Conditions: HIV Infections
Keywords: Human Immunodeficiency Virus (HIV) GSK3640254 Pharmacokinetics Radiolabeled Mass balance
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: yes

Brief summary:
This is an open-label, single-center, single group, non-randomized, two-period, single sequence, mass balance study which will enroll 6 healthy male participants. This study will assess the pharmacokinetics, balance/excretion, and metabolism of GSK3640254 in humans using \[14C\]-radiolabeled drug substance administered as an intravenous (IV) infusion and via the oral route. The study will also provide an assessment of GSK3640254 absorption, metabolism and excretion following administration of a \[14C\]-radiolabeled oral suspension. Each participant will be involved in the study for up to 10 weeks which will include a screening period, two treatment periods (treatment Periods 1 and 2) separated by a washout of at least 13 days between oral doses, and a follow-up visit 7-14 days after the last assessment in treatment Period 2.

Detailed description:

Arms:
arm 1: Participants will receive a single oral dose of GSK3640254 200 milligram (mg) (2×100 mg) tablets with a moderate fat meal. Participants will then be administered a 100 microgram (mcg) dose (approximately 3.7 kilobecquerel; 100 nano Curie) of \[14C\]-GSK3640254 as an IV infusion for 1 hour on Day 1 in treatment Period 1, On Day 1 in treatment Period 2, participants will receive a single oral dose of 85 mg (approximately 3.15 megabecquerel; 85 micro Curie) \[14C\]-GSK3640254 administered as an oral suspension with a moderate fat meal. A wash out period of at least 13 days will be maintained between oral doses of treatment periods.

Interventions: intervention 1: GSK3640254 Oral tablet intervention 2: [14C]-GSK3640254 intravenous infusion intervention 3: [14C]-GSK3640254 powder
Intervention descriptions: intervention 1: GSK3640254 will be available as white film-coated round tablets to be administered via oral route with meal in the morning with 240 milliliter (mL) of water at room temperature. intervention 2: \[14C\]-GSK3640254 will be available as clear, colorless solution free from visible particulates to be administered via the IV route. intervention 3: \[14C\]-GSK3640254 will be available as white powder to be reconstituted into a suspension with 25 mL of vehicle before dosing so as to administer 85 mg dose with meal in the morning.

Protocol document:
Prot_000.pdf: 
2019N417919_01
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ViiV Healthcare group of companies
213051
1
TITLE PAGE
Protocol Title: A two-period study in healthy male participants to determine the 
pharmacokinetics, balance/excretion, and metabolism of [14C]-GSK3640254 following a 
single intravenous radiolabeled microtracer dose (concomitant with a non-radiolabeled 
oral dose) and a single oral radiolabeled dose
Protocol Number: 213051
Compound Number:
GSK3640254
Study Phase: Phase 1 
Short Title: Pharmacokinetics and metabolism of [14C]-GSK3640254
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. 
Regulatory Agency Identifying Number(s):
IND: 139,838
EudraCT: 2019-004444-30
Approval Date: 10-JUN-2020
Copyright 2020 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.


1
From:
Sent:
Wednesday, June 10, 2020 8:23 PM
To:
Subject:
FW: Prot-213051-sponsign
From: Max Lataillade 
 
Sent: 10 June 2020 14:04 
To: 
 
Cc: 
 
Subject: RE: Prot-213051-sponsign 
I approve. 
Best, 
Max 
From: 
  
Sent: Wednesday, June 10, 2020 7:29 AM 
To: Max Lataillade 
 
Cc: 
 
Subject: Prot-213051-sponsign 
Importance: High 
Dear Sponsor, 
To approve the clinical protocol indicated below, reply to this email and state your approval. 
PROTOCOL NUMBER: 213051 
DOCUMENT IDENTIFIER: 2019N417919_01 
AMENDMENT NUMBER: 01 
PROTOCOL TITLE: A two-period study in healthy male participants to determine the pharmacokinetics, 
balance/excretion, and metabolism of [14C]-GSK3640254 following a single intravenous radiolabeled microtracer dose 
(concomitant with a non-radiolabeled oral dose) and a single oral radiolabeled dose 
Name of Sponsor Signatory: Max Lataillade 
Title of Sponsor Signatory: VP and Head, Global Research Strategy, ViiV Research and Development 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 01
10-JUN-2020
2019N417919_01
Original Protocol
11-MAR-2020
2019N417919_00
Amendment [01] [10-JUN-2020]
Overall Rationale for the Amendment:The primary driver for the protocol amendment 
was to add the new rash risk. Following recent events involving COVID-19, additional 
changes around COVID-19 guidance was added.  


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Section # and 
Name
Description of Change
Brief Rationale
1.3 SoA
Minor typological changes.
Daily temperature check added
Withdrawal and discharge COVID-
19 text
Minor typological changes.
Daily temperature check added to follow 
GSK/ViiV COVID-19 guidelines.
Withdrawal and discharge COVID-19 text
2.3.1 Risk 
Assessment
Addition of rash as potential risk of 
clinical significance.
In previous ‘254 clinical studies episodes of 
rash have been reported and some cases 
have led to study discontinuation. As a 
result, rash has been included as a risk for 
participants who are dosed with ‘254.
5.1 Inclusion 
Criteria
Upper age limit changed
Changed from 55 to 50 to follow GSK/ViiV 
COVID-19 guidelines
5.2 Exclusion 
Criteria
Liver chemistry updated
12 months changed to 3 years for 
monitoring occupation radiation 
exposure.
WHO COVID-19 update
Liver chemistry updated as per the VSLC 
liver safety guidence April 2020.
To ensure compliance with SOP 416111 
‘Enrolment of Human Subjects in Studies 
which involve their Exposure to Ionising 
Radiation’.
Addition of WHO COVID-19 exclusion 
guidance
7.1.5 
Discontinuation 
of Study 
Intervention
Addition of COVID-19 as 
discontinuation criteria.
Addition of moderate or severe COVID-19 
infection as discontinuation criteria.
8.3 Adverse 
Events and 
Serious 
Adverse 
Events
Reference to Appendix for AE’s 
and SAE’s related to COVID-19
Reference to Appendix for AE’s and SAE’s 
related to COVID-19.
9.7 Other 
Analyses
Addition of special statistical and 
data analysis considerations.
Special statistical and data analysis 
considerations may be warranted in the 
event that the COVID-19 or related 
epidemics or natural disasters may affect 
the study and data integrity.
10.9 COVID-19 
Pandemic and 
Clinical Trial 
Addition of appendix to document 
requirements to mitigate for any 
This appendix outlines the measures which 
are approved for implementation within this 
clinical trial, to protect patient safety, 


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Section # and 
Name
Description of Change
Brief Rationale
Continuity
actions related to COVID-19
welfare and rights, and to ensure data 
integrity and the integrity of the clinical trial, 
as a result of COVID-19 only.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................9
1.1.
Synopsis.......................................................................................................9
1.2.
Schema ......................................................................................................13
1.3.
Schedule of Activities (SoA)........................................................................13
2.
INTRODUCTION....................................................................................................20
2.1.
Study Rationale ..........................................................................................20
2.2.
Background ................................................................................................20
2.3.
Benefit/Risk Assessment ............................................................................20
2.3.1.
Risk Assessment .........................................................................22
2.3.2.
Benefit Assessment.....................................................................25
2.3.3.
Overall Benefit: Risk Conclusion..................................................25
3.
OBJECTIVES AND ENDPOINTS...........................................................................25
4.
STUDY DESIGN ....................................................................................................27
4.1.
Overall Design ............................................................................................27
4.1.1.
Screening Period .........................................................................27
4.1.2.
Treatment Period 2 (14C-oral suspension)....................................28
4.1.3.
Demonstration of radioactivity recovery before discharge 
(Period 2).....................................................................................28
4.1.4.
Follow-up.....................................................................................29
4.2.
Scientific Rationale for Study Design ..........................................................29
4.3.
Justification for Dose ..................................................................................30
4.3.1.
GSK3640254 Oral Dose (Treatment Periods 1 and 2) .................31
4.3.2.
GSK3640254 Intravenous Dose (Treatment Period 1).................31
4.3.3.
Radiolabel Dose ..........................................................................31
4.3.4.
Total Radiation Exposure.............................................................32
4.4.
End of Study Definition ...............................................................................32
5.
STUDY POPULATION...........................................................................................33
5.1.
Inclusion Criteria.........................................................................................33
5.2.
Exclusion Criteria........................................................................................34
5.3.
Lifestyle Considerations..............................................................................37
5.3.1.
Meals and Dietary Restrictions ....................................................37
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................38
5.3.3.
Activity .........................................................................................38
5.4.
Screen Failures...........................................................................................38
6.
STUDY INTERVENTION........................................................................................39
6.1.
Study Intervention(s) Administered .............................................................39
6.2.
Preparation/Handling/Storage/Accountability..............................................39
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................40
6.4.
Study Intervention Compliance ...................................................................40
6.5.
Concomitant Therapy..................................................................................41
6.6.
Dose Modification .......................................................................................41


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6.7.
Intervention after the End of the Study........................................................41
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................42
7.1.
Discontinuation of Study Intervention..........................................................42
7.1.1.
Liver Chemistry Stopping Criteria ................................................42
7.1.2.
QTc Stopping Criteria ..................................................................42
7.1.3.
Individual Participant Laboratory Abnormality and AE 
Stopping Criteria..........................................................................43
7.1.4.
Columbia-Suicide Severity Rating Scale Criteria..........................43
7.1.5.
COVID-19....................................................................................44
7.1.6.
Other study stopping criteria ........................................................44
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................44
7.3.
Lost to Follow Up........................................................................................44
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
8.1.
Efficacy Assessments.................................................................................46
8.2.
Safety Assessments ...................................................................................46
8.2.1.
Physical Examinations.................................................................47
8.2.2.
Vital Signs....................................................................................47
8.2.3.
Electrocardiograms......................................................................47
8.2.4.
Clinical Safety Laboratory Assessments ......................................47
8.2.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms..................................................................48
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan.............49
8.3.
Adverse Events and Serious Adverse Events.............................................51
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................51
8.3.2.
Method of Detecting AEs and SAEs.............................................52
8.3.3.
Follow-up of AEs and SAEs.........................................................52
8.3.4.
Regulatory Reporting Requirements for SAEs .............................52
8.3.5.
Pregnancy ...................................................................................52
8.4.
Treatment of Overdose...............................................................................53
8.5.
Pharmacokinetics .......................................................................................53
8.5.1.
Plasma Sample Collection ...........................................................53
8.5.2.
Urine Sample Collection ..............................................................54
8.5.3.
Fecal Sample Collection ..............................................................54
8.5.4.
Vomitus collection (if occurs) .......................................................54
8.5.5.
Bile Sample Collection.................................................................55
8.5.6.
Sample Analysis ..........................................................................55
8.6.
Pharmacodynamics ....................................................................................56
8.7.
Genetics .....................................................................................................56
8.8.
Biomarkers .................................................................................................56
8.9.
Immunogenicity Assessment ......................................................................56
8.10.
Medical Resource Utilization and Health Economics ..................................56
9.
STATISTICAL CONSIDERATIONS........................................................................57
9.1.
Statistical Hypotheses.................................................................................57
9.2.
Sample Size Determination ........................................................................57
9.3.
Populations for Analyses ............................................................................57
9.4.
Statistical Analyses.....................................................................................58
9.4.1.
Efficacy Analyses.........................................................................58


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9.4.2.
Safety Analyses...........................................................................58
9.4.3.
Pharmacokinetic Analyses...........................................................58
9.5.
Metabolite profiling......................................................................................59
9.6.
Interim Analyses .........................................................................................59
9.7.
Other Analyses ...........................................................................................59
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................60
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................60
10.1.1.
Regulatory and Ethical Considerations ........................................60
10.1.2.
Financial Disclosure.....................................................................60
10.1.3.
Informed Consent Process ..........................................................60
10.1.4.
Data Protection............................................................................61
10.1.5.
Dissemination of Clinical Study Data ...........................................61
10.1.6.
Data Quality Assurance ...............................................................62
10.1.7.
Source Documents ......................................................................63
10.1.8.
Study and Site Closure ................................................................63
10.1.9.
Publication Policy.........................................................................63
10.2.
Appendix 2:  Clinical Laboratory Tests........................................................64
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
10.3.1.
Definition of AE............................................................................65
10.3.2.
Definition of SAE..........................................................................66
10.3.3.
Recording and Follow-Up of AE and SAE....................................67
10.3.4.
Reporting of SAE to GSK.............................................................68
10.4.
Appendix 4: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Correct Version 2.1, July 2017.....................70
10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................71
10.5.1.
Collection of Pregnancy Information: ...........................................71
10.6.
Appendix 6:  An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study 
intervention.................................................................................................72
10.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................83
10.8.
Appendix 8: Abbreviations and Trademarks................................................85
10.9.
Appendix 9: COVID-19 Pandemic and Clinical Trial Continuity...................89
10.9.1.
Changes to Study Visits and Study Procedures...........................89
10.9.2.
COVID-19 Experimental Agents ..................................................89
10.9.3.
COVID-19 Specific Data Capture.................................................90
10.9.3.1.
Capturing COVID-19 Specific Protocol 
Deviations ..................................................................90
10.9.3.2.
Capturing COVID-19 Specific AEs and SAEs.............90
10.9.3.2.1.
WHO Case Definition (March 20, 
2020 Version): ........................................91
10.10. Protocol Amendment History ......................................................................92
11. REFERENCES.......................................................................................................93


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A two-period study in healthy male participants to determine the 
pharmacokinetics, balance/excretion, and metabolism of [14C]-GSK3640254 following a 
single intravenous radiolabeled microtracer dose (concomitant with a non-radiolabeled 
oral dose) and a single oral radiolabeled dose 
Short Title: Pharmacokinetics and metabolism of [14C]-GSK3640254 
Rationale:
Absorption, metabolism and excretion of GSK3640254 have been studied in pre-clinical 
animal models, in vitro, and in previous clinical trials. However, no dedicated clinical 
studies of drug absorption, metabolism, and excretion have been conducted for 
GSK3640254. Using radiolabelled GSK3640254 with Accelerator Mass Spectrometry 
(AMS) will enable quantitative measurement of GSK3640254 concentrations and 
comprehensive identification and quantification of drug metabolites that would not 
otherwise be possible.
This open-label study in 6 healthy male participants will assess the pharmacokinetics, 
balance/excretion, and metabolism of GSK3640254 in humans using [14C]-radiolabelled 
drug substance administered as an intravenous (IV) infusion and orally.  [14C]-
GSK3640254 administered by IV infusion will be a microtracer dose; therefore, it will be 
administered concomitantly with an oral non-radiolabelled dose, to ensure that the 
pharmacokinetics (PK) are representative of a clinically-relevant dose. Use of a bile 
string collection device for sampling duodenal bile after IV infusion and oral dose of 
[14C]-GSK3640254 will enable a qualitative assessment of drug metabolites in this matrix 
to characterise biliary elimination pathways.  The study will also provide an assessment 
of GSK3640254 absorption, metabolism and excretion following administration of a 
[14C]-radiolabelled oral suspension.


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Objectives and Endpoints:
Objectives
Endpoints1
Primary

To determine parent GSK3640254 and total 
drug-related radioactivity systemic 
concentrations following a single IV 
microtracer dose of [14C]-GSK3640254 
(with an oral dose of non-radiolabelled 
GSK3640254) and oral dose of [14C]-
GSK36402541

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 
of parent and total drug-related material 
(radioactivity) in plasma and blood.

Volume of distribution at steady state (Vss) 
and clearance (CL) of parent after IV dose 
(Period 1 only).

Renal clearance of parent (CLr) after both 
IV and oral dose

Oral clearance (CL/F) and apparent volume 
of distribution (Vz/F) for the parent following 
oral administration

To calculate the absolute oral bioavailability 
of GSK3640254

Direct estimation of absolute oral 
bioavailability (F), indirect calculation of 
fraction of drug escaping first pass hepatic 
clearance (Fh), fraction absorbed (Fa) and 
fraction of drug escaping gut metabolism
(Fg).

To determine the rate and extent of 
excretion of total radioactivity in urine and 
feces and the total recovery of radioactivity, 
following IV and oral administrations of 
[14C]-GSK3640254

Urinary and fecal cumulative excretion as a 
percentage of the total radioactive dose
Secondary

To evaluate the safety and tolerability of 
GSK3640254 after single IV and oral doses 
in healthy participants.

Characterize observed adverse events, and 
abnormal laboratory, 12-lead ECG, and vital 
signs assessments observed.

To determine the blood:plasma ratio of 
[14C]-GSK3640254-related materials (total 
radioactivity) associated with blood cellular 
components  

Blood:plasma ratio of [14C]-GSK3640254-
related materials (total radioactivity).
Exploratory

To generate samples that will be used to 
characterize the metabolite profile of 
GSK3640254 following a single IV 
microtracer dose of [14C]-GSK3640254 

Characterization and quantification of 
metabolites in plasma, urine, feces, and 
duodenal bile (qualitative identification in 
bile).  These analytical investigations will be 


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Objectives
Endpoints1
concomitant with an oral dose of non-
radiolabelled GSK3640254 (plasma, urine, 
feces, duodenal bile) and a single, oral dose 
of [14C]- GSK3640254 (plasma, urine, 
feces, duodenal bile).
conducted, and the results reported under a 
separate nonclinical GSK protocol.

To evaluate the PK and relative 
bioavailability of GSK3640254 following 
administration of the 85 mg suspension 
compared to the 200 mg tablet

AUC(0-inf), AUC(0-t) and Cmax
AUC(0–inf): Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time, 
AUC(0–t): Area under the plasma concentration-time curve from time zero (pre-dose) to last time of quantifiable 
concentration within a participant across all treatments, Cmax: Maximum observed plasma concentration, tmax: time of 
occurrence of Cmax, t1/2: terminal phase half-life, ECG: electrocardiogram.
1 For measured concentrations of GSK3640254 in plasma, the nomenclature [14C]-GSK3640254 describes the parent 
GSK3640254 concentration derived via analysis by liquid chromatography (LC) + AMS, whereas GSK3640254
describes the parent GSK3640254 concentration derived via liquid chromatography-tandem mass spectrometry (LC-
MS/MS).
Overall Design:
This open-label, single-center, non-randomised, 2-period, single-sequence, mass balance 
study will enroll a cohort of 6 healthy male participants. The pharmacokinetics, 
balance/excretion, and metabolism of GSK3640254 will be assessed across two treatment 
periods. In Treatment Period 1, [14C]-radiolabelled drug substance will be administered 
as an IV infusion of a microtracer dose along with an oral tablet, non-radiolabelled dose. 
In Treatment Period 2, [14C]-radiolabelled drug substance will be administered orally.
Disclosure Statement: This is a single group, single center, [14C]-GSK3640254 mass 
balance study with a two-period, single sequence and no blinding. 
Number of Participants:  Approximately six participants will be enrolled to achieve at 
least 4 participants completing the two treatment periods. 
Replacement participants will be sought if it is likely the total number of participants who 
complete dosing and all critical assessments will drop below 4. Any replacement 
participants will be required to complete both treatment periods.
Intervention Groups and Duration:
Each participant will be involved in the study for up to 10 weeks.  Each participant will 
have:
A screening visit (up to 30 days before first dose)
Two inpatient treatment periods (Treatment Periods 1 and 2), with at least 13 days 
between doses.
A follow-up or early withdrawal visit 7 – 14 days after the last assessment performed.


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During both treatment periods, participants will reside in the unit from Day -1 until all 
procedures are completed 168 h post-dose on Day 8.  Participants may be asked to stay 
for up to 1 week longer in Treatment Period 2, if required, to demonstrate sufficient 
recovery of drug-related material. Thereafter, if deemed necessary to demonstrate 
sufficient recovery of radioactivity, participants may be asked to collect excreta at home.
Data Monitoring Committee: No
Treatment Period 1 (oral tablets and 14C-intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant 
will take a single 200 mg oral dose (2 x 100 mg tablets) of GSK3640254 with a moderate
fat meal (approximately 600 calories with approximately 30% of calories from fat); the 
IV infusion of 100 µg of [14C]-GSK3640254 (approximately 3.7 kBq; 100 nCi) will 
begin 5 h after oral dose and continue over 1 h.  Blood samples, all voided urine, and 
feces will be collected continuously from Day 1 through Day 8, while duodenal bile will 
be collected as described below.  Participants will be discharged on study Day 8 after 
completion of the 168-h sample collection and other planned assessments and instructed 
to return to the clinic on Day 1 of Treatment Period 2. 
A non-invasive device (Entero-tracker) to collect duodenal bile will be used in Treatment 
Period 1.  The bile string will be swallowed 2 h after the oral dose and 3 h before the IV
infusion starts, a duration recommended to allow transit of the string to the duodenum.
Participants will fast from insertion of the bile string until the completion of the IV 
infusion, at which point a food cue (small standard high-fat meal) will be given to 
stimulate gall bladder emptying. The Entero-tracker will be removed about 1.5 h after the 
IV infusion stops (7.5 h after the oral dose).
Treatment Period 2 (14C-oral suspension)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant 
will receive approximately 85 mg [14C]-GSK3640254 (approximately 3.15 MBq; 85 µCi) 
as an oral suspension with a moderate fat meal (approximately 600 calories with 
approximately 30% of calories from fat). A non-invasive device (Entero-tracker) to 
collect duodenal bile will be used in Treatment Period 2.  The Entero-tracker will be 
swallowed 2 h after oral dose. At 5.5 h after the start of oral dose, a food cue (small 
standard high-fat meal) will be given to stimulate gall bladder emptying. The collection 
bile string will be removed 1.5 h post the food cue (7 h after the oral dose) to capture the 
duodenal bile samples expelled from the gall bladder. 
Blood, urine and fecal samples will be collected continuously from Day 1 through Day 8.
Radioactivity quantification using liquid scintillation counting (LSC) will be performed 
on each 24-h urine collection and each 24-h fecal homogenate.  Criteria for discharge for 
Period 2 are based on demonstrated cumulative recovery of radioactivity >90% or <1% in 
two consecutive samples The inpatient stay may be extended by up to 7 days to meet the 
discharge criteria. In the unlikely event that excretion is still >1% in the 24-h collection 
period prior to discharge on Day 15, the participant will continue to collect fecal samples 
only, at home, at 24-h intervals.  Samples will be returned to the unit every 2 to 3 days for 
analysis.


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Total Radiation Exposure
The total amount of radiation exposure in the study is ~3.15 MBq (~85.1 µCi). 
1.2.
Schema
Figure 1
Study Intervention Schematic  
1.3.
Schedule of Activities (SoA)
The timing and number of planned study assessments, including safety and 
pharmacokinetic assessments, may be altered during the study based on newly available 
data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. Participants who withdraw from the study early should be subject 
to those assessments that would be required at discharge in that treatment period, if 
participants agree.
Participants who are withdrawn and discharged from the study due to COVID-19 
infection will return to the site for follow up assessments after 2 weeks.
Any changes in the timing or addition of time points for any planned study assessments 
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 require alteration of the safety monitoring scheme or amendment 
of the Informed Consent (ICF).
If assessments are scheduled for the same nominal time, the assessments should occur in 
the following order:
1. vital signs
2. 12-lead electrocardiogram (ECG)
3. blood draws
4. other assessments


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Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.


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Table 1
SoA Screening, Follow up and Early Withdrawal
Procedure
Screening1
(Up to 30 days before first dose)
Follow up/Early Withdrawal
(7 – 14 days after the last 
assessment)
Comments
Informed consent
X
Medical history (including drug/alcohol use)
X
Demography
X
12-lead ECG
X
X
Single ECG measurements will be obtained at screening. Repeats 
can be obtained if the original reading cannot be interpreted. See 
Section 8.2.
Vital signs 
X
X
Single measurements will be obtained for all parameters. Repeats 
can be obtained if the original reading cannot be interpreted. See 
Section 8.2.
Drugs of abuse screen 
X
Alcohol, cotinine, & CO breath tests 
X
HIV and hepatitis B and C screen
X
Laboratory safety tests (incl. LFTs)
X
X
Physical exam 
X-full
X-brief
Details of full and brief physical exams in Section 8.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
X
X
Details included in Section 8.2.5
Blood samples for total background radioactivity 
X
AE/SAE and concomitant meds review
X
X
AEs will be collected from the start of study intervention until the 
final follow-up visit.  All SAEs will be recorded from the time each 
participant consents to participate in the study
Abbreviations: AE: adverse event; ECG: electrocardiogram; HIV: human immunodeficiency virus; LFTs: liver function tests; SAE: serious adverse event


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Table 2
SoA: Treatment Period 1 (oral tablets and 14C-labelled intravenous infusion)
Procedure
D
a
y 
-
1
Day 1 (hours)
2
3
4
5
6
7
8
Notes
Pre 
dose
0
1
2
3
4
5
6
7
8
9
10
12
24
36
48
72
96
120
144
168
.0 .5
.0
.5
.0 .5 .0
.25
.5
.0 .5
Admission
X
Discharge
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Single measurements for all 
timepoints except pre-dose 
which should be taken in 
triplicate. See Section 8.2.
Vital signs
X
X
X
X
Single measurements will be 
obtained for all parameters. 
Repeats can be obtained if 
the original reading cannot 
be interpreted. See Section 
8.2.
Temperature 
Check
X
X
X
X
X
X
Single for all measurements. 
Drugs of 
abuse 
screen 
X
Alcohol, 
cotinine, & 
CO breath 
tests 
X
Laboratory 
safety tests 
X
X
X
X
See Appendix 2 for details.
Brief 
Physical 
X
X
See Section 8.2.1
Columbia-
Suicide 
Severity 
Rating Scale
X
X
See Section 8.2.5


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Procedure
D
a
y 
-
1
Day 1 (hours)
2
3
4
5
6
7
8
Notes
Pre 
dose
0
1
2
3
4
5
6
7
8
9
10
12
24
36
48
72
96
120
144
168
.0 .5
.0
.5
.0 .5 .0
.25
.5
.0 .5
Entero 
tracker
X
X
See Section 8.5.5
Oral 
GSK364025
4
X
Participants will fast for at 
least 8 h before oral dosing.
14C-
GSK364025
4 IV
1 hour long IV infusion to 
start 5 h after oral dose
Monitor local 
IV tolerability
To be monitored during 1 h 
long infusion
Meal
X
X
Meal time is specified for 
Day 1 breakfast and mid-
day only. On all other days, 
meals will be served at the 
unit’s standard times. Refer 
to Section 5.3.1.
Blood 
samples for 
plasma total 
radioactivity, 
PK and 
metabolite 
ID
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
From this sample, 
background radiation will be 
measured on admission 
(Day –1), and pre-dose on 
Day 1.
See Section 8.5.1
Fecal 
collection
X
See Section 8.5.3
Urine 
collection
X
See Section 8.5.2
AE/SAE/Con
comitant 
med. review
See Section 8.3
Abbreviations: AE: adverse event; ECG: electrocardiogram; IV: intravenous; LFTs: liver function tests; PK: Pharmacokinetic; SAE: serious adverse event.


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Table 3
SoA: Treatment Period 2 (14C-labelled oral suspension)
Procedure
Day -1
Day 1 (hours)
2
3
4
5
6
7
8
Notes
Pre-
dose
0
1
2
3
4
5
6
7
8
10
12
24
36
48
72
96
120 144 168
.0 .5 .0 .5
.0 .5 .0 .5
Admission to 
unit
X
Discharge 
from unit
X
Discharge will be contingent upon 
demonstration of adequate recovery of 
radioactivity (see Section 4.1.3). If discharge 
is delayed all Day 8 assessments should be 
performed on day of discharge.
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Single measurements for all timepoints 
except pre-dose which should be taken in 
triplicate. See Section 8.2.3 for ECG details.
Vital signs
X
X
X
X
Single for all measurements. 
Temperature 
check
X
X
X
X
X
X
Single for all measurements. 
Drugs of 
abuse screen 
X
Alcohol, 
cotinine, & CO 
breath tests
X
Laboratory 
safety tests)
X
X
X
X
[14C]-
GSK3640254
oral 
suspension
X
Brief physical 
exam 
X
X
See Section 8.2.1
Columbia-
Suicide 
Severity 
Rating Scale
X
X
See Section 8.2.5


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Procedure
Day -1
Day 1 (hours)
2
3
4
5
6
7
8
Notes
Pre-
dose
0
1
2
3
4
5
6
7
8
10
12
24
36
48
72
96
120 144 168
.0 .5 .0 .5
.0 .5 .0 .5
Entero tracker
X
X
See Section 8.5.5
Defined meal
X
X
Meal time is specified for Day 1 breakfast 
and mid-day only. On all other days, meals 
will be served at the unit’s standard times.
Refer to Section 5.3.1.
Blood samples 
for plasma 
total 
radioactivity, 
PK and 
metabolite ID
X
X
X X
X
X
X X
X X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.5.1
Blood samples 
for 
blood/plasma 
ratio and 
metabolite ID
X
X
X
X
X
2 mL blood samples for measuring total 
radioactivity in whole blood to calculate 
blood/plasma ratio. At 4 h only a 10 mL 
sample will be obtained for metabolite ID.
Urine 
collection
X
See Section 8.5.2
Fecal 
collection
X
See Section 8.5.3
AE/SAE/
concomitant 
medication 
review 
See Section 8.3
Abbreviations: AE: adverse event; ECG: electrocardiogram; LFTs: liver function tests; SAE: serious adverse event


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2.
INTRODUCTION
GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI); this novel class of 
anti-HIV-1 medicines prevents the maturation of HIV-1 virions by binding near a key 
structural element within the group-specific antigen (Gag) polyprotein that is required for 
virion maturation and assembly. MIs block the last protease cleavage event between Gag 
protein segments designated as 24-kilodalton (kDa) HIV capsid (CA) protein p24 (CA 
[p24]) and spacer peptide 1 (SP1). Blockage at this step results in the release of immature 
non-infectious virus particles. GSK3640254 is potent and has a broad pan-genotypic 
spectrum in vitro. There are no MIs approved for the treatment of HIV infection.
2.1.
Study Rationale
This study will assess the pharmacokinetics, balance/excretion, and metabolism of 
GSK3640254 in humans using [14C]-radiolabelled drug substance administered as an IV 
infusion and orally.  [14C]-GSK3640254 administered by IV infusion will be a 
microtracer dose; therefore, it will be administered concomitantly with an oral non-
radiolabelled dose, to ensure that the PK are representative of a clinically-relevant dose. 
Use of a string bile collection device (Entero-tracker) for sampling duodenal bile after IV 
[14C]-GSK3640254 infusion will enable a qualitative assessment of drug metabolites in 
this matrix to characterise biliary elimination pathways. 
Absorption, metabolism and excretion of GSK3640254 have been studied in pre-clinical 
animal models, in vitro, and in previous clinical trials. However, no dedicated clinical 
studies of drug absorption, metabolism, and excretion have been conducted for 
GSK3640254. Using radiolabelled GSK3640254 with Accelerator Mass Spectrometry 
(AMS) will enable quantitative measurement of GSK3640254 concentrations and 
comprehensive identification and quantification of drug metabolites in plasma that would 
not otherwise be possible. 
2.2.
Background
GSK3640254 is an HIV MI which is improved over prior developmental MIs in the 
following ways: (1) it exhibits significantly improved pan-genotypic coverage and 
potency against polymorphic variants; (2) in vitro data suggest that GSK3640254 exhibits 
a higher barrier to emergence of resistant viruses (except for A364V); (3) GSK3640254 
has improved potency in vitro toward all HIV-1 subtypes; and (4) it has a projected lower 
once-daily human dose (see Dose Justification, Section 4.3). 
A detailed description of the chemistry, pharmacology, drug metabolism and 
pharmacokinetics (DMPK) and safety of GSK3640254 is provided in the Investigator 
Brochure (IB) (see GSK Document Number 2018N379610_01).
2.3.
Benefit/Risk Assessment
As of 24 August 2019, an estimated 143 participants have been exposed to GSK3640254. 
This includes healthy participants or HIV-1 infected treatment naïve patients across 6
randomized clinical studies: Phase 1 studies (207187 [Part 1 and 2], 208131, 209712, 
208134 and ongoing study 208135) and Phase 2a Study 208132 (Part 1). A detailed 


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summary of the above-mentioned studies, along with more information about the known 
and expected risks, and reasonably expected AEs associated with GSK3640254 can be 
found in the IB. Risks, along with their mitigation plans are outlined in the table below. 
Finally, there are no benefits to individuals participating in this trial.


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2.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention: GSK3640254
Prolongation of QT 
interval
Preclinically, GSK3640254 inhibited cardiac hERG/IKr potassium, cardiac SCN5A 
sodium and L-type calcium channel currents recorded from HEK 293 cells stably 
transfected with complementary Deoxyribonucleic acid (DNA) from the ion channels. In 
a single-dose safety pharmacology study in telemeterized dogs, increases in QT 
interval (up to 20 ms) occurred primarily in 1 dog given 17 mg/kg. Later, there were no 
GSK3640254-related effects on ECG parameters in dogs given up to 25 mg/kg/day for 
4 weeks. 
In the first time in human Study 207187, no participant exhibited corrected QT interval 
(QTc) change from Baseline >60 ms or QTc >500 ms. In the concentration- QTc 
analysis, a QT duration corrected for heart rate by Fridericia’s formula (QTcF) effect 
above 10 ms could be excluded for GSK3640254 plasma concentrations of up to 
approximately 2000 ng/mL (corresponding to doses approximately ≤200 mg QD).

Protocol exclusion criteria based on Screening ECG 
parameters and cardiac medical history. 

Participants will have ECG monitoring during the course of 
the study with QTc stopping criteria.
Gastrointestinal (GI)
intolerability
Clinical signs indicative of GI intolerability (sporadic vomiting and abnormal feces 
beginning on Day 1 and continuing throughout the dosing periods) occurred mainly in 
dogs at ≥1 mg/kg/day. Additionally, toxicity findings of single-cell necrosis of parietal 
cells and/or chief cells were present in preclinical species. These findings were 
reversible. Gastrointestinal intolerability (predominantly abdominal pain and diarrhea) 
was seen with a structurally related compound GSK3532795, which was evaluated 
through Phase 2b dosing. 
In the multiple ascending dose part of the first time in human Study 207187, clinically 
relevant GI AEs (abdominal pain lower, diarrhoea, feces soft, gastro-esophageal reflux 
disease, nausea, abdominal distention, and abdominal pain) were experienced by 9 
participants. The greatest incidences were in the GSK3640254 200 mg arms (Cohorts 
5 and 7) but ultimately, no dose/AE relationship was apparent. One participant each in 
the GSK3640254 200 mg arm and 320 mg arm reported nausea (mild in intensity), 
considered by the investigator in each case to be related to study drug.

Protocol exclusion criterion based on pre-existing GI 
pathology or Baseline GI signs/symptoms. 

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)
Neurologic/psychiatric 
safety
Two psychiatric SAEs in previous maturation inhibitor GSK3532795 clinical program 
(acute psychosis, homicidal/suicidal ideation) were seen at supratherapeutic doses in 
healthy participants in the thorough QT (TQT) study. 
From a neurologic and psychiatric AE summary and PK/pharmacodynamic analysis for 

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 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK3532795 across all studies, Grade 1 headache and Grade 1 sleep abnormalities 
were the predominant AEs, with a trend for increasing neurologic and psychiatric AEs 
with increasing dose (based on TQT and Phase 2b studies). No exposure-response 
relationship was seen for select neurologic and psychiatric AEs (based on TQT and 
Phase 2b studies). Central nervous system penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low brain distribution/penetration. In the 
multiple ascending dose part of first time in human Study 207187, clinically relevant 
preferred terms from the system organ class nervous system were experienced by 5 
participants (somnolence, disturbance in attention, and lethargy) and showed that the 
greatest incidence arose in the GSK3640254 200 mg arms (Cohorts 5 and 7), but no 
dose/AE relationship was apparent. Seven participants experienced five psychiatric 
AEs: agitation, abnormal dreams, insomnia, depressed mood, and nightmare. All 
events were mild in intensity and considered by the investigator to be unrelated to 
study drug, apart from one participant from the 320 mg arm who experienced lethargy 
which was considered related to study drug.
will be included given no positive (abnormal) response. 

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. Participants will be 
housed during key aspects of the study to ensure rapid 
diagnosis and management of any potential event. The C-
SSRS will be administered during and after the treatment 
phase of the study. In case of positive (abnormal) response 
confirmed by the investigator, the participant will undergo 
immediate clinical assessment of suicidality (by the 
investigator or a consulting psychiatrist). Emergence of new 
onset suicidal ideation or a Grade 3 or higher psychiatric 
AE will result in immediate discontinuation and urgent 
specialist psychiatric evaluation and management.
Guidance for the investigator on the management of 
emergent psychiatric symptoms will be available.
Rash
Across clinical trials, AEs leading to discontinuation have included urticaria and 
maculopapular rash.

Participants will undergo continuous evaluation for adverse 
events during their participation in the trial supplemented by 
the use of physical exams.

Protocol includes individual participant stopping 
criteria, including: 

Any Grade 3 or higher rash or Grade 2 rash with 
evidence of systemic involvement

Any allergic or hypersensitivity reactions 

(see Section 7.1 for complete list of stopping criteria)


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Radiolabelled Investigational Product: [14C]-GSK3640254
Radioactivity exposure 
risk ([14C]-GSK3640254)
The total effective dose associated with IV and oral administrations of [14C]-
GSK3640254 is <1 mSv. 
The Period 1 dose is a microdose for which the associated radioactivity is less than the 
International Commission on Radiological Protection (ICRP, 1992) recommended 
threshold for clinical research projects with intermediate level of societal benefit. It is 
below the level identified as trivial risk by the ICRP, 1992 and below the maximum 
exposure threshold for the level of risk that is within variations of natural background 
radiation according to the World Health Organization (WHO, 1977)
See Appendix 6.
In Period 2, participants will be monitored for recovery of 
radioactivity.
Study Procedures
Local extravasation of 
intravenous microdose at 
the infusion site
GSK3640254 has not previously been administered by IV infusion in humans. 
In preclinical studies, no irritancy at site of injection was reported. 
Usual IV care will include flushing the IV before administration 
of the dose and monitoring for correct positioning of the IV. 
Participants will be monitored for signs of pain at the injection 
site. 
Entero-tracker for bile 
collection
Streaks of blood on the string due to local irritation have been infrequently noted. 
Gagging upon retrieval of the string can occur.
On a few occasions, an entire string has been swallowed without ill effects and passes 
out from the body in the feces.  
The string will be securely taped in place (to the cheek of each 
individual) during the collection time to minimise risk of 
swallowing the entire string.  


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2.3.2.
Benefit Assessment
The healthy participants will receive no clinical benefit for participation in this study.
2.3.3.
Overall Benefit: Risk Conclusion
Overall, the available data from non-clinical and clinical studies have not identified 
prohibitive risks associated with GSK3640254 at the exposures planned for this study.  
While there are a number of important potential risks identified for GSK3640254 and the 
study procedures, these can be addressed in this clinical trial with proper participant 
selection, close safety monitoring, and specific risk characterisation and mitigation.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine parent GSK3640254 and total drug-
related radioactivity systemic concentrations 
following a single IV microtracer dose of [14C]-
GSK3640254 (with an oral dose of non-radiolabelled 
GSK3640254) and oral dose of [14C]-GSK36402541

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of 
parent and total drug-related material (radioactivity) 
in plasma and blood.

Volume of distribution at steady state (Vss) and 
clearance (CL) of parent after IV dose (Period 1 
only).

Renal clearance of parent (CLr) after both IV and 
oral dose

Oral clearance (CL/F) and apparent volume of 
distribution (Vz/F) for the parent following oral 
administration

To calculate the absolute oral bioavailability of 
GSK3640254

Direct estimation of absolute oral bioavailability (F), 
indirect calculation of fraction of drug escaping first 
pass hepatic clearance (Fh), fraction absorbed (Fa)
and fraction of drug escaping gut metabolism (Fg)

To determine the rate and extent of excretion of total 
radioactivity in urine and feces and the total recovery 
of radioactivity, following IV and oral administration 
of [14C]-GSK3640254

Urinary and fecal cumulative excretion as a 
percentage of the total radioactive dose
Secondary

To evaluate the safety and tolerability of 
GSK3640254 after single IV and oral doses in 
healthy participants.

Characterize observed adverse events, and 
abnormal laboratory, 12-lead ECG, and vital signs 
assessments observed.

To determine the blood:plasma ratio of [14C]-
GSK3640254-related materials (total radioactivity) 
associated with blood cellular components  

Blood:plasma ratio of [14C]-GSK3640254-related 
materials (total radioactivity)


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Exploratory

To generate samples that will be used to 
characterize the metabolite profile of GSK3640254 
following a single IV microtracer dose of 
[14C]-GSK3640254 with an oral dose of non-
radiolabelled GSK3640254 (plasma, urine, feces, 
duodenal bile) and a single, oral dose of 
[14C]-GSK3640254 (plasma, urine and feces, 
duodenal bile).

Characterization and quantification of metabolites in 
plasma, urine, feces, and duodenal bile (qualitative 
identification in bile). These analytical investigations 
will be conducted, and the results reported under a 
separate GSK nonclinical protocol.

To evaluate the PK and relative bioavailability of 
GSK3640254 following administration of the 85 mg 
suspension compared to the 200 mg tablet

AUC(0-inf), AUC(0-t) and Cmax
AUC(0–inf): Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time, 
AUC(0–t): Area under the plasma concentration-time curve from time zero (pre-dose) to last time of quantifiable 
concentration within a participant across all treatments, Cmax: Maximum observed plasma concentration, tmax: time of 
occurrence of Cmax, t1/2: terminal phase half-life.
1 For measured concentrations of GSK3640254 in plasma, the nomenclature [14C]-GSK3640254 describes the parent 
GSK3640254 concentration derived via analysis by liquid chromatography (LC) + AMS, whereas GSK3640254
describes the parent GSK3640254 concentration derived via liquid chromatography-tandem mass spectrometry (LC-
MS/MS). 


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4.
STUDY DESIGN
4.1.
Overall Design
This is a single group, single center, [14C]-GSK3640254 mass balance study with a two-
period, single sequence, and no masking. 
This open-label, single-center, non-randomised, 2-period, single-sequence, mass balance 
study will enroll a cohort of 6 healthy male participants. The aim of the study is to assess 
the pharmacokinetics, balance/excretion, and metabolism of GSK3640254 using [14C]-
radiolabelled drug substance administered as an IV infusion of a microtracer dose with an 
oral tablet, non-radiolabelled dose (Treatment period 1) and a [14C]-radiolabelled drug 
substance administered orally (Treatment Period 2).
Four to six healthy participants are deemed sufficient. To minimise the number of 
exposed to radiation, participants who discontinue early will not be replaced unless the 
total number of participants who complete dosing and all critical assessments drops 
below 4.
Each participant will be involved in the study for up to 10 weeks.  He will have a 
screening visit, two treatment periods (Treatment Periods 1 and 2), separated by a 
washout period of at least 13 days between oral doses, and a follow-up visit 7 – 14 days
after the last assessment in Treatment Period 2.  During both treatment periods, 
participants will reside in the unit from the morning of Day -1 until all procedures are 
completed at 168 h post-dose (on Day 8).  Participants may be asked to stay for up to 1 
week longer in Treatment Period 2, if excretion of drug-related material takes longer than 
anticipated (see Figure 1). 
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety 
tests.  Blood will be sampled extensively on the day of dosing and daily until Day 8, for 
assessing the PK of GSK3640254 and metabolites.
4.1.1.
Screening Period
Participants must be screened within 30 days before the first dose of GSK3640254 and 
must meet all eligibility criteria.
Treatment Period 1 (oral tablets and 14C-intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant 
will take a single 200 mg oral dose (2 x 100 mg tablets) of GSK3640254 with a moderate
fat meal (approximately 600 calories with approximately 30% of calories from fat); the 
IV infusion of 100 µg of [14C]-GSK3640254 (approximately 3.7 kBq; 100 nCi) will 
begin 5 h after oral dose and continue over 1 h.  Blood samples, all voided urine, and 
feces will be collected continuously from Day 1 through Day 8, while duodenal bile will 
be collected as described below.  Participants will be discharged on study Day 8 after 
completion of the 168-h sample collection and other planned assessments and instructed 
to return to the clinic on Day -1 of Treatment Period 2. 


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A non-invasive device (Entero-tracker) to collect duodenal bile will be used in Treatment 
Period 1.  The bile string will be swallowed 2 h after the oral dose and 3 h before the IV 
infusion starts, a duration recommended to allow transit of the string to the duodenum.
Participants will fast from insertion of the bile string until the completion of the IV 
infusion, at which point a food cue (small standard high-fat meal) will be given to 
stimulate gall bladder emptying. The Entero-tracker will be removed about 1.5 h after the 
IV infusion stops (7.5 h after the oral dose).
4.1.2.
Treatment Period 2 (14C-oral suspension)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant 
will receive approximately 85 mg [14C]-GSK3640254 (approximately 3.15 MBq; 85 µCi)
as an oral suspension with a moderate fat meal (approximately 600 calories with 
approximately 30% of calories from fat). A non-invasive device (Entero-tracker) to 
collect duodenal bile will be used in Treatment Period 2.  The Entero-tracker will be 
swallowed 2 h after oral dose. At 5.5 h after the start of oral dose, a food cue (small 
standard high-fat meal) will be given to stimulate gall bladder emptying. The collection 
bile string will be removed 1.5 h post the food cue (7 h after the oral dose) to capture the 
duodenal bile samples expelled from the gall bladder. 
Blood, urine and fecal samples will be collected continuously from Day 1 through Day 8.
Radioactivity quantification using liquid scintillation counting (LSC) will be performed 
on each 24-h urine collection and each 24-h fecal homogenate.  Criteria for discharge for 
Period 2 are based on demonstrated cumulative recovery of radioactivity as outlined in 
Section 4.1.3. The inpatient stay may be extended by up to 7 days to meet the discharge 
criteria. In the unlikely event that excretion is still >1% in the 24-h collection period prior 
to discharge on Day 15, the participant will continue to collect fecal samples only, at 
home, at 24-h intervals.  Samples will be returned to the unit every 2 to 3 days for 
analysis.
4.1.3.
Demonstration of radioactivity recovery before discharge 
(Period 2) 
LSC radio-quantification results from samples collected for Days 1 through 6 (through 
144 h post-dose) will be reviewed on Day 8.  The GlaxoSmithKline (GSK) In vitro / In 
vivo Translation (IV/IVT) Study Monitor should be consulted to agree with release of a 
participant. This process is outlined in detail in the Study Reference Manual (SRM). 

If >90% of the administered radioactivity has been recovered from the Day 1-6 
samples, then the participant may be discharged on Day 8 after all scheduled 
assessments have been completed, including complete collection of Day 7 urine and 
feces samples (24 h collection period ending on Day 8). 

If ≤90% has been recovered, then the radio-quantification results will be re-evaluated 
on Day 9 with Day 7 results included. 
On Day 9, if >90% has been recovered or <1% of the dose has been excreted on both Day 
6 (120-144 h) and Day 7 (144-168 h), then the participant may be discharged on Day 9.    


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If the participant is not eligible for discharge on Day 9, or if the results are inconclusive,
the participant will remain at the unit. Urine and fecal collections will continue at 24-h 
intervals for up to 7 additional days (until the morning of Day 15).  Once <1% of the dose 
is recovered in 2 consecutive 24-h periods where samples are provided (and the samples 
were of sufficient size to make this assessment), or once >90% of the radioactivity has 
been recovered, the participant will be discharged.  
All remaining participants will be discharged from the unit no later than Day 15. In the 
unlikely event that excretion is still ≥1% in the 24-h collection period prior to discharge 
on Day 15, the participant will continue to collect fecal samples only, at home, over 24-h 
intervals.  Samples will be returned to the unit every 2 to 3 days for analysis.
4.1.4.
Follow-up
Follow-up procedures will be done 7-14 days after the participant’s last assessment in 
Treatment Period 2.  The follow-up period may be extended if:
(i)
radioactivity excretion is still higher than 1%;
(ii) a participant has an unresolved AE at the follow-up visit, which, in the opinion of 
the investigator, merits further follow-up; or
(iii) new information becomes available that supports an extended follow-up period.
The investigator and GSK IV/IVT Monitor and/or GSK Medical Monitor as appropriate 
will agree on the nature of the extended follow-up.  For example, participants may have a 
telephone follow-up at which they are asked about AEs, or participants may be asked to 
attend extra outpatient visits for additional monitoring of plasma radioactivity levels 
and/or for extra safety tests.  The extra safety tests might include tests that are not 
described in this protocol.  The investigator reserves the right, during or after the study, to 
repeat safety tests or to do any extra safety tests that are in the best interest of the 
participants.  Those extra tests may or may not be described in this protocol. 
4.2.
Scientific Rationale for Study Design
In the first treatment period of this study, an IV microtracer dose of [14C]-GSK3640254
will be infused over 1 h, beginning 5 h after an oral dose of non-radiolabelled 
GSK3640254 (tablets). The non-radiolabelled 200 mg dose of GSK3640254 is to ensure 
that the PK of the microdose represents a therapeutically relevant total body exposure to 
the drug. In the second treatment period, an 85 mg oral suspension of [14C]-GSK3640254
will be used for comparison.
Biliary elimination pathways will be characterised after the IV and oral doses by 
inclusion of duodenal bile collection in both Treatment Periods 1 and 2.  Complexities in 
human fecal sample analysis such as extraction, stability in the gastrointestinal tract, and 
endogenous contamination are minimised through assessment of the metabolite profile in 
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In order to characterize potential biliary elimination pathways, this study will also 
employ the Entero-Tracker for sampling of duodenal bile to conduct qualitative 
assessment of drug metabolites in this matrix.  The Entero-Tracker is based on a similar 
device, Entero-Test which has been shown to be an easy-to-use and minimally-invasive 
method for sampling bile from the duodenum (Guiney, 2011). The Entero-Tracker is a 
recent replacement device for Entero-Test that is an Food and Drug Administration
(FDA) 510k exempt device. Information on the biliary disposition of drug-related 
material derived in the current study may avoid the need for invasive methods of bile 
collection in future studies
Details of blood, bile, urine and fecal sample collection and processing, storage and 
shipping procedures are detailed in the SRM.
4.3.
Justification for Dose
Based on modelling and simulation of virology and PK data, coupled with an ongoing 
proof of concept (POC) study for GSK3640254 (208132) in HIV-infected participants, 
the currently projected therapeutic dose range to be investigated in Phase IIb is 50-200
mg once daily. The population PK model of GSK3640254, including parameter 
uncertainty, was integrated with the PK/Pharmacodynamic (PD) model of GSK3532795 
and the distribution of protein binding adjusted (PBA) EC90 values obtained with 
GSK3640254 from an in vitro experiment with 36 Gag/PR genotyped viruses (e.g. mean 
of 19.1 ng/mL with CV% of 33%). Further details of the findings in this study are 
provided in the IB.  
The 100 μg microtracer dose administered as a 1 h IV infusion in Treatment period 1 is 
projected (based on allometry and a conservative assumption of 15% oral bioavailability) 
to achieve a GSK3640254 Cmax ~3 ng/mL, which is >200-fold lower than the geometric 
mean Cmax following a single 200 mg dose in healthy participants (Study 207187) and 
>400 fold lower than the geometric mean Cmax following a single 200 mg dose in HIV-
infected patients. This dose can be categorised as a microdose and as such the required 
safety cover is detailed in International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) M3 (R2) (International 
Conference on Harmonisation, 2009.) In Treatment Period 2, the 14C labelled solution 
dose of GSK3640254 is 85 mg (85 uCi) which is partly based on practical limitations and 
is well within the target dose range to be evaluated in Phase IIb studies.
Preclinical toxicology species provide safety cover for systemic exposure to 
GSK3640254. Predicted steady-state exposures for a projected 200 mg QD maximum 
dose in Phase IIb are essentially equal to the no-observed adverse-effect-level (NOAEL) 
exposure in a 4-week oral toxicity study in rats, although no NOAEL was identified in 
dogs for GI intolerability and minimal effects of parietal cells following 4 weeks of 
dosing. However, in this single dose design absorption, distribution, metabolism, and 
excretion (ADME) study of very limited drug exposure these findings become less 
relevant. 
In vitro studies using hepatocytes from nonclinical species and humans show that there is 
generally no qualitative difference in metabolites formed. Preliminary non-radiolabelled 


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studies showed that GSK3640254 was the predominant drug-related component with low 
levels of oxidative metabolites in human plasma following repeat oral doses of 320 
mg/day (see IB, Section 1.1). 
4.3.1.
GSK3640254 Oral Dose (Treatment Periods 1 and 2)
The oral GSK3640254 dose is within the therapeutic range for the treatment of HIV. The 
200 mg dose is lower than the highest once-daily dose (320 mg QD) in the first time in 
human (FTIH) study 207187. In Study 207187 (single Ascending Dose [SAD]/ multiple 
Ascending Dose [MAD]), doses up to 200 mg QD for 14 days were well tolerated.
4.3.2.
GSK3640254 Intravenous Dose (Treatment Period 1)
The dose of [14C]-GSK3640254 to be administered intravenously is a microdose of 100 
μg, which will be infused over 1 h. A microdose was selected because GSK3640254 has 
not previously been administered by IV infusion to humans.  That dose level meets the 
criterion for a microdose, for the following reasons:
•
It is ≤ 100 µg.
•
It is ≤ 1/100th of the lowest predicted pharmacologically-active oral dose in HIV-
patients (i.e., 5 mg single, oral dose) based on a PK/PD model of GSK3532795 and 
the distribution of PBAEC90 obtained with GSK3640254 in in vitro experiment with 
36 Gag/PR genotyped viruses (e.g. mean of 19.1 ng/mL with CV% of 33%).
•
Predicted steady-state exposures for a higher 200 mg QD dose are essentially equal to 
the NOAEL exposure in a 4-week oral toxicity study in rats, although no NOAEL 
was identified in dogs for GI intolerability and minimal effects of parietal cells 
following 4 weeks of dosing. Predicted steady-state exposures over the proposed dose 
range along with fold cover to rat and dog lowest-observed-adverse-effect level 
(LOAEL) exposures, the lowest exposures where minimal, reversible effects on 
parietal and/or chief cells were identified.
To ensure clinically-relevant systemic exposure during the microdose, the IV infusion of 
[14C]-GSK3640254 will be administered with an oral non-radiolabelled dose of 200 mg 
GSK3640254. 
The 100 μg microtracer dose administered as a 1-h IV infusion is projected (based on 
allometry) to achieve a GSK3640254 Cmax ~3 ng/mL, which is >200-fold lower than the 
lowest observed geometric mean human Cmax following a 200 mg dose (Study 207187).
This dose can be categorised as a microdose and as such required safety cover is detailed 
in ICH M3 (R2).
4.3.3.
Radiolabel Dose
The effective dose of radiolabelled drug administered in human mass balance studies is 
calculated from data on the distribution and elimination of the radioactive drug from 
laboratory animals, considering the nature of the isotope, the route of administration, the 


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concentration of radioactivity in individual tissues/organs and the residence or 
elimination half-life of the radioactivity from those tissues/organs.
4.3.4.
Total Radiation Exposure
In this study, each participant will receive the following doses of radioactivity:
•
approximately 3.7 kBq (100 nCi) in Treatment Period 1.
•
approximately 3.15 MBq; (85 µCi) in Treatment Period 2.
The total amount of radiation exposure in the study is ~3.15 MBq; (~85.1 µCi). 
It is estimated that the combined total effective dose for the two treatment periods will be 
<1 mSv.  On this basis, the maximum administered activity would comply with the ICRP, 
1992 recommendation of a 1 mSv maximum for Category IIa projects (0.1 – 1 mSv ; 
minor risk), further details are in Appendix 6.
4.4.
End of Study Definition
A participant is considered to have completed the study if he has completed all phases of 
the study including the follow-up visit (end of study visit). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply: 
Age
1.
Participant must be 30 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, vital signs and ECG. A 
participant with a clinical abnormality or laboratory parameter (i.e. outside the 
reference range for the population being studied), which is not specifically listed in 
the eligibility criteria, may be included only if the investigator agrees and documents 
that the finding is unlikely to introduce additional risk factors and will not interfere 
with the study procedures.
3.
History of regular bowel movements (averaging one or more bowel movements per 
day).
4.
Non-smoker, or ex-smoker who hasn’t regularly smoked for the 6 months before 
screening.
Weight
5.
Body weight of 50 kg and above, and body mass index (BMI) within the range 19.0 
to 31.0 kg/m2 (inclusive).
Sex
6.
Male only.
Male participants are eligible to participate if they agree to the following during the 
study, including washout periods: 

Refrain from donating sperm

And Either: 
1) be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 


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abstinent
OR 
2) Agree to use a male condom when having penile-vaginal intercourse with a 
woman of childbearing potential unless vasectomised.
Informed Consent
7.
Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). Participants 
with a history of cholecystectomy must be excluded.
2. Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting 
a risk when taking the study intervention ; or interfering with the interpretation of 
data. 
3. Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history) clinical laboratory tests, or 12-lead ECG.
4. Current episode, recent history, or chronic history of diarrhoea. 
5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell 
or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
6. Any history of significant underlying psychiatric disorder, including, but not limited
to, schizophrenia, bipolar disorder with or without psychotic symptoms, other
psychotic disorders, or schizotypal (personality) disorder.
7. Any history of major depressive disorder with or without suicidal features, or anxiety
disorders that required medical intervention (pharmacologic or not) such as
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient
treatment. Participants with other conditions such as adjustment disorder or
dysthymia that have required shorter term medical therapy (<6 months) without
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the VH/GSK Medical


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Monitor.
8. Any pre-existing physical or other psychiatric condition (including alcohol or drug
abuse), which, in the opinion of the investigator (with or without psychiatric
evaluation), could interfere with the participant’s ability to comply with the dosing
schedule and protocol
9. Regular use of known drugs of abuse or history of drug abuse or dependence within 6 
months of the study.
10. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a glass 
(~240 mL) of beer, 1 small glass (~100 mL) of wine or 1 (~25 mL) measure of spirits.
11. History of or regular use of tobacco- or nicotine-containing products in the 3 months 
prior to screening. 
12. 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.
13. QTcF >450 msec
NOTES:
The QTc must be the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF).
For purposes of data analysis, QTcF will be used as specified in the Reporting and 
Analysis Plan (RAP).
14. At Screening or prior to the first dose, a supine blood pressure (BP) that is 
persistently higher than 140/90 mmHg.
15. At Screening or prior to the first dose, a supine mean heart rate (HR) outside the 
range of 50–100 bpm. A heart rate from 100 to 110 bpm can be rechecked by 
electrocardiogram or vital signs within 30 minutes to verify eligibility.
16. 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 (WHO 
definitions Section 10.9.3.2)
Prior / Concomitant Therapy
17. Past or intended use of over-the-counter or prescription medication, including 
analgesics (eg, paracetamol), herbal medications, or grapefruit and Seville orange 
juices within 14 days prior to the first dose of study intervention until completion of 
the follow-up visit unless approved by the Investigator in conjunction with a ViiV 
Healthcare (VH)/GSK Medical monitor. 
18. Treatment with any vaccine within 30 days prior to receiving study intervention.


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Prior / Concurrent Clinical Study Experience
19. Current enrolment in a clinical trial; recent participation in a clinical trial and has 
received an investigational product within 3 months before the first dose in the 
current study. 
20. Exposure to more than 4 new chemical entities within 12 months before the first dose 
in the current study.
21. Participation in a clinical trial involving administration of 14C-labelled compound(s) 
within the last 12 months.  A participant’s previous effective dose will be reviewed 
by the medical investigator to ensure there is no risk of contamination/carryover into 
the current study.
22. Received a total body radiation dose of greater than 10.0 mSv (upper limit of IRCP
category II) or exposure to significant radiation (e.g., serial x-ray or computed 
tomography [CT] scans, barium meal, etc.) in the 3 years before this study.
Diagnostics Assessments
23. Alanine transaminase (ALT) ≥1.5x upper limit of normal (ULN). A single repeat of 
ALT is allowed within a single Screening period to determine eligibility.
24. Bilirubin ≥1.5xULN (isolated bilirubin ≥1.5xULN 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.
25. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening or within 3 months before the first dose of study 
intervention AND positive on reflex to hepatitis C ribonucleic acid (RNA).
26. Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
27. Any positive (abnormal) response confirmed by the investigator or qualified 
designee-administered C-SSRS.
28. Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine 
phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides), 
and ALT (described above), will exclude a participant from the study unless the 
investigator can provide a compelling explanation for the laboratory result(s) and has 
the assent of the sponsor. A single repeat of any laboratory abnormality (other than a 
viral screening test for HIV-1/2, hepatitis B Virus [HBV], or hepatitis C Virus
[HCV]) is allowed within a single Screening period to determine eligibility.
29. Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the 
past 3 months, symptomatic bradycardia, non-sustained or sustained atrial 
arrhythmias, non-sustained or sustained ventricular tachycardia, second-degree 
atrioventricular block Mobitz Type II, third-degree atrioventricular block, complete 
heart block, orconduction abnormality) which, in the opinion of the investigator or 
VH/GSK Medical Monitor, will interfere with the safety for the individual 


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participant. Any acute laboratory abnormality at Screening which, in the opinion of 
the investigator, should preclude participation in the study of an investigational 
compound. 
OTHER EXCLUSIONS
30. Has had an occupation which requires monitoring for radiation exposure, nuclear 
medicine procedures, or excessive x-rays within the past 3 years. 
31. Loss of more than 400 mL blood during the 3 months before screening, eg as a blood 
donor, or plan to donate blood or blood products in the 3 months after the end of the 
trial.
32. Unwillingness or inability to follow the procedures outlines in the protocol, including 
the use of the string bile collection device. 
33. History of sensitivity to GSK3640254, or their components thereof, or a history of 
drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, 
contraindicates their participation. 
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
In both Treatment Periods, participants will be required to take their oral dose of 
GSK3640254 with a moderate fat meal (approximately 600 calories with approximately 
30% of calories from fat). The meal will be given 30 minutes before dosing and must be 
consumed within 25 minutes.
In Treatment Period 1, participants will be required to fast from insertion of the bile 
string until the completion of the IV infusion, a period of approximately 4 hours. In 
Treatment Period 2, participants will also be required to fast from insertion of the bile 
string until 5.5 hours post dose. 
In both treatment periods at the times defined in the SoA a standard, small high-fat meal 
will be provided. Meal times are specified in both treatment periods for Day 1, on all 
other days, meals will be served at the standard times of the clinical site.
Participants will refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or their fruit juices from 7 days 
before the start of study intervention until the follow-up visit. 
During the inpatient stays, participants will refrain from consumption of nuts and seeds, 
or other foods that may cause issues with homogenization of feces. Peas must not be 
consumed from Day -1 until 48 hours after each oral dose in both treatment periods (to
avoid potential complications with retrieval of the steel ball from the bile string device 
prior to sample homogenization).
No water is allowed until 2 h after oral dosing (apart from rinsing the oral suspension
dose of [14C]-GSK3640254); water is allowed ad libitum at all other times.


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Adequate hydration should be encouraged to help facilitate stool sample production.  If 
needed, participants may consume prunes or prune juice to facilitate stool samples.
5.3.2.
Caffeine, Alcohol, and Tobacco
Participants will abstain from alcohol for 24 h before the screening visit until the follow-
up visit.
Participants must not be current smokers (no smoking for at least 6 months before the 
screening visit). Use of tobacco- or nicotine-containing products (including nicotine 
patches and other delivery devices such as vaporizers) will not be allowed from screening 
until after the final follow-up visit.
5.3.3.
Activity
Participants will abstain from strenuous exercise for 24 hours before each blood
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.


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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 (see Table 4).
6.1.
Study Intervention(s) Administered
Detailed instructions for dosing will be provided in the SRM.
Table 4
Treatments administered during the study
Study Intervention 
Name:
[14C]-GSK3640254 IV 
Solution-for-Infusion
[14C]-GSK3640254
Oral Powder-in-Bottle
GSK3640254 Oral 
Tablet
Dosage formulation:
IV solution
Powder-in-bottle
Oral tablet
Treatment Period
1
2
1
Unit dose strengths:
Strength:  10 µg/mL
Dosage Level: 100 µg
Strength:  85 mg
Dosage Level: 85 mg
Strength: 2 x 100 mg 
tablet
Dosage Level: 200 mg
Route of 
Administration:
IV infusion
Oral
Oral
Dosing instructions:
Administer 10 mL 
intravenously over 1 h.
Administer total 85 mg 
dose (reconstituted into 
a suspension using 25
mL vehicle just before 
dosing) with meal in the 
morning.  
Two tablets taken with 
meal in the morning 
with 240 mL of room 
temperature water
Manufacturer:
Drug product:  
Hammersmith 
Medicines Research
(HMR)
Drug product:  HMR
GSK Ware, UK
Physical Description:
A clear, colourless 
solution free from 
visible particulates
White powder (white to 
slightly coloured for the 
reconstituted 
suspension)
White, round shaped, 
film coated tablets 
containing no markings
6.2.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.


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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).
A description of the methods and materials required for preparation of 
[14C]-GSK3640254 solutions for IV infusion and oral administration is provided in the 
Technical Agreement (TA). A Quality Agreement will be in place with the contract 
research organization (CRO) performing the manufacturing operations. 
Further guidance and information for the final disposition of unused study intervention 
are provided in the TA. 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
Dose administrators must follow site-specific procedures for handling radiolabelled 
GSK3640254. 
6.3.
Measures to Minimize Bias: Randomization and Blinding

This is an open-label study with no randomization and no blinding of participants, site 
personnel, or sponsor personnel. 

Eligibility will be established during the Screening Period. A cohort of six 
participants will be admitted to the clinical research unit on the same day and will 
complete Period 1 and Period 2 on the same schedule with the same study 
interventions. This approach minimizes potential bias associated with temporal 
effects. 
6.4.
Study Intervention Compliance
Individual doses will be prepared for each participant from a bulk supply and will be 
confirmed by a second member of the study site staff. 
All participants will receive their doses 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 and reported in the case report form (CRF).  The dose 
of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.  For oral doses, study site personnel will examine each participant’s mouth 
to ensure that the study intervention was ingested. For IV doses, administration will be 
documented in the source documents and reported in the CRF.


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6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment must be discontinued by 15 days before the start of the study intervention. 
These must be recorded along with:

reason for use

dates of administration, including start and end dates

dosage information, including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription and non-prescription drugs (including 
vitamins and dietary and herbal supplements) within 14 days before the start of study 
intervention until completion of the follow-up visit unless approved by the Investigator in 
conjunction with a VH/GSK Medical monitor.
Special warnings and precautions for use of GSK3640254 are given in the IB, Section 6. 
6.6.
Dose Modification
No dose modification is allowed. 
6.7.
Intervention after the End of the Study
Participants will not receive any additional study intervention from GSK after completion 
of the study because only healthy participants are eligible for study participation. 


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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Study intervention will be discontinued and be discontinued from the study for a 
participant if liver chemistry stopping criteria are met:
Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7: Liver Safety: Required Actions and Follow-up Assessments.
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.2.
QTc Stopping Criteria
The same correction formula (QTcF) must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled. 

The ECG taken on Day –1 of each treatment period will be a single reading to 
confirm eligibility. In each study period, the Day 1 pre-dose timepoint will have 
triplicate averaged QTcF (over a brief approximately 5 to 10 minute recording 


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period). This pre-dose triplicate averaged QTcF value will serve as the baseline 
for each applicable study period. 

An enrolled participant that develops an on-treatment QTcF >500 ms or an 
increase from Baseline QTcF >60 ms should have two repeat unscheduled ECGs 
within 10 minutes. Using these triplicate ECGs, if the average QTcF>500 ms or 
an increase from Baseline QTcF >60 ms, the participant will be withdrawn from 
the study. Finally, this participant should have repeated unscheduled ECGs until 
their QTcF measurement returns to their original averaged QTcF value at Day 1 
pre-dose. 
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed. 
7.1.3.
Individual Participant Laboratory Abnormality and AE Stopping 
Criteria
A participant must permanently discontinue study intervention and be discontinued from 
the study for the pre-specified reasons below. Please refer to Section 8.2.5 and Section
8.2.6 for details on suicidal risk and GI toxicity monitoring, respectively. 

Severe pain, redness, bleeding or swelling at the infusion site.

Liver chemistry abnormalities exceeding the threshold criteria (see Section 7.1.1).

QTc result meeting the stopping criteria (see Section 7.1.2)

SAE considered related to study intervention  

Any clinically significant AE deemed to require discontinuation of study 
intervention

Any Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement 

Any allergic or hypersensitivity reactions to either formulation 

Any Grade 3 or higher psychiatric AE 

New onset suicidal ideation 

Any Grade 3 or higher AE related to study intervention 

Any Grade 4 AE or laboratory abnormalities (with the exception of an 
asymptomatic Grade 4 cholesterol, CPK, or triglyceride) 
7.1.4.
Columbia-Suicide Severity Rating Scale Criteria
Emergence of any positive (abnormal) response confirmed by the investigator on a
clinician (or qualified designee) administered C-SSRS during the treatment phase of the
study, the participant will undergo immediate clinical assessment of suicidality (by the 
investigator or a consulting psychiatrist). Emergence of new onset suicidal ideation or a 


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Grade 3 or higher psychiatric AE will result in immediate discontinuation and urgent 
specialist psychiatric evaluation and management. 
Refer to the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. See Section 8.2.5 for 
more details.
7.1.5.
COVID-19
A participant must permanently discontinue study intervention and be discontinued from 
the study if they have COVID infection as clinically determined by the investigator 
(suspect, probable, or confirmed using the most recent version of the WHO case 
definition) or by laboratory testing. 
7.1.6.
Other study stopping criteria
The study will be halted if there is a SAE or 2 severe AEs, considered to be related to the 
investigational medicinal product (IMP). If following an internal safety review, it is 
appropriate to restart the trial, a substantial amendment will be submitted to the 
Medicines and Healthcare Regulatory Authority (MHRA) and Research Ethics 
Committee (REC). The trial will not restart until the amendment has been approved by 
the MHRA and REC.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance or administrative reasons. If study intervention is permanently discontinued, 
the participant will remain in the study for confirmation of excretion of radioactivity (see 
Section 4.1.3). Participants who withdraw from the study early should undergo an early 
withdrawal visit as defined in the SoA.
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 may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
The investigator will record in the source documents the results of follow-up examination 
of withdrawn participants, if the participant gives their consent.  
In the event of vomiting directly after oral dosing withdrawal may be considered. Refer 
to Section 8.5.4 for details. 
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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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 will be considered to have 
withdrawn from the study. 


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8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the GSK Medical Monitor
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 and 
obtained before signing the ICF may be utilized for screening purposes provided 
the procedure met the protocol-specified criteria and was performed within the 
time frame defined in the SoA.

The timing and number of planned study assessments, including safety, and 
pharmacokinetic assessments may be altered during the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.

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 600 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1.
Efficacy Assessments
Efficacy of GSK3640254 as a treatment for HIV or any other indication is not assessed in 
this study. 
8.2.
Safety Assessments
Safety assessments include AEs, SAEs, ECGs, vital signs, and clinical laboratory tests. 
Planned time points for all safety assessments are provided in the SoA.


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Baseline is defined as the value for clinical laboratory, ECG, VS, and physical exam 
results that is collected closest to but before the first dose on Day 1 in each Treatment 
Period.
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the eyes, 
skin, joints, and the cardiovascular, respiratory, gastrointestinal and neurological 
systems.  Height and weight will also be measured and recorded, and BMI 
calculated and recorded. 

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). Weight will also be 
measured and recorded. 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Blood pressure, pulse, respiratory rate and temperature will be assessed.

Vital signs will be measured in a resting position after 5 minutes rest. Single 
measurements will be obtained for all parameters. Repeats can be obtained if the 
original reading cannot be interpreted. 

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
8.2.3.
Electrocardiograms

ECG measurements will be obtained as outlined in the SoA. Full 12 lead ECGs will 
be recorded with the participant in a resting position after 5 minutes rest.  Heart rate, 
PR interval, QRS duration, and QT (uncorrected) interval will be measured.  QTcF 
will be calculated (machine read or manually).

At each time point at which ECGs are required, single ECG measurements are 
appropriate with the exception of the following: a) Day 1 pre-dose ECGs for each 
treatment period will be performed in triplicate and b) two additional ECGs are 
required if the initial ECG measurement indicates prolonged QTc (i.e., QTcF >500 
msec) using the automated or manually calculated QTcF value.  The average QTcF 
value of all three ECGs will be used to determine eligibility.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2:  Clinical Laboratory Tests for the list of clinical laboratory tests 
to be performed and to the SoA for the timing and frequency.


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
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF.  The laboratory reports must be filed with the source documents.

All laboratory tests with values considered clinically-significantly abnormal during 
participation in the study or within 14 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 GSK Medical Monitor.

If such values do not return to normal/baseline within a period judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified. 

All protocol-required laboratory assessments, as defined in Appendix 2:  Clinical 
Laboratory Tests must be conducted in accordance with the local laboratory manual 
and the SoA.
8.2.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms
GSK3640254 is not a central nervous system active drug nor is it being developed for a 
neurologic or psychiatric condition. However, given the risk of suicidal ideation 
identified with previous MI GSK3532795, all participants will undergo screening using 
the C-SSRS administered by a clinician (or qualified designee); any positive (abnormal) 
response confirmed by the investigator, will exclude them from participating. A repeat 
assessment will be done during the treatment phase of the study. In case of positive 
(abnormal) response confirmed by the investigator, the participant will 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 Grade 1 or 2 psychiatric AE: A Grade 1 or 2 psychiatric AE may result in 
additional unscheduled visits (in-clinic or at home) as clinically indicated. This may 
include a more in-depth assessment of AE through interview, additional unscheduled 
clinical labs, and/or imaging. Psychiatric consultation may be required at the 
discretion of the investigator. Any pharmacotherapy should be discussed with the 
medical monitor. 

Any Grade 3 or 4 psychiatric AE: As described in Section 7.1.3, a Grade 3 or 4 
psychiatric AE will result in discontinuation from the trial and emergency psychiatric 
evaluation (including potential hospitalization and pharmacotherapy as indicated). 


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8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan 
Preclinical toxicology studies in rats and dogs have suggested a potential for GI-related 
toxicity with GSK3640254. This section provides general guidance to the investigator on 
the evaluation and management of primarily upper GI symptoms (Table 5). The 
investigator may contact the VH/GSK Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the study. 
Table 5
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the 
foundation of proper evaluation and management. The 
following are potential manifestations of some GI clinical 
syndromes that may occur (possibly in combination) during the 
clinical trial. 
Nausea and 
Vomiting
The investigator should attempt to identify the etiology of these 
symptoms (and whether it is intraperitoneal, extraperitoneal, 
medication related, infection related, or due to a metabolic disorder
(Hasler, 2012). Medications can cause nausea and vomiting 
acutely. 
Dyspepsia
The Investigator should identify the presence of red flags 
(odynophagia, unexplained weight loss, recurrent vomiting, GI 
bleeding, jaundice, palpable mass or adenopathy, or family history 
of GI malignancy). Symptoms of dyspepsia could include early 
satiety, bloating, or belching. Additionally, atypical symptoms of 
dyspepsia could include: pharyngitis, asthma, bronchitis, 
hoarseness, chest pain, or abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially 
encountered in the clinical trial are available elsewhere (Rome 
Foundation, 2014).
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained 
from the history (Hasler, 2012). Acutely, the investigator may 
assess for signs of intravascular volume depletion 
(eg, orthostasis) and/or aspiration of vomitus as appropriate. 
Abdominal tenderness and guarding may indicate 
inflammation. The presence of fecal blood can indicate mucosal 
damage (eg, from an ulcer). Complete evaluation of dyspepsia 
should include an oral examination (poor dentition or 
pharyngeal erythema) and lungs for wheezing. 


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DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a participant with 
upper GI symptoms is to quickly arrive at a final diagnosis 
without exposing the participant to unnecessary (invasive) 
testing; Investigators should exercise good clinical judgment in 
this regard (Soll, 2009). A major goal of therapy is directed at 
correcting the underlying identifiable medical or surgical 
abnormalities. Consultation (eg, gastroenterologist) is 
recommended as clinically indicated.
Grade 1 symptoms
Participants may be treated symptomatically. If participants
develop dyspepsia alone, generally only limited and direct 
diagnostic testing should be performed. If the participant has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, 
and eating directly before bedtime. 
Grade 2 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):
Serum chemistries and assessment of hemoglobin if not recently 
performed. 
Testing for Helicobacter pylori
Polymerase chain reaction (PCR) for viruses (eg, Cytomegalovirus
[CMV])
For participants who are infected with H. pylori discontinuation 
from the trial is necessary. Management should be targeted at 
addressing the underlying pathology.
Grade 3 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):

The testing outlined above in Grade 2

A barium swallow 

CT scan to identify gastrointestinal inflammation 

Upper endoscopy with biopsy as indicated (eg, mucosal injury
or the presence of red flags).
Management should be targeted at addressing the underlying 
pathology.


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Grade 4 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series
Initial management can include correction of hemodynamic and 
electrolyte abnormalities as clinically indicated. After stabilization, 
management should be targeted at addressing the underlying 
pathology.
a.
A Grade 4 or related Grade 3 AE: the Investigator will discontinue the participant from the study and perform an
evaluation/management plan incorporating elements above.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3: Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting
As described in Section 10.4, intensity of AEs (and lab abnormalities) will be graded 
using the division of acquired immunodeficiency syndrome (DAIDS) Grading table.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study.
See Section 10.9.3.2 for the assessment and capture 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 informed consent form start of
study intervention until the follow-up visit at the time points specified in the SoA.

All AEs will be collected from start of study intervention until the follow-up visit at
the time points specified in the SoA.

Medical occurrences that begin before the start of study intervention but after
obtaining informed consent will be recorded on the Medical History/Current Medical
Conditions section of the CRF, not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately and
under no circumstance should this exceed 24 h, as indicated in Appendix 3: Adverse
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting. The investigator will submit any updated SAE data to the sponsor within
24 h of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion of
study participation. However, if the investigator learns of any SAE, including a


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death, at any time after a participant has been discharged from the study, and he 
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 3: 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
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 the 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, IRB/IEC, and investigators.

Investigator safety reports must be prepared for Suspected Unexpected Serious 
Adverse Reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary. 

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention and until the participant’s final visit.


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
If a pregnancy is reported, the investigator should inform GSK within 24 h of
learning of the pregnancy and should follow the procedures outlined in Appendix 5: 
Contraceptive Guidance and Collection of Pregnancy Information

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than 700 mg within a 24-hour period 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose as there is no specific 
antidote for GSK3640254.  In the event of a suspected overdose, it is recommended that 
the appropriate supportive clinical care should be instituted, as dictated by the 
participant’s clinical status.
In the event of an overdose, the investigator should:
1. Contact the GSK Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities as agreed 
with the Medical Monitor on a case-by-case basis.
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or discontinuation will be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical 
evaluation of the participant.
8.5.
Pharmacokinetics
Pharmacokinetics will be assessed in whole blood, plasma, urine, and faeces.  Samples 
collected as part of this study for metabolite profiling will be analysed under a separate 
non-clinical protocol. The results of those analyses will be reported separately.  
8.5.1.
Plasma Sample Collection
Blood samples will be collected at timepoints specified in the SoA for measurement of 
each of the following: 

blood and plasma total radioactivity

plasma [14C]-GSK3640254

plasma concentrations of GSK3640254

plasma metabolite profiling. 


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The actual date and time of each blood sample collection will be recorded.  
Details of PK blood sample collection, including the volumes to be collected, processing, 
storage and shipping procedures are provided in the SRM. 
Samples will be stored for no longer than 15 years after the end of the trial.
8.5.2.
Urine Sample Collection
Urine samples will be collected over the time periods specified in the SoA. Urine samples 
will be used to determine total radioactivity excreted in urine and for subsequent 
metabolite profiling (to be analysed under a separate protocol). 
All participants will be asked to void their bladders before study intervention 
administration.  A blank (pre-dose) urine sample will be collected pre-dose (up to 3.5 h 
before oral dosing) in Treatment Periods 1 and 2. After oral dosing, in each Treatment 
Period, urine will be collected over 24 h collection periods as follows: 0-24 h, 24-48 h, 48 
– 72 h, 72 – 96 h, 96 – 120 h, 120-144 h, 144-168 h. Further details of urine sample 
collection, processing, storage and shipping procedures are provided in the SRM.
8.5.3.
Fecal Sample Collection
Fecal samples will be collected over the time periods specified in the SoA. Fecal samples 
will be used to determine total radioactivity excreted in feces and for subsequent 
metabolite profiling (to be conducted in a separate study).  A fecal sample will be 
collected from each participant before dosing in Treatment Periods 1 and 2 (the pre-dose 
sample can be collected up to 48 h before oral dosing). After oral dosing, in each 
Treatment Period, faeces will be collected over 24 h collection periods as follows: 0-24 h, 
24 – 48 h, 48 – 72 h, 72 – 96 h, 96 – 120 h, 120-144 h, 144-168 h. Further details of fecal 
sample collection, processing, storage and shipping procedures are provided in the SRM.
8.5.4.
Vomitus collection (if occurs)
Any episodes of vomiting should be recorded in the CRF as an adverse event.
If a participant vomits within the first 4 h after oral dosing, the participant will be 
considered unsuitable for evaluation and will be withdrawn from the study. Even if 
withdrawn, participants should remain in the clinic and samples collected until the 
discharge criteria outlined in Section 4.1.3 are met. Should the participant vomit after the 
first 4 h post oral dosing, the participant will not be withdrawn. 
If a participant vomits any time during or after IV dosing, the participant will not be 
withdrawn.
As practical, the vomitus will be collected and the amount of radioactivity present in the 
vomitus estimated, using the sample handling procedure described for quantifying 
radioactivity in stools. During dosing, staff should ensure that each participant has a 
suitable pre-weighed plastic collection vessel available for that purpose.


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8.5.5.
Bile Sample Collection
Bile samples will be collected via a non-invasive string device (Entero-tracker) in both 
Treatment Periods 1 and 2, as specified in the SoA.  The samples obtained will be used to 
investigate potential biliary metabolites in a separate GSK study. 
The string device comprises a gelatine capsule which contains either 90 cm or 140 cm of 
nylon string attached to a small steel weight.  One end of the string is attached to the 
outside of the mouth before swallowing the capsule, so that it can be retrieved at the end 
of the bile collection procedure.  The gelatine capsule dissolves in the stomach whilst the 
string and weight continue to the duodenum via peristalsis. 
In Treatment Period 1, the bile string will be swallowed at approximately 2 h post oral 
dose and 3 h before the IV infusion starts, a duration recommended to allow transit of the 
string to the duodenum. At 6 h post oral dose and upon completion of the IV infusion, a 
small moderate fat meal acting as a food cue will be used to stimulate gall bladder 
emptying. The bile string will be removed about 1.5 h after the IV infusion stops (7.5 h
after the oral dose).
In Treatment Period 2, the bile string will be swallowed at 2 h post oral dose. A food cue 
will be used to stimulate gall bladder emptying at 5.5 h after the oral dose, and the string 
will be withdrawn 7 h post dose. 
On withdrawal of the string through the mouth the steel weight separates from the string 
at the pyloric sphincter and is excreted in the feces. Once the string has been removed 
from the participant it will be frozen and shipped for metabolite profiling (to be 
conducted in a separate study).  Full details of the bile sample collection, processing, 
storage and shipping procedures are provided in the SRM.
8.5.6.
Sample Analysis
Total radioactivity measurements in urine samples and fecal homogenates will be 
determined by LSC and/or by AMS.  Total radioactivity measurements from plasma 
derived from blood will be analysed, as appropriate, by AMS in Treatment Period 1 and 
by LSC and/or by AMS, for Treatment Period 2, as detailed in the SRM.
[14C]-GSK3640254 and GSK3640254 plasma concentrations will be analysed, as 
appropriate, as detailed in the SRM.
Aliquots of plasma, urine, fecal homogenates and duodenal bile will be provided for 
metabolite analysis.  Metabolite analysis will be performed and reported separately, 
under a separate nonclinical GSK study.
Analysis of all samples (plasma, urine, feces, and duodenal bile) will be performed under 
the control of DMPK and Bioanalysis, Immunogenicity and Biomarkers (BIB), GSK, the 
details of which will be included in the SRM. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).


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8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetic samples will not be taken in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessment
Immunogenicity will not be assessed in this study.
8.10.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.


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9.
STATISTICAL CONSIDERATIONS
Final analyses will be performed after the completion of the study and final dataset 
authorization. 
9.1.
Statistical Hypotheses
This study is not designed for statistical testing and therefore has no formal statistical 
hypothesis. 
9.2.
Sample Size Determination
No formal sample size calculation has been performed for this study. However, the 
sample size reflects an accepted industry standard for human ADME studies using 14C-
radiolabelled drug. Additionally, the design of the study in terms of the concomitant 
administration of intravenous with oral administration (Period 1) inherently reduces 
variability in the parameters determined, versus a cross-over design for absolute 
bioavailability assessment, while enabling cross-over to Period 2 in the same participants.
The primary objective of the study is to gain a better understanding of the compound’s 
pharmacokinetic, excretory, and metabolic profile and 4 to 6 participants are deemed 
sufficient for this purpose.  Six participants will be enrolled into the study.  To minimise 
the number of participants exposed to radiation, those participants that discontinue early 
will not be replaced unless the total number of participants who complete both Periods 1 
and 2 drops below 4.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Screened Population
All participants who were screened for 
eligibility.  This will be the population for 
reporting screened population data.
Safety Population
All participants who take at least 1 dose of 
study intervention.  Participants will be 
analysed according to the treatment they 
received.  This will be the population for 
reporting safety and study population 
data.
Pharmacokinetic Population
All participants in the Safety population 
who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values).


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9.4.
Statistical Analyses
Details of the planned statistical reporting will be described in the RAP. 
9.4.1.
Efficacy Analyses
This is not applicable. 
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular format and summarized descriptively according to GSK’s Integrated 
Data Standards Library (IDSL).  Further details will be given in the RAP. 
9.4.3.
Pharmacokinetic Analyses
Plasma GSK3640254 concentration-time data will be listed for each participant and 
summarised by treatment and planned sampling time.  [14C]-GSK3640254 and 
radioactivity concentrations in whole blood and plasma will be reported similarly.  
Individual participant, mean and median plasma GSK3640254, [14C]-GSK3640254, and 
total radioactivity concentration–time profiles will be plotted for each treatment on both a 
linear and semi-log scale.
Pharmacokinetic analysis will be performed by or under the direct auspices of Clinical 
Pharmacology Modelling & Simulation, GSK.  Plasma GSK3640254, [14C]-
GSK3640254, and total radioactivity concentration–time data will be analysed by non-
compartmental methods with WinNonlin Version 6.3 or above.  Calculations will be 
based on the actual sampling times recorded during the study.  From the plasma 
concentration-time data the following pharmacokinetic parameters will be determined, 
for GSK3640254, [14C]-GSK3640254, and total radioactivity (whole blood and plasma)
as data permits: maximum observed plasma  concentration (Cmax), time to Cmax (tmax), 
AUC(0–t) and AUC(0-inf), terminal phase rate constant (λz), and apparent terminal phase 
half-life (t1/2) following oral and IV dosing.  Additionally, Vss, CLr, and CL will be 
derived following IV dosing and CL/F and Vz/F will be derived following oral dosing.  
These parameters will be summarised descriptively. 
Absolute bioavailability will be estimated for oral dose for each participant and will be 
summarized.
Derivation of the urine and fecal radioactivity parameters will be through support 
provided by CRO partners.  The following radioactivity parameters will be determined 
from the urine and fecal radiolabelled drug-related material (total radioactivity) data, and 
will be listed and summarised by treatment:

Percentage excreted in urine (Fe%[urine]) within each collection period and 
cumulative urinary recovery and fraction excreted over the total collection period.

Percentage excreted in feces (Fe%[fecal]) with each collection period and 
cumulative fecal recovery and fraction excreted over the total collection period 
and cumulatively over the collection period.


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
Total excretion (sum of urine and fecal excretion), Fe% [total] will be calculated 
by collection interval for each participant. 
The urine, fecal and total radioactivity parameters will be listed, summarised and plotted, 
as appropriate.
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.  Production of the summaries, listings and figures of the plasma, 
urine and feces data will be performed under the direct auspices of Clinical Statistics, 
GSK. 
Further details regarding the tables, figures and listings to be produced for the study 
report will be given in the RAP.
9.5.
Metabolite profiling
The metabolic profiling/structural characterisation aspect of this work will be performed 
by GSK (or a GSK representative) and CRO partners in a separate nonclinical study and 
reported separately.
9.6.
Interim Analyses
No interim analyses will be performed. 
9.7.
Other Analyses
Special statistical and data analysis considerations may be warranted in the event that the 
COVID-19 or related epidemics or natural disasters may affect the study and data 
integrity. To the extent possible, these will be described in the main study SAP; 
alternatively, a separate SAP focussing on modified data handling rules and analyses may 
be prepared, taking into account applicable regulatory guidance and industry best 
practices for handling such situations [DHHS, 2020; EMA, 2020a; EMA, 2020b].


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations.
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 


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
Participants must be informed that their participation is voluntary. will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location. 

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate.

The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with GSK Policy.

GSK intends to make anonymized participant-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 


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by trial participants are used to maximum effect in the creation of knowledge and 
understanding. 
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).

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 (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 

Quality tolerance limits (QTLs) will be pre-defined in the QTL report to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These pre-defined parameters will be monitored during the study and deviations from 
the QTLs and remedial actions taken will be summarized in the clinical study report.


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10.1.7.
Source Documents

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

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.

Definition of what constitutes source data can be found in the SRM. 
10.1.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. The study site will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9.
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.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.2.
Appendix 2:  Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by the local laboratory. 

The requirement for fasting before laboratory sample collection will be determined 
by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
mean 
corpuscular 
volume (MCV),
mean 
corpuscular 
hemoglobin
(MCH)
Absolute and % 
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
red blood cell (RBC)
Count
Hemoglobin
Haematocrit
Clinical Chemistry1
Urea
Creatinine
Uric acid
Fasting glucose
Total cholesterol
Low density lipoprotein 
(LDL) cholesterol,
High density lipoprotein 
(HDL cholesterol)
Triglycerides
Potassium
Sodium
Chloride
Calcium
Phosphate
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic-
Oxaloacetic 
Transaminase (SGOT),
ALT/ Serum Glutamic-
Pyruvic Transaminase
(SGPT)
Alkaline phosphatase
Total and 
direct bilirubin
Total Protein
Albumin
Globulin
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if leukocyte esterase, nitrites, blood or protein is 
abnormal)
Screening only Tests

Alcohol breath test, urine cotinine test

Carbon Monoxide (CO) breath test

Drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)

Serology (HIV antigen/antibody immunoassay, HBsAg, and hepatitis C virus 
antibody with reflexive HCV RNA)
NOTES:
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Appendix 7. 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. 


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


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10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent 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, diarrhoea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
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
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records 
before submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the DAIDS grading table (See Section 10.4).
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 IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he 
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 


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minimal information to include in the initial report to 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 GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by 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 GSK with a copy of any post-
mortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to 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 of 
review and verification of the relationship of each SAE to IP/study participation 
(causality) within 72 hours of each SAE being reported.

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 or SAE coordinator by 


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telephone.

Contacts for SAE reporting can be found in the SRM. 
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor or the SAE coordinator.

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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10.4.
Appendix 4: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Correct Version 2.1, 
July 2017
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the hyperlink here to the U.S, 2017 Grading Table.
Alternatively, paste this into your browser: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
The PI/SI may contact the VH Medical Monitor with questions on estimating the severity 
grade for parameters not identified in the original table.
All deaths related to an AE are to be classified as Grade 5.


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10.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
10.5.1.
Collection of Pregnancy Information:
For male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male 
participant’s female partner of a male study participant who becomes pregnant 
while participating in this study. This applies only to male participants who 
receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure. 


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10.6.
Appendix 6:  An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study 
intervention


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PPD


PPD
PPD
PPD
PPD


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10.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event aetiology.
These protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Table 7
Phase I liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 h

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
h

Monitor participants twice weekly until liver 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis if 
requested by the Medical Monitor 
(determined on a case-by-case basis)4 

Serum CPK and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 


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chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1 Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2 All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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); INR measurement is not required and the threshold value stated will not apply to 
participants receiving anticoagulants.
3 Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); Hepatitis E IgM antibody 
4 Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention. Sample 
handling and shipping instructions are in the SRM. 


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10.8.
Appendix 8: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ADME
Absorption, distribution, metabolism, and excretion
ALT
Alanine aminotransferase 
AMS
Accelerator Mass Spectrometry
AST
Aspartate Aminotransferase
AUC(0–inf)
Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite time
AUC(0–t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a participant 
across all treatments
BIB
Bioanalysis, Immunogenicity and Biomarkers
BMI
Body mass index
BP
Blood Pressure
bpm
Beats per minute
Bq
Becquerel
CA
Capsid
Cmax
Maximum observed concentration
CIOMS
Council for International Organizations of Medical Sciences
CL
Clearance
CL/F
Oral clearance
CLr
Renal clearance
cm
Centimeter
CO
Carbon Monoxide
CONSORT
Consolidated Standards of Reporting Trials
CFR
Code of Federal Regulations (US)
CMV
Cytomegalovirus
CPK
Creatine phosphokinase
CRF
Case Report Form
CSR
Clinical Study Report
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
Computed tomography
DAIDS
Division of AIDS
DMPK
Drug metabolism and pharmacokinetics
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
F
Absolute bioavailability
Fa
Fraction absorbed
FDA
Food and Drug Administration


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Fh
Fraction of drug escaping first pass hepatic clearanc
Fg
Fraction of drug escaping gut metabolism
FTIH
First time in human
Gag
Group-specific antigen
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg 
Hepatitis B Surface Antigen 
HBV
Hepatitis B Virus
HBC
Hepatitis C Virus
HDL
High density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HMR
Hammersmith Medicines Research
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICRP
International Commission on Radiological Protection
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
IVIVT
In vitro / In vivo Translation - Investigative Safety & Drug 
Metabolism, GSK
kDa
Kilodalton
kg
Kilograms
kg/m2
Kilograms per meter square
LC
Liquid Chromatography
LC-MS/MS
Liquid Chromatography–Tandem Mass Spectrometry
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LOAEL
Lowest-observed-adverse-effect level 
LSC
Liquid Scintillation Counting
LFTs
Liver Function Tests
MBq
Megabecquerel
MCH
Mean corpuscular hemoglobin
MCV
mean corpuscular volume


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mSv
Millisievert
μCi
Micro Curie
μg
Microgram
μSv
Microsievert
MAD
Multiple Ascending Dose
mg
Milligrams
MHRA
Medicines and Healthcare Regulatory Authority
MI
Maturation Inhibitor
mL
Millilitre
mmHg
Millimeters of mercury
ms
Milliseconds
MSDS
Material Safety Data Sheet
mSv
Millisievert
nCi
Nano Curie
ng
Nanograms
NOAEL
No Observed Adverse Effect Level
PBA
Protein binding adjusted
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PK
Pharmacokinetic(s)
POC
Proof of concept
QD
Once daily
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
QTL
Quality tolerance limit
RNA
Ribonucleic acid
RAP
Reporting and Analysis Plan
RBC
Red blood cell
REC
Research Ethics Committee
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SGPT
Serum Glutamic-Pyruvic Transaminase
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SoA
Schedule of Activities
SPI
Spacer peptide 1
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA
Technical Agreement
tmax
Time of occurrence of Cmax
t½
Terminal phase half-life
TQT
Thorough QT
UK
United Kingdom


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ULN
Upper Limit of Normal
VH
ViiV Healthcare group of companies
Vss
Volume of distribution at steady state
Vz/F
Apparent volume of distribution
WHO
World Health Organisation
z
Lambda-z (Terminal Phase Rate Constant)
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
NONE
WinNonlin


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10.9.
Appendix 9: 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 
Independent Review Boards/Independent Ethics Committees 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.
10.9.1.
Changes to Study Visits and Study Procedures

There may be cases where the current principal investigator (PI) 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.
10.9.2.
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 enrolment 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.
10.9.3.
COVID-19 Specific Data Capture
10.9.3.1.
Capturing COVID-19 Specific Protocol Deviations
Please refer to the SRM for specific details on capturing protocol deviations as a result of 
COVID-19.
10.9.3.2.
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 adverse events/serious 
adverse events 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 adverse events (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 
Sites should contact the study Medical Monitor for questions related to 
definitions and reporting, and decisions around impact to study drug 
continuation.
3.
A new COVID-19 infection Case Report Form will be included in the eCRF 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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10.9.3.2.1. 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. 
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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10.10.
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).


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11.
REFERENCES
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/media/136238/download
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
GlaxoSmithKline Document Number 2018N379610_01. GSK3640254 Investigator's 
Brochure. 2019.
Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards 
D. Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the 
biliary disposition of drugs.  Br J Clin Pharmacol. 2011; 72:133-142.
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
ICRP. Radiological Protection in Biomedical Research. ICRP Publication 62. Ann ICRP 
1992; 22(3).
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3 
(R2). 2009. 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplin
ary/M3_R2/Step4/M3_R2__Guideline.pdf. Accessed 15 February 2019.  
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035–1043.


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Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal 
Disorders. Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-
898.pdf. Accessed Dec 22 2014.
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of 
Gastroenterology. 5th edition. 2009. Blackwell Publishing
U.S Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1. [July 2017]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
World Health Organization (WHO). Use of ionizing radiation and radionuclides on 
human beings for medical research, training and nonmedical purposes. Technical report 
series No. 611. 1977, Geneva.

SAP_001.pdf: 
CONFIDENTIAL 
 
Statistical Analysis Plan 213051 
 
 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: A two-period study in healthy male participants to determine the 
pharmacokinetics, balance/excretion, and metabolism of [14C]-GSK3640254 following a 
single intravenous radiolabeled microtracer dose (concomitant with a non-radiolabeled 
oral dose) and a single oral radiolabeled dose 
Protocol Number: 213051 
Compound Number: GSK3640254 
Short Title: PH 1, [14C]-GSK3640254, IV vs oral, ADME study 
Sponsor Name: ViiV Healthcare UK Limited 
 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clinicaltrials.gov NCT04507321 
EudraCT 
2019-004444-30           
IND 
139838 
 
 
 
 
 
Copyright 2020 ViiV Healthcare group of companies. All rights reserved.  Unauthorized 
copying or use of this information is prohibited. 
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Statistical Analysis Plan 213051 
 
 
 
2 
 
SAP Author(s): 
Author 
Date 
  
04-SEP-2020 
Associate Statistician, Dev Biostats India 
Stats 
 
Director, Clinical Pharmacology, CPMS 
04-SEP-2020 
 
SAP Team Review Confirmations (E-mail Confirmation): 
Reviewer 
Date of E-mail 
Confirmation 
 
04-SEP-2020 
Principal Statistician, Dev Biostats Stats Dev 
 
Director, Clinical Pharmacology, CPMS 
07-SEP-2020 
 
07-SEP-2020 
Senior Manager, Programming, Dev Biostats India Prog  
 
Discovery Medicine Scientist Manager GSK Fellow, 
R&D GCSD 
            04-SEP-2020 
 
08-SEP-2020 
DMPK Project Rep 
 
09-SEP-2020 
Physician Product Lead, ViiV Development 
 
Director, Clinical Development, ViiV Research & 
Development 
05-SEP-2020 
 
Principal Clinical Data Manager, RD PCPS GCDO DM 
ID 
04-SEP-2020 
 
07-SEP-2020 
Medical Director, SERM, SMG Pharma Safety 
SAP Biostatistics Line Approval (Vault TMF eSignature): 
Approver 
 
Manager Statistics, Dev Biostats India Stats 
 
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Statistical Analysis Plan 213051 
 
 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
1.2. 
Objectives, Endpoints and Estimands ........................................................... 6 
1.2.1. 
Objectives and Endpoints .............................................................. 6 
1.2.2. 
Estimands ...................................................................................... 9 
1.3. 
Study Design .............................................................................................. 13 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA .......................................... 14 
2.1. 
Multiple Comparisons and Multiplicity ......................................................... 14 
3. 
SAMPLE SIZE DETERMINATION ......................................................................... 14 
4. 
ANALYSIS SETS ................................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
STATISTICAL ANALYSES ..................................................................................... 16 
5.1. 
General Considerations .............................................................................. 16 
5.1.1. 
General Methodology .................................................................. 16 
5.1.2. 
Baseline Definition ....................................................................... 17 
5.2. 
Primary Endpoint(s) Analyses ..................................................................... 17 
5.2.1. 
Definition of endpoint(s) ............................................................... 18 
5.2.1.1. 
Drug concentration measures ..................................... 18 
5.2.1.2. 
Derived Pharmacokinetic Parameters......................... 18 
5.2.1.2.1. 
Derived plasma pharmacokinetic 
parameters ............................................. 18 
5.2.1.2.2. 
Derived urine and fecal 
pharmacokinetic parameters ................... 23 
5.2.2. 
Main analytical approach ............................................................. 26 
5.3. 
Secondary Endpoint(s) Analyses ................................................................ 28 
5.3.1. 
Definition of Pharmacokinetic endpoint(s) .................................... 28 
5.3.1.1. 
Derived plasma pharmacokinetic parameters ............. 28 
5.3.2. 
Main analytical approach ............................................................. 28 
5.4. 
Exploratory Endpoint(s) Analyses ............................................................... 28 
5.4.1. 
Definition of Pharmacokinetic endpoint(s) .................................... 28 
5.4.1.1. 
Metabolite profiling analyses in plasma, urine, 
feces and bile ............................................................. 28 
5.4.1.2. 
Derived plasma pharmacokinetic parameters ............. 28 
5.4.2. 
Main analytical approach ............................................................. 29 
5.5. 
(Other) Safety Analyses .............................................................................. 30 
5.5.1. 
Extent of Exposure ...................................................................... 30 
5.5.2. 
Adverse Events............................................................................ 30 
5.5.2.1. 
Adverse Events of Special Interest ............................. 31 
5.5.3. 
Additional Safety Assessments .................................................... 32 
5.5.3.1. 
Laboratory Data .......................................................... 33 
5.5.3.2. 
Vital Signs .................................................................. 33 
5.5.3.3. 
ECG ........................................................................... 33 
5.5.3.4. 
COVID 19 Related Analyses ...................................... 34 
5.6. 
Interim Analyses ......................................................................................... 34 
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Statistical Analysis Plan 213051 
 
 
 
4 
 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 35 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 35 
6.1.1. 
List of Abbreviations .................................................................... 35 
6.1.2. 
Trademarks ................................................................................. 36 
7. 
REFERENCES ....................................................................................................... 37 
 
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Statistical Analysis Plan 213051 
 
 
 
5 
 
VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study 213051 is based on the protocol 
Amendment 01 dated 10-JUN-2020.  
Table 1 
SAP Version History Summary 
SAP 
Version 
Effective Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
1 
Refer to 
Document Date 
Amendment 01 
dated 10-JUN-
2020 
Not 
Applicable 
Original version 
 
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Statistical Analysis Plan 213051 
 
 
 
6 
 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 213051. Details of the final analyses are provided. 
Descriptive study population analyses such as summary of demography and baseline 
characteristics and additional detail with regards to data handling conventions and the 
specification of data displays will be provided in the Output and Programming 
Specification (OPS) document. 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
detailed in Table 2 
Table 2 
Changes to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
Population for 
analysis 
• Enrolled population- All 
participants who passed 
screening and entered 
the study.  
• Note screening failures 
(who never passed 
screening even if 
rescreened) and 
participants screened but 
never enrolled into the 
study (Reserve, Not 
Used) are excluded from 
the Enrolled analysis set 
as they did not enter the 
study. 
• 
This population was not 
present in the protocol. It 
has been added to SAP 
as per the requirement 
for the data display 
 
1.2. 
Objectives, Endpoints and Estimands 
1.2.1. 
Objectives and Endpoints 
Objectives 
Endpoints1 
Primary 
 
• 
To determine parent GSK3640254 and 
total drug-related radioactivity systemic 
concentrations following a single IV 
microtracer dose of [14C]-GSK3640254 
(with an oral dose of non-radiolabelled 
• AUC(0–inf), AUC(0–t), Cmax, tmax and 
t1/2 of parent and total drug-related 
material (radioactivity) in plasma and 
blood. 
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Statistical Analysis Plan 213051 
 
 
 
7 
 
Objectives 
Endpoints1 
GSK3640254) and oral dose of [14C]-
GSK36402541 
• Volume of distribution at steady state 
(Vss) and clearance (CL) of parent after IV 
dose (Period 1 only). 
• Renal clearance of parent (CLr) after both 
IV and oral dose 
• 
Oral clearance (CL/F) and apparent 
volume of distribution (Vz/F) for the parent 
following oral administration 
• 
To calculate the absolute oral 
bioavailability of GSK3640254 
• 
Direct estimation of absolute oral 
bioavailability (F), indirect calculation of 
fraction of drug escaping first pass hepatic 
clearance (Fh), fraction absorbed (Fa) and 
fraction of drug escaping gut metabolism 
(Fg). 
• 
To determine the rate and extent of 
excretion of total radioactivity in urine and 
feces and the total recovery of 
radioactivity, following IV and oral 
administrations of [14C]-GSK3640254  
• 
Urinary and fecal cumulative excretion as 
a percentage of the total radioactive dose  
Secondary 
 
• 
To evaluate the safety and tolerability of 
GSK3640254 after single IV and oral 
doses in healthy participants. 
• 
Characterize observed adverse events, 
and abnormal laboratory, 12-lead ECG, 
and vital signs assessments observed. 
• 
To determine the blood:plasma ratio of 
[14C]-GSK3640254-related materials (total 
radioactivity) associated with blood cellular 
components   
• 
Blood:plasma ratio of [14C]-GSK3640254-
related materials (total radioactivity). 
Exploratory 
• 
To generate samples that will be used to 
characterize the metabolite profile of 
GSK3640254 following a single IV 
microtracer dose of [14C]-GSK3640254 
concomitant with an oral dose of non-
radiolabelled GSK3640254 (plasma, urine, 
feces, duodenal bile) and a single, oral 
dose of [14C]- GSK3640254 (plasma, 
urine, feces, duodenal bile). 
• 
Characterization and quantification of 
metabolites in plasma, urine, feces, and 
duodenal bile (qualitative identification in 
bile).  These analytical investigations will 
be conducted, and the results reported 
under a separate nonclinical GSK 
protocol. 
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CONFIDENTIAL 
 
Statistical Analysis Plan 213051 
 
 
 
8 
 
Objectives 
Endpoints1 
• To evaluate the PK and relative 
bioavailability of GSK3640254 following 
administration of the 85 mg suspension 
compared to the 200 mg tablet 
• AUC(0-inf), AUC(0-t) and Cmax 
 
AUC(0–inf): Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time, 
AUC(0–t): Area under the plasma concentration-time curve from time zero (pre-dose) to last time of quantifiable 
concentration within a participant across all treatments, Cmax: Maximum observed plasma concentration, tmax: 
time of occurrence of Cmax, t1/2: terminal phase half-life, ECG: electrocardiogram. 
1 For measured concentrations of GSK3640254 in plasma, the nomenclature [14C]-GSK3640254 describes the 
parent GSK3640254 concentration derived via analysis by liquid chromatography (LC) + AMS, whereas 
GSK3640254 describes the parent GSK3640254 concentration derived via liquid chromatography-tandem mass 
spectrometry (LC-MS/MS). 
AUC(0-inf), AUC(0-t), Cmax, tmax and t1/2 of parent and total drug-related material (radioactivity) will only be 
collected in plasma. 
 
 
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Statistical Analysis Plan 213051 
 
 
 
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1.2.2. 
Estimands 
Table 3 
Estimands 
Objective 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint 
Analysis 
Set  
Intercurrent Event Strategy 
Population Level 
Summary Measure 
Primary Objective:  
To determine parent 
GSK3640254 and 
total drug-related 
radioactivity systemic 
concentrations 
following a single IV 
microtracer dose of 
[14C]-GSK3640254 
(with an oral dose of 
non-radiolabelled 
GSK3640254) and 
oral dose of [14C]-
GSK36402541 
Primary 1 
AUC(0-inf), 
AUC(0-t), 
Cmax, tmax 
and t1/2 of 
parent and 
total drug-
related 
material 
(radioactivity) 
in plasma 
 
PK 
Subject withdrawal  
or AE occurrence (treatment 
policy) 
 
No adjustments will be 
made for the occurrence 
of any intercurrent 
events. Estimation will 
be done based upon 
observed data. 
Supplementary 
1 
Volume of 
distribution at 
steady-state 
(Vss) and 
clearance (CL) 
of parent after 
IV dose 
(Period 1 only)  
 
PK 
See Primary 1 
 
 
 
Supplementary 
2 
Renal 
clearance of 
PK 
See Primary 1 
 
 
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Objective 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint 
Analysis 
Set  
Intercurrent Event Strategy 
Population Level 
Summary Measure 
parent (CLr) 
after IV and 
oral 
administration  
 
Supplementary 
3 
Oral clearance 
(CL/F) and 
apparent 
volume of 
distribution 
(Vz/F) for the 
parent 
following oral 
administration 
PK 
See Primary 1 
 
 
To calculate the 
absolute oral 
bioavailability of 
GSK3640254 
primary 2 
Direct 
estimation of 
absolute oral 
bioavailability 
(F), indirect 
calculation of 
fraction of 
drug escaping 
first pass 
hepatic 
clearance (Fh), 
PK 
See Primary 1 
 
 
 
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Statistical Analysis Plan 213051 
 
 
 
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Objective 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint 
Analysis 
Set  
Intercurrent Event Strategy 
Population Level 
Summary Measure 
fraction 
absorbed (Fa) 
and fraction of 
drug escaping 
gut 
metabolism 
(Fg). 
To determine the rate 
and extent of 
excretion of total 
radioactivity in urine 
and feces and the total 
recovery of 
radioactivity, 
following IV and oral 
administrations of 
[14C]-GSK3640254 
Primary 3 
Urinary and 
fecal 
cumulative 
excretion as a 
percentage of 
the total 
radioactive 
dose 
 
See Primary 1 
 
 
Key Secondary 
objective : 
To determine the 
blood:plasma ratio of 
[14C]-GSK3640254-
related materials (total 
radioactivity) 
Secondary  
Blood:plasma 
ratio of [14C]-
GSK3640254-
related 
materials (total 
radioactivity). 
PK 
See Primary 1 
 
 
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Statistical Analysis Plan 213051 
 
 
 
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Objective 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint 
Analysis 
Set  
Intercurrent Event Strategy 
Population Level 
Summary Measure 
associated with blood 
cellular components   
 
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Statistical Analysis Plan 213051 
 
 
 
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1.3. 
Study Design 
Overview of Study Design and Key Features 
 ] 
Design 
Features 
• Open-label 
• Single center 
• Non-randomised 
• 2-period, single-sequence 
• Mass balance study 
• Approximately 6 healthy male participants will be enrolled 
• A screening visit (up to 30 days before first dose) 
• Two inpatient treatment periods (Treatment Periods 1 and 2), with at least 13 days 
between doses. 
A follow-up visit 7 – 14 days after the last assessment in Treatment Period 2 
 
Study 
intervention 
 
Study 
intervention 
Assignment 
Approximately six participants will be enrolled to achieve at least 4 
participants completing the two treatment periods. On Day 1 of Treatment 
Period 1, after an overnight fast of at least 8 h, each participant will take a 
single 200 mg oral dose (2 x 100 mg tablets) of GSK3640254 with a 
moderate fat meal (approximately 600 calories with approximately 30% of 
calories from fat); the IV infusion of 100 μg of [14C]-GSK3640254 
(approximately 3.7 kBq; 100 nCi) will begin 5 h after oral dose and 
continue over 1 h. On Day 1 of Treatment Period 2, after an overnight fast 
of at least 8 h, each participant will receive approximately 85 mg [14C]-
GSK3640254 (approximately 3.15 MBq; 85 μCi) as an oral suspension 
with a moderate fat meal (approximately 600 calories with approximately 
30% of calories from fat). 
Interim 
Analysis 
There will be no formal interim analyses.   
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Statistical Analysis Plan 213051 
 
 
 
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2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA 
This study is not designed for statistical testing and therefore has no formal statistical 
hypothesis.  
Study objective will be evaluated descriptively and through estimation. 
2.1. 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparison will be made. 
3. 
SAMPLE SIZE DETERMINATION 
No formal sample size calculation has been performed for this study. However, the 
sample size reflects an accepted industry standard for human ADME studies using   
14Cradiolabelled drug. Additionally, the design of the study in terms of the concomitant 
administration of intravenous with oral administration (Period 1) inherently reduces 
variability in the parameters determined, versus a cross-over design for absolute 
bioavailability assessment, while enabling cross-over to Period 2 in the same participants 
The primary objective of the study is to gain a better understanding of the compound’s 
pharmacokinetic, excretory, and metabolic profile and 4 to 6 participants are deemed 
sufficient for this purpose. Six participants will be enrolled into the study. To minimize 
the number of participants exposed to radiation; those participants that discontinue early 
will not be replaced unless the total number of participants who complete both Periods 1 
and 2 drops below 4. 
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4. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who were 
screened for eligibility. This 
will be the population for 
reporting screened population 
data. 
• Study Population 
Enrolled 
• All participants who passed 
screening and entered the study.  
• Note screening failures (who 
never passed screening even if 
rescreened) and participants 
screened but never enrolled into 
the study (Reserve, Not Used) 
are excluded from the Enrolled 
analysis set as they did not enter 
the study. 
• Study Population 
Safety 
• All participants who take at 
least 1 dose of study 
intervention. Participants will be 
analysed according to the 
treatment they received. This 
will be the population for 
reporting safety and study 
population data. 
• Study / Safety 
Population 
Pharmacokinetic 
(PK) 
• All participants in the Safety 
population who had at least 1 
non-missing PK assessment 
(Non-quantifiable [NQ] values 
will be considered as non-
missing values).  
 
• PK Population 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study.  
These protocol deviations will be reviewed to identify those considered as important as 
follows: 
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o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorized in the protocol deviations SDTM dataset.  
o This dataset will be the basis for the summaries of important 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 eCRF. 
To facilitate presenting protocol deviations that occurred due to the COVID-19 
pandemic, the description of protocol deviations occurring because of COVID-19 will 
include the standard text “COVID-19” as per the Data Management guidance issued on 
“COVID-19 Designation of protocol deviations”. 
After a discussion with the study team, the following analyses will be included:  
[1] Protocol deviations that occurred due to the COVID-19 pandemic 
[2] List which subjects were impacted due to the COVID-19 pandemic and how their 
participation was impacted 
[3] Summarize the number of missed visits due to the COVID-19 pandemic 
[4] Summarize the number of missed assessments for key endpoints due to the COVID-
19 pandemic (if not fully described based on the summary of missed visits) 
[5] Summarize the number of visits where assessments were performed using alternative 
methods due to the COVID-19 pandemic. 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
5.1.1. 
General Methodology 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Summary tables (except for Safety and PK analyses) will provide the following 
descriptive 
statistics: 
- Continuous data (normal data): n, mean, standard deviation (SD), median, interquartile 
range, minimum and maximum. 
- Continuous data (log normal data): n, geometric mean, standard deviation (SD) on the 
log 
scale, and between subject variability(%CVb) 
- Categorical data: number and percentage of participants in each category. 
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5.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment in each 
treatment period (Prior to the oral dose) in each treatment period), with a non-missing 
value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. For subjects 
who did not receive study treatment during the study, baseline will be defined as the 
latest, non-missing collected value. Day 1 pre-dose ECGs for each treatment period will 
be performed in triplicate. In such case of triplicate measurement for pre-dose average 
will be used as baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.2. 
Primary Endpoint(s) Analyses 
The PK analyses will be based on the pharmacokinetic analysis set. 
The plasma pharmacokinetic concentrations will have different nomenclatures dependent 
on the method of measuring. For measured concentrations of GSK3640254 in plasma, the 
nomenclature [14C]-GSK3640254 describes the parent GSK3640254 concentration 
derived via analysis by liquid chromatography (LC) + Accelerator Mass Spectrometry 
(AMS), whereas GSK3640254 describes the parent GSK3640254 concentration derived 
via liquid chromatography-tandem mass spectrometry (LC-MS/MS). It is expected that, 
for period 1, the radiolabelled iv dose will be measured using LC+AMS and will be 
labelled “[14C]-GSK3640254”, the non-radiolabelled oral dose will be measured using 
LC-MS/MS and will be labelled “GSK3640254”. For period 2, the radiolabelled oral 
dose will be measured using LC-MS/MS and will be labelled “GSK3640254”.  For the 
reporting of displays a footnote will be added to detail the nomenclature used to 
discriminate between labelled and non-labelled drug (and the analytical methods used to 
provide the data).  
Total radioactivity measurements in urine samples and faecal homogenates will be 
determined by Liquid Scintillation Counting (LSC) and/or by AMS. Total radioactivity 
measurements from plasma derived from blood will be analysed, as appropriate, by AMS 
in Treatment Period 1 and by LSC and/or by AMS, for Treatment Period 2, as detailed in 
the SRM. 
The reconciliation of the Plasma PK Case Report Form (CRF) and SMS2000 data will be 
provided by DM(GSK) and the analytical CROs – Pharmaron, and Covance will also 
perform reconciliation and provided via their analytical reports. 
Derivation of plasma pharmacokinetic parameters for [14C]- GSK3640254, total 
radioactivity and GSK3640254 will be performed by, or under the direct auspices of, 
Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline. 
Derivation of urine/faeces total radioactivity parameters will be performed by the 
analytical CROs – Pharmaron, and Covance via their analytical reports. 
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5.2.1. 
Definition of endpoint(s) 
• 
AUC(0-inf), AUC(0-t), Cmax, tmax and t1/2 of parent and total drug-related 
material (radioactivity) in plasma. 
• 
Volume of distribution at steady-state (Vss) and clearance (CL) of parent after IV 
dose (Period 1 only)  
• 
Renal clearance of parent (CLr) after IV and oral administration  
• 
Oral Clearance (CL/F) and apparent volume of distribution (Vz/F) for the parent 
following oral administration  
• 
Direct evaluation of absolute bioavailability (F), indirect calculation of fraction of 
drug escaping first pass hepatic clearance (Fh), fraction absorbed (Fa) and fraction of 
drug escaping gut metabolism (Fg)  
• 
Urinary and fecal cumulative excretion of total radioactivity as a percentage of the 
total radioactive dose (Period 1 and Period 2) 
5.2.1.1. 
Drug concentration measures  
Refer to the Output and Programing Specification (OPS) document for Data Display 
Standards & Handling Conventions for Pharmacokinetic Data.  
Plasma GSK3640254, [14C]- GSK3640254 and blood and Plasma total radioactivity 
concentration-time data will be listed for each participant and standard summary statistics 
will be calculated (i.e. arithmetic mean, standard deviation, median, minimum and 
maximum) by treatment and planned sampling time.  
Individual participant, mean and median plasma GSK3640254, [14C]- GSK3640254 and 
total radioactivity concentration-time profiles will be plotted for each treatment on both a 
linear and semi-log scale.  
For urine and feces, the total radioactivity excreted in urine and feces per sample or 
collection interval will be listed by subject. The cumulative total and the cumulative 
percentage of the total radioactive dose will be calculated and listed by subject. The 
concentration of radioactivity in urine, feces and fecal homogenates will be expressed as 
ng equivalents/g.   
5.2.1.2. 
Derived Pharmacokinetic Parameters  
5.2.1.2.1. Derived plasma pharmacokinetic parameters 
PK Parameters will be calculated by standard non-compartmental analysis according to 
current working practices and using the currently supported version of WinNonlin 
version 6.3 or above. All calculations of non-compartmental parameters will be based on 
actual sampling times. PK parameters listed will be determined from plasma 
GSK3640254, [14C]-GSK3640254, total radioactivity as data permits and unless 
otherwise stated. 
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Table 4 
Derived Pharmacokinetic Plasma Parameters 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration (C(t)) will be calculated using 
the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
λz 
The first order rate constant associated with the terminal (log-linear) 
portion of the concentration-time curve. 
AUC(0-) 
Area under the concentration-time curve extrapolated to infinity 
will be calculated as: 
𝐴𝑈𝐶(0 −∞) = 𝐴𝑈𝐶(0 −𝑡) + 𝐶(𝑡)
𝜆𝑧  
%AUCex 
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) 
will be 
calculated as: 
[𝐴𝑈𝐶(0 −∞) −𝐴𝑈𝐶(0 −𝑡)] 
𝐴𝑈𝐶(0 −∞)
∗100 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-
time data. 
t1/2 
Apparent terminal half-life will be calculated as: 
t1/2 =  ln2 / λz  
CL 
Total clearance calculated as:  
𝐶𝐿=
𝐷𝑜𝑠𝑒(𝐼𝑉)
𝐴𝑈𝐶(0 −∞) 
Treatment Period 1, analyte [14C]-GSK3640254 only and where the 
Dose(IV) is the actual IV dose provided by Covance, Harrogate 
Vss 
Volume of distribution at steady-state, calculated as:  
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Parameter 
Parameter Description 
𝑉𝑠𝑠= 𝐶𝐿∗𝑀𝑅𝑇𝑖𝑣 
Where CL is total clearance and MRT is the mean residence time, 
calculated as AUMC(0-) [Area under the first moment 
curve]/AUC(0-) 
CLr 
If plasma AUC(0-) is calculable, then  
𝐶𝐿𝑟= 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑒[𝑈𝑟𝑖𝑛𝑒] 𝑓𝑜𝑟 𝑃𝑒𝑟𝑖𝑜𝑑 1
𝑃𝑙𝑎𝑠𝑚𝑎 𝐴𝑈𝐶(0 −¥)
 
If plasma AUC(0-) is not calculable, then 
𝐶𝐿𝑟= 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑒[𝑈𝑟𝑖𝑛𝑒] 𝑓𝑜𝑟 𝑃𝑒𝑟𝑖𝑜𝑑 1
𝑃𝑙𝑎𝑠𝑚𝑎 𝐴𝑈𝐶(0 −𝑡)
 
Where cumulative urine Ae from excretion data for treatment 
Period 1 and AUC from NCA PK analysis of Treatment Period 1, 
analyte [14C]-GSK3640254 only 
ML(iv) 
Metabolite load following intravenous administration, calculated as: 
𝑀𝐿(𝑖𝑣)
=
[𝑇𝑜𝑡𝑎𝑙 𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝐴𝑈𝐶(0 −∞) −[14𝐶]𝐺𝑆𝐾3640254 𝐴𝑈𝐶(0 −∞)]
𝑇𝑜𝑡𝑎𝑙 𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝐴𝑈𝐶(0 −∞)
 
Treatment Period 1 
ML(po) 
Metabolite load following oral administration, calculated as:  
𝑀𝐿(𝑝𝑜) = 
[𝑇𝑜𝑡𝑎𝑙 𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝐴𝑈𝐶(0 −∞) −𝐺𝑆𝐾3640254 𝐴𝑈𝐶(0 −∞)]
𝑇𝑜𝑡𝑎𝑙 𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝐴𝑈𝐶(0 −∞)
 
Treatment Period 2 
Note: GSK3640254 AUC(0-∞) may be updated depending on the 
sample analysis conducted but refers to the parent GSK3640254 
from oral dose 
Fg 
Fraction metabolized by gut wall as a fraction of the oral dose, 
calculated as: 
𝐹𝑔= 1 −[𝑀𝐿(𝑝𝑜) −𝑀𝐿(𝑖𝑣)] 
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Parameter 
Parameter Description 
CLh,iv,blood 
 Hepatic blood clearance, calculated as:  
 
CLh,iv,blood  = CLh,iv,plasma * blood to plasma ratio 
Where CLh,iv,plasma is the hepatic plasma clearance calculated as:  
CLh,iv,plasma = CL - CLr 
Eh 
Hepatic extraction ratio, calculated as:  
EH = CLh,iv,blood/ Qh 
Where Qh = hepatic blood flow (literature value of 1660 mL/min, 
Edginton, 2006)  
 
Note: if assumption that hepatic CL accounts for 100% of the 
clearance (i.e. CLr is negligible), then Eh = CL*blood to plasma 
ratio*Qh 
Fh 
Fh=1-Eh 
Fa 
Fraction absorbed following an oral dose, calculated as follows 
𝐹𝑎=  𝐹(0 −∞)]/(1 −𝐸𝐻)
𝐹𝑔
  
 
Dose(iv)  
Radiometric IV dose calculated by Covance 
Dose(oral) 
Radiometric oral dose calculated by Covance 
F(0-∞) 
Oral absolute bioavailability based on AUC(0-∞), calculated as: 
𝐹(0 −∞) = GSK3640254 AUC(0 −∞)(oral)
Dose(oral)
∗
Dose(iv)
[14𝐶]𝐺𝑆𝐾3640254 𝐴𝑈𝐶(0 −∞)(𝑖𝑣) 
Per Subject 
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Parameter 
Parameter Description 
Note: Radiometric dose will be used for IV. GSK3640254 AUC(0-
∞) (0ral) refers to the parent GSK3640254 from oral dose, but may 
be updated depending on the sample analysis 
F(0-t) 
Oral absolute bioavailability based on AUC(0-t), calculated as: 
𝐹(0 −𝑡) = GSK3640254 AUC(0 −t)(oral)
Dose(oral)
∗
Dose(iv)
[14𝐶]𝐺𝑆𝐾3640254 𝐴𝑈𝐶(0 −𝑡)(𝑖𝑣) 
Per Subject 
Note: Radiometric dose will be used for IV. GSK3640254 AUC(0-
t) (0ral) refers to the parent GSK3640254 from oral dose, but may 
be updated depending on the sample analysis 
CL/F 
Apparent oral clearance, calculated as: 
𝐶𝐿/𝐹=
𝐷𝑜𝑠𝑒
𝐴𝑈𝐶(0 −∞) 
Vz/F 
Apparent volume of distribution based on the terminal phase  
𝑉𝑧/𝐹=
𝐷𝑜𝑠𝑒
[𝜆𝑧∗𝐴𝑈𝐶(0 −∞)] 
GSK3640254/ 
Total 
radioactivity 
ratio for Cmax 
Cmax Ratio = Exp {[loge(GSK3640254 Cmax] - [loge(Total 
radioactivity Cmax]} 
Per subject for radiolabelled oral dose. GSK3640254 may be 
updated depending on the sample analysis conducted but refers to 
the parent GSK3640254 from oral dose 
GSK3640254/ 
Total 
radioactivity 
ratio for 
AUC(0-∞) 
Cmax Ratio = Exp {[loge(GSK3640254 AUC(0-∞)] - [loge(Total 
radioactivity AUC(0-∞)]} 
Per subject for radiolabelled oral dose. GSK3640254 may be 
updated depending on the sample analysis conducted but refers to 
the parent GSK3640254 from oral dose 
GSK3640254/ 
Total 
radioactivity 
Cmax Ratio = Exp {[loge(GSK3640254 AUC(0-t)] - [loge(Total 
radioactivity AUC(0-t)]} 
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Parameter 
Parameter Description 
ratio for 
AUC(0-t) 
Per subject for radiolabelled oral dose. GSK3640254 may be 
updated depending on the sample analysis conducted but refers to 
the parent GSK3640254 from oral dose 
[14C]-
GSK3640254/ 
Total 
radioactivity 
ratio for Cmax 
Cmax Ratio = Exp {[loge([14C]-GSK3640254 Cmax] - [loge(Total 
radioactivity Cmax]} 
Per subject for radiolabelled IV dose 
[14C]-
GSK3640254/ 
Total 
radioactivity 
ratio for 
AUC(0-∞) 
Cmax Ratio = Exp {[loge([14C]-GSK3640254 AUC(0-∞)] - 
[loge(Total radioactivity AUC(0-∞)]} 
Per subject for radiolabelled IV dose 
[14C]-
GSK3640254/ 
Total 
radioactivity 
ratio for 
AUC(0-t) 
Cmax Ratio = Exp {[loge([14C]-GSK3640254 AUC(0-t)] - 
[loge(Total radioactivity AUC(0-t)]} 
Per subject for radiolabelled IV dose 
Notes:  
• Additional parameters may be included as required 
• Lambda_z is the terminal phase rate constant 
• The following PK parameters AUC(0-∞), AUC(0-t), %AUCex, Cmax, tmax, 
t1/2, CL, Vdss, Vz/F and CL/F, will be derived in Phoenix and sent to S&P. 
The radiometric IV and oral doses will be calculated by Covance and sent to 
S&P. Additional parameters will be derived by S&P including CLr, ML(iv), 
ML(po), Fg, Eh,Fh Fa, F(0-∞), F(0-t) and the [14C]-GSK3640254/total 
radioactivity ratios.  
5.2.1.2.2. Derived urine and fecal pharmacokinetic parameters 
• Derivation of urine and faecal radioactivity parameters will be the responsibility, 
or under the direct auspices, of the DMPK department within GSK.  
• When summarizing urine and faecal parameters, ‘NS’ (i.e., no sample provided as 
subject not voided at particular collection period) or ‘NQ’ values for these 
parameters will be imputed with zero. 
 
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Table 5 
Derived urine and faeces pharmacokinetic parameters 
Parameter 
Parameter Description 
Ae[urine] 
Total radioactivity recovered in the urine (Ae[urine]) calculated 
for each collection interval per subject and treatment period as: 
Ae[urine]= (concentration in urine sample x collected sample 
weight) for each urine collection interval, eg 0-24, 24-48, etc. 
Cumulative 
Ae[urine] 
Cumulative total radioactivity recovered in the urine (Cumulative 
Ae[urine]) calculated for each cumulative collection interval per 
subject and treatment period as:  
Cumulative Ae[urine] = summation of Ae[urine] 
For each urine collection with the cumulative urine collection 
interval  
Fe%[urine] 
% of total dose excreted as total radioactivity (Fe%[urine]) for 
each collection interval per subject and treatment period, 
estimated as:  
Fe%[urine]=(Ae[urine]) for each collection period)/Dose*100. 
Where the dose is the radiolabelled [14C]-GSK3640254, that is in 
period 1 radiometric iv dose, in period 2 radiometric oral dose 
 Cumulative 
Fe%[urine] 
Cumulative % of total dose excreted as total radioactivity 
(Cumulative Fe%[urine]) for each cumulative collection interval 
per subject and treatment period, estimated as:  
Cumulative Fe%[urine]= summation of Fe[urine] 
Where the dose is the radiolabelled [14C]-GSK3640254, that is in 
period 1 radiometric iv dose, in period 2 radiometric oral dose 
Ae[faeces] 
Total radioactivity recovered in the urine (Ae[faeces]) calculated 
for each collection interval per subject and treatment period as: 
Ae[urine]= (concentration in urine sample x collected sample 
weight) for each urine collection interval, eg 0-24, 24-48, etc. 
Cumulative 
Ae[faeces] 
Cumulative total radioactivity recovered in the urine (Cumulative 
Ae[faeces]) calculated for each cumulative collection interval per 
subject and treatment period as:  
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Parameter 
Parameter Description 
Cumulative Ae[faeces] = summation of Ae[faeces] 
For each urine collection with the cumulative urine collection 
interval  
Fe%[ faeces] 
% of total dose excreted as total radioactivity (Fe%[ faeces]) for 
each collection interval per subject and treatment period, 
estimated as:  
Fe%[urine]=(Ae[faeces]) for each collection period)/Dose*100. 
Where the dose is the radiolabelled [14C]-GSK3640254, that is in 
period 1 radiometric iv dose, in period 2 radiometric oral dose 
 Cumulative 
Fe%[faeces] 
Cumulative % of total dose excreted as total radioactivity 
(Cumulative Fe%[faeces]) for each cumulative collection interval 
per subject and treatment period, estimated as:  
Cumulative Fe%[faeces]= summation of Fe[faeces] 
Where the dose is the radiolabelled [14C]-GSK3640254, that is in 
period 1 radiometric iv dose, in period 2 radiometric oral dose 
Ae[total] 
Total radioactivity recovered in total excretum (sum of urine and 
faecal exvretion) Ae[total] will be estimates by collection interval 
for each subject and treatment period as: 
Ae[total]=Ae[urine]+ Ae[faeces] 
Cumulative 
Ae[total] 
Total radioactivity recovered in total excretion (sum of urine and 
faecal excretion), cumulative Ae[total] will be estimates by 
cumulative collection interval per subject and treatment period as: 
Cumulative Ae[total]= summation of Ae[total] 
for each total excretion collection within the cumulative total 
excretion collection interval, eg 0-24, 0-48, etc 
Fe%[total] 
% of total dose excreted as total radioactivity (Fe%[ total]) for 
each collection period will be estimated for each subject and 
treatment period as: 
Fe%[total]= Fe%[urine]+ Fe%[faeces] 
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Parameter 
Parameter Description 
 Cumulative 
Fe%[total] 
Cumulative % of total dose excreted as total radioactivity 
(Cumulative Fe%[ total]) for each cumulative collection period 
will be estimated for each subject and treatment period as: 
Cumulative Fe%[total]= Cumulative Fe%[urine]+ Cumulative 
Fe%[faeces]  
for each total excretion collection within the cumulative total 
excretion collection interval, eg 0-24, 0-48, etc 
Notes: additional parameters may be included as required 
5.2.2. 
Main analytical approach 
A primary objective is to determine parent GSK3640254 and total drug-related 
radioactivity systemic concentrations following a single IV microtracer dose of [14C]-
GSK3640254 (with an oral dose of non-radiolabelled GSK3640254) and oral dose of 
[14C]-GSK36402541. To assess this, the plasma PK parameters: AUC(0–inf), AUC(0–t), 
Cmax, tmax and t1/2 of parent and total drug-related material (radioactivity) will be 
summarized and listed. The volume Vss and clearance (CL) of parent after IV dose 
(Period 1 only) , renal clearance of parent (CLr) after both IV and oral dose, oral 
clearance (CL/F) and apparent volume of distribution (Vz/F) for the parent following oral 
administration will also be summarized and listed.  
To assess the absolute oral bioavailability of GSK3640254 absolute oral bioavailability 
(F), Fh  Fa  and Fg  will be summarized and listed. 
To determine the rate and extent of excretion of total radioactivity in urine and feces and 
the total recovery of radioactivity, following IV and oral administrations of [14C]-
GSK3640254 the PK parameters: Ae and Fe% will be summarized and listed for urine 
faeces and total (Urine + Faeces) 
 
 
 
 
 
 
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Table 6 
Statistical methodology specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses (Absolute Bioavailability assessment in Treatment 
Period 1) 
Primary Endpoint / Variables 
• AUC(0-t), AUC (0-∞) PK parameters of Plasma GSK3640254 (radiolabeled/non-
radiolabeled) from IV and oral dose in Period 1 will be analyzed after loge 
transformation (PK parameters should be divided by corresponding dose) 
Model Specification 
• Will be statistically analyzed using a mixed model (MM) for Period1. 
• Terms fitted in the mixed effect ANOVA model will include: 
o Fixed effect                   : Treatment (IV dose/Oral dose in Period1) 
o Random Effect               : Subject 
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• Point estimates for the adjusted means on the loge scale, the mean difference 
between treatments and associated 90% confidence interval for the contrast (test-
reference) will be constructed using the residual variance.  
Model Checking & Diagnostics 
• Dose normalized PK parameters should be used for the analysis. 
• For the Mixed Model analysis, Model assumptions will be applied, but appropriate 
adjustments maybe made based on the data. 
• Distributional assumptions underlying the model used for analysis will be 
examined by obtaining a normal probability plot of the residuals and a plot of the 
residuals versus the fitted values (i.e. checking the normality assumption and 
constant variance assumption of the model respectively) to gain confidence that the 
model assumptions are reasonable.  
• If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared, or square root of data, will be explored. 
Model Results Presentation 
• The point estimate and confidence interval obtained from MM analysis will be 
exponentially back transformed to obtain Adjusted (least square) geometric means 
for each treatment.  
• Point estimates (Absolute Bioavailability of GSK3640254) and associated 90% 
confidence interval for the ratio IV dose/Oral dose along with within-subject 
variability (%CVw) will be reported. 
• Plots showing the adjusted geometric mean ratio(F) of IV dose to Oral dose in 
Period1 for AUC (0-∞) and AUC(0-t) together with 90% confidence intervals will 
be provided. 
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5.3. 
Secondary Endpoint(s) Analyses 
The PK analyses will be based on the pharmacokinetic analysis set. 
5.3.1. 
Definition of Pharmacokinetic endpoint(s) 
• Blood: plasma ratio of [14C]-GSK3640254 – related materials (total radioactivity)  
5.3.1.1. 
Derived plasma pharmacokinetic parameters 
The blood: plasma ratio of total radioactivity will be calculated in period 2 according to 
the following equation:  
Ratio Cb_Cp= Radioactivity Concentration in blood (Cb)/ Radioactivity Concentration in 
plasma (Cp) 
5.3.2. 
Main analytical approach 
The blood: plasma ratio of total radioactivity (Cb/Cp) will be calculated at each time 
point and will be summarized and reported by Pharmaron. 
5.4. 
Exploratory Endpoint(s) Analyses 
The PK analyses will be based on the pharmacokinetic analysis set. 
5.4.1. 
Definition of Pharmacokinetic endpoint(s) 
• 
Characterization and quantification of metabolites in plasma, urine, faecal and 
duodenal bile (qualitative identification in bile). These analytical investigations will 
be conducted, and the results reported under a separate nonclinical GSK protocol 
• 
AUC (0-∞), AUC(0-t), and Cmax for the evaluation of the PK and the relative 
bioavailability of GSK3640254 following administration of the 85mg suspension 
compared to the 200 mg tablet 
5.4.1.1. 
Metabolite profiling analyses in plasma, urine, feces and bile  
The metabolic profiling/structural characterization aspect of this work will be performed 
by GSK (or a GSK representative) in a separate DMPK study report. Data from the 
quantification of unchanged GSK3640254 in urine following IV administration will be 
used in the estimate of renal clearance, as detailed above. 
5.4.1.2. 
Derived plasma pharmacokinetic parameters 
The PK parameters for GSK3640254 following oral administration of a 200 mg tablet or 
of 85 mg suspension will be reported as described in Section 5.2. Subsequently, the 
following parameters will be used for the assessment of the relative bioavailability of 
GSK3640254 following administration of the 85 mg suspension compared to the 200 mg 
tablet as described in Section 5.4.2.   
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5.4.2. 
Main analytical approach 
Table 7 
Statistical methodology specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
Endpoint / Variables 
Derived PK parameters: 
• AUC(0-inf) 
• AUC(0-t) 
• Cmax 
Model Specification 
• To evaluate the relative bioavailability of GSK3640254 following 
administration of the 85 mg suspension compared to the 200 mg tablet, the PK 
parameters will be analysed using a mixed effect model as described below: 
 
 
 
 
 
 
 
loge (PK parameter) = 0 +i + j + εij 
where, 
 
0: intercept 
 
i: random effect for ith participant, following N(0, 2) 
 
j: treatment effect (j = 85 mg suspension or 200 mg tablet Treatment) 
 
εij: random error for participant i, treatment effect j, following N(0, w2). 
• The model parameters will be estimated using Restricted Maximum Likelihood 
with the Newton-Raphson algorithm. 
• The Kenward-Roger degree of freedom approach will be used. 
• Given the random effect for subject “i", the random error is assumed to be 
independently distributed within the subject. 
• The least square means for each treatment formulation (85 mg suspension and 200 
mg tablet) will be estimated based on the fitted model. The mean difference 
between the treatment formulations (85 mg suspension and 200 mg tablet) and its 
90% CIs will be also estimated using the within-subject variance. 
• The estimates of least square means for each treatment formulation, the treatment 
difference between treatment formulations and the 90% CIs will be exponentially 
back-transformed to obtain the estimates of geometric means of AUC(0-t), AUC(0-inf) 
and Cmax for each treatment formulation, the ratio of geometric means (85 mg 
suspension and 200 mg tablet) and its 90% CIs, respectively. 
• Within-subject variability (%CVw) for the PK parameters will be estimated using 
within-subject variance from the analysis model as follows: 
 
 
 
%CVw (%) = [exp(w2) – 1]1/2 x 100 
 
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Model Checking & Diagnostics 
In case there is a problem with model convergence, the arithmetic means for loge-
transformed AUC(0-t) and Cmax and the treatment differences 85 mg suspension and 200 
mg tablet) within each participant will be calculated using only data from the 
participants who have completed both the periods for 85 mg suspension and 200 mg 
tablet. The mean treatment difference and paired-t test based 90% CIs for treatment 
difference in loge scale will be estimated. The results will be provided in an 
exponentially back-transformed scale. 
Model Results Presentation 
Based on the relative bioavailability, the bioequivalence between 85 mg suspension 
and 200 mg tablet will be evaluated as follows:  
• The bioequivalence is established when the 90% CI of the ratio for AUC(0-t), 
AUC(0-inf) and Cmax between treatment formulations (85 mg suspension and 200 
mg tablet) are within the range of 0.80 to 1.25. 
5.5. 
(Other) Safety Analyses 
The safety analyses will be based on the Safety analysis set, unless otherwise specified. 
5.5.1. 
Extent of Exposure 
Extent of exposure to GSK3640254 will be summarized. 
Duration of exposure in days = Treatment stop date –(Treatment start date)+ 1. For 
Period1 consider oral start date and IV stop date for duration of exposure. Participants 
who were allocated to treatment but did not report a treatment start date will be 
categorized as having zero days of exposure. It will be listed. 
5.5.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. 
The following categories and subcategories will be used: 
- AE 
o Any AEs 
▪ Maximum Grade 
o Drug-related AEs 
▪ Grade 
o AEs leading to 
▪ Permanent discontinuation  
▪ Withdrawal 
o Common AEs 
o  Common non-serious AEs 
- SAE 
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o Any SAEs 
▪ Grade 
o Drug-related SAEs 
o Fatal SAEs 
Each summary will contain: 
- the number of participants with the AE 
- the percentage of participants with the AE 
- the number of events of the AE 
AEs will be displayed by 
- Column: Treatment arm or intensity. 
- Row: in descending order by SOC and PT, or PT only 
A summary of number and percentage of participants with any adverse events by 
maximum grade will be produced. 
The frequency and percentage of AEs (all grades) will be summarized and displayed in 
two ways: 1) in descending order by PT only and 2) in descending order by SOC and PT.   
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary) and graded by the investigator according to the DAIDS 
(Version 2.1) grading table  
5.5.2.1. 
Adverse Events of Special Interest 
The identification and classification of the adverse events of special interest (AESI) will 
be done programmatically by GSK Biostatistics team. 
Table 8 presents the AESI groups. Groups which are not SMQs are made up of a 
selection of preferred terms (PTs) defined by GSK. The complete list, including the PTs 
which contribute to each of the groups will be provided by Pharma Safety using the 
MedDRA version current at the time of reporting. 
The summary of event characteristics will be provided for each AESI., including the 
number of events and occurrences. 
 
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Table 8 
Adverse Event of Special Interest (AESI) 
AESI Group 
SMQ 
Other 
QT prolongation 
Torsade de pointes/QT 
prolongation (SMQ) 
Cardiac Disorders SOC; 
seizures 
Gastrointestinal 
intolerability/toxicity 
Narrow ± Broad PTs from 
three sub-SMQs within the 
Gastrointestinal 
nonspecific inflammation 
and dysfunctional 
conditions SMQ 
 
Psychiatric events 
Psychosis and psychotic 
disorders (SMQ; narrow 
terms);  
Suicide/self-injury sub-
SMQ (narrow terms);  
Depression (excl suicide 
and self-injury) sub-SMQ 
(narrow terms)  
Additional PTs for 
symptoms and 
complications of 
Psychiatric events 
including bipolar disorder, 
anxiety and sleep disorders 
Nervous system disorders 
 
PTs from HLGTs for 
symptoms and 
complications of Nervous 
system disorders 
Skin and subcutaneous 
tissue disorders 
 
Selection of PTs from 
different HLGTs.  
5.5.3. 
Additional Safety Assessments 
The safety data to be summarised are as follows: 
Routine laboratory data for haematology, clinical chemistry and urinalysis will be 
collected, as well as data from additional tests (see Table 6 of the protocol). The key 
laboratory data to be summarized are as follows: 
▪ Haematology: Platelet Count, red blood cell (RBC) Count, haemoglobin, 
haematocrit, RBC Indices mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH) Absolute and %Reticulocytes, WBC count with Differential: 
Neutrophils, Lymphocytes Monocytes, Eosinophils, Basophils 
▪ Clinical chemistry: Urea Creatinine, Uric acid Fasting glucose etc… 
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▪ Routine Urinalysis: Routine Urinalysis, pH, glucose, protein, blood, ketones, 
bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick 
▪ Microscopic examination (if leukocyte esterase, nitrites, blood or protein is 
abnormal) 
▪ Screening only Tests: -  
o Alcohol breath test, urine cotinine test 
o  Carbon Monoxide (CO) breath test 
o  Drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
o Serology (HIV antigen/antibody immunoassay, HBsAg, and hepatitis C 
virus antibody with reflexive HCV RNA) 
5.5.3.1. 
Laboratory Data 
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced. Liver function laboratory tests will be included with chemistry lab tests. 
Shift tables of worst-case increase from baseline will be provided for all the laboratory 
tests and will be used to detect any laboratory parameter clinical important changes: 
- For lab test gradable by DAIDS grading table: worst-case grade increase from baseline 
grade 
- For lab tests not gradable by DAIDS grading table, worst-case changes from baseline 
relative to normal range. 
 
- For urinalysis, worst-case results post-baseline relative to baseline 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. The summary will be produced 
for worst-case postbaseline only. 
5.5.3.2. 
Vital Signs 
Values of vital signs (temperature, systolic and diastolic blood pressure, pulse rate and 
respiratory rate as well as the change from baseline will be summarized by scheduled 
visit using mean, median, standard deviation, minimum and maximum. 
Shift tables of worst-case results from baseline to potential clinical importance (PCI) 
criteria will be provided for systolic blood pressure (SBP), diastolic blood pressure 
(DBP) and heart rate and will be used to detect any clinical important changes.  
5.5.3.3. 
ECG 
A 12-lead ECG will be performed at Screening to calculate the heart rate and 
measurements such as PR, QRS, and QT (uncorrected) intervals. QTcF will be calculated 
(machine read or manually). ECG after Screening will be performed as clinically 
indicated. 
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5.5.3.4. 
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, and summaries will be based on subjects with COVID-19 adverse event:  
• Number of subjects with suspected, probable or confirmed for COVID-19 
infection 
• Number of subjects who had a SARS-COV-2 diagnostic 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 SAE or AE of COVID-19 infection 
• Severity, duration, and outcome of COVID-19 AEs 
 
Further display details are provided in OPS. 
5.6. 
Interim Analyses  
No interim analyses will be performed. 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
AE 
Adverse Event  
ADME 
Absorption, distribution, metabolism, and excretion 
AMS 
Accelerator Mass Spectrometry 
AUC(0–inf) 
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
AUC(0–t) 
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a participant 
across all treatments 
BIB 
Bioanalysis, Immunogenicity and Biomarkers 
BMI 
Body mass index 
BP 
Blood Pressure 
Cmax 
Maximum observed concentration 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
CL/F 
Oral clearance 
CLr 
Renal clearance 
cm 
Centimeter 
CRO 
Contract research organization 
DAIDS 
Division of AIDS 
DMPK 
Drug metabolism and pharmacokinetics 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
F 
Absolute bioavailability 
Fa 
Fraction absorbed 
Fh 
Fraction of drug escaping first pass hepatic clearanc 
Fg 
Fraction of drug escaping gut metabolism 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIVT 
In vitro / In vivo Translation - Investigative Safety & Drug 
Metabolism, GSK 
kDa 
Kilodalton 
kg 
Kilograms 
kg/m2 
Kilograms per meter square 
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LSC 
Liquid Scintillation Counting 
μSv 
Microsievert 
MAD 
Multiple Ascending Dose 
mg 
Milligrams 
PK 
Pharmacokinetic(s) 
POC 
Proof of concept 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
QTL 
Quality tolerance limit 
RNA 
Ribonucleic acid 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
tmax 
Time of occurrence of Cmax 
t½ 
Terminal phase half-life 
TQT 
Thorough QT 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
VH 
ViiV Healthcare group of companies 
Vss 
Volume of distribution at steady state 
Vz/F 
Apparent volume of distribution 
WHO 
World Health Organisation 
z 
Lambda-z (Terminal Phase Rate Constant) 
 
6.1.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
HARP 
 
SAS 
 
 
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7. 
REFERENCES 
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/vol10/guidanceclinicaltrials_co
vid19_en.pdf 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3 
(R2). 2009. 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplin
ary/M3_R2/Step4/M3_R2__Guideline.pdf. Accessed 15 February 2019. 
 
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Date of signature: 11-Sep-2020 04:34:47 GMT+0000
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