Clinical trial NCT04563845
Conditions: HIV Infections
Keywords: GSK3640254 Moxifloxacin Electrocardiogram Cardiac Conduction Supratherapeutic dose
Sponsor: ViiV Healthcare
Start date: 2020-11-09; Completion date: 2021-10-30
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will aim to evaluate the effect of therapeutic and supratherapeutic oral doses of GSK3640254 on cardiac conduction compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. The study has 2 parts: Part 1 will determine the supratherapeutic dose for Part 2, which will be the main corrected QT interval (QTc) study. Part 1 will evaluate once daily (QD) dosing of GSK3640254 or placebo and Part 2 will investigate the safety, tolerability and Pharmacokinetics (PK) of GSK3640254 doses on cardiac conduction as compared to placebo and a single oral dose of Moxifloxacin in healthy adult participants. Moxifloxacin will be included as a positive control.

Detailed description:

Arms: arm 1: Participants will receive a single dose of placebo once daily for 7 days following ingestion of a moderate fat meal. arm 2: Participants will receive a single dose of GSK3640254 500 mg once daily for 7 days following ingestion of a moderate fat meal. arm 3: Participants will be randomized to 1:1:1:1 ratio to receive Treatment T- Therapeutic dose of GSK3640254 (100 mg QD) on Days 1 through 7 or Treatment ST- Supratherapeutic dose of GSK3640254 (to be determined from Part 1) on Days 1 through 7 or Treatment P- Placebo for GSK3640254 on Days 1 through 7 or Treatment M- Moxifloxacin (GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin \[400 mg\] on Day 7 in 4 treatment periods. There will be at least 7 days wash out period between each period.
Interventions: intervention 1: GSK3640254 intervention 2: Placebo intervention 3: Moxifloxacin
Intervention descriptions: intervention 1: GSK3640254 will be administered. intervention 2: Placebo will be administered. intervention 3: Moxifloxacin will be administered.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Study to Evaluate the Effect of Therapeutic and Supratherapeutic Oral 
Doses of GSK3640254 on Cardiac Conduction as Assessed by 12-Lead 
Electrocardiogram Compared to Placebo and a Single Oral Dose of Moxifloxacin in 
Healthy Adult Participants
Protocol Number: 213053
Compound Number
or Name:
GSK3640254
Study Phase: Phase 1
Short Title: Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on 
Cardiac Conduction
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.
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual.
Regulatory Agency Identifying Number: IND 139,838
Approval Date: 10-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 ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................11
2.
INTRODUCTION....................................................................................................22
2.1.
Study Rationale ..........................................................................................22
2.2.
Background ................................................................................................22
2.2.1.
Key Safety Data with a Prior Maturation Inhibitor 
(GSK3532795).............................................................................22
2.2.2.
Preclinical Summary with GSK3640254.......................................23
2.2.2.1.
Pharmacokinetics and Product Metabolism in 
Animals ......................................................................23
2.2.2.2.
Toxicology in Animals.................................................23
2.2.3.
Summary of GSK3640254 Clinical Pharmacokinetics..................24
2.2.4.
Summary of GSK3640254 Metabolism ........................................25
2.2.5.
Summary of GSK3640254 Safety................................................25
2.2.5.1.
Cardiac Safety............................................................26
2.3.
Benefit/Risk Assessment ............................................................................27
2.3.1.
Risk Assessment .........................................................................28
2.3.2.
Benefit Assessment.....................................................................31
2.3.3.
Overall Benefit: Risk Conclusion..................................................31
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................32
4.1.
Overall Design ............................................................................................32
4.2.
Scientific Rationale for Study Design ..........................................................34
4.3.
Justification for Dose ..................................................................................35
4.4.
End of Study Definition ...............................................................................36
5.
STUDY POPULATION...........................................................................................36
5.1.
Inclusion Criteria.........................................................................................36
5.2.
Exclusion Criteria........................................................................................38
5.3.
Lifestyle Considerations..............................................................................41
5.3.1.
Meals and Dietary Restrictions ....................................................41
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................42
5.3.3.
Activity .........................................................................................42
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................43
6.1.
Study Intervention(s) Administered .............................................................44
6.2.
Preparation/Handling/Storage/Accountability..............................................44
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................45
6.4.
Study Intervention Compliance ...................................................................45
6.5.
Concomitant Therapy..................................................................................46
6.6.
Dose Modification .......................................................................................46
6.7.
Intervention after the End of the Study........................................................46


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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................46
7.1.
Discontinuation of Study Intervention..........................................................46
7.1.1.
Liver Chemistry Stopping Criteria ................................................47
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................47
7.1.2.
Safety ECG QTc Stopping Criteria...............................................47
7.1.3.
Columbia-Suicide Severity Rating Scale Criteria..........................48
7.1.4.
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria................................................................48
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................48
7.3.
Lost to Follow-Up........................................................................................49
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
8.1.
Efficacy Assessments.................................................................................50
8.2.
Safety Assessments ...................................................................................50
8.2.1.
Physical Examinations.................................................................50
8.2.2.
Vital Signs....................................................................................50
8.2.3.
Safety Electrocardiograms...........................................................51
8.2.4.
Clinical Safety Laboratory Assessments ......................................51
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring ...........................52
8.2.6.
Gastrointestinal Intolerability Evaluation and Monitoring 
Plan (with Stopping Criteria) ........................................................52
8.2.7.
COVID-19 Measures ...................................................................54
8.3.
Adverse Events and Serious Adverse Events.............................................54
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
8.3.2.
Method of Detecting AEs and SAEs.............................................55
8.3.3.
Follow-up of AEs and SAEs.........................................................55
8.3.4.
Regulatory Reporting Requirements for SAEs .............................56
8.3.5.
Pregnancy ...................................................................................56
8.3.6.
Adverse Events of Special Interest ..............................................56
8.4.
Treatment of Overdose...............................................................................57
8.5.
Pharmacokinetics .......................................................................................57
8.6.
Cardiodynamic Assessments......................................................................57
8.6.1.
Continuous Holter Electrocardiograms.........................................58
8.6.2.
Cardiodynamic Sample Analysis..................................................58
8.7.
Genetics .....................................................................................................59
8.8.
Biomarkers .................................................................................................59
8.9.
Immunogenicity Assessments.....................................................................59
8.10.
Medical Resource Utilization and Health Economics ..................................59
9.
STATISTICAL CONSIDERATIONS........................................................................59
9.1.
Statistical Hypotheses.................................................................................59
9.2.
Sample Size Determination ........................................................................59
9.3.
Populations for Analyses ............................................................................62
9.4.
Statistical Analyses.....................................................................................62
9.4.1.
Cardiodynamic Analyses .............................................................62
9.4.1.1.
QT Correction Methods ..............................................62
9.4.1.2.
Concentration-QTc Analysis (Primary Analysis) .........63
9.4.1.3.
By-Time Point Analysis (Secondary Analysis) ............64
9.4.1.4.
Categorical Analysis...................................................65


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9.4.1.5.
Assay Sensitivity ........................................................65
9.4.2.
Pharmacokinetic Analyses...........................................................65
9.4.3.
Safety Analyses...........................................................................66
9.4.4.
Other Analysis .............................................................................66
9.5.
Interim Analyses .........................................................................................66
9.6.
Data Monitoring Committee or Other Review Board ...................................67
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................68
10.1.
Appendix 1: Abbreviations and Trademarks................................................68
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................71
10.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................73
10.3.1.
Definitions:...................................................................................73
10.3.2.
Contraception Guidance: .............................................................74
10.3.3.
Collection of Pregnancy Information: ...........................................74
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................76
10.4.1.
Regulatory and Ethical Considerations ........................................76
10.4.2.
Financial Disclosure.....................................................................76
10.4.3.
Informed Consent Process ..........................................................76
10.4.4.
Data Protection............................................................................77
10.4.5.
Committees Structure ..................................................................78
10.4.6.
Dissemination of Clinical Study Data ...........................................78
10.4.7.
Data Quality Assurance ...............................................................78
10.4.8.
Source Documents ......................................................................79
10.4.9.
Study and Site Start and Closure.................................................79
10.4.10. Publication Policy.........................................................................80
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................81
10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................83
10.6.1.
Definition of AE............................................................................83
10.6.2.
Definition of SAE..........................................................................84
10.6.3.
Recording and Follow-Up of AE and SAE....................................85
10.6.4.
Reporting of SAE to VH/GSK.......................................................87
10.7.
Appendix 7: COVID-19 Pandemic and Clinical Trial Continuity...................88
10.7.1.
Changes to Study Visits and Study Procedures...........................88
10.7.2.
COVID-19 Experimental Agents ..................................................88
10.7.3.
COVID-19 Specific Data Capture.................................................89
10.7.3.1.
Capturing COVID-19 Specific Protocol 
Deviations ..................................................................89
10.7.3.2.
Capturing COVID-19 Specific AEs and SAEs.............89
10.7.3.2.1.
WHO Case Definition (March 20, 
2020 Version): ........................................90
11. REFERENCES.......................................................................................................92


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Study to Evaluate the Effect of Therapeutic and Supratherapeutic Oral 
Doses of GSK3640254 on Cardiac Conduction as Assessed by 12-Lead 
Electrocardiogram Compared to Placebo and a Single Oral Dose of Moxifloxacin in 
Healthy Adult Participants
Short Title: Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on 
Cardiac Conduction
Rationale: The International Council for Harmonisation (ICH) E14 guidance, as adopted 
in the US Food and Drug Administration (FDA) Guidance for Industry, E14 Clinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs, emphasizes the need to obtain clear and robust data through 
“thorough” studies that assess the effect of new chemical entities on electrocardiogram 
(ECG) parameters. Specifically, “thorough” studies are defined as trials dedicated to 
evaluating a compound’s effect on cardiac repolarization, as measured by the corrected 
QT interval (QTc). Although many Phase 1, 2, and 3 studies may be conducted with a 
new compound, they typically utilize insufficient sample sizes, infrequent sampling of 
ECG data, or inadequate controls to overcome high variance in cardiac repolarization due 
to spontaneous change. Therefore, this thorough QT (TQT)/QTc study will be conducted 
to evaluate the effect of GSK3640254 on cardiac repolarization.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary
Part 1:

To determine the safety and 
pharmacokinetics of a supratherapeutic 
dose of GSK3640254 administered for 
7 days in healthy participants
Part 1:

Area under the plasma concentration-time curve 
from time zero to time t (AUC[0-t]), area under the 
plasma concentration-time curve from time zero to 
the end of the dosing interval at steady state
(AUC[0-]), maximum observed concentration
(Cmax), plasma concentration at the end of the 
dosing interval (C), and time of maximum 
observed concentration (Tmax) of GSK3640254 in 
plasma 

Remaining Plasma will be analyzed for compound 
related metabolites

Safety and tolerability parameters for adverse 
events (AEs)/serious adverse events (SAEs), 
observed and change from baseline in clinical 
laboratory assessments, electrocardiograms 
(ECGs), and vital sign measurements
Part 2:

To determine the effect of therapeutic and 
supratherapeutic concentrations of 
Part 2:

Placebo-corrected change from baseline in QTcF 
(ΔΔQTcF) for GSK3640254 using 


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Objectives
Endpoints
multiple dose GSK3640254 on the QT 
interval corrected with Fridericia’s formula
(QTcF) in healthy participants
concentration-QTc (C-QTc) analysis (primary 
analysis)

Remaining Plasma will be analyzed for compound 
related metabolites
Secondary
Secondary
Part 2:

To evaluate the effect of multiple oral 
therapeutic and supratherapeutic doses of 
GSK3640254 on other ECG parameters 
(heart rate [HR], PR, QRS, and QTcF 
intervals, treatment-emergent T-wave 
morphology, and appearance of U-waves)
Part 2:

Change from baseline in HR, QTcF, PR, QRS 
(ΔHR, ΔQTcF, ΔPR, and ΔQRS) intervals using 
by-time point analysis (secondary analysis); the 
placebo-corrected change from baseline in HR, 
PR, QTcF, and QRS (ΔΔHR, ΔΔPR, ΔΔQTcF, and 
ΔΔQRS) using by-timepoint analysis; categorical 
outliers for QTcF, HR, PR, and QRS; and the 
frequency of treatment-emergent changes of 
T-wave morphology and U-wave presence

To demonstrate assay sensitivity of the 
study design to detect a QTc effect using 
a single 400 mg oral moxifloxacin as a 
positive control.

ΔΔQTcF for moxifloxacin (primary: C-QTc analysis 
and secondary: by-time point analysis)

To evaluate the pharmacokinetics of 
multiple oral therapeutic and 
supratherapeutic doses of GSK3640254 
and a single dose of moxifloxacin. 

AUC(0-t), AUC(0-), Cmax, C, and Tmax of
GSK3640254 in plasma

Cmax and Tmax of moxifloxacin in plasma

To assess the safety and tolerability of 
multiple therapeutic and supratherapeutic 
doses of GSK3640254

Safety and tolerability parameters for AEs/SAEs, 
observed and change from baseline in clinical 
laboratory assessments, ECGs, and vital sign 
measurements
Overall Design: This study has an adaptive 2-part design, where projected doses will be 
identified and may be modified according to assessment of accrued data. Part 1 will 
consist of up to 2 sentinel cohorts to determine the supratherapeutic dose for Part 2, 
which will be the main QTc study.
Part 1, Sentinel Cohorts: Part 1 will be a randomized, double-blind study in up to 
2 sequential cohorts of approximately 8 healthy participants each (3:1 ratio to receive 
GSK3640254 or placebo) to evaluate the safety, tolerability, and pharmacokinetics (PK)
following multiple-dose administration of GSK3640254 for 7 days. 
Part 1 of the study will consist of a screening period and a treatment period for each 
cohort conducted. The first cohort will evaluate once daily (QD) dosing of GSK3640254 
or placebo. On Day 1 of the treatment period, 8 participants will be randomly assigned in 
a 3:1 ratio to receive GSK3640254 500 mg or placebo. All doses of study intervention 
will be administered under fed conditions. The participants will fast overnight for at least 
8 hours prior to breakfast before the morning dose and will receive a moderate-fat meal 
(defined as approximately 600 calories, 30% from fat) 30 minutes prior to dosing. 
Participants will eat this meal within 25 minutes or less. Dose administration will occur 
within 5 minutes of completion of meal consumption.


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The second cohort if conducted would evaluate twice daily (BID) dosing of 
GSK3640254. The second cohort would only be used if GSK3640254 PK or 
safety/tolerability endpoints defined above showed that an alternative supratherapeutic 
dose (other than 500 mg QD) would need to be evaluated in Part 2. The maximum dose 
would be 500 mg BID. The morning dose will be administered with a moderate-fat meal 
as previously described for Cohort 1. Participants will fast at least 2 hours prior to dinner 
before the evening dose. Participants will eat this meal within 25 minutes or less and dose 
administration will occur within 5 minutes of completion of meal consumption.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be collected at 
selected time points pre-dose and up to 48 hours after the Day 7 morning dose.
Safety and tolerability will be assessed by monitoring and recording of adverse events 
(AEs), clinical laboratory results, vital sign measurements, safety 12-lead ECG results, 
and physical examination findings.
Study participants will be confined to the clinic from Day -1 until discharge on Day 9. 
The total duration of the study for a participant in Part 1, including screening, is 37 days.
Part 2, Main QTc Study: Part 2 will be a double-blind (to GSK3640254 and Placebo 
only), randomized, placebo-controlled study to investigate the safety, tolerability, and PK 
of GSK3640254 doses on cardiac conduction as compared to placebo and a single oral 
dose of moxifloxacin in healthy adult participants. Moxifloxacin is included as a positive 
control and will be open label. Approximately 42 participants will be randomized to 
ensure 34 evaluable participants with data from all treatment periods. Participants will be 
randomly assigned to 1 of 12 treatment sequences, with at least a 7-day washout after the 
final dose in each period. The supratherapeutic dose will be determined based on the 
results of preliminary safety and PK data from Part 1 and will be decided upon by the 
study team and the investigator.
All doses of study intervention will be administered under fed conditions. The 
participants will fast overnight for at least 8 hours prior to breakfast before the morning 
dose and will receive a moderate-fat meal (defined as approximately 600 calories, 30% 
from fat) 30 minutes prior to dosing. If participants will receive a BID dose, they will fast 
at least 2 hours prior to dinner before the evening dose. In both cases, participants will eat 
this meal within 25 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption.
Part 2 of the study will consist of a screening period, a check-in visit (Day -2), a baseline 
visit (Day -1), and 4 sequential treatment periods. Prior to dosing on Day 1 of Period 1, 
participants will be randomly assigned to a treatment sequence.
Continuous Holter ECG monitoring will be performed on Day -1 (full set of replicates 
mirroring pre- and post-dose time points). In each treatment period, continuous Holter 
ECG monitoring will be performed pre-dose on Day 1, and pre-dose and up to 24 hours 
after dosing on Day 7.


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Pharmacokinetic blood samples for the analysis of GSK3640254 and moxifloxacin will 
be collected at selected time points pre-dose and up to 24 hours after the Day 7 morning 
dose.
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory results, vital sign measurements, safety 12-lead ECG results, and physical 
examination findings. The same ECG machine will be used for any individual participant 
in order to minimize undue machine generated bias. 
Study participants will be confined to the clinic starting on Day -2 of Period 1. Final 
discharge will be on Day 9 of Period 4. The total duration of the study for a participant in 
Part 2, including screening, is approximately 82 days.
Disclosure Statement: This is a 2-part study. Part 1 is a sequential treatment study with 
2 arms that is participant and investigator blinded. Part 2 is a single group, single arm, 
crossover treatment study that is participant and investigator blinded (open-label for 
moxifloxacin).
Number of Participants: In Part 1, up to 16 participants may be enrolled (8 participants 
per cohort). In Part 2, approximately 42 participants will be enrolled to achieve 
34 evaluable participants.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study are not considered enrolled unless 
otherwise specified by the protocol.
Intervention Groups and Duration:
Part 1:

Sentinel Cohort 1: GSK3640254 500 mg or placebo orally QD for 7 days. 

Sentinel Cohort 2 (optional): If needed, a dose of GSK3540254 or placebo 
orally BID for 7 days (13 doses), with only a single morning dose administered 
on the seventh day. The specific dose in sentinel Cohort 2 will be determined 
based on the results of preliminary safety and PK data from sentinel Cohort 1 
and decided upon by the study team and the investigator. The dose will no 
exceed 500 mg BID.


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Part 2: Participants will receive treatments in 1 of the 12 following sequences:
Sequence
Period 1
Period 2
Period 3
Period 4
1
T
ST
P
M
2
ST
M
T
P
3
P
T
M
ST
4
M
P
ST
T
5
ST
P
T
M
6
P
M
ST
T
7
T
ST
M
P
8
M
T
P
ST
9
P
T
ST
M
10
T
M
P
ST
11
ST
P
M
T
12
M
ST
T
P
Treatment T: Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 through 7.
Treatment ST: Supratherapeutic dose of GSK3640254 (to be determined from Part 1) Days 1 through 7.
Treatment P: Placebo for GSK3640254 Days 1 through 7.
Treatment M: Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin (400 mg) on 
Day 7.
To maintain the blind, the number of tablets administered for therapeutic, supratherapeutic, (Days 1 through 6 only), 
and placebo doses will be identical. The total number of tablets will be based on the actual supratherapeutic dose 
derived from Part 1 of the study. For example, if the supratherapeutic dose is determined to be 500 mg QD, the 
therapeutic dose would consist of one 100 mg GSK3640254 tablet and four placebo tablets, the supratherapeutic 
dose would consist of five 100 mg GSK3640254 tablets, and the placebo dose would consist of five placebo tablets.
Data Monitoring or Other Committee: No
1.2.
Schema
Figure 1
Study Design Schematic – Part 1
1.
Sentinel Cohort 1: GSK3640254 500 mg or placebo once daily.
Sentinel Cohort 2 (if needed): GSK3640254 or placebo twice daily, with only a single morning dose administered 
on the seventh day; dose to be determined after completion of Sentinel Cohort 1.
Days 1 - 7
GSK36402541 or
Placebo
Discharge
Day 9
Screening
≤ 28 Days
Randomization
3:1


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Figure 2
Study Design Schematic – Part 2
1.
Washout will be at least 7 days minus 4 hours to allow for flexibility in scheduling in the clinic.
Treatment T: Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 through 7.
Treatment ST: Supratherapeutic dose of GSK3640254 (to be determined from Part 1) Days 1 through 7
Treatment P: Placebo for GSK3640254 Days 1 through 7.
Treatment M: Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin (400 mg) on 
Day 7.
1.3.
Schedule of Activities (SoA)

Screening procedures may be done over more than 1 visit, but must all be 
completed within 28 days prior to Day 1 in Part 1, and 29 days prior to Day -2 in 
Part 2. Subjects outside of these screening windows will not be able to 
participate in their respective portions of the study.

The following demographic parameters will be captured: year of birth, sex, race, 
and ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria.
Screening ≤ 29  days
Randomization 1:1:1:1
Days  1 -  7
Treatment T 
or
Treatment ST 
or
Treatment P
or
Treatment M
Washout  of 7 days1
Days  1 -  7
Treatment T
or
Treatment ST 
or
Treatment P
or
Treatment M
Washout  of 7 days1
Days  1 -  7
Treatment T 
or
Treatment ST 
or
Treatment P 
or
Treatment M
Washout  of 7 days1
Days  1 -  7
Treatment T
or
Treatment ST 
or
Treatment P 
or
Treatment M
Discharge Day 9 
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment Period 4


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Screening Visit – Part 1
Procedure
Screening
(up to 28 days before Day 1)
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight1
X
Laboratory assessments (haematology, chemistry, urinalysis)
X
12-lead electrocardiogram 
X
24-hour Holter monitor recording2
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-23
X
1.
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.
2.
May be performed either during Screening or on Day -1 upon admission.
3.
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 – Part 1, Supratherapeutic Dose Selection
Procedure
Check-
in
Baseline
Treatment
Follow-up
Notes
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 91
Admit to clinic
X
Discharge from clinic
X
Discharge from clinic following 
completion of the last study procedure 
on Day 14.
Brief physical 
examination
X
X
X
An interim symptom-targeted brief 
physical examination will be performed 
at the discretion of the investigator. See 
Section 8.2.1 for a description of the 
brief physical examination.
Vital sign 
measurements
X
X
X
X
X
X
X
X
X
X
X
Blood pressure and pulse will be 
measured in triplicate pre-dose on Day 
1. Single blood pressure and pulse will 
be measured on other study days.
Daily temperature 
check
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
The pre-dose ECG on Day 1 will be 
collected in triplicate. Other ECGs will 
be single. The ECGs on Days 1, 4, and 
7 will be collected at pre-dose and 
post-dose at 2, 4, and 6 hours.
Drug, alcohol, and 
cotinine screen
X
See Appendix 2 for specific tests to be 
performed.


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Procedure
Check-
in
Baseline
Treatment
Follow-up
Notes
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 91
Molecular Test for 
SARS-CoV-2
X1
X
X
1This 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.
Laboratory 
assessments 
(haematology, 
chemistry, urinalysis)
X
X
X
X
See Appendix 2 for specific tests to be 
performed.
Pregnancy test
X
X
Serum testing on Day -1.
Columbia-Suicide 
Severity Rating Scale
X
X
X
X
X
Randomization
X
Study intervention:
Sentinel Cohort 1: 
GSK3640254 500 mg 
or placebo once daily
Sentinel Cohort 2
(optional): To be 
determined after 
completion of Cohort 1
and not to exceed 500 
mg BID.
X
X
X
X
X
X
X


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Procedure
Check-
in
Baseline
Treatment
Follow-up
Notes
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 91
GSK3640254 PK
sampling
X
X
X
X
X
X
Blood collection for PK analysis of 
GSK3640254 will be collected within 40 
minutes prior to the morning dose on 
Days 1, 5, 6, and 7, and after dosing on 
Day 7 at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 
12, 24, and 48 hours.
AE review
==============================X===============================
SAE review
====================================X===================================
Concomitant 
medication review
====================================X===================================
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event.
1.
Evaluations scheduled for Day 9 will also be performed for participants who discontinue early.


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Screening Visit – Part 2, Thorough QT Study
Procedure
Screening
(up to 29 days before Day -2)
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
12-lead electrocardiogram 
X
24-hour Holter monitor recording2
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-23
X
1.
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.
2.
May be performed either during Screening or on Day -2 upon admission.
3.
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 – Part 2, Thorough QT study
Procedure
Check
-in
Baseline
Periods 1, 2, and 3
W
Period 4
Follow-up
Notes
D -2
D -1
D1
D2
D3
D4
D5
D6
D7
D8-141
D1
D2
D3
D4
D5
D6
D7
D8
D92
Admit to clinic
X
Discharge from clinic
X
Final discharge from clinic 
following completion of the last 
study procedure on Day 9 of 
Period 4.
Brief physical 
examination
X
D14
X
An interim symptom-targeted 
brief physical examination will 
be performed at the discretion 
of the investigator. See 
Section 8.2.1 for description of 
the brief physical examination.
Vital signs
X
X
X
X
X
X
X
X
X
D8, 
D14
only
X
X
X
X
X
X
X
X
X
Blood pressure and pulse will 
be measured in triplicate pre-
dose on Day 1 of each period 
and single blood pressure and 
pulse will be measured on other 
study days. On Day 7 of each 
period, blood pressure and 
pulse to be measured before 
dosing and 4 and 24 hours after 
dosing.
Daily temperature check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
While confined to clinic.


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Procedure
Check
-in
Baseline
Periods 1, 2, and 3
W
Period 4
Follow-up
Notes
D -2
D -1
D1
D2
D3
D4
D5
D6
D7
D8-141
D1
D2
D3
D4
D5
D6
D7
D8
D92
Safety 12-lead ECG
X
X
X
X
X
X
X
D8, 
D14
X
X
X
X
X
X
X
The pre-dose ECGs on Day 1 
of each period will be collected 
in triplicate. All other ECGs will 
be single. On Days 1, 4, and 7, 
ECGs will be collected at 
pre-dose and post-dose at 1, 2, 
3, 4, 6, and 24 hours. 
Drug, alcohol, and 
cotinine screen
X
D14
See Appendix 2 for specific 
tests to be performed. Day 14 
drug, alcohol, and cotinine 
screen required only for 
participants that are furloughed 
during the washout period.
Laboratory assessments 
(hematology, chemistry, 
urinalysis)
X
D8, 
D14
X
See Appendix 2 for specific 
tests to be performed.


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Procedure
Check
-in
Baseline
Periods 1, 2, and 3
W
Period 4
Follow-up
Notes
D -2
D -1
D1
D2
D3
D4
D5
D6
D7
D8-141
D1
D2
D3
D4
D5
D6
D7
D8
D92
Molecular Test for 
SARS-CoV-2
X1
X
D13
X
X
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.
Test to be obtained every 
7 days from Check-in 
(regardless of period or 
washout) while in-house.
Pregnancy test
X
D14
X
Serum testing on Day -2.
Day 14 pregnancy test required 
only for participants that are 
furloughed during the washout
period.
Columbia Suicide 
Severity Rating Scale
X
D8
X
Randomization
X
Period 1 only.
Study intervention: 
GSK3640254 
therapeutic or 
supratherapeutic dose, 
placebo, or moxifloxacin
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Moxifloxacin treatment consists 
of GSK3640254 placebo on 
Days 1 through 6 with 
moxifloxacin on Day 7 only.
Holter ECG recording3
X
X
X
D8
X
X
X


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Procedure
Check
-in
Baseline
Periods 1, 2, and 3
W
Period 4
Follow-up
Notes
D -2
D -1
D1
D2
D3
D4
D5
D6
D7
D8-141
D1
D2
D3
D4
D5
D6
D7
D8
D92
GSK3640254 PK 
sampling
X
X
X
X
D8
X
X
X
X
X
Blood collection for PK analysis 
will be collected within 
40 minutes prior to dosing on 
Days 1, 5, 6, and 7. Day 7 
post-dose samples will be 
collected at 0.5, 1, 2, 3, 3.5, 4, 
4.5, 5, 6, 8, 10, 12, and 
24 hours.
Moxifloxacin PK 
sampling
X
D8
X
X
Blood collection for PK analysis 
of moxifloxacin will be collected 
within 40 minutes prior to the 
dose on Day 7. Day 7 
post-dose samples will be 
collected at 0.5, 1, 2, 3, 3.5, 4, 
4.5, 5, 6, 8, 10, 12, and 24 
hours.
AE review
===================================X===================================
SAE review
=============================================X=======================================
Concomitant medication 
review
=============================================X=======================================
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; W = washout.
1.
Participants may be furloughed during the washout portion of the respective period following Day 8 procedures after discussion with and approval of the investigator. If participants 
are furloughed during the washout period, they should return to the clinic on Day 14 for scheduled assessments prior to initiating the next period.
2.
Evaluations scheduled for Day 9 of Period 4 will also be performed for participants who discontinue early.
3.
Holter ECG recordings:

On Day -1 (Baseline), continuous ECG recordings (Holter) will be extracted at the following time points (relative to the time of planned dosing on the next day): pre-dose
at -45, -30, and -15 minutes, and then after the time of planned dosing at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours.

On Day 1 of each period, continuous ECG recordings (Holter) will be performed starting approximately 2 hours before dosing and digital 12-lead ECGs will be extracted in 
replicates at -45, -30, and -15 minutes prior to dosing.

On Day 7 of each period, continuous ECG recordings (Holter) will be performed starting approximately 2 hours before dosing and digital 12-lead ECGs will be extracted in 
replicates at pre-dose (single time point), and then at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours after dosing.


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
The timing and number of planned study assessments, including safety, pharmacokinetic (PK), or other assessments may be 
altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging PK data from
this study must be documented and approved by the relevant study team member and then archived in the sponsor and site study 
files but will not constitute a protocol amendment. The Institutional Review Board (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 competent authorities and the 
ethics committee before implementation.


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2.
INTRODUCTION
2.1.
Study Rationale
The International Council for Harmonisation (ICH) E14 guidance, as adopted in the US 
Food and Drug Administration (FDA) Guidance for Industry, E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic 
Drugs [DHHS, 2005], emphasizes the need to obtain clear and robust data through 
“thorough” studies that assess the effect of new chemical entities on electrocardiogram 
(ECG) parameters. Specifically, “thorough” studies are defined as trials dedicated to 
evaluating a compound’s effect on cardiac repolarization, as measured by the corrected 
QT interval (QTc). Although many Phase 1, 2, and 3 studies may be conducted with a 
new compound, they typically utilize insufficient sample sizes, infrequent sampling of 
ECG data, or inadequate controls to overcome high variance in cardiac repolarization due 
to spontaneous change. Therefore, this thorough QT (TQT)/QTc study will be conducted 
to evaluate the effect of GSK3640254 on cardiac repolarization.
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 (PD) relationship 
and longer-term efficacy through Phase 2a to 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, Study 205891 (maximum dose 180 mg daily). 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 to 2 diarrhoea in 38% to 
61% of participants and abdominal pain in 8% to 22% of participants) and higher rate of 
nucleoside reverse transcriptase inhibitor resistance (6.5%) with clinically significant 
changes in GSK3532795 susceptibility were observed across all three GSK3532795 


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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 1 TQT study AI468044/206220 [Bristol-Myers Squibb, 2017] at 
supratherapeutic 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 at 240 mg twice daily (BID) 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 study with GSK3532795. The 
most frequent neuropsychiatric adverse events (AEs) in studies with GSK3532795 were 
headache, dizziness, and sleep abnormalities (e.g., insomnia, abnormal dreams).
Importantly, neither of these GI or psychiatric safety findings have been reproduced in
the completed clinical studies of GSK3640254 in healthy volunteers or HIV-1 infected 
treatment-naïve participants.
2.2.2.
Preclinical Summary with GSK3640254
2.2.2.1.
Pharmacokinetics and Product Metabolism in Animals
Following intravenous administration, GSK3640254 exhibited low systemic clearance, 
high volume distribution, and elimination half-lives 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 humans, there is a potential risk for
GSK3640254 to act as a perpetrator of drug-drug interactions (DDIs) of substrates of 
organic anion-transporting polypeptide 1B3 and multi-drug resistance protein 2.
GSK3640254 was an inhibitor of uridine diphosphate glucuronosyltransferase 
(UGT) 1A1 and clinical DDI via this mechanism could be possible.
2.2.2.2.
Toxicology in Animals
The primary target organ of toxicity in non-clinical studies with GSK3640254 was the
stomach, with microscopic changes affecting parietal and chief cells in both rats and
dogs. Due to microscopic changes in the stomach of rats at the lowest dose tested after
26 weeks, a no observed adverse effect level (NOAEL) in rats was unable to be
determined. Microscopic findings in the stomach of rats were minimal to mild at the
lowest observed adverse effect level (LOAEL) of 10 mg/kg/day (area under the plasma 
concentration-time curve [AUC] = 18.9 μg.hr/mL), corresponding to 0.63-fold the 


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measured highest mean human exposure in the planned Phase 2b clinical study. 
Following 39 weeks of dosing in dogs, the NOAEL for microscopic changes in the 
stomach was 0.2 mg/kg/day, and exposures were 0.28-fold the highest mean clinical 
exposure. Microscopic stomach changes were associated with increases in serum gastrin 
when evaluated in the 26- and 39-week studies in rats and dogs, respectively. All 
microscopic findings in the stomach of rats and dogs and changes in serum gastrin were 
shown to be partially reversible following a 4-week recovery period. Microscopic 
findings in the stomach were minimal to mild at the LOAELs of 10 mg/kg/day 
(AUC = 18.9 μg.hr/mL) and 1 mg/kg/day (AUC = 46.4 μg/hr/mL) in rats and dogs, 
respectively, corresponding to 0.63-fold and 1.6-fold highest mean clinical exposure in 
the planned Phase 2b clinical study. Potential effects in the stomach of humans during 
clinical studies are being investigated in a gastric safety sub-study.
With correction for protein binding, compared to the half maximal inhibitory 
concentration for the hERG/IKr potassium channel, there is a 7.9-fold margin above the 
predicted average clinical maximum observed concentration (Cmax) exposure for the 
highest dose planned in this study. Exposure where a minimal increase in QT interval 
was seen in a single dog in the single dose safety pharmacology study in telemeterized 
dogs was 1.8-fold higher than the predicted Cmax at the highest planned dose in this
study. In addition, there were no effects on ECG parameters in dogs given up to 
25 mg/kg/day for 4 weeks at 9.75-fold above the predicted average Cmax at the highest 
dose in this study.
2.2.3.
Summary of GSK3640254 Clinical Pharmacokinetics
Pharmacokinetic data for clinical studies performed to date are summarized as follows:

Following single oral doses from 1 to 700 mg, AUC from time zero extrapolated 
to infinity, and Cmax tended to increase in a dose-proportional manner through 
100 mg. Higher doses showed a less than dose-proportional increase in exposure 
and there was no apparent increase in exposure from 400 to 700 mg.

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 28 hours.
o
There was a slightly less than dose-proportional increase in Cmax and AUC 
from time zero to the end of the dosing interval at steady state (AUC[0-τ])
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-τ) compared to those on Day 1.


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
Clinically notable AEs of elevated transaminases occurred in Studies 207187 
(SAD/MAD, n = 1 healthy participant [17%], Grade 1) and 208135 (DDI with 
oral contraceptive Portia [ethinyl estradiol/levonorgestrel], n = 8 healthy 
participants [35%], 3 Grade 1 and 5 Grade 2). Subsequent analysis in 
Study 208135 showed no PK/PD relationship with either GSK3640254 or Portia 
and elevated transaminases. The elevated transaminases were likely due to the 
recent initiation of hormonal contraception in study participants.

Treatment-related AEs reported in more than 1 study included headache 
(Studies 207187, 208131, and 208132) and nausea (Studies 207187 and 208132).

Across studies, the most common AEs regardless of grade, relationship, and 
concomitant medication administration were headache (11.9%), contact dermatitis 
and related events (7.8%), diarrhoea (5.5%), and abdominal pain (4.1%).

Across studies, low grade GI intolerability has been observed; the majority were 
mild. Both Study 207187 (SAD/MAD) and Study 208312 (proof of concept) are 
relevant to this study given dosing of 7 to 14 days; most AEs in Study 207187 
were unrelated and most AEs in Study 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 ms, or increase from 
baseline >60 ms.
The full safety profile for GSK3640254 can be found in the CIB [GSK Document 
Number 2018N379610_01, 2019].
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 (placebo-corrected change 
from baseline in QTcF [∆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).


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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 diarrhoea)
and gastric toxicity (effects on parietal cell and chief cells), prolongation of QTc, 
neuropsychiatric safety, and rash.
Gastrointestinal intolerability will be assessed using clinical monitoring as outlined in 
Section 8.2.6. 
Prolongation of the QTc interval is a risk. One preclinical study 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 summarized in 
Section 2.2.5.1. Importantly, in GSK3640254 clinical studies to date, there have been no
abnormal clinically significant arrhythmias, and no participants met the study-based QTc
stopping criteria for QTcF prolongations: values >500 ms or increases >60 ms from
baseline. This study contains specific cardiac exclusion criteria (Section 5.2), has ECG 
monitoring (at Tmax once GSK3640254 attains steady state concentration [Section 1.3]), 
and has QTcF-based stopping criteria (Section 7.1.2).
Given the risk of psychiatric events as seen with GSK3532795 (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; Section 5.2). 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 (Section 1.3 and Section 8.2.5).
Across clinical studies, 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 (Section 7.1.4).
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 
the known and expected benefits and risks and reasonably expected AEs of GSK3640254 
may be found in the CIB [GSK Document Number 2018N379610_01, 2019].


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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 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 (NOAEL) in the 
study was 12.5 mg/kg, which produced similar systemic 
exposures (8.79 μg/mL), 6.4 × the mean Cmax associated with 
the 200 mg multiple dose (1.4 μg/mL) in the FTIH 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, screening 24-hour Holter monitor, and cardiac medical 
history.
On-Treatment: Participants will have safety 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).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 
(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]). Additionally, toxicity findings of single-cell 
necrosis of parietal cells and/or chief cells were present in 
preclinical species. These findings were reversible. 
Gastrointestinal intolerability (predominantly abdominal pain and 
diarrhea) was seen with a structurally related compound 
GSK3532795 which was evaluated through Phase 2b dosing.
No clinical trends in the system organ class of GI AEs have been 
seen across Phase 1 to 2a GSK3640254 clinical studies.
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 will be
available to guide investigators should GI AEs emerge (see 
Section 8.2.6).
Neurologic/psychiatric 
safety
Two psychiatric SAEs in previous maturation inhibitor (MI)
GSK3532795 clinical program (acute psychosis, 
homicidal/suicidal ideation) were seen at supratherapeutic doses 
in healthy participants in the TQT study.
From a neurologic and psychiatric AE summary and PK/PD
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 studies.
Screening: Protocol exclusion criterion based on any pre-existing 
psychiatric condition (including results of psychological assessment) 
for participants. Participants will have a clinician (or qualified 
designee) administered C-SSRS and will be included given no 
positive (abnormal) response.
On-Treatment: Participants will undergo physical examinations and 
laboratory testing. In addition, participants will undergo continuous 
evaluation for AEs during their participation in the study; there are 
individual clinical stopping criteria and monitoring based upon 
incidence and intensity of treatment-emergent psychiatric AEs 
(Section 7.1.4 and Section 8.2.5). 
Participants will be housed throughout study 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 behaviour, as determined by the investigator (in consultation with 
psychiatry, as needed), the participant will discontinue from the 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
study and the investigator will arrange for urgent specialist 
psychiatric evaluation and management. Guidance for the 
investigator on the management of emergent psychiatric symptoms 
will be available.
Rash
Across clinical studies, 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 study supplemented by the use 
of physical examinations.
Protocol includes individual participant stopping criteria
(Section 7.1.4), including: 

Any Grade 3 or higher rash or Grade 2 rash with evidence of 
systemic involvement.

Any allergic or hypersensitivity reactions.
Moxifloxacin
GI and cardiovascular 
toxicity
Nausea and vomiting are the most common AEs associated with 
oral moxifloxacin administration. Other less common side effects 
include vasodilation, tachycardia, dizziness, and allergic 
reactions. The risk of side effects from a single dose of 
moxifloxacin 400 mg is estimated to be minimal.
Screening: Protocol exclusion criteria based on pre-existing GI 
pathology or baseline GI signs/symptoms and screening ECG 
parameters and cardiac medical history.
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 toxicity evaluation and monitoring plan will be available to 
guide investigators should GI AEs emerge (see Section 8.2.6).
Safety ECG monitoring will be performed (at a clinically reasonable 
frequency) during the course of the study (see SoA, Section 1.3) 
Participants with a history of sensitivity to moxifloxacin are excluded 
from the study.


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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 are low, evaluable, and manageable.
Moxifloxacin is commonly used in clinical practice and has 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, 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.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Primary
Part 1:

To determine the safety and 
pharmacokinetics of a supratherapeutic 
dose of GSK3640254 administered for 
7 days in healthy participants
Part 1:

Area under the plasma concentration-time curve 
from time zero to time t (AUC[0-t]), area under the 
plasma concentration-time curve from time zero to 
the end of the dosing interval at steady state
(AUC[0-]), maximum observed concentration
(Cmax), plasma concentration at the end of the 
dosing interval (C), and time of maximum 
observed concentration (Tmax) of GSK3640254 in 
plasma 

Remaining Plasma will be analyzed for compound 
related metabolites

Safety and tolerability parameters for adverse 
events (AEs)/serious adverse events (SAEs), 
observed and change from baseline in clinical 
laboratory assessments, electrocardiograms 
(ECGs), and vital sign measurements
Part 2:

To determine the effect of therapeutic and 
supratherapeutic concentrations of 
multiple doses GSK3640254 on the QT 
interval corrected with Fridericia’s formula
(QTcF) in healthy participants
Part 2:

Placebo-corrected change from baseline in QTcF 
(ΔΔQTcF) for GSK3640254 using 
concentration-QTc (C-QTc) analysis (primary 
analysis)

Remaining Plasma will be analyzed for compound 
related metabolites


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Objectives
Endpoints
Secondary
Secondary
Part 2:

To evaluate the effect of multiple oral 
therapeutic and supratherapeutic doses of 
GSK3640254 on other ECG parameters 
(heart rate [HR], PR, QRS, and QTcF 
intervals, treatment-emergent T-wave 
morphology, and appearance of U-waves)
Part 2:

Change from baseline in HR, QTcF, PR, QRS 
(ΔHR, ΔQTcF, ΔPR, and ΔQRS) intervals using 
by-time point analysis (secondary analysis); the 
placebo-corrected change from baseline in HR, 
PR, QTcF, and QRS (ΔΔHR, ΔΔPR, ΔΔQTcF, and 
ΔΔQRS) using by-timepoint analysis; categorical 
outliers for QTcF, HR, PR, and QRS; and the 
frequency of treatment emergent changes of 
T-wave morphology and U-wave presence

To demonstrate assay sensitivity of the 
study design to detect a QTc effect using 
a single 400 mg oral moxifloxacin as a 
positive control.

ΔΔQTcF for moxifloxacin (primary: C-QTc analysis 
and secondary: by-time point analysis)

To evaluate the pharmacokinetics of 
multiple oral therapeutic and 
supratherapeutic doses of GSK3640254 
and a single dose of moxifloxacin. 

AUC(0-t), AUC(0-), Cmax, C, and Tmax of
GSK3640254 in plasma

Cmax and Tmax of moxifloxacin in plasma

To assess the safety and tolerability of 
multiple therapeutic and supratherapeutic 
doses of GSK3640254

Safety and tolerability parameters for AEs/SAEs, 
observed and change from baseline in clinical 
laboratory assessments, ECGs, and vital sign 
measurements
4.
STUDY DESIGN
4.1.
Overall Design
This study has an adaptive 2-part design, where projected doses will be identified and 
may be modified according to assessment of accrued data. Part 1 will consist of up to 
2 sentinel cohorts to determine the supratherapeutic dose for Part 2, which will be the 
main QTc study.
Part 1, Sentinel Cohorts: Part 1 will be a randomized, double-blind study in up to 
2 sequential cohorts of approximately 8 healthy participants each (3:1 ratio to receive 
GSK3640254 or placebo) to evaluate the safety, tolerability, and PK following 
multiple-dose administration of GSK3640254 for 7 days.
Part 1 of the study will consist of a screening period, a check-in visit, and a treatment 
period for each cohort conducted. The first cohort will evaluate QD dosing of 
GSK3640254 or placebo. On Day 1 of the treatment period, 8 participants will be 
randomly assigned in a 3:1 ratio to receive GSK3640254 500 mg or placebo. All doses of 
study intervention will be administered under fed conditions. The participants will fast 
overnight for at least 8 hours prior to breakfast before the morning dose and will receive a 
moderate-fat meal (defined as approximately 600 calories, 30% from fat) 30 minutes 
prior to dosing. Participants will eat this meal within 25 minutes or less. Dose 
administration will occur within 5 minutes of completion of meal consumption.


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The second cohort would evaluate BID dosing of GSK3640254. The second cohort 
would only be used if GSK3640254 PK or safety/tolerability endpoints defined above 
showed that an alternative supratherapeutic dose (other than 500 mg QD) would need to 
be evaluated in Part 2. The maximum dose for Cohort 2 will be 500 mg BID. The 
morning dose will be administered with a moderate-fat meal as previously described for 
Cohort 1. Participants will fast at least 2 hours prior to dinner before the evening dose. 
Participants will eat this meal within 25 minutes or less and dose administration will 
occur within 5 minutes of completion of meal consumption.
Participants will receive 1 of the following treatments:

Sentinel Cohort 1: GSK3640254 500 mg or placebo orally QD for 7 days.

Sentinel Cohort 2 (optional): If needed, a dose of GSK3540254 or placebo 
orally BID for 7 days (13 doses), with only a single morning dose administered 
on the seventh day. The specific dose in sentinel Cohort 2 will be determined 
based on the results of preliminary safety and PK data from sentinel Cohort 1 
and decided upon by the study team and the investigator. Written confirmation 
of the dose decision for sentinel Cohort 2 will be provided to the IRB.
Pharmacokinetic blood samples for the analysis of GSK3640254 will be collected at 
selected time points pre-dose and up to 48 hours after the Day 7 morning dose.
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory results, vital sign measurements, safety 12-lead ECG results, and physical 
examination findings.
Study assessments will be performed as indicated in the SoA (Section 1.3). Study 
participants will be confined to the clinic from Day -1 until discharge on Day 9. The total 
duration of the study for a participant in Part 1, including screening, is 37 days.
Part 2, Main QTc Study: Part 2 will be a double-blind (to GSK3540254 or placebo
only), randomized, placebo-controlled study to investigate the safety, tolerability, and PK
of GSK3640254 doses on cardiac conduction as compared to placebo and a single oral 
dose of moxifloxacin in healthy adult participants. Moxifloxacin is included as a positive 
control and will be open label. Approximately 42 participants will be randomized to 
ensure 34 evaluable participants with data from all treatment periods. Participants will be 
randomly assigned to 1 of 12 treatment sequences, with at least a 7-day washout after the 
final dose in each period. The supratherapeutic dose will be determined based on the 
results of preliminary safety and PK data from Part 1 and decided upon by the study team 
and the investigator.
All doses of study intervention will be administered under fed conditions. The 
participants will fast overnight for at least 8 hours prior to breakfast before the morning 
dose and will receive a moderate-fat meal (defined as approximately 600 calories, 30%
from fat) 30 minutes prior to dosing. If participants will receive a BID dose, they will fast 
at least 2 hours prior to dinner before the evening dose. In both cases, participants will eat 
this meal within 25 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption.


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Part 2 of the study will consist of a screening period, a check-in visit (Day -2), a baseline 
visit (Day -1), and 4 sequential treatment periods. Prior to dosing on Day 1 of Period 1, 
participants will be randomly assigned to a treatment sequence.
Participants will receive treatments in 1 of the 12 following sequences:
Sequence
Period 1
Period 2
Period 3
Period 4
1
T
ST
P
M
2
ST
M
T
P
3
P
T
M
ST
4
M
P
ST
T
5
ST
P
T
M
6
P
M
ST
T
7
T
ST
M
P
8
M
T
P
ST
9
P
T
ST
M
10
T
M
P
ST
11
ST
P
M
T
12
M
ST
T
P
Treatment T: Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 through 7.
Treatment ST: Supratherapeutic dose of GSK3640254 (to be determined from Part 1) Days 1 through 7.
Treatment P: Placebo for GSK3640254 Days 1 through 7.
Treatment M: Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin (400 mg) on 
Day 7.
To maintain the blind, the number of tablets administered for therapeutic, supratherapeutic, (Days 1 through 6 only), 
and placebo doses will be identical. The total number of tablets will be based on the actual supratherapeutic dose 
derived from Part 1 of the study. For example, if the supratherapeutic dose is determined to be 500 mg QD, the 
therapeutic dose would consist of one 100 mg GSK3640254 tablet and four placebo tablets, the supratherapeutic 
dose would consist of five 100 mg GSK3640254 tablets, and the placebo dose would consist of five placebo tablets.
Continuous Holter ECG monitoring will be performed on Day -1 (full set of replicates 
mirroring pre- and post-dose time points). In each treatment period, continuous Holter 
ECG monitoring will be performed pre-dose on Day 1, and pre-dose and up to 24 hours 
after dosing on Day 7.
Pharmacokinetic blood samples for the analysis of GSK3640254 and moxifloxacin will 
be collected at selected time points pre-dose and up to 24 hours after the Day 7 morning 
dose.
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory results, vital sign measurements, safety 12-lead ECG results, and physical 
examination findings.
Study assessments will be performed as indicated in the SoA (Section 1.3). Study 
participants will be confined to the clinic starting on Day -2 of Period 1. Final discharge 
will be on Day 9 of Period 4. The total duration of the study for a participant in Part 2, 
including screening, is approximately 82 days.
4.2.
Scientific Rationale for Study Design
The purpose of this study is to provide an assessment of the effects of GSK3640254 on 
the QT interval. The design of the study follows the general design principles outlined in 


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the E14 guidance for the clinical evaluation of the QT/QTc with non-antiarrhythmic 
drugs [DHHS, 2005]. Both a therapeutic dose and a supratherapeutic dose of 
GSK3640254 will be evaluated in the main QTc study. As the supratherapeutic dose of 
GSK3640254 has not been determined, this study will be conducted as an adaptive 2-part 
design, where projected doses will be identified and may be modified according to 
assessment of accrued data. In Part 1, a sentinel cohort will be used to determine the 
supratherapeutic dose. If needed, a second sentinel cohort employing BID dosing may be 
added.
In accordance with ICH E14, this study will be conducted in healthy participants to 
eliminate variables known to influence ECG parameters (e.g., concomitant medications 
or diseases). The sample size will accommodate a time-matched statistical analysis on the 
primary endpoint, and a positive-control group will be utilized to establish assay 
sensitivity. Further, the half-life of GSK3640254 (i.e., 22 to 28 hours) allows for a 
crossover design, wherein the participants will act as their own controls.
As outlined in the ICH E14 guideline, the study will use a randomized, partially double-
blind (open label for moxifloxacin), placebo- and positive-controlled design. The positive 
control, moxifloxacin, will be used to confirm assay sensitivity for QTc prolongation.
Moxifloxacin is a widely used positive reference substance for assaying the sensitivity of 
a TQT study to detect changes in the QTc interval at a single dose of 400 mg.
GSK3640254 will be administered under double-blind conditions to avoid bias. The 
central ECG laboratory will be blinded to dose consistent with FDA standards.
4.3.
Justification for Dose
A single dose of GSK3640254 will likely not be able to achieve therapeutic or 
supratherapeutic exposures; thus, multiple-dose administration will be needed. A 
projected therapeutic dose of 100 mg GSK3640254 was selected for this study (the dose 
range in a planned Phase 2b dose range finding study in HIV-1 infected adults is 100 to 
200 mg QD). The initial planned dose for Part 1 was selected based on a population PK 
model referenced on the single-dose (1 to 400 mg) and multiple-dose (50 to 320 mg QD 
for 14 days) data from healthy participants from the FTIH study 207187, as well as the 
multiple-dose data in HIV-1 infected participants (10 to 200 mg QD for 7 to 10 days). 
The PK of GSK3640254 (given with food) was described by a two-compartment model 
with sequential zero-order absorption (in the depot compartment) followed by first order 
absorption (from depot to the central compartment) and first order elimination. Weight 
was found to be a significant covariate on Ka. In addition, study (as a surrogate for 
subject type and differences in GSK3640254 salt formulations between the 2 studies) was 
also found to be significant covariates on bioavailability (F was ~27% lower in the FTIH 
Study 207187 compared to that from the proof of concept Study 208132).
As indicated in Section 4.2, the supratherapeutic dose of GSK3640254 has not been 
determined. The target supratherapeutic exposure (steady-state Cmax) is approximately 
4.4 µg/mL, which provides approximately 4-fold cover for 100 mg QD therapeutic dose, 
2-fold for 200 mg QD, 1:1 for inhibitors with a 200 mg dose or 2:1 with 100 mg dose 
(assuming an increase in exposure with CYP-inhibitors of approximately 2-fold).


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This study will be conducted as an adaptive 2-part design, where projected 
supratherapeutic doses will be identified and may be modified according to assessment of 
accrued data. In Part 1, a sentinel cohort will be used to determine whether 500 mg QD 
elicits the target supratherapeutic exposure as predicted by the population PK model, and 
assuming dose linearity. The requirement to conduct sentinel Cohort 2 in Part 1 will be 
determined based on the results of preliminary safety and PK data from sentinel Cohort 1 
and decided upon by the study team and investigator. Cohort 2 (where a BID dosing 
regimen would be evaluated not to exceed 500 mg BID) will be conducted only if the 500 
mg QD evaluated in Cohort 1 fails to result in approximately c µg/mL at steady state. In 
Part 2, the supratherapeutic dose will represent a dose that is equal to or less than the 
highest total dose that was evaluated in the sentinel cohorts.
Written confirmation of the decision to conduct sentinel Cohort 2 (Part 1) and the 
supratherapeutic dose for QTc evaluation (Part 2) will be provided to the investigator,
and the IRB will be notified for informational purposes only
4.4.
End of Study Definition
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the final date on which data were or are expected to be 
collected.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA (Section 1.3) for the last participant 
in the study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. Efforts will be made to 
recruit at least 30% of each gender.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
Participants who are healthy as determined by the investigator or medically qualified 
designee based on a medical evaluation including medical history, physical 
examination (including cardiopulmonary examination), laboratory tests, and cardiac 
monitoring (history and ECG).


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Weight
Body weight ≥50.0 kg (110 lbs) for men and ≥45.0 kg (99 lbs) for women and body 
mass index within the range 18.5 to 31.0 kg/m2 (inclusive).
Sex
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Male or female
a.
Male participants:
1. Male participants should not engage in intercourse while confined in the 
clinic. There is no need for an extended period of double barrier use or 
prolonged abstinence after study discharge.
b. Female participants:
1. A female participant is eligible to participate if she is not pregnant, planning 
to become pregnant within the next 6 months, or breastfeeding, and at least 
1 of the following conditions applies:

Is not a woman of childbearing potential (WOCBP) as defined in 
Appendix 3.
OR

Is a WOCBP and using a non-hormonal contraceptive method that is 
highly effective, with a failure rate of <1%, as described in Appendix 3
for 28 days before intervention, during the intervention period, and for 
at least 28 days after the last dose of study intervention. The 
investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
2. A WOCBP must have a negative highly sensitive serum pregnancy test 
(Appendix 2) at Screening and Check-in.
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
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.


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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
A pre-existing condition interfering with normal GI anatomy or motility 
(e.g., gastro-esophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal 
function, that could interfere with the absorption, metabolism, and/or excretion of the 
study intervention or render the participant unable to take oral study intervention.
Prior cholecystectomy (prior appendectomy is acceptable).
Clinically significant illness, including viral syndromes, within 3 weeks of dosing.
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, Section 10.7.3.2.1).
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.
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.
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.
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.
History indicative of an increased risk of a cardiac arrhythmia or cardiac disease, 
including the following:
a.
History of symptomatic cardiac arrhythmias or palpitations associated with 
presyncope or syncope, or history of unexplained syncope.
b.
History of cardiac arrest.
c.
History of clinically relevant cardiac disease including symptomatic or 
asymptomatic arrhythmias (including but not limited to ventricular fibrillation, 
ventricular tachycardia, any degree of atrioventricular block, Brugada syndrome, 


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Wolff-Parkinson-White Syndrome, and sinus bradycardia, defined as heart rate 
(HR) less than 50 beats per minute [bpm] based on vital signs or ECG), 
presyncope or syncopal episodes, or additional risk factors for torsades de 
pointes (e.g., heart failure).
d.
History of clinically relevant structural cardiac disease including hypertrophic 
obstructive cardiomyopathy.
e.
History of hypokalemia.
History of heart disease (e.g., coronary heart disease, angina).
Laboratory Assessments
Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study intervention.
Positive hepatitis C antibody test result at Screening or within 3 months prior to 
starting study intervention.
Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
Alanine aminotransferase (ALT) ≥1.5 × upper limit of normal (ULN). A single 
repeat of ALT is allowed within a single Screening period to determine eligibility.
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.
Any acute laboratory abnormality (including hypokalemia, hypercalcemia, or 
hypomagnesemia) at Screening which, in the opinion of the investigator, should 
preclude participation in the study of an investigational compound.
Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of lipid 
abnormalities (e.g., total cholesterol, triglycerides), and ALT (previously described), 
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.
Urine drug screen positive (showing presence of): amphetamines, barbiturates, 
cocaine, MDMA, cannabinoids, methamphetamines, phencyclidine, or 
non-prescribed opiates, oxycodone, benzodiazepines, methadone, or tricyclic 
antidepressants at screening or before dosing of study intervention.
Prior/Concomitant Therapy
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 g/day and topical hydrocortisone 
cream 1% are permitted for use any time during the study.)
Treatment with any vaccine within 30 days prior to receiving study intervention.


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Unwillingness to abstain from consumption of any food or drink containing 
grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their 
fruit juices within 7 days prior to the first dose of study intervention(s) until the end 
of the study.
Prior/Concurrent Clinical Study Experience
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).
Prior exposure to GSK3640254 in this or another clinical study.
Prior intolerance to moxifloxacin.
Prior participation in this clinical study (i.e., participants may not participate in both 
Part 1 and Part 2 of the study).
Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
Diagnostic Assessments
Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS.
A sustained supine systolic blood pressure >150 mm Hg or <90 mm Hg or a supine 
diastolic blood pressure >95 mm Hg or <50 mm Hg at Screening or Check-in 
(Day -2). Blood pressure may be retested once in the supine position. The blood 
pressure abnormality is considered sustained if either the systolic or the diastolic 
pressure values are outside the stated limits after 2 assessments, in which case the 
participant may not be randomized.
A resting HR of <50 bpm or >100 bpm when vital signs are measured at Screening 
or Check-in (Day -2). A HR from 100 to 110 bpm can be rechecked by ECG or vital 
signs within up to 2 hours to verify eligibility.
An uninterpretable ECG or any significant arrhythmia or ECG finding (e.g., prior 
myocardial infarction in the past 3 months, significant pathological Q-waves 
[defined as Q-wave >40 ms or depth greater than 0.4-0.5 mV], symptomatic 
bradycardia, non-sustained or sustained atrial arrhythmias, ventricular pre-excitation, 
non-sustained or sustained ventricular tachycardia, any degree of atrioventricular 
block, complete left bundle branch block, or conduction abnormality) which, in the 
opinion of the investigator or VH/GSK Medical Monitor, will interfere with the 
safety of the individual participant.


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Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility 
determination):
HR
<50 or >100 bpm
QTcF interval1
>450 ms
QRS interval
>110 ms
PR interval
>200 ms
1.
The QTc is the QT interval corrected for HR 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.
Screening Holter (24 hours) with any of the following:

Sinus bradycardia ≤35 bpm or junctional arrhythmia >60 bpm for 10 seconds or 
longer.

Non-sustained ventricular tachycardia or more than 30 ventricular premature 
depolarizations during an hour.

Atrial arrhythmia >100 bpm for 3 seconds or longer or more than 40 atrial 
premature depolarizations during an hour.
Other Exclusions
History of alcoholism and/or drug/chemical abuse or regular alcohol consumption 
within 6 months of screening, defined as an average weekly intake of >14 units. 
One unit is equivalent to 8 grams of alcohol: a half-pint (~240 mL) of beer, 1 glass 
(125 mL) of wine, or 1 (25 mL) measure of spirits.
Unable to refrain from tobacco or nicotine-containing products within 3 months prior 
to Screening and for the duration of the study.
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

Participants will abstain from consumption of 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.

The participants will fast overnight for at least 8 hours prior to dosing and will 
be provided a breakfast 30 minutes prior to morning dosing. Participants will eat 
this meal in 25 minutes or less. Dose administration will occur within 5 minutes 
of completion of meal consumption. Participants will not receive any further 
food until 4 hours post-dose on serial PK sampling days (Day 7 of each period). 
The moderate-fat meal will contain about 600 calories with approximately 30% 
of the calories coming from fat.


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
A standard lunch will be provided 4 hours after morning dosing. A standard 
dinner will be served approximately 10 hours after morning dosing. Participants 
will eat this meal in 25 minutes or less. Evening dose administration (if needed 
for BID dosing) will occur within 5 minutes of completion of meal 
consumption. A snack may be provided approximately 13 hours after morning 
dosing. The overnight fast will start after the evening snack (within at least 
8 hours relative to the morning dose on the following day). The food content of 
meals must be identical on serial ECG and PK sampling days (i.e., Day 7 of 
each period).

No water is allowed from 1 hour prior to dosing until 1 hour after dosing except 
for the glass of water needed to administer the study intervention (e.g., 240 mL). 
Water is allowed ad libitum at all other times. 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, energy 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 Check-in 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 96 hours (4 days) prior to 
entry into the clinic on Day -1 (Part 1) or Day -2 (Part 2) and throughout the 
study.

In Part 2, participants should refrain from activities or conversations leading to 
increased stimulation during the serial ECG collection period (approximately 
1 hour before dosing on Day 1 and up to 24 hours after the morning dose on 
Day 7). During serial ECG sampling, participants will not be allowed to have 
electronic devices (e.g., cellular telephone, tablet, computer) or watch television.

In Part 2, participants should maintain a supine position for at least 1.5 hours 
before dosing and for the first 4 hours after dosing except for study intervention 
administration. At all other serial ECG time points, participants are required to 
remain in the supine position for at least 15 minutes prior and 10 minutes after 
the nominal ECG time point.


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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations
and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
should not be rescreened.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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6.1.
Study Intervention(s) Administered
Intervention Name
GSK3640254
GSK3640254 Placebo
Moxifloxacin
Type 
Drug
Drug
Drug
Dose Formulation
Tablet
Tablet
Capsule
Unit Dose Strength
100 mg
N/A
400 mg
Dosage Levels
Therapeutic: 100 mg
Supratherapeutic: TBD
N/A
400 mg
Route of 
Administration
Oral
Oral
Oral
IMP and NIMP
IMP
IMP
IMP
Sourcing
Sponsor
Sponsor
Investigator
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.
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; TBD = to be determined.
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 that 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 labelled 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 


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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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a partially double-blind study (moxifloxacin is open label in Part 2). Study 
participants will be randomly assigned to a treatment (Part 1) or treatment sequence 
(Part 2) in accordance with the randomization schedule generated by PPD prior to the 
start of the study and using validated software. On Period 1 Day 1 (both Part 1 and 
Part 2), participants will be assigned a unique number (randomization number) in 
ascending numerical order at the study site. The randomization number encodes the 
participant’s assignment to study intervention, according to the randomization schedule. 
Each participant will be dispensed blinded study intervention (open label for 
moxifloxacin), labelled with his or her unique randomization number throughout the 
study.
Participants will be randomly assigned to receive study intervention. Investigators will 
remain blinded to each participant’s assigned study intervention (GSK3640254 or 
placebo) throughout the course of the study. In order to maintain this blind, an unblinded 
pharmacist will be responsible for the reconstitution and preparation of GSK3640254 or 
placebo and will endeavour to ensure there are no differences in time taken to dispense 
study intervention following randomization. Unblinded monitors and the auditor(s), in the 
event of a quality assurance audit, will be allowed access to unblinded study intervention 
records at the site to verify that randomization/dispensing have been performed
accurately.
A participant will be withdrawn if the participant’s intervention code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the case report form (CRF).
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the intervention
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
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 


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will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. Study site personnel will 
examine each participant’s mouth to ensure that the study intervention was 
ingested.
6.5.
Concomitant Therapy
Acetaminophen/paracetamol at doses of ≤2 g/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.
6.6.
Dose Modification
In Part 1, each participant in sentinel Cohort 1 will be administered GSK3640254 500 mg 
or placebo QD for 7 days. If sentinel Cohort 2 is needed, it is planned that each 
participant will be administered GSK3640254 or placebo BID for 7 days, with only a 
single morning dose administered on the seventh day. The decision to proceed to sentinel 
Cohort 2 and the actual dose of GSK3640254 (either an increase or a decrease) will be 
made by the study team and the investigator based on preliminary safety and PK data 
from Cohort 1. Written confirmation of proceeding to sentinel Cohort 2 will be provided 
to the IRB for informational purposes only
In Part 2, the main QTc study, the therapeutic dose of GSK3640254 will be 100 mg QD 
for 7 days. The supratherapeutic dose will be determined based on the results of 
preliminary safety and PK data from the sentinel cohort(s). The supratherapeutic dose 
will represent a dose that is equal to or less than the highest total dose that was evaluated 
in the sentinel cohort(s). Written confirmation of the dose decision for the 
supratherapeutic dose for QTc evaluation (Part 2) will be provided to the investigator and 
the IRB will be notified for informational purposes only
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment from VH/GSK or with 
GSK3640254 after the completion of the study because only healthy volunteers are 
eligible for study participation.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
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 and follow-up and for any further evaluations that need to be completed.


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7.1.1.
Phase 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 FDA
premarketing clinical liver safety guidance: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf).
Discontinuation of study intervention for abnormal liver tests is required when a
participant has an ALT ≥3 × ULN or when, in the presence of abnormal liver chemistries 
not meeting protocol-specified stopping rules, the investigator believes study intervention
discontinuation is in the best interest of the participant.
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.
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
Safety ECG QTc Stopping Criteria

The same QT 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 intra-period pre-dose Day 1 time point ECGs 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 Period 1, the pre-dose triplicate ECGs 
on Day 1 will serve as the basis for the baseline QTcF for Period 1 only.

A randomized participant who 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 the following: 1) a complete 
unscheduled chemistry panel, 2) an unscheduled GSK3640254 PK sample and 
3) repeated unscheduled ECGs until their QTcF measurement returns to their 
original averaged QTcF value at intra-period Day 1 pre-dose.
Refer to 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.


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7.1.3.
Columbia-Suicide Severity Rating Scale Criteria
Emergence of any positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered C-SSRS during the treatment phase of the 
study will be cause for 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 treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.4.
Individual Participant Laboratory Abnormality and Adverse Event 
Stopping Criteria
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) 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, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.


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
A participant who is withdrawn from the study for any reason related to safety 
(listed in Section 7.1.4 or otherwise) will be continued to be followed to assess 
the outcome of the safety event that triggered discontinuation of study 
intervention.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 4.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3).

Protocol waivers or exemptions are not allowed.


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
Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in 
the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

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 at Screening.

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, forehead, or tympanic temperature; pulse rate; respiratory rate; and blood 
pressure will be assessed.

Blood pressure and pulse measurements will be assessed in the semi-recumbent 
or supine position with a completely automated device. The site will follow their 
standard process for repeating vital signs, as needed.


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
Blood pressure and pulse measurements will be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones).

At each time point at which triplicate measurements are required, 3 consecutive 
blood pressure and pulse readings will be recorded at intervals of at least 
1 minute. Each measurement will be recorded in the CRF.

When vital signs are scheduled at the same time as blood collections for 
laboratory tests, vital signs are to be taken first.
8.2.3.
Safety Electrocardiograms

Twelve-lead ECGs will be obtained using an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT, and QTcF intervals. Refer to 
Section 7.1.2 for QTcF withdrawal criteria and additional QTcF readings that 
may be necessary.

Twelve-lead ECGs will be performed with the participant in a supine position 
after a rest of at least 10 minutes.

At each time point at which triplicate ECGs are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed over a brief 
(e.g., 5 to 10 minutes) recording period. Each measurement will be recorded in 
the CRF.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be available with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal by 
the investigator during participation in the study or within 7 days after the last 
dose of study intervention should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator 
or Medical Monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.


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8.2.5.
Suicidal Ideation and Behaviour 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. Repeat assessments will be performed during the treatment phase of the 
study. In case of a 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 7.1.4, 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).
8.2.6.
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 trials have not evaluated for the presence of gastric toxicity in humans. 
Thus, it is unclear if any of the GI AEs observed in any clinical trial were representative 
of, associated with, or resulted from gastric toxicity (if present). This section provides 
general guidance to the investigator on the evaluation and management of primarily 
upper GI symptoms (Table 1). The investigator may contact the VH/GSK Medical 
Monitor to discuss evaluation and management (including discontinuation of a 
participant) of any GI symptoms throughout the study.


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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 gastrointestinal (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 the following: 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 they are 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 the following: 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 the 
following: 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 
exercise good clinical judgment in this regard [Soll, 2009]. A major goal 
of therapy is directed at correcting the underlying identifiable medical or 


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PPD


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Common Terminology Criteria for Adverse Events v 4.0). Thus, participant safety 
evaluation and monitoring will be more conservative.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up 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).
See Section 10.7.3.2 for the assessment and recording of AEs and SAEs related to 
COVID-19.
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 of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6.

Care will be taken not to introduce bias when detecting an AE and/or SAE. 
Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence. Participants will be 
questioned prior to each dose of study intervention.
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 non-serious AEs of special 
interest (as defined in Section 8.3.6) will be followed until the event is resolved, 


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stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 6.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of 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.

For all studies except those utilizing medical devices, investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of 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
through the end of pregnancy (termination or delivery).

If a pregnancy is reported, the investigator should inform GSK within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.

A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 
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, 
rash, or psychiatric) may be defined in the reporting and analysis plan.


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8.4.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than the planned dose within a 24-hour 
time period (±2 hours) will be considered an overdose.
VH/GSK does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 can no longer be detected systemically (at least 5 days).
3. Obtain a plasma sample for PK analysis immediately and through 7 days after the 
date of the last dose of study intervention if requested by the Medical Monitor
(determined on a case-by-case basis).
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3640254 and moxifloxacin 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 moxifloxacin.
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 analysed for GSK3640254 and moxifloxacin, any 
remaining plasma will be analysed for other compound-related metabolites and 
the results provided in a separate report.
8.6.
Cardiodynamic Assessments
Not Applicable


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8.6.1.
Continuous Holter Electrocardiograms
Pre-dose digital 12-lead ECGs will be extracted in replicates from continuous Holter 
recordings. On Day -1 (Baseline), continuous Holter ECG recordings will be extracted at 
the following time points (relative to the time of planned dosing on the next day): 
pre-dose at -45, -30, and -15 minutes, and then after the time of planned dosing at 0.5, 1, 
2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours. The Holter ECG should be started 
approximately 2 hours before dosing on Day 1 of each period, and ECG extractions will 
occur at -45, -30, and -15 minutes before dosing. On Day 7, 12-lead ECGs will be 
extracted from continuous Holter recordings pre-dose (single time point) and after the 
morning dose at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours in each period. 
Electrocardiograms will be extracted from the continuous recording by a central ECG 
laboratory (ERT, Rochester, NY). The ECGs will be extracted from the continuous 
recording during an extraction window of 5 minutes prior to the nominal time point. Each 
ECG extraction window will be preceded by an approximate 15-minute supine rest period
in an undisturbed environment.
The ECG extractions will be time-matched to the PK samples, but will be obtained before 
the actual PK sampling time to avoid changes in autonomic tone associated with the 
psychological aspects of blood collection as well as the reduction in blood volume 
subsequent to blood collection. When time points for assessments coincide, the order 
should be safety ECGs, vital signs, ECG extraction, and then PK blood collection.
The following ECG parameters will be measured and calculated: HR, PR interval, QTcF, 
QRS interval, T-wave morphology, and U-wave presence.
8.6.2.
Cardiodynamic Sample Analysis
The primary analysis will be based on C-QTc modeling of the relationship between 
GSK3640254 plasma concentration and change-from-baseline QTcF (∆QTcF) with the 
intent to exclude an effect of ΔΔQTcF >10 ms at clinically relevant plasma levels of 
GSK3640254. 
In addition, the effect of GSK3640254 on placebo-corrected change-from-baseline in 
QTcF, HR, PR, and QRS (∆∆QTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) will be evaluated at 
each post-dose time point (“by-time point” analysis) using the intersection union test. An 
analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, 
T-wave morphology, and U-wave presence.
Assay sensitivity will be evaluated by C-QTc analysis of the effect on (∆∆QTcF) of 
moxifloxacin using the same model as for the primary analysis. Assay sensitivity will be 
deemed met if the slope of the C-QTc relationship is statistically significant at the 10% 
level in a 2-sided test and the predicted QTc effect (i.e., the lower bound of the 2-sided 
90% CI of ΔΔQTcF) is above 5 ms at the observed geometric mean Cmax of 400 mg 
moxifloxacin.
For all continuous ECG parameters from each period, baseline will be the average of the 
derived ECG intervals from the 3 ECG time points prior to dosing (-45, -30, 


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and -15 minutes) on Day 1 for the respective period. For T-wave morphology and U-
wave presence, baseline includes any findings observed in any replicates from the 3 pre-
dose time points (-45, -30, and -15 minutes) on Day 1 in each period.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Immunogenicity is not evaluated in this study.
8.10.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There is no formal statistical hypothesis to be tested in Part 1.
For Part 2, the statistical hypothesis to be tested for the primary assessment of QT 
prolongation at the highest clinically relevant exposure using the C-QTc analysis for each 
active dose group is:
H0: ΔΔQTcF ≥10 ms
H1: ΔΔQTcF <10 ms
where ΔΔQTcF is the mean ΔΔQTcF at the mean Cmax for each active dose group, 
respectively.
In addition, the statistical hypothesis to be tested for the assay sensitivity using the 
C-QTc analysis is:
H0: ΔΔQTcF ≤5 ms
H1: ΔΔQTcF >5 ms
where ΔΔQTcF is the mean ΔΔQTcF at the mean Cmax for the moxifloxacin group.
9.2.
Sample Size Determination
Part 1: A total of up to 16 participants are planned to be randomized, 8 participants per 
cohort (6 participants to receive GSK3640254 and 2 participants to receive placebo). For 


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Part 1, as there is no formal research hypothesis being statistically tested, the sample size 
is not selected based on statistical considerations but was determined using feasibility.
Part 2: A sample size of approximately 42 participants is chosen to obtain 34 evaluable 
participants to complete the study. A sample size of 34 evaluable participants will 
provide more than 90% power to exclude that active drug causes more than a 10-ms QTc 
effect at clinically relevant plasma levels, as shown by the upper bound of the 2-sided 
90% CI of the model predicted QTc effect (∆∆QTcF) at the observed geometric mean 
Cmax of active drug in the study.
This power is estimated approximately using a paired t-test. The calculation assumes a 
one-sided 5% significance level, an underlying effect of GSK3640254 of 4 ms and a 
standard deviation (SD) of the ΔQTc of 8.5 ms for both active drug and placebo. Table 2
provides the sample sizes for power of 90% and 95% with underlying effect of 3, 4, and 
5 ms and SD of 8, 8.5, and 9.5 ms.
The C-QTc analysis method is supported by Darpo, 2015 and Ferber, 2015 and consistent 
with the experiences from 25 recent TQT studies in ERT, which provided SD=8 ms as a 
conservative estimate for general TQT studies. Note that this calculation is conservative 
also because it does not take into account any gain in precision due to the use of all data 
of each participant with the help of a linear mixed effects model. An SD of 9.5 ms is a 
conservative value used in previous MI compound BMS-663068 and AI compound 
Fostemsavir TQT studies in GSK. In the previous GSK3640254 FTIH Study 207187 
SAD/MAD study, the within-participant SD based on by-time point analysis was 8.5 ms, 
which provides the conservative estimated SD for this compound. Therefore, the 
underlying effect 4 ms and SD=8.5 ms with 90% of power for the study sample size of 
34 participants was chosen for this study. With the dropout rate of 20%, approximately 
42 participants will be enrolled to ensure the evaluable number of participants is greater 
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Table 2
Sample Size Determination - Power
Sample size
Number of Participants for
90% Power
Number of Participants for
95% Power
Underlying effect 3 ms
SD =  8 ms
22
28
Underlying effect 3 ms
SD =  8.5 ms
25
32
Underlying effect 3 ms
SD =  9.5 ms
32
40
Underlying effect 4 ms
SD = 8 ms 
30
38
Underlying effect 4 ms
SD =  8.5 ms
34
43
Underlying effect 4 ms,
SD =  9.5 ms
43
54
Underlying effect 5 ms
SD = 8 ms
44
55
Underlying effect 5 ms
SD =  8.5 ms
49
63
Underlying effect 5 ms
SD =  9.5 ms
62
78
Sample Size for Assay Sensitivity: To demonstrate assay sensitivity with C-QTc analysis, 
it must be shown that the ΔΔQTcF of a single dose of 400 mg moxifloxacin exceeds 5 ms 
(i.e., the lower bound of the 2-sided 90% CI of the predicted QTc effect [ΔΔQTcF] 
should exceed 5 ms). 
In a similarly designed, recent crossover study with 24 healthy participants (on-file data, 
ERT), the standard error (SE) for the prediction of the QT effect of moxifloxacin based 
on the C-QTc analysis was 1.24 ms. The within-subject SD of ΔQTcF in this study was 
5.4 ms based on the by-time point analysis. If the effect of moxifloxacin is assumed to be 
10 ms, the SE of 1.24 ms corresponds to an effect size of (10-5)/(1.24×sqrt[24])=0.82, 
where the effect size is the effect assumed under the alternative hypothesis divided by the 
SD of the test variable. This value should be compared to the effect size of 0.62 required 
to guarantee a power of at least 95% in a paired t-test situation with a sample size of 
30 evaluable participants. In other words, based on this calculation, a power of at least 
95% for 30 evaluable participants will be obtained as long as the variability of the 
ΔQTcF, as measured by its within-subject SD, does not exceed 7.1 ms (i.e., 132% of the 
5.4 ms observed in the above referenced study [on-file data, ERT]) assuming the ratio of 
effective sizes is consistent with inverse ratio of within-subject SD. The number also 
agrees with recent recommendations of the FDA, which propose at least 20 participants
[Huang, 2019].


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9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Screened
All participants who sign the ICF.
Randomized
All participants who are randomly assigned to a treatment/treatment 
sequence.
Safety
All randomized participants who receive at least 1 dose of study 
intervention. Participants will be analysed according to the intervention 
they actually received. This population will be used for all demographic 
and safety summaries.
QT/QTc
The QT/QTc population will include all participants in the safety population 
with measurements at baseline as well as on-treatment with at least 1 
post-dose time point with a valid ΔQTcF value. The QT/QTc population 
will be used for the by-time point assay sensitivity, and categorical 
analyses of the cardiodynamic ECG parameters.
PK 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.
PK Parameter
The PK Parameter Population will include all participants who undergo 
plasma PK sampling and have evaluable PK parameters estimated. This 
population will be used for PK parameter listings and summary tables.
PK/QTc
The PK/QTc Population will include all participants who are in both the 
QT/QTc and PK concentration populations with at least 1 pair of post-dose 
PK and QTcF data from the same time point as well as participants in the 
QT/QTc population who received placebo. The PK/QTc population will be 
used for the C-QTc analysis. The PK/QTc Population will be defined for 
GSK3640254 and for moxifloxacin.
9.4.
Statistical Analyses
9.4.1.
Cardiodynamic Analyses
9.4.1.1.
QT Correction Methods
The QT and RR value for each beat will be used for HR correction. The primary HR 
correction method will be the Fridericia's correction (QTcF) defined as 
QTcF (ms) = QT (ms)/[RR (ms)/1000]1/3 if there is no effect of GSK3640254 on HR.
If a substantial HR effect is observed (i.e., the largest least squares [LS] mean ΔΔHR is 
greater than 10 bpm in the by-time point analysis), other correction methods such as 
optimized HR-corrected QT interval (QTcI), and individual HR-corrected QT interval 
(QTcS) will be explored using the drug-free QT/RR data extracted from the full range of 
HR in the 24-hour Holter recording on Day -1. The method that removes the HR 


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dependence of the QT interval most efficiently will be chosen as the primary correction 
method. More details will be described in a separate statistical analysis plan.
9.4.1.2.
Concentration-QTc Analysis (Primary Analysis)
The relationship between GSK3640254 plasma concentrations and ∆QTcF will be 
quantified using a linear mixed-effects modelling approach. The model will have ΔQTcF 
as the dependent variable, GSK3640254 plasma concentration as the exploratory variate 
(0 for placebo), centred baseline QTcF (i.e., baseline QTcF for individual participant
minus the population mean baseline QTcF for all participants in the same treatment 
period) as an additional covariate, treatment (active = 1 or placebo = 0) and time (i.e., 
post-dose time point) as fixed effects, and random intercept and slope per participant
[Garnett, 2018]. An unstructured covariance matrix will be specified for the random 
effects. If convergence cannot be achieved even after appropriate rescaling of the 
concentrations, the random effect on the slope and intercept will be dropped, in this 
order, until convergence is achieved. The degrees of freedom of estimates will be 
determined by the Kenward-Roger method. From the model, the slope (i.e., the 
regression parameter for concentration) and the treatment effect-specific intercept 
(defined as the difference between active and placebo) will be estimated together with the 
2-sided 90% CI. The estimates for the time effect will be reported with degrees of 
freedom and SE.
The geometric mean of the individual Cmax values for participants in each of the active 
dose groups will be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTcF 
(i.e., slope estimate × concentration + treatment effect-specific intercept) at this 
geometric mean Cmax of GSK3640254 will be obtained. If the upper bound of the 
2-sided 90% CI of the predicted effect of ΔΔQTcF at clinically relevant plasma levels of
GSK3640254 is below 10 ms, it will be concluded that GSK3640254 does not cause 
clinically relevant QTc prolongation.
The plot of the observed median-quantile GSK3640254 concentrations and associated 
mean placebo-adjusted ΔQTcF (i.e., ΔΔQTcF) with 2-sided 90% CI adjusted for diurnal 
effects, together with the regression line presenting the predicted ΔΔQTcF (2-sided 90% 
CI) [Tornøe, 2011] will be used to evaluate the adequacy of the model fit to the 
assumption of linearity and the impact on quantifying the C-QTc relationship. The 
observed ΔQTcF values from the active group will be adjusted by the estimated time 
effect from the C-QTc model (i.e., the estimated diurnal effect under the placebo 
treatment). The individually estimated placebo-adjusted ΔQTcFi,j equals the individual 
ΔQTcFi,j for participant i administered GSK3640254 at time point j minus the estimation 
of time effect at time point j. For evaluation of the HR-corrected QT interval, a scatter 
plot and quantile plot of QTcF and RR intervals by treatment with regression line and a 
linear mixed-effects line (90% CI), respectively, will also be given. Additional 
exploratory analyses (via graphical displays and/or model fitting) will include accounting 
for a delayed effect (hysteresis) and the justification for the choice of cardiodynamic
model (linear versus nonlinear) as follows.
Hysteresis will be assessed based on joint graphical displays of the LS mean difference 
between ΔQTcF under GSK3640254 and under placebo (ΔΔQTcF) for each post-dose 
time point from the by-time point analysis and the mean concentrations of GSK3640254 


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at the same time points. In addition, hysteresis plots will be given for LS mean ΔΔQTcF 
and the mean concentrations. If a QT effect (∆∆QTcF) >10 ms cannot be excluded in the 
by-time point analysis in the 2 active dose groups, and if the mean peak ΔΔQTcF effect is 
observed at the same time point in the by-time point analysis in the 2 active dose groups, 
and if a delay between peak ∆∆QTcF and peak plasma concentration in the plot 
(ΔΔQTcF versus GSK3640254) of more than 1 hour is observed in a consistent way for 
the 2 active dose groups, other C-QTc models, such as a model with an effect 
compartment, may be explored. With the provision stated above, hysteresis will be 
assumed if the curve of the hysteresis plot shows a counterclockwise loop. A significant 
treatment effect-specific intercept is not biologically plausible and therefore may be 
indicative of hysteresis or model misspecification, if it cannot be explained by a nonlinear 
relationship.
To assess the appropriateness of a linear model, normal Q-Q plots for the standardized 
residuals and the random effects, and plots of standardized residuals versus 
concentration, fitted values, centered baseline QTcF, nominal time, and active treatment 
will be produced. Scatter plots for standard residuals versus continuous covariates and 
box plots for standard residuals versus discrete covariates will be provided. The scatter 
plots of standardized residuals versus concentration and versus centered baseline QTcF 
by LOESS fitting (i.e., locally weighted scatter plot smoothing as described by 
[Cleveland, 1979]) will also be produced with optimal smoothing parameters selected by 
the Akaike information criterion with a correction (AICC [Hurvich, 1998]). A scatter plot 
of observed concentration and ΔQTcF with a LOESS smooth line with 90% CI and a 
linear regression line will also be provided to check the assumption of a linear C-QTc 
relationship. If there is an indication that a linear model is inappropriate, additional 
models will be fitted, in particular an Emax model. The C-QTc analysis will then be 
repeated for the model found to best accommodate the nonlinearity detected.
9.4.1.3.
By-Time Point Analysis (Secondary Analysis)
The “by-time point analysis” for QTcF will be based on a linear mixed-effects model 
with ΔQTcF as the dependent variable, period, sequence, time (i.e., time point: 
categorical), treatment (GSK3640254, moxifloxacin, and placebo), and time-by-treatment 
interaction as fixed effects, and baseline QTcF as a covariate. An unstructured covariance 
matrix will be specified for the repeated measures at post-dose time points for participant
within treatment period. If the model with an unstructured covariance matrix fails to 
converge, other covariance matrices such as autoregressive and compound symmetry will 
be considered. The model will also include a participant-specific random effect. If the 
fixed effects for period and/or sequence should prove to be not significant (that is, if the 
p-value >0.1), these effects may be removed from the model and the analysis will be 
repeated without those covariates. From this analysis, the LS mean and 2-sided 90% CI 
will be calculated for the contrast “GSK3640254 versus placebo” for each dose of 
GSK3640254 at each post-dose time point, separately.
For HR, PR, and QRS interval, the analysis will be based on the change-from-baseline 
post-dosing (ΔHR, ΔPR, and ΔQRS). The same (by-time point analysis) model will be 
used as described for QTcF. The LS mean, SE, and 2-sided 90% CI from the statistical 


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modeling for both change-from-baseline and placebo-corrected change-from-baseline 
values will be listed in the tables and graphically displayed.
9.4.1.4.
Categorical Analysis
The analyses results for categorical outliers, T-wave morphology, and U-wave presence 
will be summarized in frequency tables with counts (percentages) for both number of 
participants and number of time points. For categorical outliers, the number (percentage) 
of participants as well as time points who had increases in absolute QTcF interval values 
>450 and ≤480 ms, >480 and ≤500 ms, and >500 ms, and changes from pre-dose baseline 
of >30 and ≤60 ms, and >60 ms; increase in PR interval from pre-dose baseline >25% to 
a PR >200 ms; increase in QRS interval from pre-dose baseline >25% to a QRS >120 ms; 
decrease in HR from pre-dose baseline >25% to a HR <50 bpm; and increase in HR from 
pre-dose baseline >25% to a HR >100 bpm will be determined. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be 
assessed, i.e., changes not present at baseline. For each category of T-wave morphology 
and of U-waves, the category will be deemed as present if observed in any replicates at 
the time point.
9.4.1.5.
Assay Sensitivity
Assay sensitivity will be evaluated by C-QTc analysis of the effect on Δ∆QTcF of 
moxifloxacin using the same model as for the primary analysis. If the slope of the 
moxifloxacin plasma concentration/∆QTcF relationship is statistically significant at the 
10% level in a 2-sided test and the lower bound of the 2-sided 90% CI of the predicted 
QTc effect at the geometric mean Cmax of the 400 mg dose is above 5 ms, assay 
sensitivity will be deemed to have been demonstrated.
9.4.2.
Pharmacokinetic Analyses
Plasma GSK3640254 concentration-time data will be analysed by PPD, under the 
oversight of Clinical Pharmacology Modelling & 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.
Endpoint
Statistical Analysis Methods
Primary

For Part 1, plasma concentrations of GSK3640254 will be subjected to PK 
analyses using noncompartmental methods. Based on the individual 
concentration-actual time data the following plasma PK parameters will be 
estimated:
o
AUC(0-t), AUC(0-), Cmax, C, and Tmax

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma 
GSK3640254 PK parameter values will be presented by treatment.

Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 will be 
summarized and used to assess achievement of steady state.


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Endpoint
Statistical Analysis Methods
Secondary

For Part 2, plasma concentrations of GSK3640254 and moxifloxacin will be 
subjected to PK analyses using noncompartmental methods. Based on the 
individual concentration-actual time data the following plasma PK parameters will 
be estimated:
o
Treatments T and ST: AUC(0-t), AUC(0-), Cmax, C, and Tmax of 
GSK3640254
o
Treatment M: Cmax and Tmax of moxifloxacin

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma
GSK3640254 and moxifloxacin PK parameter values will be presented.

Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 will be 
summarized and used to assess achievement of steady state.
9.4.3.
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.
9.4.4.
Other Analysis
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 in to account applicable regulatory guidance and industry best 
practices for handling such situations [DHHS, 2020; EMA, 2020a; EMA, 2020b].
9.5.
Interim Analyses
After completion of the study Part 1 Cohort 1 (and Cohort 2 if conducted), preliminary 
safety & PK data based on nominal time will be analyzed by PPD as soon as PK data are 
available under the oversight of Clinical Pharmacology Modeling & Simulation within 
GSK; the data will be used to determine selection of the supratherapeutic dose to be used 
in Part 2.


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9.6.
Data Monitoring Committee or Other Review Board
Not applicable.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Trademarks
ΔHR
Change from baseline in heart rate
ΔPR
Change from baseline in PR interval
ΔQRS
Change from baseline in QRS interval
ΔQTcF
Change from baseline in QT interval corrected for heart rate using 
Fridericia’s formula
ΔΔHR
Placebo-corrected change from baseline in heart rate
ΔΔPR
Placebo-corrected change from baseline in PR interval
ΔΔQRS
Placebo-corrected change from baseline in QRS interval
ΔΔQTcF
Placebo-corrected change from baseline in QT interval corrected for heart 
rate using Fridericia’s formula
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC(0-)
Area under the plasma concentration-time curve from time zero to the end of 
the dosing interval at steady state
AUC(0-t)
Area under the plasma concentration-time curve from time zero to time t
BID
Twice daily
bpm
Beats per minute
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
Cmax
Maximum observed concentration 
CONSORT
Consolidated Standards of Reporting Trials 
C-QTc
Concentration-corrected QT interval
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
C
Plasma concentration at the end of the dosing interval
CYP
Cytochrome P450
DAIDS
Division of AIDS
DDI
Drug-drug interaction
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone


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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
HR
Heart rate
HRT
Hormonal replacement therapy
ICF
Informed consent form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee 
IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional Review Board 
LOAEL
Lowest observed adverse effect level
LS
Least squares
MAD
Multiple-ascending dose
mg
Milligram
MI
Maturation inhibitor
mL
Milliliter
ms
Millisecond
NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
QD
Once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using the Fridericia formula
QTL
Quality tolerance limit
SAD
Single-ascending dose
SAE
Serious adverse event 
SD
Standard deviation
SE
Standard error
SoA
Schedule of activities
SRM
Study Reference Manual 
SUSAR
Suspected unexpected serious adverse reactions


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Tmax
Time of maximum observed concentration 
TQT
Thorough QT
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal 
VH
ViiV Healthcare
WHO
World Health Organization
WOCBP
Woman of childbearing potential 
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV
Healthcare
NONE
DAIDS
Phoenix WinNonlin
Portia


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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.

Pregnancy Testing
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the time points indicated in the SoA (Section 1.3).
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study.
Table 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
Aspartate aminotransferase
Albumin
Glucose (fasting)
Alanine aminotransferase
Globulin
Potassium
Gamma-glutamyl transferase
Anion gap
Sodium
Total and direct bilirubin
Alkaline phosphatase
Calcium
Lactate dehydrogenase
Uric acid
Chloride
Total cholesterol
Creatine phosphokinase
Phosphorus
Triglycerides
Serum lipase
Magnesium
Serum amylase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and 
leukocyte esterase by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is abnormal)


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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serology: HIV-1 and -2 antigen/antibody immunoassay, hepatitis B surface 
antigen, hepatitis C antibody

Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, unprescribed opiates, cannabinoids, benzodiazepines, 
MDMA, methamphetamines, phencyclidine, oxycodone, methadone, or 
tricyclic antidepressants)

Pregnancy 2
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Appendix 5. All events of ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).
2.
Local serum testing will be standard for the protocol.


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10.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
10.3.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
Premenarchal
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented bilateral tubal ligation
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Müllerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (>40 IU/L or mIU/mL) is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment.


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10.3.2.
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.

Nonhormonal intrauterine device

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential (WOCBP) and the 
absence of sperm has been confirmed. The documentation on male sterility can come from 
the site personnel’s review of participant’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle 
is approximately 90 days.

For the 28 days after study exit, women may resume oral hormonal contraceptives but 
double barrier methods (a combination of male condom with either cervical cap, diaphragm, 
or sponge with spermicide) must be used in addition.
Highly Effective Methodsb That Are User Dependent: Failure rate of <1% per year when used
consistently and correctly.

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
10.3.3.
Collection of Pregnancy Information:
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. 

The initial information will be recorded on the appropriate form and submitted 
to VH/GSK within 24 hours of learning of a participant's pregnancy. 


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
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on participant and neonate, which 
will be forwarded to VH/GSK. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator will be reported 
to VH/GSK as described in Appendix 6. While the investigator is not obligated 
to actively seek this information in former study participants, he or she may 
learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.


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10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations
10.4.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines

Applicable 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 SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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 their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 Code of Federal Regulations 


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Part 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study centere.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.

Participants who are rescreened are required to sign a new ICF.
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 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 participants, as appropriate.

VH/GSK will provide the investigator with the randomization codes for their 
site only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with 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.
10.4.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

Monitoring details describing strategy (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).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
clinical study report/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the 
sponsor.
10.4.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic CRF that are transcribed 
from source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
10.4.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first participant screened and will be the 
study start date.
VH/GSK or its designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of VH/GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IRB/IEC, 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 INR 
>1.5, report as an SAE.
See additional Actions and Follow-Up Assessments listed below
Required Actions and Follow-up Assessments 
Actions
Follow-Up Assessments

Immediately discontinue study intervention

Report the event to VH/GSK within 
24 hours

Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2

Perform liver event follow-up assessments

Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow-up assessments 
within 24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and 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 


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Liver Chemistry Stopping Criteria 
performance liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]. 
NOTE: not required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete liver Imaging and/or 
liver biopsy CRF.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3 × ULN and bilirubin 2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, which 
may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants.
3.
Includes: hepatitis A immunoglobulin (IgM) antibody, hepatitis B surface antigen, and hepatitis B core antibody; 
hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing) and hepatitis E IgM antibody.
4.
Pharmacokinetic sample may not be required for participants known to be receiving placebo or non-GSK 
comparator interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM.


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10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.6.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.


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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.6.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 


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PPD


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the 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 completed CRF.

The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information.


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10.6.4.
Reporting of SAE to VH/GSK
SAE Reporting to VH/GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to VH/GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically qualified sub-investigator must show evidence 
within the electronic CRF (e.g., check review box, signature, etc.) of review and 
verification of the relationship of each SAE to study intervention/study 
participation (causality) within 72 hours of SAE entry into the electronic CRF.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the Medical Monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to VH/GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the SRM.


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10.7.
Appendix 7: 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 resource and 
operations, site closures, travel limitations and the inability of an individual participant to 
attend clinic visit, 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 patient 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 for 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 PI 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 (NCA)/IRB/IEC regulations.
10.7.2.
COVID-19 Experimental Agents
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study Medical Monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate.


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The protocol does not allow for concurrent enrollment in other interventional studies, 
though, there may be exceptions in this pandemic. If a participant is being considered for 
enrolment into clinical studies for COVID-19 treatment or vaccinations, please reach out 
to the Medical Monitor who will discuss with the study team (to include Safety Review 
Team and input from the PK Scientist/Clinical Pharmacologist) who will consider 
relevant drug interactions and to ensure that continued study participation remains 
appropriate.
10.7.3.
COVID-19 Specific Data Capture
10.7.3.1.
Capturing COVID-19 Specific Protocol Deviations
Please refer to the SRM for specific details on capturing protocol deviations as a result of 
COVID-19.
10.7.3.2.
Capturing COVID-19 Specific AEs and SAEs
ViiV Healthcare are 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 
analysis. 
Please use the following guidance: 
1.
AEs 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. SAEs 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 
and reporting, and decisions around 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 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.


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10.7.3.2.1. WHO Case Definition (March 20, 2020 Version):
Suspected case: 
A. A patient 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 patient with any acute respiratory illness AND having been in contact (see 
definition of “contact” below) with a confirmed or probable COVID-19 case (see 
definition of contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient 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. 


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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.
REFERENCES
Bristol-Myers Squibb Company Document Control Number 930109388. A randomized, 
double-blind, double-dummy, positive-controlled, crossover study to determine 
electrocardiographic effects of BMS-955176 in healthy subjects. Report Date: 
January 13, 2017.
Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat 
Assoc. 1979;74(368):829-836.
Darpo B, Benson C, Dota C, et al. Results From the IQ-CSRC Prospective Study Support 
Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase. 
Clin Pharmacol Ther. 2015;97(4):326-335.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005 [cited 
25 Jan 2020] [20 screens]. Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073153.pdf.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry, Investigators, and Institutional Review Boards. FDA 
Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 
Public Health Emergency. April 2020. Available from: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-
medical-products-during-covid-19-public-health-emergency.
European Medicines Agency (EMA). Science Medicines Health, Committee for Human 
Medicinal Products. Points to Consider on Implications of Coronavirus (COVID-19) on 
methodological Aspects of Ongoing Clinical Trials. March 2020a. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-
implications-coronavirus-disease-covid-19-methodological-aspects-ongoing-
clinical_en.pdf.
European Medicines Agency (EMA). Science Medicines Health, Heads of Medicines 
Agencies. Guidance on the Management of Clinical Trials During the COVID-19 
(Coronavirus) Pandemic. April 2020b. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf.
Ferber G, Zhou M, Darpo B. Detection of QTc Effects in Small Studies--Implications for 
Replacing the Thorough QT Study. Ann Noninvasive Electrocardiol. 2015;20(4):368-
377.


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Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc 
modeling. [published correction appears in J Pharmacokinet Pharmacodyn. 
2018;45(3):399]. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397.
GlaxoSmithKline Document Number 2018N379610_01. GSK3640254 Investigator’s 
Brochure, Version 02. Effective Date: 24 Oct 2019.
GlaxoSmithKline Document Number 2020N430256_00. A Double-Blind (Sponsor 
Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation 
Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3640254 in 
Healthy Participants,. 09 Sep 2018.
Hasler WL. Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrison’s 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill.
Huang DP, Chen J, Dang Q, et al. Assay sensitivity in “hybrid thorough QT/QTc (TQT)” 
study. J Biopharm Stat. 2019;29(2):378-384.
Hurvich CM, Simonoff JS,Tsai CL. Smoothing parameter selection in nonparametric 
regression using an improved Akaike Information Criterion. J R Stat Soc Series B Stat 
Methodol. 1998;60(2):271-293.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen - protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779-1784.
Malagelada JR and Malagelada C. Nausea and Vomitting. Chapter 15. Sleisenger and 
Fordtran's Gastrointestinal and Liver Disease 10th edition. 2016. Elsevier.
Millham FH Acute Abdominal Pain. Chapter 11. Sleisenger and Fordtran's 
Gastrointestinal and Liver Disease 10th edition. 2016. Elsevier.
Morales-Ramirez J, Bogner JR, Molina JM, et al. Safety, efficacy, and dose response of
the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus
tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24
primary analysis from a randomized Phase IIb trial. PLoS ONE. 2018; 13(10): e0205368.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164(7):1035-1043.
Rome Foundation. Rome IV Diagnostic Criteria for Functional Gastrointestinal 
Disorders. 2019. Available from: https://romeonline.org/?product=rome-iv-diagnostic-
algorithms-for-common-gi-symptoms-second-edition. Accessed 18 Feb 2020.
Schiller LR and Sellin J. Diarrhea. Chapter 16. Sleisenger and Fordtran's Gastrointestinal
and Liver Disease 10th edition. 2016. Elsevier.


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Soll AH, Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of Gastroenterology. 
5th edition. 2009. Blackwell Publishing.
Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-1042.
Yarze JC and Friedman LS Chronic Abdominal Pain. Chapter 12. Sleisenger and 
Fordtran's Gastrointestinal and Liver Disease 10th edition. 2016. Elsevier.

SAP_001.pdf: 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
213053 
 
 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: A Study to Evaluate the Effect of Therapeutic and 
Supratherapeutic Oral Doses of GSK3640254 on Cardiac 
Conduction as Assessed by 12-Lead Electrocardiogram 
Compared to Placebo and a Single Oral Dose of 
Moxifloxacin in Healthy Adult Participants 
Compound Number  : GSK3640254 
Effective Date  
: 01/07/2021 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 213053. 
• 
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. 
 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 5 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 5 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 5 
2.3. 
Study Design ................................................................................................ 7 
2.4. 
Statistical Hypotheses................................................................................... 9 
2.5. 
Sample Size Determination .......................................................................... 9 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 14 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 15 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 15 
5.2. 
Baseline Definitions .................................................................................... 15 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 16 
6. 
STUDY POPULATION ANALYSES ....................................................................... 17 
6.1. 
Overview of Planned Study Population Analyses ........................................ 17 
7. 
PHARMACOKINETIC ANALYSES ......................................................................... 18 
7.1. 
Primary Pharmacokinetic Analyses ............................................................. 18 
7.1.1. 
Endpoint / Variables ..................................................................... 18 
7.1.1.1. 
Drug Concentration Measures .................................... 18 
7.1.1.2. 
Derived Pharmacokinetic Parameters......................... 18 
7.1.2. 
Summary Measure ...................................................................... 18 
7.1.3. 
Population of Interest ................................................................... 18 
7.1.4. 
Statistical Analyses / Methods ..................................................... 19 
7.2. 
Secondary Pharmacokinetic Analyses ........................................................ 19 
7.2.1. 
Endpoint / Variables ..................................................................... 19 
7.2.1.1. 
Drug Concentration Measures .................................... 19 
7.2.1.2. 
Derived Pharmacokinetic Parameters......................... 19 
7.2.2. 
Summary Measure ...................................................................... 20 
7.2.3. 
Population of Interest ................................................................... 20 
7.2.4. 
Statistical Analyses / Methods ..................................................... 20 
8. 
CARDIODYNAMIC ANALYSES (PART 2 ONLY) ................................................... 21 
8.1. 
Cardiodynamic ECG Endpoints .................................................................. 21 
8.2. 
Early Precision QT Analysis (EPQT) ........................................................... 21 
8.3. 
General Methodology ................................................................................. 22 
8.4. 
Baseline ...................................................................................................... 23 
8.5. 
QT Correction Methods ............................................................................... 23 
8.6. 
Evaluation of QT/RR correction methods .................................................... 24 


 
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8.7. 
Concentration-QTc Analysis (Primary Analysis) .......................................... 24 
8.7.1. 
Investigation of Hysteresis ........................................................... 25 
8.7.2. 
Appropriateness of a Linear Model .............................................. 26 
8.8. 
Assay Sensitivity ......................................................................................... 26 
8.9. 
By-Time Point Analysis (Secondary Analysis) ............................................. 26 
8.10. 
Categorical Analysis ................................................................................... 27 
8.11. 
Terminology and Definitions: Placebo-corrected ΔQTc and Placebo-
adjusted ΔQTc (ΔΔQTc) ............................................................................. 29 
9. 
SAFETY ANALYSES ............................................................................................. 30 
9.1. 
Adverse Events Analyses ........................................................................... 30 
9.2. 
Clinical Laboratory Analyses ....................................................................... 30 
9.3. 
Adverse Events of Special Interest ............................................................. 30 
9.4. 
Other Safety Analyses ................................................................................ 31 
10. REFERENCES ....................................................................................................... 33 
11. APPENDICES ........................................................................................................ 34 
11.1. 
Appendix 1: Schedule of Activities .............................................................. 34 
11.1.1. 
Protocol Defined Schedule of Events ........................................... 34 
11.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 42 
11.2.1. 
Study Phases .............................................................................. 42 
11.2.1.1. Study Phases for Lab, Electrocardiograms, and 
Vital Signs .................................................................. 42 
11.2.1.2. Study Phases for Concomitant Medication ................. 42 
11.2.2. 
Treatment Emergent Flag for Adverse Events ............................. 42 
11.3. 
Appendix 3: Data Display Standards & Handling Conventions .................... 43 
11.3.1. 
Reporting Process ....................................................................... 43 
11.3.2. 
Reporting Standards .................................................................... 43 
11.3.3. 
Reporting Standards for Pharmacokinetics .................................. 45 
11.4. 
Appendix 4: Derived and Transformed Data ............................................... 45 
11.4.1. 
General ........................................................................................ 45 
11.4.2. 
Study Population .......................................................................... 47 
11.4.3. 
Safety .......................................................................................... 47 
11.5. 
Appendix 5: Reporting Standards for Missing Data ..................................... 47 
11.5.1. 
Premature Withdrawals ................................................................ 47 
11.5.2. 
Handling of Missing Data ............................................................. 47 
11.5.2.1. Handling of Missing and Partial Dates ........................ 49 
11.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events .......................................... 50 
11.6.1. 
Laboratory Values ........................................................................ 50 
11.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 53 
11.7.1. 
ECG ............................................................................................. 53 
11.7.2. 
Vital Signs .................................................................................... 53 
11.8. 
Appendix 8: Abbreviations & Trade Marks .................................................. 54 
11.8.1. 
Abbreviations ............................................................................... 54 
11.8.2. 
Trademarks ................................................................................. 55 
11.9. 
Appendix 9: List of Data Displays ............................................................... 56 
11.9.1. 
Data Display Numbering .............................................................. 56 
11.9.2. 
Mock Example Shell Referencing ................................................ 56 
11.9.3. 
Deliverables ................................................................................. 56 


 
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11.9.4. 
Study Population Tables .............................................................. 57 
11.9.5. 
Safety Tables ............................................................................... 58 
11.9.6. 
Pharmacokinetic Tables ............................................................... 60 
11.9.7. 
Cardiodynamic Tables (Part 2) .................................................... 62 
11.9.8. 
Pharmacokinetic Figures ............................................................. 64 
11.9.9. 
Chardiodynamic Figures (Part 2) ................................................. 65 
11.9.10. ICH Listings ................................................................................. 68 
11.9.11. Non-ICH Listings .......................................................................... 71 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 213053. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
This is a 2-part study. Part 1 is a sequential treatment study with 2 arms that is participant 
and investigator blinded. Part 2 is a single group, single arm, crossover treatment study 
that is participant and investigator blinded (open-label for moxifloxacin). 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
None. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
Part 1: 
• 
To determine the safety and 
pharmacokinetics of a 
supratherapeutic dose of 
GSK3640254 administered for 7 days 
in healthy participants 
Part 1: 
• 
Area under the plasma concentration-time curve from 
time zero to time t (AUC[0-t]), area under the plasma 
concentration-time curve from time zero to the end of the 
dosing interval at steady state (AUC[0-]), maximum 
observed concentration (Cmax), plasma concentration at 
the end of the dosing interval (C), and time of maximum 
observed concentration (Tmax) of GSK3640254 in 
plasma  
• 
Remaining plasma will be analysed for compound related 
metabolites 
• 
Safety and tolerability parameters for adverse events 
(AEs)/serious adverse events (SAEs), observed and 
change from baseline in clinical laboratory assessments, 
electrocardiograms (ECGs), and vital sign measurements 
Part 2: 
• 
To determine the effect of therapeutic 
and supratherapeutic concentrations 
of multiple dose GSK3640254 on the 
QT interval corrected with Fridericia’s 
formula (QTcF) in healthy participants 
Part 2: 
• 
Placebo-corrected change from baseline in QTcF 
(ΔΔQTcF) for GSK3640254 using concentration-QTc 
(C-QTc) analysis (primary analysis) 
• 
Remaining plasma will be analysed for compound related 
metabolites 
 


 
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Secondary Objectives 
Secondary Endpoints 
Part 2: 
• 
To evaluate the effect of multiple oral 
therapeutic and supratherapeutic 
doses of GSK3640254 on other ECG 
parameters (heart rate [HR], PR, 
QRS, and QTcF intervals, 
treatment-emergent T-wave 
morphology, and appearance of 
U-waves) 
Part 2: 
• 
Change from baseline in HR, QTcF, PR, QRS (ΔHR, 
ΔQTcF, ΔPR, and ΔQRS) intervals using by-time point 
analysis (secondary analysis); the placebo-corrected 
change from baseline in HR, PR, QTcF, and QRS 
(ΔΔHR, ΔΔPR, ΔΔQTcF, and ΔΔQRS) using by-time 
point analysis; categorical outliers for QTcF, HR, PR, and 
QRS; and the frequency of treatment emergent changes 
of T-wave morphology and U-wave presence 
• 
To demonstrate assay sensitivity of 
the study design to detect a QTc 
effect using a single dose of 400 mg 
oral moxifloxacin as a positive control. 
• 
ΔΔQTcF for moxifloxacin (primary: C-QTc analysis and 
secondary: by-time point analysis) 
• 
To evaluate the pharmacokinetics of 
multiple oral therapeutic and 
supratherapeutic doses of 
GSK3640254 and a single dose of 
moxifloxacin.  
• 
AUC(0-t), AUC(0-), Cmax, C, and Tmax of 
GSK3640254 in plasma 
• 
Cmax and Tmax of moxifloxacin in plasma 
• 
To assess the safety and tolerability of 
multiple therapeutic and 
supratherapeutic doses of 
GSK3640254 
• 
Safety and tolerability parameters for AEs/SAEs, 
observed and change from baseline in clinical laboratory 
assessments, ECGs, and vital sign measurements 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Figure 2.3.1 Study Design Schematic – Part 1 
Days 1 - 7 
GSK36402541 or 
Placebo 
Discharge 
Day 9 
Screening 
≤ 28 Days 
Randomization 
3:1 
 
1. Sentinel Cohort 1: GSK3640254 500 mg or placebo once daily. 
Sentinel Cohort 2 (if needed): GSK3640254 or placebo twice daily, with only a single morning dose 
administered on the seventh day; dose to be determined after completion of Sentinel Cohort 1. 
Figure 2.3.2 Study Design Schematic – Part 2 
Screening ≤ 29  days 
Randomization 1:1:1:1 
Days  1 -  7 
 
Treatment T  
or 
Treatment ST  
or 
Treatment P 
or 
Treatment M 
Washout  of 7 days1 
Days  1 -  7 
 
Treatment T 
or 
Treatment ST  
or 
Treatment P 
or 
Treatment M 
Washout  of 7 days1 
Days  1 -  7 
 
Treatment T  
or 
Treatment ST  
or 
Treatment P  
or 
Treatment M 
Washout  of 7 days1 
Days  1 -  7 
 
Treatment T 
or 
Treatment ST  
or 
Treatment P  
or 
Treatment M 
Discharge Day 9  
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Treatment Period 4 
 
1. Washout will be at least 7 days minus 4 hours to allow for flexibility in scheduling in the clinic. 
Treatment T: Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 through 7. 
Treatment ST: Supratherapeutic dose of GSK3640254 (to be determined from Part 1) Days 1 through 7 
Treatment P: Placebo for GSK3640254 Days 1 through 7. 
Treatment M: Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a single dose of Moxifloxacin 
(400 mg) on Day 7 
Design 
Features 
This study has an adaptive 2-part design, where projected doses will be identified and may 
be modified according to assessment of accrued data. Part 1 will consist of up to 2 sentinel 
cohorts to determine the supratherapeutic dose for Part 2, which will be the main QTc 
study.  
Part 1 will be a randomized, double-blind study. Part 2 will be a double-blind, randomized, 
placebo-controlled study. Moxifloxacin is included as a positive control and will be open 
label. 
• 
Part 1 of the study will consist of a screening period and a treatment period for 
each cohort. 
o Sentinel Cohort 1: GSK3640254 500 mg or placebo orally QD for 7 days. 
o Sentinel Cohort 2 (optional): If needed, a dose of GSK3540254 or 
placebo orally BID for 7 days (13 doses), with only a single morning 
dose administered on the seventh day. The specific dose in sentinel 
Cohort 2 will be determined based on the results of preliminary safety 
and PK data from sentinel Cohort 1 and decided upon by the study team 
and the investigator. 
o Up to 16 participants may be enrolled (8 participants per cohort) 
 


 
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Overview of Study Design and Key Features 
Part 2, Main QTc Study:  
Part 2 of the study will consist of a screening period, a check-in visit (Day -2), a baseline 
visit (Day -1), and 4 sequential treatment periods. Participants will receive treatments in 1 
of the 12 following sequences: 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
1 
T 
ST 
P 
M 
2 
ST 
M 
T 
P 
3 
P 
T 
M 
ST 
4 
M 
P 
ST 
T 
5 
ST 
P 
T 
M 
6 
P 
M 
ST 
T 
7 
T 
ST 
M 
P 
8 
M 
T 
P 
ST 
9 
P 
T 
ST 
M 
10 
T 
M 
P 
ST 
11 
ST 
P 
M 
T 
12 
M 
ST 
T 
P 
Treatment T: Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 through 7. 
Treatment ST: Supratherapeutic dose of GSK3640254 (to be determined from Part 1) 
Days 1 through 7. 
Treatment P: Placebo for GSK3640254 Days 1 through 7. 
Treatment M: Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a single dose of 
Moxifloxacin (400 mg) on Day 7. 
To maintain the blind, the number of tablets administered for therapeutic, supratherapeutic, 
moxifloxacin (Days 1 through 6 only), and placebo doses will be identical. The total 
number of tablets will be based on the actual supratherapeutic dose derived from Part 1 
of the study. For example, if the supratherapeutic dose is determined to be 500 mg QD, 
the therapeutic dose would consist of one 100 mg GSK3640254 tablet and four placebo 
tablets, the supratherapeutic dose would consist of five 100 mg GSK3640254 tablets, 
and the placebo dose would consist of five placebo tablets. 
Approximately 42 participants will be enrolled to achieve 34 evaluable participants. 
Dosing 
Intervention 
GSK3640254 
GSK3640254 
Placebo 
Moxifloxacin 
Type  
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Capsule 
Unit Dose Strength 
100 mg 
N/A 
400 mg 
Dosage Levels 
Therapeutic: 100 mg 
Supratherapeutic: TBD 
N/A 
400 mg 
Route of 
Administration 
Oral 
Oral 
Oral 
IMP = investigational medicinal product; NIMP = non-investigational medicinal product; 


 
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Overview of Study Design and Key Features 
TBD = to be determined.  
Time & 
Events 
• 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
• 
Part 1: up to 2 sequential cohorts of approximately 8 healthy participants each (3:1 
ratio to receive GSK3640254 or placebo). 
• 
Part 2: Approximately 42 participants will be randomized to ensure 34 evaluable 
participants with data from all treatment periods. Participants will be randomly 
assigned to 1 of 12 treatment sequences in Part 2 of Design Features. 
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 Part 1 of this study. 
For Part 2, the statistical hypothesis to be tested for the primary assessment of QT 
prolongation at the highest clinically relevant exposure using the C-QTc analysis for each 
active dose group is: 
H0: ΔΔQTc ≥10 ms 
H1: ΔΔQTc <10 ms 
where ΔΔQTc is the mean ΔΔQTc (primary endpoint) at the mean Cmax for each active 
dose group, respectively. 
In addition, the statistical hypothesis to be tested for the assay sensitivity using the 
C-QTc analysis is: 
H0: ΔΔQTc ≤5 ms 
H1: ΔΔQTc >5 ms 
where ΔΔQTc is the mean ΔΔQTc (primary endpoint) at the mean Cmax for the 
moxifloxacin group. 
2.5. 
Sample Size Determination 
Part 1: A total of up to 16 participants are planned to be randomized, 8 participants per 
cohort (6 participants to receive GSK3640254 and 2 participants to receive placebo). For 
Part 1, as there is no formal research hypothesis being statistical tested, the sample size is 
not selected based on statistical considerations but was determined using feasibility. 
Part 2: A sample size of approximately 42 participants is chosen to obtain 34 evaluable 
participants to complete the study. A sample size of 34 evaluable participants will 
provide more than 90% power to exclude that active drug causes more than a 10-ms QTc 
effect at clinically relevant plasma levels, as shown by the upper bound of the 2-sided 
90% CI of the model predicted QTc effect (∆∆QTc: primary endpoint) at the observed 
geometric mean Cmax of active drug in the study.  


 
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This power is estimated approximately using a paired t-test. The calculation assumes a 
one-sided 5% significance level, an underlying effect of GSK3640254 of 4 ms and a 
standard deviation (SD) of the ΔQTc of 8.5 ms for both active drug and placebo. Table 1 
provides the sample sizes for power of 90% and 95% with underlying effect of 3, 4, and 
5 ms and SD of 8, 8.5 and 9.5 ms.  
The C-QTc analysis method is supported by Darpo, 2015 and Ferber, 2015, and 
consistent with the experiences from 25 recent TQT studies in ERT, which provided 
SD=8 ms as a conservative estimate for general TQT studies. Note that this calculation is 
conservative also because it does not take into account any gain in precision due to the 
use of all data of each subject with the help of a linear mixed effects model. An SD of 9.5 
ms is a conservative value used in previous MI compound BMS-663068 and AI 
compound Fostemsavir TQT studies in GSK. In the previous GSK3640254 first time in 
human study 207187 SAD/MAD study, the within-subject SD based on by-time point 
analysis is 8.5 ms, which provides the conservative estimated SD for this compound. 
Therefore, the underlying effect 4 ms and SD=8.5 ms with 90% of power for the study 
sample size of 34 participants was chosen for this study. With the dropout rate of 20%, 
approximately 42 participants will be enrolled to ensure the evaluable number of 
participants is greater or equal to 34. 


 
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Table 1 
Sample Size Determination - Power 
Sample size 
Number of Participants for 90% Power 
Number of Participants for 95% power 
Underlying effect 3 ms, 
SD =  8 ms 
22 
28 
Underlying effect 3 ms, 
SD =  8.5 ms 
25 
32 
Underlying effect 3 ms, 
SD =  9.5 ms 
32 
40 
Underlying effect 4 ms,  
SD = 8 ms  
30 
38 
Underlying effect 4 ms, 
SD =  8.5 ms 
34 
43 
Underlying effect 4 ms, 
SD =  9.5 ms 
43 
54 
Underlying effect 5 ms,  
SD = 8 ms 
44 
55 
Underlying effect 5 ms, 
SD =  8.5 ms 
49 
63 
Underlying effect 5 ms, 
SD =  9.5 ms 
62 
78 
 
Sample Size for Assay Sensitivity: To demonstrate assay sensitivity with C-QTc analysis, 
it must be shown that the ΔΔQTc of a single dose of 400 mg moxifloxacin exceeds 5 ms 
(i.e., the lower bound of the 2-sided 90% CI of the predicted QTc effect [ΔΔQTc: 
primary endpoint] should exceed 5 ms).  
In a similarly designed, recent crossover study with 24 healthy participants (on-file data, 
ERT), the standard error (SE) for the prediction of the QT effect of moxifloxacin based 
on the C-QTc analysis was 1.24 ms. The within-subject SD of ΔQTcF in this study was 
5.4 ms based on the by-time point analysis. If the effect of moxifloxacin is assumed to be 
10 ms, the SE of 1.24 ms corresponds to an effect size of (10-5)/(1.24×sqrt[24])=0.82, 
where the effect size is the effect assumed under the alternative hypothesis divided by the 
SD of the test variable. This value should be compared to the effect size of 0.62 required 
to guarantee a power of at least 95% in a paired t-test situation with a sample size of 


 
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30 evaluable participants. In other words, based on this calculation, a power of at least 
95% for 30 evaluable participants will be obtained as long as the variability of the ΔQTc, 
as measured by its within-subject SD, does not exceed 7.1 ms (i.e., 132% of the 5.4 ms 
observed in the above referenced study [on-file data, ERT] assuming the ratio of effective 
sizes is consistent with inverse ratio of within-subject SD). The number also agrees with 
recent recommendations of the FDA, which propose at least 20 participants (Huang, 
2019). 


 
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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 
Randomized 
• 
All participants who are randomly assigned to a 
treatment/treatment sequence. 
• 
Disposition  
Safety 
• 
All randomized participants who receive at least 1 dose 
of study intervention. Participants will be analyzed 
according to the intervention they actually received.  
• 
Demographic 
• 
Safety 
QT/QTc 
• 
All participants in the safety population with 
measurements at baseline as well as on-treatment with 
at least 1 post-dose time point with a valid ΔQTc value.  
• 
By-time point and 
categorical 
analyses of the 
cardiodynamic 
ECG parameters 
Pharmacokinetic 
Concentration 
• 
All participants who undergo plasma PK sampling and 
have evaluable PK assay results.  
• 
PK Concentration 
Pharmacokinetic 
Parameter 
• 
All participants who undergo plasma PK sampling and 
have evaluable PK parameters estimated. 
• 
PK Parameter 
• 
PK statistical 
analysis 
PK/QTc 
• 
All participants who are in both the QT/QTc and PK 
concentration populations with at least 1 pair of 
post-dose PK and ΔQTc data from the same time point 
as well as participants in the QT/QTc population who 
received placebo. The PK/QTc Population will be 
defined for GSK3640254 and for moxifloxacin.  
• 
C-QTc analysis 
and assay 
sensitivity 
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  
Part 1 
Placebo 
Placebo 
1 
GSK3640254 500 mg orally QD for 7 days 
Treatment A 
2 
 
Treatment B 
3 
Part 2 
Placebo for GSK3640254 Days 1 through 7. 
Placebo 
4 
Moxifloxacin; GSK3640254 placebo Days 1 through 6 and a 
single dose of Moxifloxacin (400 mg) on Day 7. 
Treatment M 
5 
Therapeutic dose of GSK3640254 (100 mg once daily) Days 1 
through 7. 
Treatment T 
6 
Supratherapeutic dose of GSK3640254 500 BID Days 1 
through 7. 
Treatment ST 
7 
 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions), baseline for Part 1 is defined as 
the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits; Baseline for Part 2 is defined as the latest pre-dose assessment with a 
non-missing value for each period, including those from unscheduled visits.  
Part 1: 
Parameter 
Study Assessments 
Baseline Used 
in Data Display 
 
Check-in (Day -2) 
Day -1 
Day 1 (Pre-Dose) 
 
Vital Sign 
X 
X 
X 
Day 1 (Pre-
Dose)[1] 
12-Lead ECG 
X 
X 
X 
Day 1 (Pre-
Dose)[1] 
Hematology 
X 
 
 
Check-in Day -2 
Clinical Chemistry 
X 
 
 
Check-in Day -2 
Urinalysis 
X 
 
 
Check-in Day -2 
[1] The average (for blood pressure and pulse) or the worst case (for interpretation) of the pre-dose triplicate 
assessments will be used as the baseline. 
 


 
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Part 2: 
Parameter 
Study Assessments  
Baseline Used in Data 
Display 
 
Check-in 
(Day -2) 
Day -1 
Periods 1, 2, 3 
Period 4 
Day 1  
(Pre-dose) 
Period 1 
Period 2, 
3, 4 
Day 1  
(Pre-dose) 
Washout 
Day 14 
Vital Sign 
X 
X 
X 
X 
X 
Day 1 
(Pre-
Dose)[1] 
Day 1 
(Pre-
Dose)[1] 
12-Lead 
ECG 
X 
X 
X 
X 
X 
Day 1 
(Pre-
Dose)[1] 
Day 1 
(Pre-
Dose)[1] 
Hematology 
X 
 
 
X 
 
Check-in 
Day -2 
Washout 
Day 14 for 
previous 
period 
Clinical 
Chemistry 
X 
 
 
X 
 
Check-in 
Day -2 
Washout 
Day 14 for 
previous 
period 
Urinalysis 
X 
 
 
X 
 
Check-in 
Day -2 
Washout 
Day 14 for 
previous 
period 
[1] The average (for blood pressure and pulse) or the worst case (for interpretation) 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 
11.1 
Appendix 1: Schedule of Activities  
11.2 
Appendix 2: Study Phase and Treatment Emergent Adverse Event 
11.3 
Appendix 3: Data Display Standards & Handling Conventions 
11.4 
Appendix 4: Derived and Transformed Data 
11.5 
Appendix 5: Reporting Standards for Missing Data 
11.6 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
11.7 
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 11.3.3 
Reporting Standards for Pharmacokinetics). For Part 1, plasma concentrations of 
GSK3640254 will be measured and presented in tabular form and will be summarized 
descriptively. Plasma GSK3640254 concentration-time data will be listed by participant, 
treatment group, and nominal sampling time and summarized by treatment group and 
nominal 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 
Phoenix WinNonlin. All calculations of non-compartmental parameters will be based on 
actual sampling times. If actual times are missing, nominal times may be used and will be 
noted in report. Plasma pharmacokinetic parameters listed below will be determined from 
the plasma concentration-time data, as data permit. 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 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the last quantifiable 
concentration, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-τ) 
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. 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
Cτ 
Plasma concentration at the end of the dosing interval 
Tmax 
Time of maximum observed concentration 
NOTES: 
• 
Additional parameters may be included as required. 
7.1.2. 
Summary Measure 
Pharmacokinetic parameters AUC(0-t), AUC(0-τ), Cmax, Cτ , and Tmax at steady state 
following administration of GSK3640254 to healthy participants. 
7.1.3. 
Population of Interest 
The primary PK analyses will be based on the PK concentration population for plasma 
PK concentrations and the PK parameter population for plasma PK parameters and 
statistical analysis. 


 
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7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.1.1 will be 
summarized using descriptive statistics and listed. 
For Part 1, primary plasma PK parameters (AUC[0-t], AUC[0-τ], Cmax, Cτ, and Tmax) 
will be estimated for GSK3640254. Summary statistics (arithmetic mean, geometric 
mean, median, standard deviation (SD), coefficient of variation (CV), minimum, 
maximum, between-subject coefficient of variation (CVb), and 95% confidence interval 
(CI) for plasma GSK3640254 PK parameter values will be summarized by treatment.  
Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 will be 
summarized and used to assess achievement of steady state. 
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 11.3.3 
Reporting Standards for Pharmacokinetics). For Part 2, plasma concentrations of 
GSK3640254 and moxifloxacin will be measured and presented in tabular form and will 
be summarized descriptively. Plasma GSK3640254 and moxifloxacin concentration-time 
data will be listed by participant, treatment group, and sampling time and summarized by 
treatment group and sampling time. 
7.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix WinNonlin. All calculations of non-compartmental parameters will be based on 
actual sampling times. If actual times are missing, nominal times may be used and will be 
noted in report. 
Plasma pharmacokinetic parameters listed below will be determined from the plasma 
concentration-time data, as data permit. 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 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the last quantifiable 
concentration, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. (GSK3640254 only) 
AUC(0-τ) 
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. 
(GSK3640254 only) 


 
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Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
(GSK3640254 and moxifloxacin) 
Cτ 
Plasma concentration at the end of the dosing interval (GSK3640254 only) 
Tmax 
Time of maximum observed concentration (GSK3640254 and moxifloxacin) 
NOTES: 
• 
Additional parameters may be included as required. 
 
7.2.2. 
Summary Measure 
Pharmacokinetic parameters AUC(0-t), AUC(0-τ), Cmax, Cτ, and Tmax of GSK3640254 
at steady state following repeat dose administration of GSK3640254 and PK parameters 
Cmax and Tmax of moxifloxacin following single dose administration of moxifloxacin 
on Day 7. 
7.2.3. 
Population of Interest 
The secondary PK analyses will be based on the PK concentration population for plasma 
PK concentrations, and the PK parameter population for plasma PK parameters, unless 
otherwise specified. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.2.1.2will be 
summarized using descriptive statistics and listed. 
For Part 2, plasma PK parameters (AUC[0-t], AUC[0-τ], Cmax, Cτ, and Tmax) will be 
estimated for GSK3640254 and plasma PK parameters Cmax and Tmax will be estimated 
for moxifloxacin. Summary statistics (arithmetic mean, geometric mean, median, 
standard deviation (SD), coefficient of variation (CV), minimum, maximum, between-
subject coefficient of variation (CVb), and 95% confidence interval (CI) for plasma 
GSK3640254 and moxifloxacin PK parameter values will be summarized by treatment.  
• Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 will 
be summarized and used to assess achievement of steady state. Assessment of 
steady-state GSK3640254 concentrations will be assessed in Part 2 by estimating 
the slope of pre-dose concentrations. The final assessment of the slope will be 
determined by at least the last 3 pre-dose concentrations. 


 
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8. 
CARDIODYNAMIC ANALYSES (PART 2 ONLY) 
8.1. 
Cardiodynamic ECG Endpoints 
The primary endpoint is placebo-corrected change-from-baseline QTc (ΔΔQTc). In the 
absence of a substantial effect on HR, the Fridericia method (QTcF) will be used for HR 
correction and corresponding primary endpoint is ΔΔQTcF. If a substantial HR effect is 
observed (i.e., the largest least squares [LS] mean ΔΔHR is greater than 10 bpm in the 
by-time point analysis), other correction methods such as QTcS and QTcI will be 
explored and compared. The method that removes the HR dependence of the QT interval 
most efficiently will be chosen as the primary correction method. 
The secondary endpoints are:  
• Change-from-baseline HR, QTcF, PR, QRS intervals (∆HR, ΔQTcF, ∆PR, and 
∆QRS) 
• If a substantial HR effect is observed: Change-from-baseline QTcS and QTcI 
(ΔQTcS, and ΔQTcI) 
• Placebo-corrected ΔHR, ΔPR, and ΔQRS (ΔΔHR, ΔΔPR, and ΔΔQRS) 
• If a substantial HR effect is observed: Placebo-corrected QTcS, and/or QTcI, 
and/or ΔQTcF (
QTcS, 
QTcI, ΔΔQTcF) if not selected as the primary 
endpoint 
• Categorical outliers for QTcF (and QTcS, and QTcI if a substantial HR effect is 
observed), HR, PR, and QRS 
• Frequency of treatment-emergent changes for T-wave morphology and U-wave 
presence  
8.2. 
Early Precision QT Analysis (EPQT) 
Twelve-lead ECGs will be extracted in up to 10 replicates from each nominal time point 
prespecified in the protocol. The median value of each parameter from the set of 
evaluable beats in each extracted replicate will be calculated, and then the mean of all 
available medians (minimum 3 medians) from the nominal time point will be used as the 
subject’s reportable value at that time point. 
Early Precision QT analysis (formerly High Precision QT analysis) will be performed on 
all analyzable (non-artifact) beats in the 10 ECG replicates (1 replicate consists of one 14 
second ECG). Statistical quality control procedures will be used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• RR values exceeding or below certain thresholds (biologically unlikely) 
• Rapid changes in QT, QTc, or RR from beat to beat 
Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) 
in all recorded beats of all replicates will be performed using the iCOMPAS software. All 
beats that are deemed “high confidence” will not be reviewed by an ERT cardiac safety 


 
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specialist. All low confidence beats will be reviewed manually by an ERT cardiac safety 
specialist and adjudicated using pass-fail criteria. The beats found acceptable by manual 
review will be included in the analysis. The beats confirmed to meet fail criteria will not 
be included in the analysis. 
For the purpose of measuring PR and QRS intervals and to assess T-wave morphology 
and presence of U-waves, the TQT Plus algorithm will select the 3 ECG replicates with 
the highest quality score from the ECG extraction window. These 3 ECGs will be 
analyzed using a semi-automated process to determine these parameters. If 3 consecutive 
usable beats cannot be identified in at least 2 of the 3 replicates, then all beats in all 
replicates will be reviewed for that time point using a manual analysis. 
If manual analysis is required, then all beats in a minimum of 3 replicates will be 
reviewed using the iCOMPAS software. The ERT cardiac safety specialist will review all 
usable beats in Lead II (or an alternate lead) for each replicate and will review and/or 
adjust the fiducial placements (onset of P, onset of Q, offset of S, and offset of T-wave 
that were electronically marked) of each waveform and also document the T-wave 
morphology and the presence of U-waves for each beat. A replicate will only be reported 
if it has 3 approved, usable beats. 
8.3. 
General Methodology 
All statistical analyses will be performed using the statistical software SAS for Windows 
Version 9.4 or higher (SAS Institute, Inc., Cary, NC). Data collected from all subjects 
enrolled in the study who receive at least 1 dose of study drug (GSK3640254, 
moxifloxacin, or placebo) will be presented in data listings. Both observed values and 
change-from-baseline values for each subject will be given where applicable. All 
continuous data will be listed with the same precision as will be presented in the 
database. Data listings will be sorted by subject ID, treatment, period, day, and time point 
and missing values will be represented by an empty cell. 
For all descriptive statistics of continuous ECG parameters (i.e., HR, PR, QRS, and 
QTcF), data will be summarized including number of subjects (n), mean, median, 
standard deviation (SD), standard error (SE), 90% confidence interval (CI), minimum, 
and maximum by treatment and time point. For all modeling results of the by-time-point 
analysis of change-from-baseline values of continuous ECG parameters, n, least squares 
(LS) mean, SE, and 90% CI will be included. Modeling results of the by-time point 
analysis of placebo-corrected change-from-baseline will also include LS mean, SE, and 
90% CI. Mean and median values will be rounded to the nearest tenth. SD, SE, and CI 
will be rounded to the nearest hundredth. For the concentration-QTc analysis, 2 decimal 
places will be shown for all effect estimates for all results which have an absolute value 
greater than 0.05. Each effect estimate with an absolute value ≤ 0.05 will be displayed 
with 2 significant figures. The CI of the effect estimate will display 1 more decimal place 
than the effect estimate. SE and P values will be reported with 4 digits and P 
values < 0.0001 will be reported as < 0.0001. Degrees of freedom (df), and t-value will be 
reported to the nearest tenth and nearest hundredth, respectively. Percentages will be 
rounded to the nearest tenths decimal place. 


 
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8.4. 
Baseline 
For all continuous ECG parameters, baseline will be the average of the derived ECG 
intervals from the 3 ECG time points (−60, −45, and −30 minutes) prior to treatment 
administration on Day 1 within each respective period. For T-wave morphology and U-
wave presence, baseline includes findings observed in any of the replicates from the 3 
time points prior to dosing on Day 1 within each respective period. 
8.5. 
QT Correction Methods  
The QT and RR value for each beat will be used for HR correction. The primary HR 
correction method will be the Fridericia's correction (QTcF) defined as 
QTcF (ms) = QT (ms)/[RR(ms)/1000]1/3. 
If a substantial HR effect is observed (i.e., the largest least squares [LS] mean ΔΔHR is 
greater than 10 bpm in the by-time point analysis), drug-free QT/RR data will be 
collected over a range of HR seen off-treatment on Day −1 to allow the generation of 
individualized QT correction methods. The QTc will be calculated from Day −1 of the 
first treatment period both during the periods of supine rest (QTcS) and from all 
evaluable QT/RR pairs in the 24-hour recording (QTcI). These data will be used to obtain 
the RR interval (HR) and QT data to enable derivation of QTcS and QTcI as follows.  
• An individualized HR-corrected QT interval (QTcS) will be calculated from QT/RR 
data obtained at supine resting time points on Day −1 of the first treatment period. 
Based on QT/RR pairs from all subjects, the QTcS correction coefficient will be 
derived from a linear mixed-effects model: log(QTij) = log(ai) + b1i × log(RRij) + 
b2i× genderi + b3i× log(RRij) × genderi + εij for i-th subject and j-th time point with 
gender included as a fixed effect for both intercept and slope, and subject included as 
a random effect for both intercept and slope. The coefficient of log(RR) for each 
subject, bi =b1i+ b3i × genderi, will then be used to calculate QTcS for each subject 
as follows: QTcS = QT/RRbi. 
• An optimized HR-corrected QT interval (QTcI) will be derived from a broader range 
of HRs by using all QT/RR data from the full 24-hour recording (all acceptable beats) 
on Day −1 of the first treatment period. The QT/RR pairs from each subject will be 
used for that subject’s individual correction coefficient, which will be derived from a 
simple linear regression model: log(QTij) = log(ai) + bi × log(RRij) + εi for i-th 
subject and j-th time point. The coefficient of log(RR) for each subject, bi, will then 
be used to calculate QTcI for that subject as follows: QTcI = QT/RRbi. 
For QTcS and QTcI, the individual correction coefficients, bi, will be listed and also 
summarized in a table using arithmetic mean, SE, number of subjects, and 90% CI (based 
on t-distribution). 
The method that removes the HR dependence of the QT interval most efficiently will be 
chosen as primary correction method.  


 
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8.6. 
Evaluation of QT/RR correction methods  
In case a substantial HR effect is observed, the relationship between QTc (QTcF and, if 
derived, QTcS [individual], and QTcI [optimized]) and RR interval will be investigated 
using on-treatment data (GSK3640254, moxifloxacin, and placebo) by a simple linear 
regression model: QTcij = ci + di × RRij +εi for i-th subject and j-th time point. Mean QTc 
and RR values from all nominal post-baseline time points (including single pre-dose and 
post-dose time points on Day 7 in each period) will be used. The RR coefficient for each 
subject, di, will then be used to calculate the average sum of squared slopes (SSS) for 
each of the different QT/RR correction methods. The correction method that results in the 
average on-treatment slope closest to 0 (the smallest average SSS, as described by 
Tornøe, 2011) for GSK3640254 and placebo will be deemed the most appropriate HR 
correction method. If different methods show similar SSS values on placebo as on 
GSK3640254, priority in the choice will be given to the placebo results. In addition, a 
scatter plot and quantile plot of QTc (QTcF, QTcS, and QTcI) and RR intervals by 
treatment with regression line and a linear mixed-effects line (90% CI), respectively, will 
also be given. (The scatter plot and quantile plot of QTcF and RR intervals will be given 
if there is not a substantial HR effect). 
8.7. 
Concentration-QTc Analysis (Primary Analysis) 
The relationship between GSK3640254 plasma concentrations and ΔQTc (ΔQTcF or 
ΔQTc corrected with the method chosen as primary if a substantial HR effect is 
observed) will be quantified using a linear mixed-effects modelling approach. The model 
will have ΔQTc as the dependent variable, GSK3640254 plasma concentration as the 
exploratory variate (0 for placebo), centred baseline QTc (i.e., baseline QTc for 
individual participant minus the population mean baseline QTc for all participants in the 
same treatment period) as an additional covariate, treatment (active = 1 or placebo = 0) 
and time (i.e., post-baseline time point on Day 7 in each period, including pre-dose and 
post-dose time points on Day 7 in each period) as fixed effects, and random effects on 
intercept and slope per participant [Garnett, 2018]. In all calculations, concentrations in 
participants who received placebo will be set to zero. GSK3640254 plasma 
concentrations below the quantifiable limit at pre-dose on Day 7 in each period will be 
set to zero and after dosing on Day 7 in each period will be set to 1/2 the lower limit of 
quantitation in the concentration-QTc analysis. 
An unstructured covariance matrix will be specified for the random effects. If 
convergence cannot be achieved even after appropriate rescaling of the concentrations, 
the random effect on the slope and intercept will be dropped, in this order, until 
convergence is achieved. The degrees of freedom of estimates will be determined by the 
Kenward-Roger method. From the model, the slope (i.e., the regression parameter for 
concentration) and the treatment effect-specific intercept (defined as the difference 
between active and placebo) will be estimated together with the 2-sided 90% CI. The 
estimates for the time effect will be reported with degrees of freedom and SE. 
The geometric mean of the individual Cmax values for participants in each of the active 
dose groups will be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTc 
(i.e., slope estimate × concentration + treatment effect-specific intercept) at this 
geometric mean Cmax of GSK3640254 will be obtained. If the upper bound of the 2-
sided 90% CI of the predicted effect of ΔΔQTc at clinically relevant plasma levels of 


 
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GSK3640254 is below 10 ms, it will be concluded that GSK3640254 does not cause 
clinically relevant QTc prolongation within the observed plasma concentration range. 
The plot of the observed median-quantile GSK3640254 concentrations and associated 
mean placebo-adjusted ΔQTc (i.e., ΔΔQTc) with 2-sided 90% CI adjusted for diurnal 
effects, together with the regression line presenting the predicted ΔΔQTc (2-sided 90% 
CI) [Tornøe, 2011] will be used to evaluate the adequacy of the model fit to the 
assumption of linearity and the impact on quantifying the C-QTc relationship. The 
observed ΔQTc values from the active group will be adjusted by the estimated time effect 
from the C-QTc model (i.e., the estimated diurnal effect under the placebo treatment). 
The individually estimated placebo-adjusted ΔQTci,j equals the individual ΔQTci,j for 
participant i administered GSK3640254 at time point j minus the estimation of time 
effect at time point j. Additional exploratory analyses (via graphical displays and/or 
model fitting) will include accounting for a delayed effect (hysteresis) and the 
justification for the choice of cardiodynamic model (linear versus nonlinear) as follows. 
The SAS code for the concentration-QTc analysis is as follows:  
 
PROC MIXED DATA=PKPD method=reml; 
CLASS SUBJID TIME; 
MODEL DQTC=TRT TIME CONC CBASE/ solution cl noint alpha=0.1 alphap=0.1 COVB DDFM=KR;  
RANDOM INT CONC /type=UN SUBJECT=SUBJID s; 
ESTIMATE 'Pred Mean Diff for T1' TRT 1 CONC &GeoMeanCmax_1 / CL ALPHA=0.1; 
RUN; 
Where PKPD=PK/QTc population, SUBJID=subject number, TRT=treatment (active=1 or placebo=0), 
TIME=nominal post-baseline time point, CONC=plasma concentration of GSK3640254, CBASE=centered 
baseline QTc, T1= active dose 1, GeoMeanCmax_1=geometric mean Cmax for active dose 1, and 
DQTC=ΔQTc. 
 
Note: the ESTIMATE statement will be repeated for other active dose groups.  
 
8.7.1. 
Investigation of Hysteresis 
Hysteresis will be assessed based on joint graphical displays of the LS mean difference 
between ΔQTc under GSK3640254 and under placebo (ΔΔQTc) for each post-baseline 
time point from the by-time point analysis and the mean concentrations of GSK3640254 
at the same time points. In addition, hysteresis plots will be given for LS mean ΔΔQTc 
and the mean concentrations. If a QT effect (ΔΔQTc) >10 ms cannot be excluded in the 
by-time point analysis in the 2 active dose groups, and if the mean peak ΔΔQTc effect is 
observed at the same time point in the by-time point analysis in the 2 active dose groups, 
and if a delay between peak ΔΔQTc and peak plasma concentration in the plot (ΔΔQTc 
versus GSK3640254) of more than 1 hour is observed in a consistent way for the 2 active 
dose groups, other C-QTc models, such as a model with an effect compartment, may be 
explored. With the provision stated above, hysteresis will be assumed if the curve of the 
hysteresis plot shows a counterclockwise loop. A significant treatment effect-specific 
intercept is not biologically plausible and therefore may be indicative of hysteresis or 
model misspecification, if it cannot be explained by a nonlinear relationship. 


 
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8.7.2. 
Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal Q-Q plots for the standardized 
residuals and the random effects, and plots of standardized residuals versus 
concentration, fitted values of ΔQTc, centered baseline QTc, nominal time, and active 
treatment will be produced. Scatter plots for standard residuals versus continuous 
covariates and box plots for standard residuals versus discrete covariates will be 
provided. The scatter plots of standardized residuals versus concentration and versus 
centered baseline QTc by LOESS fitting (i.e., locally weighted scatter plot smoothing as 
described by [Cleveland, 1979]) will also be produced with optimal smoothing 
parameters selected by the Akaike information criterion with a correction (Hurvich, 
1998). A scatter plot of observed concentration and ΔQTc with a LOESS smooth line 
with 90% CI and a linear regression line will also be provided to check the assumption of 
a linear C-QTc relationship. If there is an indication that a linear model is inappropriate, 
additional models may be fitted, in particular an Emax model. The C-QTc analysis will 
then be repeated for the model found to best accommodate the nonlinearity detected. 
8.8. 
Assay Sensitivity 
The analysis to show assay sensitivity will be based on the concentration-QTc analysis of 
the effect on ∆QTc of 400 mg oral moxifloxacin using a similar model as for the primary 
analysis. That is, the relationship between moxifloxacin plasma concentration and ∆QTc 
will be investigated by linear mixed-effects modeling. The model will include ΔQTc as 
the dependent variable, moxifloxacin plasma concentration as the explanatory variable (0 
for placebo), centred baseline QTc (i.e., baseline QTc for individual subject minus the 
population mean baseline QTc for all subjects in the same treatment period) as an 
additional covariate, treatment (moxifloxacin = 1 or placebo = 0) and time (i.e., post-dose 
time point on Day 7 in each period) as fixed effects, and  random effects on intercept 
and slope per participant (Garnett, 2018). The geometric mean of the individual Cmax 
values for participants receiving the single dose of 400 mg moxifloxacin will be 
determined. The predicted effect and its 2-sided 90% CI for ΔΔQTc (i.e., slope estimate 
× concentration + treatment effect-specific intercept) at this geometric mean Cmax will 
be obtained.  
If the slope of the moxifloxacin plasma concentration/∆QTc relationship is statistically 
significant at the 10% level in a 2-sided test and the lower bound of the 2-sided 90% CI 
of the predicted QT effect at the observed geometric Cmax of the 400 mg dose is above 5 
ms, assay sensitivity will be deemed to have been demonstrated. 
8.9. 
By-Time Point Analysis (Secondary Analysis) 
The “by-time point analysis” for QTc (QTc or QTc corrected with the method chosen as 
primary if a substantial HR effect is observed) will be based on a linear mixed-effects 
model with ΔQTc as the dependent variable, period, sequence, time (i.e., post-baseline 
time point on Day 7 in each period: categorical), treatment (therapeutic dose of 
GSK3640254, supratherapeutic dose GSK3640254, moxifloxacin, and placebo), and 
time-by-treatment interaction as fixed effects, and baseline QTc as a covariate. An 
unstructured covariance matrix will be specified for the repeated measures at post-


 
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baseline time points for participant within treatment period. If the model with an 
unstructured covariance matrix fails to converge, other covariance matrices such as 
autoregressive and compound symmetry will be considered. The model will also include 
a participant-specific random effect. If the fixed effects for period and/or sequence should 
prove to be not significant (that is, if the p-value >0.1), these effects may be removed 
from the model and the analysis will be repeated without those covariates. From this 
analysis, the LS mean, SE, and 2-sided 90% CI will be calculated for the contrast 
“GSK3640254 versus placebo” for each dose of GSK3640254 at each post-baseline time 
point, separately. 
For HR, PR, QRS interval, and QTc with the methods not selected as primary the 
analysis will be based on the change-from-baseline post-dosing (ΔHR, ΔPR, ΔQRS, and 
ΔQTc). The same (by-time point analysis) model will be used as described for QTc. The 
LS mean, SE, and 2-sided 90% CI from the statistical modeling for both change-from-
baseline and placebo-corrected change-from-baseline values will be listed in the tables 
and graphically displayed. 
The SAS code for the by-time point analysis for QTc is as follows. 
 
PROC MIXED DATA=ECG; 
CLASS SUBJID TREAT TIME PERIOD SEQUENCE; 
MODEL DQTc=BASE TREAT TIME TREAT*TIME PERIOD SEQUENCE/DDFM=KR;  
RANDOM INTERCEPT / SUBJECT =SUBJID TYPE=UN; 
REPEATED TIME / SUBJECT = PERIOD*SUBJID TYPE=UN; 
LSMEANS TREAT*TIME/CL DIFF ALPHA=0.1;  
RUN; 
 
Where ECG = QT/QTc population, SUBJID = subject identifier, TREAT = treatment (therapeutic dose of 
GSK3640254, supratherapeutic dose of GSK3640254, moxifloxacin, and placebo), TIME = nominal post-
baseline time point, BASE = baseline QTc, PERIOD = period, SEQUENCE= sequence, and DQTc = ΔQTc. 
8.10. 
Categorical Analysis 
Results for categorical outliers, T-wave morphology, and U-wave presence will be 
summarized in frequency tables with counts and percentages for both number of subjects 
and number of time points. Subject data will be summarized using the count of distinct 
subjects that fall into the category and the percentage of the total number of subjects. 
Time point data will be summarized using the count of time points at which the 
assessments fall into the category and the percentage of the total number of time points at 
which assessments are performed. Counts (either number of subjects or number of time 
points) for each treatment group (therapeutic dose of GSK3640254, supratherapeutic 
dose GSK3640254, moxifloxacin, and placebo) will be used as the denominator in the 
calculation of percentages unless otherwise specified. 
A subject or time point will be determined as an outlier if the following criteria (which 
are assessed separately) are met for the ECG intervals (Table 2). 


 
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Table 2 
Criteria for determining a subject or time point outlier 
ECG 
interval 
Categorical outlier criteria 
QTc 
(QTcF, 
QTcS, 
and  
QTcI) 
Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline 
(new onset) 
Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline 
(new onset) 
Treatment-emergent value of > 500 ms when not present at baseline (new 
onset) 
Increase of QTc from baseline of > 30 and ≤ 60 ms 
Increase of QTc from baseline > 60 ms 
PR 
Increase of PR from baseline > 25% resulting in PR > 200 ms 
QRS 
Increase of QRS from baseline > 25% resulting in QRS > 120 ms 
HR 
Decrease of HR from baseline >25% resulting in HR < 50 bpm 
Increase of HR from baseline >25% resulting in HR > 100 bpm 
 
All outliers will be summarized for each treatment group on the basis of incidence rates. 
A subject will be counted only once for a particular outlier event if the subject 
experiences more than 1 episode of that event. The total number of time points will be 
based on the number of observed time points across all subjects within a treatment group. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be 
assessed, i.e., changes not present at baseline. For each category of T-wave morphology 
and of U-waves, the category will be deemed as present if observed in any replicates at 
the time point. 
The T-wave morphology and U-wave presence categories are described as follows (Table 
3). 
Table 3 
T-wave morphology and U-wave presence categories (assessed 
manually) 
Category 
Description 
Normal T-wave (+) 
Any positive T-wave not meeting any criterion below. 
Flat T-wave 
T-amplitude < 1 mm (either positive or negative), including flat isoelectric line. 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave. 
Biphasic 
T-wave that contains a second component with an opposite phase that is at 
least 0.1 mV deep (both positive/negative and negative/positive and polyphasic 
T-waves included). 
Normal T-wave (-) 
T-amplitude that is negative, without biphasic T-wave or notches. 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave. 


 
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Category 
Description 
U-waves 
Presence of abnormal U-waves. 
 
8.11. 
Terminology and Definitions: Placebo-corrected ΔQTc and 
Placebo-adjusted ΔQTc (ΔΔQTc) 
Change-from-baseline QTc (QTc) will be used as the dependent variable in the 
concentration-QTc analysis and in the by-time point analysis.  
By-time point analysis 
Placebo-corrected ΔQTc (ΔΔQTc) 
• In the by-time point analysis on the QTc interval, LS mean, SE, and 2-sided 90% 
CI of QTc and QTc will be calculated for the active dose group and 
moxifloxacin group as well as on placebo group for ΔQTc at each post-baseline 
time point. 
Concentration-QTc analysis 
Placebo-corrected ΔQTc (ΔΔQTc) 
• In the concentration-QTc analysis, the term placebo-corrected ΔQTc (ΔΔQTc) 
will be used for the model-predicted effect across concentrations on a population 
level. 
o Definition: Model-predicted mean ΔQTc in active dose group or 
moxifloxacin group minus model-predicted mean ΔQTc in the placebo 
group, which equals slope estimate × concentration + treatment effect-
specific intercept.  
• The term placebo-corrected ΔQTc (QTc) will be used for the model-predicted 
effect on the QTc interval in the concentration-QTc prediction tables and the 
scatter plots for concentration-QTc model(s), quantile plots, and prediction plots, 
as described in Section 11.9.9. 
Placebo-adjusted ΔQTc (ΔΔQTc) 
• In the concentration-QTc analysis, the term placebo-adjusted ΔQTc (ΔΔQTc) will 
be used to illustrate the underlying data on both subject and population levels. 
• Definition for the estimated placebo-adjusted ΔQTc on a subject level: observed 
ΔQTc for each subject (on active dose group or moxifloxacin group or placebo 
group) minus the estimated time effect (i.e., the model-predicted mean ΔQTc in 
the placebo group).  
o This term will be used to illustrate the underlying data on a subject level in 
the scatter plot(s) for concentration-QTc model(s).  
• Definition for the estimated placebo-adjusted ΔQTc term on a population level: 
the average of individually estimated placebo-adjusted ΔQTc values at the 
associated median plasma concentration within each concentration decile.  
o This term will be used to illustrate the underlying data on a population 
level in the quantile plot(s).  


 
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9. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population unless otherwise specified. 
9.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of AEs, SAEs, AEs of special interest, 
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 would be counted in both periods. 
For the later period the onset date of AE with elevated grade would be the first dose date 
of the later treatment period. 
9.2. 
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). 
Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total 
bilirubin, and gamma-glutamyl transferase will be summarized versus time. The details 
of the planned displays are in Appendix 9: List of Data Displays. 
9.3. 
Adverse Events of Special Interest 
At the end of the study, QT prolongation, gastrointestinal intolerability, gastric toxicity, 
psychiatric events, skin and subcutaneous tissue disorders  and nervous system disorders 
will be summarized by treatment. A listing will also be provided accordingly. 
QT prolongation AE of special interest will be defined as cardiac disorders system organ 
class (SOC) plus preferred terms (PTs) using the Medical Dictionary for Regulatory 
Activities (MedDRA) Standardized MedDRA Query (SMQ) “Torsade de pointes/QT 
Prolongation” (narrow and broad terms) plus seizure. 
Gastrointestinal intolerability and gastric toxicity AEs of special interest will be defined 
within three narrow sub-SMQs [Gastrointestinal nonspecific symptoms and therapeutic 
procedures SMQ; Gastrointestinal nonspecific dysfunction SMQ; Gastrointestinal 
nonspecific inflammation (SMQ)] plus a selection of relevant broad PTs from the 
Gastrointestinal non-specific symptoms and therapeutic procedures SMQ.  
Psychiatric AEs of special interest will be defined within the following:  
• Sub-SMQ “Suicide/self-injury” (SMQ) from parent SMQ of “Depression and 
Suicide/Self Injury”. Only narrow terms from the sub-SMQ selected. 


 
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• Sub-SMQ “Depression (excluding suicide and self-injury)” (SMQ) from parent SMQ 
of “Depression and Suicide/Self Injury”. Only narrow terms from the sub-SMQ 
selected. 
• All preferred terms from high level group term (HLGT) “Manic and Bipolar mood 
disorders and disturbances” under SOC “Psychiatric disorders”. 
• Narrow terms from SMQ “Psychosis and psychotic disorders” selected. 
• All preferred terms from HLGT “Anxiety disorders and symptoms”, under SOC 
“Psychiatric disorders”. 
• All preferred terms from HLGT “Sleep Disorders and Disturbances” and HLGT 
“Sleep disturbances (incl subtypes)”. 
Nervous system disorders AEs of special interest will be defined within the following:  
• Four HLGTs under Nervous System Disorders SOC: “Headaches”; “Mental 
impairment disorders (excluding dementia)”; “Disturbance in consciousness” and 
“Seizures and seizure disorder” 
Skin and subcutaneous tissue disorder AEs of special interest will be defined with the 
following PTs:  
Dermatitis, Dermatitis allergic, Dermatitis atopic, Eczema, , Eczema nummular, , 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.  
9.4. 
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. 
9.5. 
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 for 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 AE of COVID-19 infection 
• Severity, duration, and outcome of COVID-19 AEs 


 
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• If percentage of COVID-19 cases is >10% (>= 2 subjects for Part 1 and >=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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10. 
REFERENCES 
Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat 
Assoc. 1979;74(368):829-836. 
Darpo B, Benson C, Dota C, et al. Results From the IQ-CSRC Prospective Study Support 
Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase. 
Clin Pharmacol Ther. 2015;97(4):326-335. 
Ferber G, Zhou M, and Darpo B. Detection of QTc Effects in Small Studies--Implications 
for Replacing the Thorough QT Study. Ann Noninvasive Electrocardiol. 2015;20(4):368-
377. 
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. [Published correction appears in J Pharmacokinet 
Pharmacodyn. 2018;45(3):399]. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
Huang DP, Chen J, Dang Q, and Tsong Y: Assay sensitivity in “Hybrid thorough 
QT/QTc (TQT)” study, Journal of Biopharmaceutical Statistics, 2019; 29(2), 378-384. 
Hurvich CM, Simonoff JS, and Tsai CL. Smoothing parameter selection in nonparametric 
regression using an improved Akaike Information Criterion. J R Stat Soc Series B Stat 
Methodol. 1998;60(2):271-293. 
Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-1042. 
ViiV Healthcare group of companies Document Number 2019N422946_00 (10SEP2020) 
A Study to Evaluate the Effect of Therapeutic and Supratherapeutic Oral Doses of 
GSK3640254 on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram 
Compared to Placebo and a Single Oral Dose of Moxifloxacin in Healthy Adult 
Participants 
 


 
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11. 
APPENDICES 
11.1. 
Appendix 1: Schedule of Activities 
11.1.1. 
Protocol Defined Schedule of Events 
Screening Visit – Part 1 
Procedure 
Screening 
(up to 28 days before Day 1) 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Full physical examination including height and weight1 
X 
Laboratory assessments (hematology, chemistry, urinalysis)  
X 
12-lead electrocardiogram  
X 
24-hour Holter monitor recording2 
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-23 
 
1. 
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 
2. 
May be performed either during Screening or on Day -2 upon admission. 
3. 
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 – Part 1, Supratherapeutic Dose Selection 
Procedure 
Check-
in 
Baseline 
Treatment 
Follow-up 
Notes 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
91 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
X 
Discharge from clinic following completion of the 
last study procedure on Day 14. 
Brief physical examination 
X 
 
 
 
 
 
 
 
X 
 
X 
An interim symptom-targeted brief physical 
examination will be performed at the discretion of 
the investigator. See Protocol Section 8.2.1 for a 
description of the brief physical examination. 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse will be measured in 
triplicate pre-dose on Day 1. Single blood 
pressure and pulse will be measured on other 
study days. 
Daily temperature check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
The pre-dose ECG on Day 1 will be collected in 
triplicate. Other ECGs will be single. The ECGs 
on Days 1, 4, and 7 will be collected at pre-dose 
and post-dose at 2, 4, and 6 hours. 
Drug, alcohol, and 
cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
See Protocol Appendix 2 for specific tests to be 
performed. 
Molecular Test for SARS-
CoV-2 
X1 
 
 
 
 
 
 
X 
 
 
X 
1This 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. 


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Procedure 
Check-
in 
Baseline 
Treatment 
Follow-up 
Notes 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
91 
Laboratory assessments 
(hematology, chemistry, 
urinalysis) 
X 
 
 
 
X 
 
 
 
X 
 
X 
See Protocol Appendix 2 for specific tests to be 
performed. 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
X 
Serum testing on Day -1. 
Columbia-Suicide Severity 
Rating Scale 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Study intervention: 
Sentinel Cohort 1: 
GSK3640254 500 mg or 
placebo once daily 
Sentinel Cohort 2 
(optional): To be 
determined after 
completion of Cohort 1 
and not to exceed 500 mg 
BID 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
GSK3640254 PK 
sampling 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Blood collection for PK analysis of GSK3640254 
will be collected within 40 minutes prior to the 
morning dose on Days 1, 5, 6, and 7, and after 
dosing on Day 7 at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 
12, 24, and 48 hours. 
AE review 
 
==============================X===============================➔ 
 
SAE review 
====================================X===================================➔ 
 
Concomitant medication 
review 
====================================X===================================➔ 
 
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 
1. 
Evaluations scheduled for Day 9 will also be performed for participants who discontinue early. 


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Screening Visit – Part 2, Thorough QT Study 
Procedure 
Screening 
(up to 29 days before Day -2) 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Full physical examination including height and weight1 
X 
Laboratory assessments (hematology, chemistry, urinalysis)  
X 
12-lead electrocardiogram  
X 
24-hour Holter monitor recording2 
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-23 
X 
1. 
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 
2. 
May be performed either during Screening or on Day -2 upon admission. 
3. 
Two consecutive approved molecular tests (polymerase chain reaction or antigen test). The first test should be 
performed >= 7 days prior to admission. 


CONFIDENTIAL 
 
 
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Time and Events Table – Part 2, Thorough QT study 
Procedure 
Check
-in 
Baseline 
Periods 1, 2, and 3 
W 
Period 4 
Follow-up 
Notes 
D -2 
D -1 
D1 D2 D3 D4 D5 
D6 D7 D8-141 
D1 
D2 
D3 D4 D5 
D6 D7 D8 
D92 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Final discharge from clinic 
following completion of the last 
study procedure on Day 9 of 
Period 4. 
Brief physical 
examination 
X 
 
 
 
 
 
 
 
 
D14 
 
 
 
 
 
 
 
 
X 
An interim symptom-targeted 
brief physical examination will 
be performed at the discretion of 
the investigator. See Protocol 
Section 8.2.1 for description of 
the brief physical examination. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D8, 
D14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse will be 
measured in triplicate pre-dose 
on Day 1 of each period and 
single blood pressure and pulse 
will be measured on other study 
days. On Day 7 of each period, 
blood pressure and pulse to be 
measured before dosing and 4 
and 24 hours after dosing. 
Daily temperature check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
While confined to clinic. 
Safety 12-lead ECG 
X 
X 
X 
X 
 
X 
X 
 
X 
D8, 
D14 
X 
X 
 
X 
X 
 
X 
X 
X 
The pre-dose ECGs on Day 1 of 
each period will be collected in 
triplicate. All other ECGs will be 
single. On Days 1, 4, and 7, 
ECGs will be collected at 
pre-dose and post-dose at 1, 2, 
3, 4, 6, and 24 hours.  


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Procedure 
Check
-in 
Baseline 
Periods 1, 2, and 3 
W 
Period 4 
Follow-up 
Notes 
D -2 
D -1 
D1 D2 D3 D4 D5 
D6 D7 D8-141 
D1 
D2 
D3 D4 D5 
D6 D7 D8 
D92 
Drug, alcohol, and 
cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol Appendix 2 for 
specific tests to be performed. 
Laboratory assessments 
(hematology, chemistry, 
urinalysis) 
X 
 
 
 
 
 
 
 
 
D8, 
D14 
 
 
 
 
 
 
 
 
X 
See Protocol Appendix 2 for 
specific tests to be performed. 
Molecular Test for 
SARS-CoV-2 
X 
 
 
 
 
 
 
X 
 
D13 
 
 
 
 
 
X 
 
 
X 
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. 
 
Test to be obtained every 7 
days from Check-in (regardless 
of period or washout) while in-
house. 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
D14 
 
 
 
 
 
 
 
 
X 
Serum testing on Day -2. 
Columbia Suicide 
Severity Rating Scale 
X 
 
 
 
 
 
 
 
 
D8 
 
 
 
 
 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Period 1 only. 


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Procedure 
Check
-in 
Baseline 
Periods 1, 2, and 3 
W 
Period 4 
Follow-up 
Notes 
D -2 
D -1 
D1 D2 D3 D4 D5 
D6 D7 D8-141 
D1 
D2 
D3 D4 D5 
D6 D7 D8 
D92 
Study intervention: 
GSK3640254 
therapeutic or 
supratherapeutic dose, 
placebo, or moxifloxacin 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Moxifloxacin treatment consists 
of GSK3640254 placebo on 
Days 1 through 6 with 
moxifloxacin on Day 7 only. 
Holter ECG recording3 
 
X 
X 
 
 
 
 
 
X 
D8 
X 
 
 
 
 
 
X 
X 
 
 
GSK3640254 PK 
sampling 
 
 
X 
 
 
 
X 
X 
X 
D8 
X 
 
 
 
X 
X 
X 
X 
 
Blood collection for PK analysis 
will be collected within 
40 minutes prior to dosing on 
Days 1, 5, 6, and 7. Day 7 
post-dose samples will be 
collected at 0.5, 1, 2, 3, 3.5, 4, 
4.5, 5, 6, 8, 10, 12, and 
24 hours. 
Moxifloxacin PK 
sampling 
 
 
 
 
 
 
 
 
X 
D8 
 
 
 
 
 
 
X 
X 
 
Blood collection for PK analysis 
of moxifloxacin will be collected 
within 40 minutes prior to the 
dose on Day 7. Day 7 post-dose 
samples will be collected at 0.5, 
1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 
12, and 24 hours. 
AE review 
 
 
===================================X===================================➔  
SAE review 
=============================================X=======================================➔ 
 
Concomitant medication 
review 
=============================================X=======================================➔ 
 
AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; W = washout. 
1. 
Participants may be furloughed during the washout portion of the respective period following Day 8 procedures after discussion with and approval of the investigator. If participants 
are furloughed during the washout period, they should return to the clinic on Day 14 for scheduled assessments prior to initiating the next period. 
2. 
Evaluations scheduled for Day 9 of Period 4 will also be performed for participants who discontinue early. 
3. 
Holter ECG recordings: 


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• 
On Day -1 (Baseline), continuous ECG recordings (Holter) will be extracted at the following time points (relative to the time of planned dosing on the next day): pre-dose 
at -45, -30, and -15 minutes, and then after the time of planned dosing at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours. 
• 
On Day 1 of each period, continuous ECG recordings (Holter) will be performed starting approximately 2 hours before dosing and digital 12-lead ECGs will be extracted in 
replicates at -45, -30, and -15 minutes prior to dosing. 
• 
On Day 7 of each period, continuous ECG recordings (Holter) will be performed starting approximately 2 hours before dosing and digital 12-lead ECGs will be extracted in 
replicates at pre-dose (single time point), and then at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours after dosing. 
• 
The timing and number of planned study assessments, including safety, pharmacokinetic (PK), or other assessments may be altered during the course of the study based on 
newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging PK data from this study must be documented and approved 
by the relevant study team member and then archived in the sponsor and site study files but will not constitute a protocol amendment. The Institutional Review Board 
(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 competent authorities and the ethics committee before implementation. 


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11.2. 
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events 
11.2.1. 
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). 
11.2.1.1. 
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 
 
11.2.1.2. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before Day 1 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
11.2.2. 
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 adverse event onset date is completely missing. 
 


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11.3. 
Appendix 3: Data Display Standards & Handling 
Conventions 
11.3.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software (9.4) will be used. 
Reporting Area 
HARP Server 
\\us1salx00259.corpnet2.com 
HARP Compound 
\gsk3640254\mid213053\final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).  
• 
For creation of ADaM datasets (ADC1/ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• 
RTF files will be generated for all reporting efforts described in the RAP. 
11.3.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings. 
Formats 
• 
All data will be reported according to the actual treatment the participant received unless otherwise 
stated. 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be rounded to integer, 
unless otherwise specified.  
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 


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Planned and Actual Time 
• 
Reporting for tables, figures, and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses, and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
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. 
 


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11.3.3. 
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) 
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. 
 
11.4. 
Appendix 4: Derived and Transformed Data 
11.4.1. 
General 
Multiple Measurements at One Analysis Time Point 


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• 
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 
Period Day 
• 
Calculated as the number of days from First Dose Date for the respective period: 
• 
Assessment Date = Missing  
  → Period Day = Missing  
• 
Assessment Date <Dose Date on Day 1  
  → Period Day = Assessment Date – Dose Date on Day 1 of that period 
• 
Assessment Date >= Dose Date on Day 1 on that period (including washout period) 
  → Period Day = Assessment Date – Dose Date on Day 1 of that period + 1 
 
 


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11.4.2. 
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] 
 
11.4.3. 
Safety 
Adverse Events 
AEs of Special Interest 
• QT prolongation 
• Gastrointestinal intolerability and gastric toxicity 
• Psychiatric events 
• Nervous system disorders 
• Skin and subcutaneous tissue disorders 
 
 
11.5. 
Appendix 5: Reporting Standards for Missing Data 
11.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e., as specified in the protocol) was defined as the 
participant had completed all phases of the study including the final date on which data 
were or are expected to be collected.  
• 
Withdrawn participants will not be replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
11.5.2. 
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 


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Element 
Reporting Detail 
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. 


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11.5.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used 
and hence the event is considered On-treatment as per Appendix 2: Study 
Phases and Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications 
o Partial dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention: 
o If the partial date is a start date, a ”01” will be used for the day and “Jan” will be 
used for the month 
o If the partial date is a stop date, a “28/29/30/31” will be used for the day 
(dependent on the month and year) and ”Dec” will be used for the month. 
o The recorded partial date will be displayed in listings. 


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11.7. 
Appendix 7: Values of Potential Clinical Importance 
11.7.1. 
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 
 
 
11.7.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>140 
Diastolic Blood Pressure 
mmHg 
<45 
>90 
Heart Rate 
bpm 
<40 
>100 
 


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11.8. 
Appendix 8: Abbreviations & Trade Marks 
11.8.1. 
Abbreviations 
Abbreviation 
Description 
ΔHR 
change from baseline in heart rate 
ΔPR 
change from baseline in PR interval 
ΔQRS 
change from baseline in QRS interval 
ΔQTcF 
change from baseline in QT interval corrected for heart rate using Fridericia’s 
formula 
ΔQTcI 
change from baseline in optimized HR-corrected QT interval 
ΔQTcS 
change from baseline in individualized HR-corrected QT interval 
ΔΔHR 
placebo-corrected change from baseline in heart rate 
ΔΔPR 
placebo-corrected change from baseline in PR interval 
ΔΔQRS 
placebo-corrected change from baseline in QRS interval 
ΔΔQTcF 
placebo-corrected change from baseline in QT interval corrected for heart rate 
using Fridericia’s formula 
ΔΔQTcI 
placebo-corrected change from baseline in optimized HR-corrected QT interval 
ΔΔQTcS 
placebo-corrected change from baseline in individualized HR-corrected QT 
interval 
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 
AUC(0-t) 
Area under the plasma concentration-time curve from time zero to time t 
BID 
Twice daily 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
Cmax 
maximum observed concentration 
C-SSRS 
Columbia suicide severity rating scale 
C 
plasma concentration at the end of the dosing interval 
CVb  
coefficient of variation (between)  
C-QTc 
concentration-corrected QT interval 
DAIDS 
division of AIDS 
DBF 
database freeze 
DBR 
database release 
DP 
decimal places 
ECG 
electrocardiogram 
EPQT 
Early Precision QT analysis technique (formerly Expert Precision QT) 
eCRF 
electronic case record form 
GSK 
GlaxoSmithKline 
HIV 
human immunodeficiency virus 
HR 
Heart rate 
ICH 
international conference on harmonization 
IDSL 
integrated data standards library 


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Abbreviation 
Description 
LLN 
lower limit of normal 
LOESS 
Locally weighted scatter plot smoothing 
LS 
Least squares 
NQ 
not quantifiable 
PK 
pharmacokinetic 
PR 
PR interval of the ECG 
QD 
once daily 
Q-Q 
Quantile-quantile 
QRS 
QRS interval of the ECG 
QT 
QT interval of the ECG 
QTc 
corrected QT interval 
QTcF 
corrected QT interval using the Fridericia formula 
QTcI 
Optimized HR-corrected QT interval 
QTcS 
individualized HR-corrected QT interval 
RAP 
reporting & analysis plan 
RR 
RR interval of the ECG 
SAC 
statistical analysis complete 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
SE 
Standard error 
SSS 
Sum of squared slopes 
Tmax 
time of maximum observed concentration 
TQT 
Thorough QT 
ULN 
upper limit of normal 
11.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group of 
Companies 
 
Trademarks not owned by the GlaxoSmithKline 
Group of Companies 
NONE 
 
Phoenix WinNonlin 
 
 
SAS 
 


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11.9. 
Appendix 9: List of Data Displays 
11.9.1. 
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 3.11 
3.1 to 3.13 
Cardiodynamic 
4.1 to 4.10.2 
4.1 to 4.19.2 
Section 
Listings 
ICH Listings 
1 to 32 
Non-ICH Listings 
33 to 43 
 
11.9.2. 
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 
Cardiodynamic 
CD_Fn 
CD_Tn 
CD_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
11.9.3. 
Deliverables 
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 


 
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11.9.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Randomized 
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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11.9.5. 
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 
2.11. 
Safety 
LB1 
Summary of Hematology Changes from Baseline 
 
SAC 
2.12. 
Safety 
LB1 
Summary of Hematology Values 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
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 
2.25. 
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation and Behavior Data 
Only include participants who have 
suicidal ideation or behavior 
SAC 
Liver Event 


 
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Safety: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
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 
PAN3 
Summary of COVID-19 Symptoms for Subjects with Adverse Events 
Conditional Display 
SAC 
 
11.9.6. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
3.1. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic Concentration-
Time Data (ng/mL) by Treatment – Part 1  
Part 1 
SAC 
3.2. 
PK 
Concentration 
PKCT1 
Summary of Pre-dose (trough) GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (ng/mL) by Treatment - Part 1 
Part 1 
SAC 
3.3. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic Concentration-
Time Data (ng/mL) by Treatment – Part 2 
Part 2 
SAC 
3.4. 
PK 
Concentration 
PKCT1 
Summary of Pre-dose (trough) GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (ng/mL) by Treatment - Part 2 
Part 2 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.5. 
PK 
Concentration 
PKCT1 
Summary of Moxifloxacin Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment – Part 2 
Part 2 
SAC 
PK Derived Parameters 
3.6. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma Pharmacokinetic 
Parameters (Non-Transformed) Based on Actual Time by Treatment – 
Part 1 
Part 1 Parameters with units  
SAC 
3.7. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma Pharmacokinetic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment – 
Part 1 
Part 1 Parameters with units  
SAC 
3.8. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma Pharmacokinetic 
Parameters (Non-Transformed) Based on Actual Time by Treatment – 
Part 2 
Part 2 Parameters with units 
SAC 
3.9. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma Pharmacokinetic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment – 
Part 2 
Part 2 Parameters with units 
SAC 
3.10. 
PK Parameter 
PKPT6 
Summary Statistics of Derived Moxifloxacin Plasma Pharmacokinetic 
Parameters Based on Actual Time by Treatment - Part 2 
Part 2 Parameters with units 
SAC 
3.11. 
PK Parameter 
PKPT4 
Statistical Analysis of Plasma GSK3640254 Pharmacokinetic 
Parameters Assessing Steady-State - Part 2 
Part 2 Parameters with units 
SAC 
 


 
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11.9.7. 
Cardiodynamic Tables (Part 2) 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
QT Correction Method 
4.1 
QT/QTc 
population 
 
QTcS, and QTcI individual correction coefficients with descriptive 
statistics 
Number of subjects (n), mean, SD, 
SE, 90% CI, median, minimum, and 
maximum will be given 
SAC 
4.2 
QT/QTc 
population 
 
Average SSS for different QT-RR correction methods 
SSS for GSK3640254, moxifloxacin, 
and placebo will be given 
SAC 
By-Time Point ECG Analysis 
4.3 
QT/QTc 
population 
 
Baseline values of ECG parameters with descriptive statistics 
n, mean, SD, SE, 90% CI, median, 
minimum, and maximum from 
descriptive analysis will be given by 
treatment for each ECG parameter 
SAC 
4.4 
QT/QTc 
population 
 
Observed values of QTc (primary correction method) with descriptive 
statistics 
n, mean, SD, SE, 90% CI, median, 
minimum, and maximum from 
descriptive statistics will be given by 
treatment and post-dose time point 
SAC 
4.5.1-4.5.6 
QT/QTc 
population 
 
Change-from-baseline QTcF, HR, PR, and QRS (and QTcS and 
QTcI if calculated) (ΔQTcF, ΔHR, ΔPR, ΔQRS, ΔQTcS, and ΔQTcI) 
at each time point 
n, LS mean, SE, and 90% CI from the 
statistical modeling will be given by 
treatment and time point 
SAC 
4.6.1-4.6.6 
QT/QTc 
population 
 
Placebo-corrected change-from-baseline QTcF, HR, PR, and QRS 
(and QTcS and QTcI if calculated) (ΔΔQTcF, ΔΔHR, ΔΔPR, ΔΔQRS, 
ΔΔQTcS, and ΔΔQTcI) at each time point 
LS mean, SE, and 90% CI from the 
statistical modeling will be given by 
treatment and time point 
SAC 
Categorical ECG Analysis 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.7 
QT/QTc 
population 
 
Categorical analyses for QTc, HR, PR, and QRS 
Number (%) of subjects and time 
points with QTc > 450 and ≤ 480 
ms, > 480 and ≤ 500 ms, or > 500 
ms by treatment;  QTc > 30 and ≤ 
60 ms, or > 60 ms by treatment; PR 
> 25% and PR > 200 ms at post-
dose; QRS > 25% and QRS > 120 
ms at post-dose; HR decrease from 
baseline > 25% and HR < 50 bpm at 
post-dose; and HR increase from 
baseline > 25% and HR > 100 bpm at 
post-dose 
SAC 
4.8 
QT/QTc 
population 
 
T-wave morphology and U-wave presence across treatments: 
treatment-emergent changes 
Number (%) of subjects and time 
points falling into each of the T-wave 
categories: Normal (+), Flat, Notched 
(+), Biphasic, Normal (-), Notched (-) 
as well as U-wave category 
SAC 
Concentration-QTc Analysis 
4.9.1 
PK/QTc 
population 
 
Concentration-QTc analysis of GSK3640254 and associated ΔQTc 
prolongation  
Fixed-effect estimations and 
corresponding P values will be given 
SAC 
4.9.2 
PK/QTc 
population 
 
Assay sensitivity analysis of moxifloxacin and associated ΔQTc 
prolongation 
Fixed-effect estimations and 
corresponding P values will be given 
SAC 
4.10.1 
PK/QTc 
population 
 
Predicted ΔΔQTc interval at geometric mean peak GSK3640254 
concentration for each model 
 
SAC 
4.10.2 
PK/QTc 
population 
 
Predicted ΔΔQTc interval at geometric mean peak moxifloxacin 
concentration 
 
SAC 


 
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11.9.8. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.1. 
PK 
Concentration 
PKCF1P 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant – Part 1 (Linear and Semi-Logarithmic) 
Part 1, Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.2. 
PK 
Concentration 
PKCF1P 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant – Part 2 (Linear and Semi-Logarithmic) 
Part 2, Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.3. 
PK 
Concentration 
PKCF1P 
Individual Moxifloxacin Plasma Concentration-Time Plots by 
Participant – Part 2 (Linear and Semi-Logarithmic) 
Part 2, Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.4. 
PK 
Concentration 
PKCF1P 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Part 1 (Linear and Semi-Logarithmic) 
 
Part 1 Paginate by Treatment 
Dashed line represents the LLQ 
Individuals Overlaid 
SAC 
3.5. 
PK 
Concentration 
PKCF1P 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Part 2 (Linear and Semi-Logarithmic) 
 
Part 2 Paginate by Treatment 
Dashed line represents the LLQ 
Individuals Overlaid 
SAC 
3.6. 
PK 
Concentration 
PKCF1P 
Individual Moxifloxacin Plasma Concentration-Time Plots by 
Participant – Part 2 (Linear and Semi-Logarithmic) 
Part 2 Spaghetti Plot 
Dashed line represents the LLQ 
Individuals Overlaid 
SAC 
Mean / Median Concentration Plots 
3.7. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) GSK3640254 Plasma Concentration-Time 
Plots by Treatment – Part 1 (Linear and Semi-Logarithmic) 
Treatments (A and B) Overlaid 
SAC 
3.8. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Part 1 (Linear and Semi-Logarithmic) 
Treatments (A and B) Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.9. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Pre-dose (Trough) GSK3640254 Plasma 
Concentration Plots by Treatment – Part 1 (Linear and Semi-
Logarithmic) 
Treatments (A and B) Overlaid 
SAC 
3.10. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) GSK3640254 Plasma Concentration-Time 
Plots by Treatment – Part 2 (Linear and Semi-Logarithmic) 
Treatments (T and ST) Overlaid 
SAC 
3.11. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time Plots by 
Treatment – Part 2 (Linear and Semi-Logarithmic) 
Treatments (T and ST) Overlaid 
SAC 
3.12. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Pre-dose (Trough) GSK3640254 Plasma 
Concentration Plots by Treatment – Part 2 (Linear and Semi-
Logarithmic) 
Treatments (T and ST) Overlaid 
SAC 
3.13. 
PK 
Concentration 
PKCF2 
Mean (Standard Deviation) Moxifloxacin Plasma Concentration-Time 
Plots – Part 2 (Linear and Semi-Logarithmic) 
 
SAC 
 
11.9.9. 
Chardiodynamic Figures (Part 2) 
Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
QT Correction Method 
4.1 
QT/QTc 
population 
 
Scatter plots of QTc and RR by treatment 
Scatter plots of QTc (QTcF, QTcS, 
and QTcI) and RR intervals by 
treatment with regression lines will be 
given 
SAC 
4.2 
QT/QTc 
population 
 
QTc-RR quantile plot by treatment 
QTc-RR quantile plots (with quantiles) 
with linear mixed-effects line and 90% 
CI will be given 
SAC 
By-Time Point ECG Analysis 


 
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Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.3.1-4.3.6 
QT/QTc 
population 
 
Observed QTc (primary correction method) across time points 
Mean and 90% CI from descriptive 
analysis will be given by treatment 
SAC 
4.4.1-4.4.6 
QT/QTc 
population 
 
Change-from-baseline QTcF, HR, PR, and QRS (and QTcS and 
QTcI if calculated) (ΔQTcF, ΔHR, ΔPR, ΔQRS, ΔQTcS, and ΔQTcI) 
across time point 
LS mean and 90% CI from the 
statistical modeling will be shown by 
treatment 
SAC 
4.5 
QT/QTc 
population 
 
Placebo-corrected change-from-baseline QTcF, HR, PR, and QRS 
(and QTcS and QTcI if calculated) (ΔΔQTcF, ΔΔHR, ΔΔPR, ΔΔQRS, 
ΔΔQTcS, and ΔΔQTcI) across time point 
LS mean and 90% CI from the 
statistical modeling will be shown by 
treatment 
SAC 
Concentration-QTc Analysis 
4.6.1 
PK/QTc 
population 
 
Mean GSK3640254 plasma concentrations over time 
 
SAC 
4.6.2 
PK/QTc 
population 
 
Mean moxifloxacin plasma concentration over time 
 
SAC 
4.7.1-4.7.2 
PK/QTc 
population 
 
Joint plot of GSK3640254 plasma concentrations and ΔΔQTc over 
time 
 
SAC 
4.8.1-4.8.2 
PK/QTc 
population 
 
Hysteresis plot of GSK3640254 plasma concentration and ΔΔQTc 
connected in temporal order 
 
SAC 
4.9.1 
PK/QTc 
population 
 
Scatter plot of observed GSK3640254 plasma concentrations and 
ΔQTc with simple linear regression line and LOESS regression 
Scatter plot of QTc versus 
concentration with LOESS line and 
90% CI and simple regression line 
SAC 
4.9.2 
PK/QTc 
population 
 
Scatter plot of observed moxifloxacin plasma concentrations and 
ΔQTc with simple linear regression line and LOESS regression 
Scatter plot of QTc versus 
concentration with LOESS line and 
90% CI and simple regression line 
SAC 
4.10.1 
PK/QTc 
population 
 
Scatter plot of observed GSK3640254 plasma concentrations and 
estimated placebo-corrected ΔQTc 
Scatter plot of placebo-corrected 
ΔQTc versus concentration with linear 
mixed-effects regression line and 
90% CI 
SAC 


 
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Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.10.2 
PK/QTc 
population 
 
Scatter plot of observed plasma concentrations of moxifloxacin and 
estimated placebo-corrected ΔQTc  
Scatter plot of placebo-corrected 
ΔQTc versus concentration with linear 
mixed-effects regression line and 
90% CI 
SAC 
4.11.1 
PK/QTc 
population 
 
Model-predicted ΔΔQTc (mean and 90% CI) and estimated placebo-
corrected ΔQTc (mean and 90% CI) across deciles of GSK3640254 
plasma concentrations  
 
SAC 
4.11.2 
PK/QTc 
population 
 
Model-predicted ΔΔQTc (mean and 90% CI) and estimated placebo-
corrected ΔQTc (mean and 90% CI) across deciles of moxifloxacin 
plasma concentrations  
 
SAC 
4.12.1 
PK/QTc 
population 
 
Model-predicted ΔΔQTc interval (mean and 90% CI) at geometric 
mean peak GSK3640254 concentrations 
 
SAC 
4.12.2 
PK/QTc 
population 
 
Model-predicted ΔΔQTc interval (mean and 90% CI) at geometric 
mean peak moxifloxacin concentrations  
 
SAC 
4.13.1 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus fitted values for 
GSK3640254 
 
SAC 
4.13.2 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus fitted values for 
moxifloxacin 
 
SAC 
4.14.1 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus concentrations with 
LOESS for GSK3640254 
 
SAC 
4.14.2 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus concentrations with 
LOESS for moxifloxacin 
 
SAC 
4.15.1 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus centered baseline QTc 
with LOESS for GSK3640254 
 
SAC 
4.15.2 
PK/QTc 
population 
 
Scatter plot of standardized residuals versus centered baseline QTc 
with LOESS for moxifloxacin 
 
SAC 
4.16.1 
PK/QTc 
population 
 
Box plot of standardized residuals versus nominal time for 
GSK3640254 
 
SAC 


 
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Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.16.2 
PK/QTc 
population 
 
Box plot of standardized residuals versus nominal time for 
moxifloxacin 
 
SAC 
4.17.1 
PK/QTc 
population 
 
Box plot of standardized residuals versus treatment for GSK3640254 
 
SAC 
4.17.2 
PK/QTc 
population 
 
Box plot of standardized residuals versus treatment for moxifloxacin 
 
SAC 
4.18.1 
PK/QTc 
population 
 
Normal Q-Q plot of standardized residuals for GSK3640254 
 
SAC 
4.18.2 
PK/QTc 
population 
 
Normal Q-Q plot of standardized residuals for moxifloxacin 
 
SAC 
4.19.1 
PK/QTc 
population 
 
Normal Q-Q plots of the estimated random effects for GSK3640254 
 
SAC 
4.19.2 
PK/QTc 
population 
 
Normal Q-Q plots of the estimated random effects for moxifloxacin 
 
SAC 
 
11.9.10. 
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 


 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
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 
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) 


 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
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 
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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11.9.11. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetics 
33. 
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentration-Time Data by 
Treatment – Part 1 
Part 1 
SAC 
34. 
PK 
Concentration 
PKCL1P 
Listing of GSK3640254 Plasma Concentration-Time Data by 
Treatment – Part 2 
Part 2 
SAC 
35. 
PK 
Concentration 
PKCL1P 
Listing of Moxifloxacin Plasma Concentration-Time Data – Part 2 
Part 2 
SAC 
36. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Part 1 
Part 1 
SAC 
37. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment – Part 2 
Part 2 
SAC 
38. 
PK Parameter 
PKPL1P 
Listing of Moxifloxacin Plasma Pharmacokinetic Parameters Based on 
Actual Time - Part 2 
Part 2 
SAC 
Cardiodynamic ECG Analysis 
39.1-6 
QT/QTc 
Population  
 
QTcF (and QTcI and QTcS intervals if calculated), HR, PR, and QRS 
intervals - observed and change-from-baseline values as well as 
categorical outliers 
Part 2 
SAC 
40. 
QT/QTc 
Population 
 
T-wave morphology and U-wave presence 
 
SAC 
41. 
PK/QTc 
Population 
 
ΔQTc and time-matched GSK3640254 and moxifloxacin 
concentrations for each subject 
Data for concentration-QTc analysis 
and assay sensitivity (Part 2) 
SAC 
COVID-19 Related AE 
42. 
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessment 
 
SAC 
43. 
Safety 
AE9CP 
Listing of Adverse Events of COVID-19 
 
SAC