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 and gastric toxicity AESIs 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 AESI 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 will be 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 will 
be selected. 


 
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• All PTs 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 PTs from HLGT “Anxiety Disorders and Symptoms”, under SOC “Psychiatric 
disorders”. 
• All PTs from HLGT “Sleep Disorders and Disturbances” and HLGT “Sleep 
disturbances (include subtypes)”. 
Nervous system disorders AESIs will be defined within the following:  
• Four HLGTs under Nervous System Disorders SOC: “Headaches”; “Mental 
impairment disorders (excluding dementia)”; “Disturbance in consciousness” and 
“Seizures and seizure disorder” 
Skin and subcutaneous tissue disorder AESIs will be defined with the following PTs:  
Dermatitis, Dermatitis allergic, Dermatitis atopic, Eczema, Eczema eyelids, Eczema 
nummular, Eyelid irritation, Skin irritation, Urticarial dermatitis, Eyelid pruritis, Pruritus, 
Pruritus allergic, Rash pruritic, Rash, Rash macular, Rash maculopapular, Rash 
morbilliform, Rash papular, Rash pruritic, Urticaria, Drug eruption and Rash pustular  
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs, vital signs, liver 
events, and Columbia Suicide Severity Rating Scale (C-SSRS) will be based on GSK 
Core Data Standards, unless otherwise specified. The details of the planned displays are 
presented in Appendix 9: List of Data Displays. 
8.5. 
COVID 19 Related Analyses 
Based on GSK’s “Impact of COVID-19 on Assessment of Safety in Clinical Trials Points 
to Consider”, it is GSK’s recommendation that study teams should capture COVID-19 
cases based on the WHO criteria using the categories of: suspected, probable, and 
confirmed cases. COVID-19 eCRF pages are used in the study for data collection and 
analysis purposes. After a discussion with the study team, the following analyses will be 
included:  
• Number of subjects with suspected, probable, or confirmed COVID-19 infection 
• Number of subjects who had a COVID-19 diagnosis test performed and the 
number of subjects with positive, negative, or indeterminate results 
• Incidence of COVID-19 as reported as an AE and SAE  
• Incidence of treatment discontinuation due to an AE of COVID-19 infection 
• Severity, duration, and outcome of COVID-19 AEs 
If percentage of COVID-19 cases is >10% (> 5 subjects with an AE of COVID-19), a 
summary of COVID-19 symptoms for subjects with COVID-19 AE will be added. 
Further display details are provided in Appendix 9: List of Data Displays. 


 
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9. 
REFERENCES 
ViiV Healthcare group of companies Document Number 2020N432810_00 (10SEP2020) 
Open-Label, Single-Sequence Study to Evaluate the Effects of Darunavir/Ritonavir 
and/or Etravirine on the Pharmacokinetics of GSK3640254 and the Effects of 
GSK3640254 on the Pharmacokinetics of Darunavir/Ritonavir and/or Etravirine in 
Heathy Adults 
 


 
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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 0 
X 
Laboratory assessments (hematology, clinical 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 
Molecular test for SARS-CoV-2b 
 
a. 
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 
b. Two consecutive approved molecular tests (polymerase chain reaction or antigen test). The first test 
should be performed ≥7 days prior to admission. 


 
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Time and Events Table - Cohort 1 
Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment B 
(Days 12-21) 
Period 3 
Treatment A +Treatment B (Days 22-31) 
Notes 
Day –2 
Day –1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-34 
Day 
35 
 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Brief physical 
examination 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Includes, at a 
minimum, 
assessments of 
the skin, lungs, 
cardiovascular 
system, and 
abdomen (liver 
and spleen). 
Vital sign 
measurements 
X 
X 
X 
D2 
X 
 
X 
D12, 
D13, 
D17 
 
X 
X 
 
X 
 
 
 
 
X 
Blood pressure 
and pulse 
measured in 
triplicate at 
pre-dose on Days 
1, 12, and 22. 
Single blood 
pressure and 
pulse will be 
measured on other 
study days. 
Temperature 
Check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment B 
(Days 12-21) 
Period 3 
Treatment A +Treatment B (Days 22-31) 
Notes 
Day –2 
Day –1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-34 
Day 
35 
 
12-lead ECG 
X 
 
X 
 
X 
 
X 
D12 
X 
X 
 
 
X 
 
 
 
 
X 
ECGs on Days 1, 
12, and 22, will be 
taken pre-dose, 
and at 2 and 4 and 
6 hours post-dose. 
Pre-dose ECGs on 
Days 1, 12, and 22 
will be taken in 
triplicate. The 
post-dose ECGs 
are single ECGs. 
Drug, alcohol, 
and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol 
Appendix 2 for 
tests. 
Laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis) 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
See Protocol 
Appendix 2 for 
tests. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment B 
(Days 12-21) 
Period 3 
Treatment A +Treatment B (Days 22-31) 
Notes 
Day –2 
Day –1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-34 
Day 
35 
 
Molecular test 
for SARS-CoV 
X1 
 
 
D6 
 
 
 
D13, 
D20 
 
 
 
 
 
D27 
 
 
 
X 
Test to be 
obtained every 7 
days from Check-
in (regardless of 
period or washout) 
while in-house. 
1The second test 
should be 
performed 
24 hours prior to 
admission to the 
unit. Participants 
should be 
quarantined within 
the unit until the 
second test result 
is negative. Once 
the second test 
result is confirmed 
to be negative, 
they can be 
released into the 
unit and follow 
infection control 
practices. 
Pregnancy 
test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy 
test to confirm 
status. 
Columbia-
Suicide 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
See Protocol 
Section 8.2.6 for 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment B 
(Days 12-21) 
Period 3 
Treatment A +Treatment B (Days 22-31) 
Notes 
Day –2 
Day –1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-34 
Day 
35 
 
Severity 
Rating Scale  
details. 
Study 
intervention: 
DRV/RTV 
(BID) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Protocol 
Section 6.1 for 
study intervention 
details. 
Study 
intervention: 
GSK3640254 
200 mg (QD) 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X` 
X 
X 
X 
 
 
 
See Protocol 
Section 6.1 for 
study intervention 
details. 
DRV/RTV PK 
sampling 
 
 
 
 
 
 
 
D19, 
D20 
X 
 
 
 
 
 
X 
 
 
 
Pre-dose Days 
19, 20 and 21. 
Post Day 21 dose 
at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, and 
12 hours 
post-dose. 
Pre-dose Day 31. 
Post Day 31 dose 
at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, and 
12 hours. 
GSK3640254 
PK sampling 
 
 
 
D5, 
D6 
X 
D8 
 
 
 
 
 
 
 
D29, 
D30 
X 
X 
 
 
Pre-dose Days 5, 
6, and 7. Post 
Day 7 dose at 0.5, 
1, 1.5, 2, 3, 4, 6, 
8, 12, 16, and 
24 hours.  
Pre-dose Days 
29, 30, and 31. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment B 
(Days 12-21) 
Period 3 
Treatment A +Treatment B (Days 22-31) 
Notes 
Day –2 
Day –1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-34 
Day 
35 
 
Post Day 31 dose 
at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 12, 16, 
and 24 hours. 
AE review 
 
 
===================================================================================→ 
 
SAE review 
 
============================================================================================→  
Concomitant 
medication 
review 
 
============================================================================================→ 
 
Abbreviations: AE = adverse event; BID = twice daily; D = day; DRV = darunavir; ECG = electrocardiogram; PK = pharmacokinetic; QD = once daily; RTV = ritonavir; SAE = serious 
adverse event. 
Time and Events Table - Cohort 2 
Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
Brief physical 
examination 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Includes, at a minimum, 
assessments of the 
skin, lungs, 
cardiovascular system, 
and abdomen (liver and 
spleen). 
Vital sign 
measurements 
X 
X 
X 
D2 
X 
 
X 
D12, 
D13, 
D17 
 
X 
X 
 
X 
 
 
 
 
X 
Blood pressure and 
pulse measured in 
triplicate at pre-dose on 
Days 1, 12, and 22. 
Single blood pressure 
and pulse will be 
measured on other 
study days. 
Temperature 
Check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
12-lead ECG 
X 
X 
X 
 
X 
 
X 
D12 
X 
X 
 
 
X 
 
 
 
 
X 
ECGs on Days 1, 12, 
and 22, will be taken 
pre--dose, and at 2, 4, 
and 6 hours post-dose. 
Pre-dose ECGs on 
Days 1, 12, and 22 will 
be taken in triplicate. 
The post-dose ECGs 
are single ECGs. 
Drug, alcohol, 
and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol Appendix 
2 for tests. 
Laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis) 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
See Protocol Appendix 
2 for tests. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
Molecular test 
for 
SARS-CoV-2 
X1 
 
 
D6 
 
 
 
D13, 
D20 
 
 
 
 
 
D27 
 
 
 
X 
Test to be obtained 
every 7 days from 
Check-in (regardless of 
period or washout) 
while in-house. 
1The second test should 
be performed 24 hours 
prior to admission to the 
unit. Participants should 
be quarantined within 
the unit until the second 
test result is negative. 
Once the second test 
result is confirmed to be 
negative, they can be 
released into the unit 
and follow infection 
control practices. 
Pregnancy 
test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test to 
confirm status. 
Columbia-
Suicide 
Severity 
Rating Scale  
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
See Protocol Section 
8.2.6 for details. 
Study 
intervention: 
ETR (BID) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Protocol Section 
6.1 for study 
intervention details. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
Study 
intervention: 
GSK3640254 
200 mg (QD) 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X` 
X 
X 
X 
 
 
 
See Protocol Section 
6.1 for study 
intervention details. 
ETR PK 
sampling 
 
 
 
 
 
 
 
D19, 
D20 
X 
 
 
 
 
 
X 
 
 
 
Pre-dose Days 19, 20 
and 21. Post Day 21 
dose at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, and 12 hours 
post-dose.  
Pre-dose Day 31. Post 
Day 31 dose at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, and 
12 hours. 
GSK3640254 
PK sampling 
 
 
 
D5, 
D6 
X 
D8 
 
 
 
 
 
 
 
D29, 
D30 
X 
X 
 
 
Pre-dose Days 5, 6, and 
7. Post Day 7 dose at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12, 16, and 24 hours. 
Pre-dose Days 29, 30, 
and 31. Post Day 31 
dose at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 12, 16, and 
24 hours. 
AE review 
 
 
====================================================================================→  
SAE review 
 
===========================================================================================→ 
 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A (Days 1-7) 
Washout (Days 8-11) 
Period 2 
Treatment 
C 
(Days 12-
21) 
Period 3 
Treatment A +Treatment C (Days 22-31) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8-
10 
Day 
11 
Days 
12-20 
Day 
21 
Day 
22 
Day 
23 
Days 
24-25 
Day 
26 
Days 
27-30 
Day 
31 
Day 
32 
Days 
33-35 
Day 
36 
 
Concomitant 
medication 
review 
 
===========================================================================================→ 
 
Abbreviations: AE = adverse event; BID = twice daily; D = day; ECG = electrocardiogram; ETR = etravirine; PK = pharmacokinetic; QD = once daily; SAE = serious adverse event. 
 
 


 
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Time and Events Table - Cohort 3 
Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A 
(Days 1-7) 
Period 2 
Treatment A + Treatment B + Treatment C (Days 8-21) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8 
Day 
9 
Days 
10-12 
Day 
13 
Day 
14 
Days 
15-16 
Day 
17 
Days 
18-20 
Day 
21 
Day 
22 
Days 
23-25 
Day 
26 
 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from 
clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Brief physical 
examination 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Includes, at a minimum, 
assessments of the skin, lungs, 
cardiovascular system, and abdomen 
(liver and spleen). 
Vital sign 
measurements 
X 
X 
X 
D2 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
Blood pressure and pulse measured 
in triplicate at pre-dose on Days 1 
and 8. Single blood pressure and 
pulse will be measured on other 
study days. 
Temperature 
Check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
ECGs on Days 1, 8, and 9 will be 
taken pre-dose, and at 2, 4, and 
6 hours post-dose. Pre-dose ECGs 
on Days 1, 8, and 9 will be taken in 
triplicate. The post-dose ECGs are 
single ECGs. 
Drug, alcohol, 
and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol Appendix 2 for tests. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A 
(Days 1-7) 
Period 2 
Treatment A + Treatment B + Treatment C (Days 8-21) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8 
Day 
9 
Days 
10-12 
Day 
13 
Day 
14 
Days 
15-16 
Day 
17 
Days 
18-20 
Day 
21 
Day 
22 
Days 
23-25 
Day 
26 
 
Laboratory 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis) 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
See Protocol Appendix 2 for tests. 
Molecular Test 
for SARS-CoV-
2 
X1 
 
 
D6 
 
 
 
 
X 
 
 
 
D20 
 
 
 
X 
Test to be obtained every 
7 days from Check-in (regardless of 
period or washout) while in-house.1 
The second test should be 
performed 24 hours prior to 
admission to the unit. Participants 
should be quarantined within the unit 
until the second test result is 
negative. Once the second test 
result is confirmed to be negative, 
they can be released into the unit 
and follow infection control practices. 
Pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test to confirm 
status. 
Columbia-
Suicide 
Severity Rating 
Scale  
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
See Protocol Section 8.2.6 for 
details. 
Study 
intervention: 
DRV/RTV and 
ETR (BID) 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Protocol Section 6.1 for study 
intervention details. 


 
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Procedure 
Check-
in 
Baseline 
Period 1 
Treatment A 
(Days 1-7) 
Period 2 
Treatment A + Treatment B + Treatment C (Days 8-21) 
Notes 
Day –2 
Day -1 
Day 
1 
Days 
2-6 
Day 
7 
Day 
8 
Day 
9 
Days 
10-12 
Day 
13 
Day 
14 
Days 
15-16 
Day 
17 
Days 
18-20 
Day 
21 
Day 
22 
Days 
23-25 
Day 
26 
 
Study 
intervention: 
GSK3640254 
200 mg (QD) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X` 
X 
X 
X 
 
 
 
See Protocol Section 6.1 for study 
intervention details. 
DRV/RTV and 
ETR PK 
sampling 
 
 
 
 
 
 
 
 
 
 
 
 
D19, 
D20 
X 
 
 
 
Pre-dose Days 19, 20, and 21. Post 
Day 21 dose at 0.5, 1, 1.5, 2, 3, 4, 6, 
8, and 12 hours. 
GSK3640254 
PK sampling 
 
 
 
D5, 
D6 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Pre-dose Days 5, 6, and 7. Post Day 
7 dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 
16, and 24 hours. 
Pre-dose Day 21. Post Day 21 dose 
at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 
and 24 hours. 
AE review 
 
 
================================================================================→ 
 
SAE review 
 
=======================================================================================→ 
 
Concomitant 
medication 
review 
 
=======================================================================================→ 
 
AE = adverse event; BID = twice daily; D = day; DRV = darunavir; ECG = electrocardiogram; ETR = etravirine; PK = pharmacokinetic; QD = once daily; RTV = ritonavir; SAE = serious 
adverse event. 
 
• Participants will fast overnight for at least 8 hours prior to breakfast and before the AM dose and for at least 2 hours prior to dinner 
and before the PM dose. Participants will receive the moderate fat meal 30 minutes prior to dosing. Participants will eat this meal 
in 25 minutes or less. Dose administration will occur within 5 minutes of completion of meal consumption.  


 
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• Serial PK blood samples will be collected before (at 0 hour) and after the AM study drug administration at the time points listed. 
For the study interventions that are administered twice daily (BID) (DRV/RTV and ETR), the 12-hour sample will be collected 
before the PM dose. 
• Day 35 for Cohort 1, Day 36 for Cohort 2, and Day 26 for Cohort 3 is study discharge. Evaluations scheduled for study discharge 
will also be performed for participants who discontinue prior to completing. 
• The timing of planned study assessments may change during the course of the study based on emerging data/in-stream data review 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
Any changes in the timing 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 health authority and the ethics committee before implementation


CONFIDENTIAL 
 
 
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10.2. 
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events 
10.2.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date(/time) and stop date(/time). 
10.2.1.1. 
Study Phases 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 
Post-Treatment  
Date and Time >Study Treatment Stop Date and Time + 5 days 
 
10.2.1.2. 
Study Phases for Concomitant Medication 
Study Phase 
Study Phase 
Prior 
Prior 
Concomitant 
Concomitant 
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. 
 
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 
AEs. Use the rules in this table if the AE onset date is completely missing. 
 


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Software 
x
The currently supported versions of SAS software (9.4) will be used. 
Reporting Area 
HARP Server 
\\us1salx00259.corpnet2.com 
HARP Compound 
\gsk3640254\mid213054\final_01 
Analysis Datasets  
x
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).  
x
For creation of ADaM datasets (ADC1/ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
x
RTF files will be generated for all reporting efforts described in the RAP. 

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General 
x
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
: 
x
4.03 to 4.23: General Principles 
x
5.01 to 5.08: Principles Related to Data Listings 
x
6.01 to 6.11: Principles Related to Summary Tables 
x
7.01 to 7.13: Principles Related to Graphics  
x
Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings. 
Formats 
x
All data will be reported according to the actual treatment the participant received unless otherwise 
stated. 
x
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be rounded to integer, 
unless otherwise specified.  
x
Numeric data will be reported at the precision collected on the eCRF. 
x
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 
x
Reporting for tables, figures, and formal statistical analyses: 
x
Planned time relative to dosing will be used in figures, summaries, statistical analyses, and 
calculation of any derived parameters, unless otherwise stated. 
x
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. 
x
Reporting for Data Listings:  
x
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
PPD


CONFIDENTIAL 
 
 
213054 
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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 PK 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, 95% CI of arithmetic mean, geometric mean, 95% CI of 
geometric mean, SD, SD of log (ln) data, CV (%), and between-subject geometric 
coefficient of variation (CVb (%)) will be reported. 
CVb (%) = √ (exp(SD2) - 1) * 100 
(SD[ln] = SD of Ln-Transformed data) 


CONFIDENTIAL 
 
 
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Parameters Not 
Being Ln-
Transformed 
Tmax, 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. 
 


CONFIDENTIAL 
 
 
213054 
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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 Day 1: 
• 
Assessment Date = Missing  
  → Study Day = Missing  
• 
Assessment Date <Dose Date on Day 1  
  → Study Day = Assessment Date –Dose Date on Day 1 
• 
Assessment Date >= Dose Date on Day 1  
  → Study Day = Assessment Date – Dose Date on 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] 
10.4.3. 
Safety 
Adverse Events 
AEs of Special Interest 
• QT prolongation 
• Gastrointestinal intolerability and gastric toxicity 
• Psychiatric events 
• Nervous system disorders 
• Skin and subcutaneous tissue disorders 
 


CONFIDENTIAL 
 
 
213054 
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12-Lead Electrocardiograms 
QTcB Interval 
• 
QTcB interval in msec will be calculated using QT interval (msec) and RR interval (msec) as 
 
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
where RR interval in msec is calculated using QT interval (msec) and QTcF interval (msec) as 
𝑅𝑅= ( 𝑄𝑇
𝑄𝑇𝑐𝐹)3 × 1000 
 


CONFIDENTIAL 
 
 
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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) is defined as the 
participant has completed all phases of the study including the final date on which data 
were or are expected to be collected.  
• 
Withdrawn participants will not be replaced in the study. 
• 
All available data from participants who are 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 clinical study report. 
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 Section 10.2.2. 
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: 
• 
If the partial date is a start date, a ”01” will be used for the day and “Jan” will be used 
for the month 
• 
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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therefore have been excluded.


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CONFIDENTIAL 
 
 
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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 
 
>450 
Absolute PR Interval 
msec 
<110 
>200 
Absolute QRS Interval 
msec 
<75 
>110 
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 
Beats per 
minute 
<40 
>100 
 


CONFIDENTIAL 
 
 
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10.8. 
Appendix 8: Abbreviations & Trademarks 
10.8.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
analysis data model 
AE 
adverse event 
ALT 
alanine aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC(0-) 
AUC from time 0 to the end of the dosing interval at steady state 
BID 
twice daily 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CSR 
clinical study report 
C-SSRS 
Columbia suicide severity rating scale 
C 
plasma concentration at the end of the dosing interval 
CVb  
coefficient of variation (between)  
CVw 
coefficient of variability (within) 
DAIDS 
division of AIDS 
DBF 
database freeze 
DBR 
database release 
DP 
decimal places 
DRV 
darunavir 
ECG 
electrocardiogram 
eCRF 
electronic case record form 
GSK 
GlaxoSmithKline 
ETR 
etravirine 
HIV 
human immunodeficiency virus 
ICH 
international conference on harmonization 
IDSL 
integrated data standards library 
LLN 
lower limit of normal 
NQ 
not quantifiable 
PK 
pharmacokinetic 
QD 
once daily 
RAP 
reporting & analysis plan 
SAC 
statistical analysis complete 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
SMQ 
Standardized MedDRA Query  
Tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 


CONFIDENTIAL 
 
 
213054 
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10.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group of 
Companies 
 
Trademarks not owned by the GlaxoSmithKline 
Group of Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 


CONFIDENTIAL 
 
 
213054 
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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 1.8 
 
Safety 
2.1 to 2.30 
2.1 to 2.1 
Pharmacokinetic 
3.1 to 3.42 
3.1 to 3.45 
Section 
Listings 
ICH Listings 
1 to 32 
Non-ICH Listings 
33 to 43 
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 


 
CONFIDENTIAL 
 
 
 
213054 
 
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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. 
Enrolled 
NS1 
Summary of Number of Subjects Enrolled by Country and Site 
ID 
 
SAC 
1.2. 
Screened 
SP1 
Summary of Study Population 
 
SAC 
1.3. 
Safety 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
 
SAC 
1.4. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failures 
 
SAC 
Protocol Deviation 
1.5. 
Safety 
DV1 
Summary of Important Protocol Deviations 
 
SAC 
Demographic and Baseline Characteristics 
1.6. 
Safety 
DM1 
Summary of Demographic Characteristics 
 
SAC 
1.7. 
Safety 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
1.8. 
Safety 
DM11 
Summary of Age Ranges 
 
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 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency 
 
SAC 
2.4. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
2.5. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
2.6. 
Safety 
AE5A 
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity 
 
SAC 
2.7. 
Safety 
AE1CP 
Summary of Adverse Events of Special Interest 
 
SAC 
Laboratory: Chemistry  
2.8. 
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline 
 
SAC 
2.9. 
Safety 
LB1 
Summary of Clinical Chemistry Values 
 
SAC 
2.10. 
Safety 
LB16 
Summary of Clinical Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
 
SAC 
Laboratory: Hematology 


 
CONFIDENTIAL 
 
 
 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.11. 
Safety 
LB1 
Summary of Hematology Changes from Baseline 
 
SAC 
2.12. 
Safety 
LB1 
Summary of Hematology Values 
 
SAC 
2.13. 
Safety 
LB16 
Summary of Hematology Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline 
 
SAC 
Laboratory: Urinalysis 
2.14. 
Safety 
UR3 
Summary of Urinalysis Dipstick Results 
 
SAC 
2.15. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline 
 
SAC 
2.16. 
Safety 
LB1 
Summary of Urine Concentration Values 
 
SAC 
2.17. 
Safety 
LB16 
Summary of Urinalysis by Maximum Grade Increase Post-
Baseline Relative to Baseline 
 
SAC 
ECG 
2.18. 
Safety 
SAFE_T1 
Summary of ECG Findings 
 
SAC 
2.19. 
Safety 
EG2 
Summary of ECG Changes from Baseline 
 
SAC 
2.20. 
Safety 
EG2 
Summary of ECG Values 
 
SAC 
2.21. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
 
SAC 
2.22. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
 
SAC 
Vital Signs 
2.23. 
Safety 
VS1 
Summary of Vital Sign Changes from Baseline 
 
SAC 
2.24. 
Safety 
VS1 
Summary of Vital Sign Values 
 
SAC 
C-SSRS 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.25. 
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation and Behaviour Data 
Only include participants who have 
suicidal ideation or behaviour 
SAC 
Liver Event 
2.26. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
 
SAC 
2.27. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
 
SAC 
COVID-19 Related AE 
2.28. 
Safety 
PAN1 
Summary of COVID-19 Assessment 
 
SAC 
2.29 
Safety 
SAFE_T2 
Summary of COVID-19 Adverse Event 
 
SAC 
2.30 
Safety 
PAN11 
Summary of COVID-19 Symptoms for Subjects with Adverse 
Events 
Conditional Display 
SAC 


 
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10.9.6. 
Safety Figures 
Safety: Figures 
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 
PK Concentration Data 
3.1. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment – Cohort 1 
 
SAC 
3.2. 
PK 
Concentration 
PKCT1 
Summary of Darunavir Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 1 
 
SAC 
3.3. 
PK 
Concentration 
PKCT1 
Summary of Ritonavir Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 1 
 
SAC 
3.4. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) GSK3640254 Plasma 
Concentration Data (units) by Treatment – Cohort 1 
 
SAC 
3.5. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Darunavir Plasma Concentration 
Data (units) by Treatment – Cohort 1 
 
SAC 
3.6. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Ritonavir Plasma Concentration 
Data (units) by Treatment – Cohort 1 
 
SAC 
3.7. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment – Cohort 2 
 
SAC 
3.8. 
PK 
Concentration 
PKCT1 
Summary of Etravirine Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 2 
 
SAC 
3.9. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) GSK3640254 Plasma 
Concentration Data (units) by Treatment – Cohort 2 
 
SAC 
3.10. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Etravirine Plasma Concentration  
Data (units) by Treatment – Cohort 2 
 
SAC 
3.11. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment – Cohort 3 
 
SAC 


 
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213054 
 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.12. 
PK 
Concentration 
PKCT1 
Summary of Darunavir Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 3 
 
SAC 
3.13. 
PK 
Concentration 
PKCT1 
Summary of Ritonavir Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 3 
 
SAC 
3.14. 
PK 
Concentration 
PKCT1 
Summary of Etravirine Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Cohort 3 
 
SAC 
3.15. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) GSK3640254 Plasma 
Concentration Data (units) by Treatment – Cohort 3 
 
SAC 
3.16. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Darunavir Plasma Concentration 
Data (units) by Treatment – Cohort 3 
 
SAC 
3.17. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Ritonavir Plasma Concentration 
Data (units) by Treatment – Cohort 3 
 
SAC 
3.18. 
PK 
Concentration 
PKCT1 
Summary of Predose (trough) Etravirine Plasma Concentration 
Data (units) by Treatment – Cohort 3 
 
SAC 
PK Derived Parameters 
3.19. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 1 
 
SAC 
3.20. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 1 
 
SAC 
3.21. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Darunavir Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 1 
 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.22. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Darunavir Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 1 
 
SAC 
3.23. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Ritonavir Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 1 
 
SAC 
3.24. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Ritonavir Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 1 
 
SAC 
3.25. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 2 
 
SAC 
3.26. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 2 
 
SAC 
3.27. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Etravirine Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 2 
 
SAC 
3.28. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Etravirine Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 2 
 
SAC 
3.29. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 3 
 
SAC 
3.30. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 3 
 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.31. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Darunavir Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 3 
 
SAC 
3.32. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Darunavir Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 3 
 
SAC 
3.33. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Ritonavir Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 3 
 
SAC 
3.34. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Ritonavir Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 3 
 
SAC 
3.35. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Etravirine Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment – Cohort 3 
 
SAC 
3.36. 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Etravirine Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time by Treatment – Cohort 3 
 
SAC 
PK Analysis Tables 
3.37. 
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 1 
AUC(0-tau) and Cmax 
SAC 
3.38. 
PK 
Parameter 
PKPT3 
Statistical Analysis of Darunavir Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 1 
AUC(0-tau) and Cmax 
SAC 
3.39. 
PK 
Parameter 
PKPT3 
Statistical Analysis of Ritonavir Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 1 
AUC(0-tau) and Cmax 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.40. 
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 2 
AUC(0-tau) and Cmax 
SAC 
3.41. 
PK 
Parameter 
PKPT3 
Statistical Analysis of Etravirine Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 2 
AUC(0-tau) and Cmax 
SAC 
3.42. 
PK 
Parameter 
PKPT3 
Statistical Analysis of GSK3640254 Plasma Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Cohort 3 
AUC(0-tau) and Cmax 
SAC 


 
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10.9.8. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.1. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant – Cohort 1 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.2. 
PK 
Concentration 
PKCF1 
Individual Darunavir Plasma Concentration-Time Plots by 
Participant – Cohort 1 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.3. 
PK 
Concentration 
PKCF1 
Individual Ritonavir Plasma Concentration-Time Plots by 
Participant – Cohort 1 (Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.4. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.5. 
PK 
Concentration 
PKCF1 
Individual Darunavir Plasma Concentration-Time Plots by 
Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.6. 
PK 
Concentration 
PKCF1 
Individual Ritonavir Plasma Concentration-Time Plots by 
Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.7. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant – Cohort 2 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.8. 
PK 
Concentration 
PKCF1 
Individual Etravirine Plasma Concentration-Time Plots by 
Participant – Cohort 2 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.9. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Cohort 2 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.10. 
PK 
Concentration 
PKCF1 
Individual Etravirine Plasma Concentration-Time Plots by 
Treatment – Cohort 2 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.11. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant – Cohort 3 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.12. 
PK 
Concentration 
PKCF1 
Individual Darunavir Plasma Concentration-Time Plots by 
Participant – Cohort 3 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
SAC 
3.13. 
PK 
Concentration 
PKCF1 
Individual Ritonavir Plasma Concentration-Time Plots by 
Participant – Cohort 3 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
SAC 
3.14. 
PK 
Concentration 
PKCF1 
Individual Etravirine Plasma Concentration-Time Plots by 
Participant – Cohort 3 (Linear and Semi-Logarithmic)  
Paginate by Participant 
Dashed line represents the LLQ 
SAC 
3.15. 
PK 
Concentration 
PKCF1 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
Paginate by Treatment 
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.16. 
PK 
Concentration 
PKCF1 
Individual Darunavir Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
Dashed line represents the LLQ 
Participants Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.17. 
PK 
Concentration 
PKCF1 
Individual Ritonavir Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
3.18. 
PK 
Concentration 
PKCF1 
Individual Etravirine Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
Dashed line represents the LLQ 
Participants Overlaid 
SAC 
Mean / Median Concentration Plots 
3.19. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) GSK3640254 Plasma 
Concentration-Time Plots by Treatment – Cohort 1 (Linear and 
Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.20. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Darunavir Plasma Concentration-
Time Plots by Treatment – Cohort 1 (Linear and Semi-
Logarithmic)  
Treatments Overlaid 
SAC 
3.21. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Ritonavir Plasma Concentration-
Time Plots by Treatment – Cohort 1 (Linear and Semi-
Logarithmic)  
Treatments Overlaid 
SAC 
3.22. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time 
Plots by Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.23. 
PK 
Concentration 
PKCF3 
Median (Range) Darunavir Plasma Concentration-Time Plots by 
Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.24. 
PK 
Concentration 
PKCF3 
Median (Range) Ritonavir Plasma Concentration-Time Plots by 
Treatment – Cohort 1 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.25. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) GSK3640254 
Plasma Concentration-Time Plots by Treatment – Cohort 1 
(Linear and Semi-Logarithmic)  
 
SAC 
3.26. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Darunavir Plasma 
Concentration-Time Plots by Treatment – Cohort 1 (Linear and 
Semi-Logarithmic)  
 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.27. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Ritonavir Plasma 
Concentration-Time Plots by Treatment – Cohort 1 (Linear and 
Semi-Logarithmic)  
 
SAC 
3.28. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) GSK3640254 Plasma 
Concentration-Time Plots by Treatment – Cohort 2 (Linear and 
Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.29. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Etravirine Plasma Concentration-
Time Plots by Treatment – Cohort 2 (Linear and Semi-
Logarithmic)  
Treatments Overlaid 
SAC 
3.30. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time 
Plots by Treatment – Cohort 2 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.31. 
PK 
Concentration 
PKCF3 
Median (Range) Etravirine Plasma Concentration-Time Plots by 
Treatment – Cohort 2 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.32. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) GSK3640254 
Plasma Concentration-Time Plots by Treatment – Cohort 2 
(Linear and Semi-Logarithmic)  
 
SAC 
3.33. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Etravirine Plasma 
Concentration-Time Plots by Treatment – Cohort 2 (Linear and 
Semi-Logarithmic)  
 
SAC 
3.34. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) GSK3640254 Plasma 
Concentration-Time Plots by Treatment – Cohort 3 (Linear and 
Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.35. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Darunavir Plasma Concentration-
Time Plots by Treatment – Cohort 3 (Linear and Semi-
Logarithmic)  
 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.36. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Ritonavir Plasma Concentration-
Time Plots by Treatment – Cohort 3 (Linear and Semi-
Logarithmic)  
 
SAC 
3.37. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Etravirine Plasma Concentration-
Time Plots by Treatment – Cohort 3 (Linear and Semi-
Logarithmic)  
 
SAC 
3.38. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time 
Plots by Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
Treatments Overlaid 
SAC 
3.39. 
PK 
Concentration 
PKCF3 
Median (Range) Darunavir Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
 
SAC 
3.40. 
PK 
Concentration 
PKCF3 
Median (Range) Ritonavir Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
 
SAC 
3.41. 
PK 
Concentration 
PKCF3 
Median (Range) Etravirine Plasma Concentration-Time Plots by 
Treatment – Cohort 3 (Linear and Semi-Logarithmic)  
 
SAC 
3.42. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) GSK3640254 
Plasma Concentration-Time Plots by Treatment – Cohort 3 
(Linear and Semi-Logarithmic)  
 
SAC 
3.43. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Darunavir Plasma 
Concentration-Time Plots by Treatment – Cohort 3 (Linear and 
Semi-Logarithmic)  
 
SAC 
3.44. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Ritonavir Plasma 
Concentration-Time Plots by Treatment – Cohort 3 (Linear and 
Semi-Logarithmic)  
 
SAC 
3.45. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Predose (Trough) Etravirine Plasma 
Concentration-Time Plots by Treatment – Cohort 3 (Linear and 
Semi-Logarithmic)  
 
SAC 


 
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10.9.9. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1. 
Safety 
ES3 
Listing of Reasons for Study Withdrawal 
 
SAC 
2. 
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
 
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_L1 
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 
15. 
Safety 
AE9CP 
Listing of Adverse Events of Special Interest 
 
SAC 
Serious and Other Significant Adverse Events 
16. 
Safety 
AE9CP 
Listing of Study Drug Related Adverse Events 
 
SAC 
17. 
Safety 
AE9CP 
Listing of Serious Adverse Events (Fatal & Non-Fatal) 
 
SAC 
18. 
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC 
19. 
Safety 
AE9CP 
Listing of Adverse Events Leading to Withdrawal from Study 
 
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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10.9.10. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Pharmacokinetics 
33. 
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentrations (ng/mL) by 
Treatment – Cohort 1 
 
SAC 
34. 
PK 
Concentration 
PKCL1P 
Listing of Darunavir Plasma Concentrations (ng/mL) by 
Treatment – Cohort 1 
 
SAC 
35. 
PK 
Concentration 
PKCL1P 
Listing of Ritonavir Plasma Concentrations (ng/mL) by 
Treatment – Cohort 1 
 
SAC 
36. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters 
Based on Actual Time by Treatment – Cohort 1 
 
SAC 
37. 
PK Parameter 
PKPL1P 
Listing of Darunavir Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 1 
 
SAC 
38. 
PK Parameter 
PKPL1P 
Listing of Ritonavir Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 1 
 
SAC 
39. 
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentrations (ng/mL) by 
Treatment – Cohort 2 
 
SAC 
40. 
PK 
Concentration 
PKCL1P 
Listing of Etravirine Plasma Concentrations (ng/mL) by 
Treatment – Cohort 2 
 
SAC 
41. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters 
Based on Actual Time by Treatment – Cohort 2 
 
SAC 
42. 
PK Parameter 
PKPL1P 
Listing of Etravirine Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 2 
 
SAC 
43. 
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentrations (ng/mL) by 
Treatment – Cohort 3 
 
SAC 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
44. 
PK 
Concentration 
PKCL1P 
Listing of Darunavir Plasma Concentrations (ng/mL) by 
Treatment – Cohort 3 
 
SAC 
45. 
PK 
Concentration 
PKCL1P 
Listing of Ritonavir Plasma Concentrations (ng/mL) by 
Treatment – Cohort 3 
 
SAC 
46. 
PK 
Concentration 
PKCL1P 
Listing of Etravirine Plasma Concentrations (ng/mL) by 
Treatment – Cohort 3 
 
SAC 
47. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters 
Based on Actual Time by Treatment – Cohort 3 
 
SAC 
48. 
PK Parameter 
PKPL1P 
Listing of Darunavir Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 3 
 
SAC 
49. 
PK Parameter 
PKPL1P 
Listing of Ritonavir Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 3 
 
SAC 
50. 
PK Parameter 
PKPL1P 
Listing of Etravirine Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Cohort 3 
 
SAC 
51. 
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessment 
 
SAC 
52. 
Safety 
AE9CP 
Listing of Adverse Events of COVID-19 
 
SAC