Clinical trial NCT03784079
Conditions: HIV Infections
Keywords: HIV-1, Antiviral Effect, GSK3640254, Proof of Concept
Sponsor: ViiV Healthcare
Start date: 2019-01-31; Completion date: 2020-02-06
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Infection with HIV-1 continues to be a serious health threat throughout the world. Chronic exposure to combination anti-retroviral therapy identified anti-retroviral associated long-term toxicities. Hence, there is a need to prevent these co-morbidities. GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI) which may be effective for HIV-1 infection. This study will evaluate the antiviral effect, safety, tolerability and pharmacokinetics/ pharmacodynamics of GSK3640254 in HIV-1 infected treatment-naive adults. This study will consists of two parts; Part 1 and Part 2. Part 1 will evaluate two active doses of GSK3640254, 200 milligrams (mg) (Cohort 1) and 10 mg (Cohort 2) along with placebo to match GSK3640254 Mesylate salt. Part 2 will evaluate three active doses of GSK3640254. Dose level 1 of GSK3640254 that can provide at least 30 percent of the maximum effect (Cohort 1), dose level 2 of GSK3640254 that can provide at least 75 percent of the maximum effect (Cohort 2) and dose level 3 of GSK3640254 that can provide at least 90 percent of the maximum effect (Cohort 3). These doses are anticipated to be 5 mg, 40 mg and 100 mg respectively, but could be modified based on data obtained in Part 1. Subjects will also receive placebo to match GSK3640254 Mesylate salt in Part 2 of the study. All doses will be administered after a moderate fat meal. This study will consist of Screening period (up to 14 days), Treatment period (Day 1- Day 10), post-dose Follow-up (Day 11- Day 17) and final Follow-up (Day 18-24). A total of approximately 34 subjects will be enrolled, of which, 14 subjects will be randomized in Part 1 and 20 in Part 2 of the study. Six subjects will be enrolled in each of the active dose cohorts and 2 subjects will be enrolled in each of the placebo cohorts.

Detailed description:

Arms: arm 1: Participants will receive GSK3640254 10 milligram (mg), capsules, orally for 10 days. arm 2: Participants will receive GSK3640254 200 mg, capsules, orally for 10 days. arm 3: Participants will receive placebo capsules, orally for 10 days. arm 4: Participants will receive GSK3640254 40 mg, capsules, orally for 7 days. arm 5: Participants will receive GSK3640254 80 mg, capsules, orally for 7 days. arm 6: Participants will receive GSK3640254 140 mg, capsules, orally for 7 days. arm 7: Participants will receive placebo capsules, orally for 7 days.
Interventions: intervention 1: GSK3640254 intervention 2: Placebo matching GSK3640254 Mesylate salt
Intervention descriptions: intervention 1: GSK3640254 will be available with dosing strengths of 5 mg, 20 mg, and 100 mg to be administered as an oral capsule along with 240 mL of water. intervention 2: Placebo to match GSK3640254 Mesylate salt will be given as an oral capsule along with 240 mL of water

Protocol documents:
Prot_000.pdf: 
2017N345802_03
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TITLE PAGE
Protocol Title: A Randomized, Double-Blind (Sponsor-unblinded), Placebo-Controlled,
Adaptive Trial to Investigate the Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in HIV-1 Infected Treatment-Naïve Adults
Protocol Number: 208132 / 03
Short Title: GSK3640254 POC in Treatment-Naïve Adults
Compound Number:  GSK3640254
Sponsor Name and Legal Registered Address (excluding US): 
ViiV Healthcare UK Limited
980 Great West Road 
Brentford Middlesex, TW8 9GS, UK
US IND Sponsor Name and Legal Registered Address: 
ViiV Healthcare Company
Five Moore Drive, 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
In some countries, local law requires that the Clinical Trial sponsor is a local company 
legal entity. In these instances, the appropriate company to be identified as Sponsor must 
be agreed with the global ViiV Healthcare clinical team and signed off by the Vice 
President, Global Research and Medical Strategy.
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline (GSK) is supporting ViiV 
Healthcare in the conduct of this study.  
Medical Monitor Name and Contact Information 
, DO, MPH
USA mobile
USA fax
Regulatory Agency Identifying Number(s):
IND #: 139,838
EudraCT#:   2018-002208-15
Approval Date: 26-AUG-2019
Copyright 2019 ViiV Healthcare group of companies. All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
26-Aug-2019
Amendment 2
10-Jan-2019
Amendment 1
28-Sep-2018
Original Protocol
15-Aug-2018
Amendment 3 26-AUG-2019
Overall Rationale for the Amendment: Data from Part 1 showed a decline in HIV-1 
RNA and reasonable PK profile. There were no clinically significant trends in AEs, vital 
signs, ECG findings, or chemistry/haematology laboratory abnormalities across dosing 
arms. However, some participants receiving GSK3640254 had treatment emergent 
resistance mutations associated with maturation inhibitors observed on or after Day 11 
(after 10 days of receiving GSK3640254 monotherapy). Additionally, no resistance to 
existing and commercially available classes of antiretroviral medications (e.g., reverse 
transcriptase, protease, integrase) was observed at Day 11 as there is no known cross-
resistance between maturation inhibitors and other classes of ARVs. Genotypic analysis 
of samples at Clinic Visit 5 (Study Day 8 or 9) revealed no treatment emergent resistance. 
As a result, Sponsor made two substantial changes to decrease the risk of treatment 
emergent resistance to participants in Part 2: 1) decrease the duration of monotherapy 
from 10 days to 7 days based on the interim genotypic analysis, and 2) start Investigator 
selected cART immediately after completion of monotherapy and the Part 2 primary 
endpoint (i.e., after the collection of HIV-1 RNA on Day 8).


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Section # and Name
Description of Change
Brief Rationale
Synopsis, Objectives and 
Endpoints
Synopsis, Overall Design
Synopsis, 208132 Study 
Schematic
Synopsis, Treatment 
Groups and Duration
Section 3.1, Study 
Rationale
Section 3.3.2, Benefit 
Assessment
Section 3.3.3, Overall 
Benefit:Risk Conclusion
Section 4, Objectives and 
Endpoints
Section 5.1, Overall 
Design
Section 5.1.1.1, Screening 
Phase
Section 5.1.1.2, Treatment 
Phase and Follow-up 
Period, and to include the 
208132 Study Schematic
Section 5.5, Dose 
Justification
Section 6.3.1, Meals and 
Dietary Restrictions
Section 6.3.2, Alcohol, 
Tobacco and Marijuana
Section 6.3.3, Activity
Section 7.8, Treatment and 
Care After the End of the 
Study
Section 8.2, Withdrawal 
from the Study
Section 9.5, 
Pharmacokinetics, and to 
include Table 4
Changes in these sections are all 
related, in total or in part, to the 
changes made to Study Part 2 
relative to Study Part 1: 

reduction of the treatment 
period from 10 days to 7 days,

reduction of the number of 
study visits

reduction of the number of days 
of overall study participation.
To decrease the risk 
of treatment 
emergent resistance 
in the setting of 
GSK3640254 
monotherapy.


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Section # and Name
Description of Change
Brief Rationale
Section 9.8, Biomarkers
Section 10.1.1, Sample 
Size Considerations
Section 10.3.2.3, 
Pharmacokinetic Analysis
Synopsis, Treatment 
Groups and Duration
Section 5.1.1.2, Treatment 
Phase and Follow-up 
Period 
Section 7.8, Treatment and 
Care After the End of the 
Study
Provided instruction that cART 
should be initiated in study Part 2 
immediately after treatment period 
ends/on Day 8
To reduce the risk to 
participants for
treatment emergent 
resistance in the 
setting of 
GSK3640254 
monotherapy.
Section 2.2, Part 1 and Part 
2 Treatment, Post-Dosing 
and Follow-up Periods
Labelled the original SoA table as 
being specific to study Part 1.
Created another SoA table specific 
to study Part 2 to include the 7-day
treatment period duration and 
abbreviated follow-up period and 
associated assessments and 
procedures:

Clinic Visit 4 was modified to 
be conducted only on Days 5 
and 6.

Clinic Visit 5 was modified to 
be conducted only on Day 7.

Clinic Visit 6 was modified to 
be conducted only on Day 8

Clinic Visit 7 was modified to 
be the Final Follow-up Visit and 
to be conducted on Days 10, 11 
or 12.

Clinic Visits 8 and 9 were 
removed

Days 13-24 were removed

A line item was added for the 
task of observing the dosing 
with cART on Day 8 

Footnotes used in study Part 1 
To reflect the 
treatment duration 
and post-dosing 
period modifications 
for Part 2 as made in 
protocol text.


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Section # and Name
Description of Change
Brief Rationale
were applied, but modified to be 
appropriate to the needs and 
requirements for study Part 2
Section 3.2.2, Preliminary 
Safety and PK Data in 
Study 207187
Provided updated information
regarding the 207187 study.
More current 
information is now 
available.
Section 3.2.4, Justification 
for Part 2 Treatment 
Duration and Initiation of 
cART
Described the data-driven decisions 
made with the resistance data from 
study Part 1, resulting in the 2 key 
changes to be applied in study Part 
2 – to treat for 7 days instead of 10 
days, and to initiate cART 
immediately after the treatment 
period instead of at the end of the 
post-doing period.
To justify the 2 
primary changes in 
this amendment.
Section 3.3, Benefit/Risk 
Assessment
Provided updated information
relative to the risk of treatment 
emergent resistance in the setting of 
GSK3640254 monotherapy
More current 
information is now 
available.
Section 3.3.1, Risk 
Assessment
Cardiovascular category, Risks 
column: Updated with new 
information pertaining to the risks 
for Cardiovascular (QT 
Prolongation)
More current 
information is now 
available.
HIV Resistance to GSK3640254 
category, Risks column: 
Summarized the analyses of the 
treatment emergent resistance that 
was observed after 10 days of
monotherapy in Part 1.
Full analyses of 
resistance data 
revealed additional 
risk for treatment 
emergent resistance.
HIV Resistance to GSK3640254 
category, Mitigation Strategy 
column: Summarized the actions to 
be taken in study Part 2 to reduce 
the risk to participants for treatment 
emergent resistance.
To provide 
additional mitigation 
corresponding to the 
additional risk.
Section 6.1, Inclusion 
Criteria
Inserted new criterion #10 
The addition was 
made to reinforce the 
requirement that 


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Section # and Name
Description of Change
Brief Rationale
cART must be 
started on Day 8.
Section 12.2, Clinical 
Laboratory Tests, Table 7, 
Protocol Required Safety 
Assessments
Add the caveat that glucose cannot 
be done in a non-fasted state on 
clinic days when fasting lipids are 
also collected.
For clarity.
Other administrative
changes
Minor editorial and document 
formatting revisions
Minor, therefore not 
summarized


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................11
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................17
2.1.
Part 1 and Part 2 Screening........................................................................17
2.2.
Part 1 and Part 2 Treatment, Post-Dosing and Follow-up Periods ..............18
3.
INTRODUCTION....................................................................................................31
3.1.
Study Rationale ..........................................................................................31
3.2.
Background ................................................................................................31
3.2.1.
Background Key Safety Data with a Prior Maturation 
Inhibitor (GSK3532795) ...............................................................31
3.2.2.
Preliminary Safety and PK Data in Study 207187 ........................32
3.2.3.
Preliminary Safety and PK Data in Study 208131 ........................34
3.2.4.
Justification for Part 2 Treatment Duration and Initiation of 
cART ...........................................................................................34
3.3.
Benefit/Risk Assessment ............................................................................34
3.3.1.
Risk Assessment .........................................................................36
3.3.2.
Benefit Assessment.....................................................................39
3.3.3.
Overall Benefit:Risk Conclusion...................................................39
4.
OBJECTIVES AND ENDPOINTS...........................................................................39
5.
STUDY DESIGN ....................................................................................................40
5.1.
Overall Design ............................................................................................40
5.1.1.
Treatment Groups and Duration ..................................................41
5.1.1.1.
Screening Phase........................................................41
5.1.1.2.
Treatment Phase and Follow-up Period......................41
5.2.
Number of Participants ...............................................................................44
5.3.
Participant and Study Completion...............................................................44
5.4.
Scientific Rationale for Study Design ..........................................................45
5.5.
Dose Justification........................................................................................45
5.5.1.
Dose Justification for Part 1 .........................................................45
5.5.2.
Dose Justification for Part 2 .........................................................46
6.
STUDY POPULATION...........................................................................................47
6.1.
Inclusion Criteria.........................................................................................48
6.2.
Exclusion Criteria........................................................................................49
6.3.
Lifestyle Restrictions...................................................................................51
6.3.1.
Meals and Dietary Restrictions ....................................................51
6.3.2
Alcohol, Tobacco and Marijuana..................................................51
6.3.3
Activity .........................................................................................52
6.3.4
Counsel regarding Safe Sex Practices.........................................52
6.4.
Screen Failures...........................................................................................52
7.
TREATMENTS.......................................................................................................52
7.1.
Treatments Administered............................................................................53
7.2.
Dose Modification .......................................................................................53


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7.3.
Method of Treatment Assignment ...............................................................53
7.4.
Blinding and Interim Analysis......................................................................54
7.5.
Preparation/Handling/Storage/Accountability..............................................54
7.6.
Treatment Compliance................................................................................55
7.7.
Concomitant Therapy..................................................................................55
7.8.
Treatment and Care after the End of the Study...........................................56
8.
DISCONTINUATION CRITERIA.............................................................................56
8.1.
Discontinuation of Study Treatment ............................................................56
8.1.1.
Liver Chemistry Stopping Criteria ................................................56
8.1.2.
QTc Stopping Criteria ..................................................................57
8.1.3.
Individual Participant Laboratory Abnormality and AE 
Stopping Criteria..........................................................................58
8.1.4.
Temporary Discontinuation ..........................................................58
8.1.5.
Rechallenge.................................................................................58
8.1.5.1.
Study Treatment Restart or Rechallenge....................58
8.2.
Withdrawal from the Study..........................................................................58
8.3.
Lost to Follow Up........................................................................................59
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................59
9.1.
Efficacy Assessments.................................................................................60
9.1.1.
HIV-1 RNA Sampling ...................................................................60
9.1.2.
Lymphocyte Subsets by Flow Cytometry .....................................60
9.2.
Adverse Events...........................................................................................61
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................61
9.2.2.
Method of Detecting AEs and SAEs.............................................61
9.2.3.
Follow-up of AEs and SAEs.........................................................62
9.2.4.
Regulatory Reporting Requirements for SAEs .............................62
9.2.5.
Cardiovascular and Death Events................................................62
9.2.6.
Pregnancy ...................................................................................63
9.3.
Treatment of Overdose...............................................................................63
9.4.
Safety Assessments ...................................................................................63
9.4.1.
Physical Examinations.................................................................63
9.4.2.
Vital Signs....................................................................................63
9.4.3.
Electrocardiograms......................................................................64
9.4.4.
Clinical Safety Laboratory Assessments ......................................64
9.4.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms..................................................................65
9.4.6.
GI Toxicity Evaluation and Monitoring Plan..................................65
9.5.
Pharmacokinetics .......................................................................................68
9.6.
Pharmacodynamics ....................................................................................70
9.7.
Genetics .....................................................................................................70
9.8.
Biomarkers .................................................................................................71
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................71
10. STATISTICAL CONSIDERATIONS........................................................................71
10.1.
Sample Size Determination ............................................................................71
10.1.1.
Sample Size Considerations........................................................71
10.1.2.
Sample Size Sensitivity................................................................72
10.1.3.
Sample Size Re-estimation or Adjustment...................................73


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10.2.
Populations for Analyses ............................................................................73
10.3.
Statistical Analyses.....................................................................................74
10.3.1.
Interim Analysis ...........................................................................74
10.3.2.
Primary Analyses.........................................................................74
10.3.2.1.
Safety Analyses..........................................................75
10.3.2.2.
Efficacy Analyses .......................................................75
10.3.2.3.
Pharmacokinetic Analyses..........................................75
10.3.3.
Secondary Analyses ....................................................................76
10.3.3.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........76
10.3.3.2.
Viral Genotyping and Phenotyping Analyses ..............76
11. REFERENCES.......................................................................................................77
12. APPENDICES........................................................................................................79
12.1.
Appendix 1: Abbreviations and Trademarks................................................79
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................85
12.3.
Appendix 3: Study Governance Considerations..........................................87
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................91
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................97
12.6.
Appendix 6: Genetics..................................................................................99
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................100
12.8.
Appendix 8: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, March 2017............................102
12.9.
Appendix 9: CDC Classification for HIV-1 Infection (2014)........................103
12.10. Appendix 10: Protocol Amendment History...............................................105


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1.
SYNOPSIS
Protocol Title: A Randomized, Double-Blind (Sponsor-unblinded), Placebo-Controlled, 
Adaptive Trial to Investigate the Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in HIV-1 Infected Treatment-Naïve Adults
Short Title: GSK3640254 POC in Treatment-Naïve Adults 
Rationale:
Infection with HIV-1 continues to be a serious health threat throughout the world, with 
more than one million infected individuals in the U.S. and more than 40 million 
worldwide. The now chronic exposure to combination anti-retroviral therapy (cART) has 
identified anti-retroviral (ARV)-associated long-term toxicities (e.g. central nervous 
system (CNS) or cardiovascular (CV)/metabolic effects, renal disease, etc.), creating a 
need to address and prevent these co-morbidities. Also, treatment failure remains a 
continuing concern in clinical care due to the presence and emergence of resistant strains 
and tolerability issues; in addition, the ageing HIV-1-infected population drives a need 
for drugs with fewer drug-drug interactions. In this environment, medicines with novel 
mechanisms of action (MoA) that can be used as part of the preferred cART regimen 
have an important role to play. However, to be successful, a new ARV agent must be safe
and effective, provide a relatively high barrier to resistance, have low toxicity, have 
minimal drug-drug interactions, and preferably be a relatively low-dose once-a-day drug 
that can be combined with other agents as part of a fixed-dose regimen. GSK3640254, an 
HIV-1 maturation inhibitor (MI), has the potential to meet such valued features for a new 
ARV medicine. 
GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI) which binds near a 
key structural element within the group-specific antigen (Gag) polyprotein that is 
required for virion maturation and assembly. 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. 
The clinical development of GSK3640254 is progressing.  Study 207187 is the First Time 
in Human (FTIH) study of GSK3640254 investigating the safety, tolerability, and 
pharmacokinetics (PK) of single and repeated escalating doses in healthy participants.  
Healthy participants not receiving placebo have received GSK3640254 to a maximum 
single dose of 700 mg and multiple doses up to 320 mg QD for 14 days.  Study 207187 
has shown GSK3640254 to be generally well-tolerated in healthy volunteers to date and 
has thus far demonstrated a PK profile suitable for progression to HIV-1 infected 
treatment naïve (TN) patients in this Phase 2a proof of concept (POC) 10-day, 
monotherapy study. 
The FTIH Study 207187 uses a bis-hydrochloride salt capsule formulation of 
GSK3640254, which is not suitable for long term clinical development. The relative 
bioavailability Study 208131 assessed the relative bioavailability of a mesylate salt 
capsule formulation of GSK3640254 intended for use in this POC study, compared to the 
hydrochloride salt capsule formulation used in the FTIH study. Preliminary results from 


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study 208131 showed that in the presence of a moderate fat meal, the relative 
bioavailability of GSK3640254 following 200 mg GSK3640254 Mesylate Salt 
administration relative to 200 mg GSK3640254 Bis Hydrochloride salt administration 
was 107% and 110% based on AUC(0-) and maximum observed concentration (Cmax),
respectively.
Data from these studies will be utilized to support future clinical development of 
GSK3640254.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1 infected TN participants 
during 10 days of monotherapy in Part 1 and 
during 7 days of monotherapy in Part 2

Maximum change from baseline (Day 
1) in plasma HIV-1 ribonucleic acid (RNA)
Key Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in Part 1 and over 7 
days in Part 2 in HIV-1 infected TN participants

GSK3640254 safety and tolerability 
parameters: adverse events (AE); post-
baseline values and changes over time of 
clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters.

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 infected 
patients 

GSK3640254 PK parameters at the 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax), 
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
curve (Area under the plasma drug 
concentration-time curve from pre-dose to the 
end of the dosing interval at steady state (AUC 
[0-]), Cmax, tmax, pre-dose concentration 
(C0), concentration at end of dosing interval 
(C), apparent terminal phase half-life (t1/2), 
and apparent oral clearance (CL/F), if data 
permit.

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline


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Objectives
Endpoints

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in Part 1 and for 7 
days in Part 2 in HIV-1 infected patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 
GSK3640254 PK parameters following dosing 
for 10 days in Part 1 and for 7 days in Part 2

Relationship between Day 1 AUC (0-
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
Overall Design:
This is a Phase 2a, global, multicenter, randomized, double-blind (Sponsor-unblinded), 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability and PK/ pharmacodynamics (PD) of GSK3640254 over 10 days in study Part 
1 and over 7 days in study Part 2 in ART-naïve HIV-1 infected adults who are termed
“participants” in rest of this protocol.  
This study will be conducted in two parts, separated to allow for an unblinded interim 
analysis performed after Part 1 (see Figure 1 Schematic for Study 208132).  
Part 1 will evaluate two active doses of GSK3640254 in cohorts of 6 participants each. 

The 200 mg dose in Part 1 will be a well-tolerated dose of GSK3640254 based on 
the prior Phase I study (207187) that is predicted to provide at least 90% of the maximum 
anticipated effect for a maturation inhibitor on HIV-1 RNA reduction in a 10-day study. 
It is anticipated that this dose will be the highest dose to be tested in this study unless
actual exposure in this population is lower than seen in healthy volunteers in studies
207187 and 208131.

The 10 mg in Part 1 will target approximately fifty percent of the maximum 
anticipated effect on HIV-1 RNA reduction. 
Part 1 will also include a cohort of 2 participants who will receive placebo. The 
justification for the use of a placebo control allows for blinded assessment of safety and 
tolerability. Since Investigators and patients will be blinded, any safety event (AE, lab 
abnormality, ECG abnormality, etc) will be evaluated and managed in the same fashion. 
Finally, the use of placebo control does allow for a comparison of antiviral effect 
between GSK3640254 and placebo. 
Part 2 will evaluate up to three active doses of GSK3640254 (depending upon the data 
obtained in Part 1) in cohorts of 6 participants each. 

Part 2 doses may include one dose lower than the Part 1 10 mg dose, with the 
remaining doses between the range of Part 1 doses; one or two doses in Part 2 may be 
higher than the Part 1 200 mg dose if exposure in participants is lower than those 
observed from healthy participants in study 207187 and 208131. 


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Part 2 will also include a cohort of 2 participants to receive placebo. The justification for 
the use of placebo in Part 2 is the same as Part 1 above.
In study Part 1, following a screening visit, qualified participants will be randomized 
within 14 days (up to 28 days in some cases) into one of the treatment arms, each 
consisting of a 10-day treatment and minimum of 8 visits over 17 days. Then participants 
will receive follow-up evaluations during approximately 1-2 weeks following the last 
dose.
In study Part 2, following a screening visit, qualified participants will be randomized 
within 14 days (up to 28 days in some cases) into one of the treatment arms, each 
consisting of a 7-day treatment and minimum of 6 visits over 8 days. Then participants 
will receive follow-up evaluations during approximately 3-5 days following the last dose.
This study will explore a wide dose range of GSK3640254. It will provide data to explore 
the safety, PK, and PK/PD relationship of GSK3640254 in HIV-1 infected participants
and facilitate choice of doses for future studies.
Figure 1
Schematic for Study 208132
1.
10 and 200 mg once daily GSK3640254 mesylate salt
2.
Part 1 safety/PK/viral load data will be evaluated at interim, prior to initiating other cohorts in Part 2, which are 
planned to run in a parallel, randomized fashion.
3.
Part 2 doses are an illustration of the projected doses per cohort. The actual doses for each cohort are subject to
modification based upon safety, PK and antiviral activity data from Part 1. 
Number of Participants:
A total of approximately 34 participants will be randomized into the 2-part trial. 
Part 1 of the study will include approximately 14 randomized participants; Part 2 of the 
study will include approximately 20 randomized participants.  In each study part, 6


2017N345802_03
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participants will be enrolled in each of the GSK3640254 cohorts and 2 participants will 
be enrolled in each of the placebo cohorts, as shown in the Schematic for Study 208132. 
It is estimated that approximately 68 participants will be screened in order to have 34 
randomized and evaluable participants (screen failure rate of 50%).
If participants prematurely discontinue the study, additional participants may be 
randomized and assigned to the same cohort in consultation with the Investigator.
Treatment Groups and Duration:
The various treatment cohorts are shown in the Schematic for Study 208132.
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period in Part 1 and into a 7-day treatment period 
in Part 2. The 14-day screening period may be extended to 28 days in some cases to allow 
receipt of all screening results and/or to accommodate scheduling. 
A qualified participant will be randomized into the treatment phase of the study and will 
administer study treatments, once daily, from Day 1 through Day 10 in Part 1 and from 
Day 1 through Day 7 in Part 2. On Day 1, an appropriate number of bottles will be 
dispensed, with a supply sufficient to cover the entire treatment period.  The blinded 
bottles will contain capsules of either the active dose or placebo.  Dosing instructions will 
be indicated on each bottle.  Participants will bring the bottles of study treatments to each 
visit, so that study treatment can be administered in the clinic after the study procedures 
have been performed.
Each dose of study medication will be taken with approximately 240 mL (8 ounces) of 
water following ingestion of a moderate calorie and fat meal (i.e. at least 400 calories, 
with at least 120 calories from fat), that is required to be completed within 30 minutes 
prior to dosing. A moderate calorie and fat breakfast is planned to be similar to the 
following (additional meal suggestions will be included in the Study Reference Manual 
[SRM]): 

2 slices of bread

10 g of butter

20 g of jam

15 g of cheese

175 mL of apple juice
Study treatments should be administered near the same time each morning, within a 2-hr 
window.
On days when the participant self-administers the study treatments, observed dosing with 
a site staff member may be achieved as locally permitted using various forms of video 
calling (when at all possible) such as FaceTime, Skype, WhatsApp.


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Participants will then enter the post-dosing period:
Study Part 1:
There are 4 in-clinic visits in the Part 1 post-dosing period: 3 visits for PK and 
other assessments during the 7 days immediately following the last dose, and a
final follow-up visit primarily for safety (e.g., to follow any AEs to resolution)
approximately 8-14 days after the last dose, as shown in the Part 1 Schedule of 
Activities (SOA, Section 2). In Part 1, participants should not start other 
medicines and will not start ARVs during the post-dosing period until they have 
completed the final follow-up visit.  
In the shortest course for Part 1, a participant can be screened/qualified, treated
and assessed for all the planned visits (including the final follow-up visit) in 
approximately 30 days (if, for example, only 10-14 days are needed for the 
screening period and the final follow-up visit is performed on Day 18).  In the 
longest course for Part 1, a participant can be screened/qualified, treated and 
assessed for all the planned visits (including the final follow-up visit) in 52 days 
(if, for example, 28 days are needed for the screening period and the final follow-
up visit is performed on Day 24).
Study Part 2: 
There are 2 in-clinic visits in the Part 2 post-dosing period: 1 visit for PK and 
other assessments on the day immediately following the last dose, and a final 
follow-up visit primarily for safety (e.g., to follow any AEs to resolution) 3-5 
days after the last dose, as shown in the Part 2 Schedule of Activities (SOA, 
Section 2).
In Part 2, participants will start Investigator-selected, prescribed and provided
cART immediately following the completion of the primary endpoint, i.e., the 
measurement of HIV-1 RNA on Day 8.
In the shortest course for Part 2, a participant can be screened/qualified, treated 
and assessed for all the planned visits (including the final follow up visit) in 
approximately 24 days (if, for example, only 10-14 days are needed for the 
screening period and the final follow-up visit is performed on Day 10.  In the 
longest course, a participant can be screened/qualified, treated and assessed for all 
the planned visits (including the final follow-up visit) in 40 days (if, for example, 
28 days are needed for the screening period and the final follow-up visit is 
performed on Day 12).


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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Part 1 and Part 2 Screening
1.
Procedures should be performed in this order: 1: ECG, Vital Signs, Blood Draws
2.
Participants will be randomized within 14 days of the start of Screening; up to 28 days maximum
may be allowed in some cases.
3.
If test was otherwise performed within 3 months prior to first dose of study treatment, testing at 
Screening is not required.
4.
Log in to RAMOS to complete a registration for participant ID assignment.  If the participant fails 
screening, log in to RAMOS to register the participant as a Screen Fail.
Procedure1
Screening 
(14 days2 before Day 1)
Notes
Clinical Assessments
Outpatient Visit
X
Informed Consent
X
Medical/medication/drug/alcohol history
X
Prior anti-retroviral therapy
X
Serious Adverse events (SAE) Assessment
X
Section 9.2
Center for Disease Control and Prevention
(CDC) Classification 
X
Human immunodeficiency virus (HIV)-associated 
conditions assessment
X
Height, Weight, Body Mass Index (BMI)
X
Section 9.4.1
Vital Signs
X
Section 9.4.2
Columbia Suicide Severity Rating Scale         
(C-SSRS) administration – Baseline form
X
Section 9.4.5
Clinical Procedures
Electrocardiogram (ECG)(single reading)
X
Section 9.4.3
Pregnancy Test (Urine or Serum Human 
chorionic gonadotropin [β-hCG]) 
X
Section 9.2.6
Hematology/Chemistry/Urine 
X
Section 9.4.4
Fasting Lipid Panel (approximately 8 hours)
X
Section 9.4.4
Hepatitis B Virus (HBV) and Hepatitis C Virus
(HCV)serologies3
X
Lymphocyte T-cell subsets (Cluster of 
designation 4 [CD4], CD8)
X
Section 9.1.2
HIV-1 Ribonucleic Acid (RNA)
X
Section 9.1.1
Drugs of Abuse 
X
Interactive Web Response System (IWRS)
(RAMOS) activity4
X


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2.2.
Part 1 and Part 2 Treatment, Post-Dosing and Follow-up Periods
Study Part 1:
Procedure1
Treatment Period 
Day 1 – Day 10
Post-Dosing Follow Up Period
Day 11 – 17
Final 
Follow-up
Day 18-24
Day 1
Day 2
Day 3, 4
Choose one day for 
the Clinic Visit 3. 
The other day will 
be a virtual event.
Day 5, 6, 7
Choose one day for the   
Clinic Visit 4. 
The other days 
will be virtual events.
Day 8, 9, 10
Choose one day for the     
Clinic Visit 5. 
The other days 
will be virtual events.
Day 11
Day 12
Day 13, 14, 
15, 16 or 17
Day 18, 19, 
20, 21, 22, 
23 or 24
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic 
Visit 4
Virtual
Virtual
Clinic 
Visit 5
Virtual
Virtual
Clinic 
Visit 6
Clinic 
Visit 7
Clinic        
Visit 8
Clinic        
Visit 9
Clinical 
Assessments
Outpatient Visit2
X
X
X
X
X
X
X
X
X
Video/Phone Call
X
X
X
X
X
Verify Inclusion/
Exclusion Criteria
X
Medical/medicatio
n/drug/alcohol 
history
X
Prior Anti-retroviral 
(ARV) Check
X
CDC Classification
X
X


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Procedure1
Treatment Period 
Day 1 – Day 10
Post-Dosing Follow Up Period
Day 11 – 17
Final 
Follow-up
Day 18-24
Day 1
Day 2
Day 3, 4
Choose one day for 
the Clinic Visit 3. 
The other day will 
be a virtual event.
Day 5, 6, 7
Choose one day for the   
Clinic Visit 4. 
The other days 
will be virtual events.
Day 8, 9, 10
Choose one day for the     
Clinic Visit 5. 
The other days 
will be virtual events.
Day 11
Day 12
Day 13, 14, 
15, 16 or 17
Day 18, 19, 
20, 21, 22, 
23 or 24
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic 
Visit 4
Virtual
Virtual
Clinic 
Visit 5
Virtual
Virtual
Clinic 
Visit 6
Clinic 
Visit 7
Clinic        
Visit 8
Clinic        
Visit 9
HIV-associated 
conditions 
assessments3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
(AE)/SAE 
assessment3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication review3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, BMI and 
Physical exam4 
X
Vital Signs
X
X
X
X
X
C-SSRS
Administration          
(Since Last Visit
form)
X


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Procedure1
Treatment Period 
Day 1 – Day 10
Post-Dosing Follow Up Period
Day 11 – 17
Final 
Follow-up
Day 18-24
Day 1
Day 2
Day 3, 4
Choose one day for 
the Clinic Visit 3. 
The other day will 
be a virtual event.
Day 5, 6, 7
Choose one day for the   
Clinic Visit 4. 
The other days 
will be virtual events.
Day 8, 9, 10
Choose one day for the     
Clinic Visit 5. 
The other days 
will be virtual events.
Day 11
Day 12
Day 13, 14, 
15, 16 or 17
Day 18, 19, 
20, 21, 22, 
23 or 24
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic 
Visit 4
Virtual
Virtual
Clinic 
Visit 5
Virtual
Virtual
Clinic 
Visit 6
Clinic 
Visit 7
Clinic        
Visit 8
Clinic        
Visit 9
Clinical 
Procedures
12-lead ECG 
(triplicate reading, 
pre-dose; single 
readings at PK 
draws 2hr, 4hr, 
and 6hr)
X
12-lead ECG
(single reading, 
pre-dose at Visits 
2 and 3)
X
X
X
12-lead ECG 
(single reading 
pre-dose and at 
PK draws 2hr, 4hr, 
and 6hr)
X
Pharmacogenetics 
(PGX) Collection      
(if consented)
X


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Procedure1
Treatment Period 
Day 1 – Day 10
Post-Dosing Follow Up Period
Day 11 – 17
Final 
Follow-up
Day 18-24
Day 1
Day 2
Day 3, 4
Choose one day for 
the Clinic Visit 3. 
The other day will 
be a virtual event.
Day 5, 6, 7
Choose one day for the   
Clinic Visit 4. 
The other days 
will be virtual events.
Day 8, 9, 10
Choose one day for the     
Clinic Visit 5. 
The other days 
will be virtual events.
Day 11
Day 12
Day 13, 14, 
15, 16 or 17
Day 18, 19, 
20, 21, 22, 
23 or 24
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic 
Visit 4
Virtual
Virtual
Clinic 
Visit 5
Virtual
Virtual
Clinic 
Visit 6
Clinic 
Visit 7
Clinic        
Visit 8
Clinic        
Visit 9
Hematology/Chem
istry/Urine
X
X
X
X
X
X
X
Fasting Lipid 
Panel
(approximately 8 
hrs)
X
X
X
Lymphocyte T-cell 
subsets (CD4, 
CD8)
X
X
Plasma for HIV-1 
genotype/phenoty
pe5
X
X
X
X
X
X
X
X
X
Plasma for 
storage6
X
X
X
X
X
X
X
X
X
HIV-1 RNA
X
X
X
X
X
X
X
X
X


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Procedure1
Treatment Period 
Day 1 – Day 10
Post-Dosing Follow Up Period
Day 11 – 17
Final 
Follow-up
Day 18-24
Day 1
Day 2
Day 3, 4
Choose one day for 
the Clinic Visit 3. 
The other day will 
be a virtual event.
Day 5, 6, 7
Choose one day for the   
Clinic Visit 4. 
The other days 
will be virtual events.
Day 8, 9, 10
Choose one day for the     
Clinic Visit 5. 
The other days 
will be virtual events.
Day 11
Day 12
Day 13, 14, 
15, 16 or 17
Day 18, 19, 
20, 21, 22, 
23 or 24
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic 
Visit 4
Virtual
Virtual
Clinic 
Visit 5
Virtual
Virtual
Clinic 
Visit 6
Clinic 
Visit 7
Clinic        
Visit 8
Clinic        
Visit 9
Single, 
Pharmacokinetic 
(PK) sample (pre-
dose at Visits 3 
and 4)
X
X
X7
X
X
Intensive PK 
sampling8 (with 
sample at 24hr 
time point the next 
morning)
X
X9
Observed dosing 
with 
GSK3640254/plac
ebo3
X
X
X
X
X
X
X
X
X
X
IWRS (RAMOS) 
activity10
X


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1.
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration.
2.
The study requires 9 in-clinic visits.  Flexibility is offered for Visits 3, 4, 5, 8 and 9.  The visit schedule for each participant should be pre-
planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the treatment period can 
be greater than 3 days.
3.
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not in the 
clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al.
4.
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen).
5.
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 11 samples, with other visits tested as appropriate.
6.
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study completion, 
they will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response (excluding any human 
genetic testing)
7.
If the Intensive PK day occurs on Day 10, do not collect the Day 11 pre-dose PK sample (as it is redundant with the 24-hr PK collection 
(completing the sample set started on Day 10).
8.
Intensive Plasma PK samples will be collected as outlined in Table 4 in Section 9.5
9.
If Day 8 or 9 is the Clinic Visit 5 to include the Intensive PK collection, the participant must return the following day for the 24-hr PK 
collection, meal and dosing.  The assessments to be done as indicated on what is a “virtual visit day” should be captured as a virtual visit, 
even if the questions are asked in the clinic.
10.
Log in to RAMOS on Day 1 to randomize the participant and to receive blinded study treatment.  Subsequently log-in to RAMOS for study 
treatment supply as needed. If a participant is discontinued from the study early, log in to RAMOS to record the discontinuation.

The timing and number of planned study assessments, including safety, efficacy, pharmacokinetic, pharmacodynamic/biomarker assessments 
may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments 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 IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the ICF.


2017N345802_03
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24
Study Part 2:
Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Clinical 
Assessments
Outpatient Visit2
X
X
X
X
X
X
X
Video/Phone Call
X
X
Verify Inclusion/ 
Exclusion Criteria
X
Medical/medicatio
n/drug/alcohol 
history
X
Prior Anti-retroviral 
(ARV) Check
X
CDC Classification
X
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
HIV-associated 
conditions 
assessments3
X
X
X
X
X
X
X
X
X
Adverse event 
(AE)/SAE 
assessment3
X
X
X
X
X
X
X
X
X
Concomitant 
medication 
review3
X
X
X
X
X
X
X
X
X
Weight, BMI and 
Physical exam4 
X
Vital Signs
X
X
X
X
X
C-SSRS 
Administration          
(Since Last Visit
form)
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Clinical 
Procedures
12-lead ECG 
(triplicate reading, 
done pre-dose; 
single readings at 
PK draws 2hr, 4hr, 
and 6hr)
X
12-lead ECG
(single reading, 
done pre-dose at 
Visits 2 and 3)
X
X
X
12-lead ECG 
(single reading 
done pre-dose and 
at PK draws 2hr, 
4hr, and 6hr)
X


2017N345802_03
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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Pharmacogenetics 
(PGX) Collection 
(if consented)
X
Hematology/Chem
istry/Urine
X
X
X
X
X
X
X
Fasting Lipid 
Panel
(approximately 8 
hrs)
X
X
X
Lymphocyte T-cell 
subsets (CD4, 
CD8)
X
X
Plasma for HIV-1 
genotype/phenoty
pe5
X
X
X
X
X
X
Plasma for 
storage6
X
X
X
X
X
X
X


2017N345802_03
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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
HIV-1 RNA
X
X
X
X
X
X
X
Single, 
Pharmacokinetic 
(PK) sample done 
pre-dose 
X
X
Intensive PK 
sampling(to 
include the 24hr 
samples drawn the 
next day)
X
X
Observed dosing 
with GSK3640254
/placebo3
X
X
X
X
X
X
X


2017N345802_03
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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Observed dosing 
with Investigator-
selected, 
prescribed and 
provided CART, 
and eCRF 
completion
X
IWRS (RAMOS) 
activity8
X


2017N345802_03
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1.
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration.
2.
The study requires 7 in-clinic visits.  Flexibility is offered for Visits 3, 4 and 7.  The visit schedule for each participant should be pre-
planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the treatment period can 
be greater than 3 days.
3.
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not in the 
clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al.
4.
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen).
5.
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 8 samples, with other visits tested as appropriate.
6.
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study completion, 
they will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response (excluding any human 
genetic testing)
7.
Intensive Plasma PK samples will be collected as outlined in Table 4 in Section 9.5
8.
Log in to RAMOS on Day 1 to dispense blinded study treatment.  Subsequently log-in to RAMOS for study treatment supply as needed. If 
a participant is discontinued from the study early, log in to RAMOS to record the discontinuation.

The timing and number of planned study assessments, including safety, efficacy, pharmacokinetic, pharmacodynamic/biomarker assessments 
may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments 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 IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the ICF


2017N345802_03
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3.
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 Maturation Inhibitors (MIs) approved for the treatment of 
HIV infection. 
3.1.
Study Rationale
The proposed Study 208132 is a proof of concept (POC), randomized double blind 
(Sponsor-unblinded) study to characterize antiviral activity, safety/tolerability, PK, and 
the relationship between PK and antiviral activity of GSK3640254 given once daily 
(QD), administered across a range of doses over 10 days in study Part 1 and over 7 days 
in study Part 2 in HIV-1 infected treatment-naïve adults.  To minimize the number of 
participants exposed to suboptimal or redundant doses, a two-part, adaptive and dose-
ranging design is applied in this study. This two-part, adaptive design will allow an early 
understanding of the potential of GSK3640254, while not exposing HIV-infected 
participants to longer courses and possible development of resistance.  Data from this 
study will be utilized to select doses for further studies in Phase 2b.
3.2.
Background
GSK3640254 is an HIV MI which is improved over prior developmental MIs in the 
following ways: (1) it exhibits significantly improved pangenotypic coverage and 
potency against polymorphic variants; (2) in vitro data suggest that GSK3640254 exhibits 
a higher barrier to emergence of resistant viruses (except for A364V); (3) GSK3640254 
has improved potency in vitro toward all HIV-1 subtypes; (4) it has potential for 
improved GI tolerability; and (5) it has a projected lower once-daily human dose (see 
Dose Justification, Section 5.5). Summaries of the pre-clinical and clinical studies are 
included in the Clinical Investigator's Brochure (CIB) [GSK Document Number 
2018N379610_00]
3.2.1.
Background Key Safety Data with a Prior Maturation Inhibitor 
(GSK3532795)
Bristol-Myers Squibb (BMS), and later ViiV Healthcare (VH), developed a structurally 
similar HIV-1 MI (BMS-955176/GSK3532795), which was studied through Phase 2b 
studies in both treatment-naïve (AI468038/205891) and experienced (AI468048/205892) 
HIV-1 infected adults. In study AI468038/205891, a greater number of participants who 
received GSK3532795 experienced gastrointestinal (GI) intolerability (specifically Grade 
1-2 diarrhea and abdominal pain). A detailed examination of all GI adverse events (AEs) 
(regardless of Grade/Relationship) revealed a relationship with dose [GSK Document 
Number 2016N302783_00]. Ultimately, the rate of GI intolerability in the GSK3532795 
dose groups in the Phase 2b study 205891, led in part to VH’s decision to end all trials 


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and not progress to Phase 3 studies.  GI AEs were also previously observed in healthy 
participants in Phase 1 studies with varying doses, durations, and formulations of 
GSK3532795. In all three studies, the most common GI AEs were abdominal pain and 
diarrhea.
Aside from mild-moderate GI intolerability, two serious adverse events (SAEs) occurred
in the Phase I Thorough QT study AI468044/206220 [CSR, BMS] at supra-therapeutic 
doses: one healthy participant had an episode of acute psychosis and another had suicidal 
ideation/homicidal ideation as diagnosed through an interview by a psychiatrist. The two 
participants received GSK3532795 240 mg twice daily (BID) and 240 mg QD for 3 days 
with food, respectively. These events were assessed as related to study drug but were not 
observed in any other clinical study with GSK3532795. The most frequent 
neuropsychiatric AEs in studies with GSK3532795 were headache, dizziness and sleep 
abnormalities (e.g. insomnia, abnormal dreams).
3.2.2.
Preliminary Safety and PK Data in Study 207187
The First Time in Human Clinical Trial’s (207187) primary objective was to investigate 
the safety and tolerability of GSK3640254 following single and repeated daily 
administration. A total of 78 healthy men were ultimately randomized: 20 in the single 
ascending dose (SAD, doses ranging from 1-700 mg) and 58 in the multiple ascending 
dose (MAD, 50-320 mg QD for 14 days). A comprehensive summary of results is
described in the Investigator Brochure [GSK Document Number 2018N379610_00] and 
the Study Synopsis [GSK Document Number 2018N375461_00]. A concise summary of 
the data is presented below.
No deaths or SAEs have been reported. There were 4 AEs leading to discontinuation. 
Only one of these was related to study medication. A subject who received GSK3640254
200 mg QD developed a maculopapular rash after 8 days of study medication. The rash 
lasted for 6 days and there were no laboratory abnormalities. A Dermatology Consultant 
concluded this was a drug rash and the subject later received fexofenadine 180 mg once 
daily/a topical steroid cream with resolution. The other three AEs occurred in SAD 
portion of the study (depression in a subject who received placebo and two subjects with 
viral infection).
There were 9 subjects with 12 AEs assessed as related to study medication by the 
principle investigator (11 Grade 1; 1 Grade 2). The most clinically notable was a subject 
who developed elevated transaminases while receiving GSK3640254 50 mg QD for 14 
days. Specifically, they had a progressive rise in alanine aminotransferase (ALT) during 
treatment with a peak ALT of 83 IU/L on Day 16. The remaining liver chemistries were 
normal throughout. An Ultrasound showed a subcapsular area of heterogenous 
echogenicity within segment 7, measuring approximately 35 x 23 x 36 mm. A follow up 
MRI and liver chemistries were normal. This subject also had three unrelated AEs during 
the course of an isolated increased ALT: musculoskeletal stiffness, contact dermatitis, 
and headache. All other related AEs are described in the Investigator’s Brochure (IB)
[GSK Document Number 2018N379610_00] and the Study Synopsis [GSK Document 
Number 2018N375461_00].


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In the SAD, seventeen subjects experienced 60 individual AEs (58 Grade 1; 2 Grade 2). 
The 2 Grade 2 AEs were headache and depression (both unrelated). The most frequent 
AEs were Headache (6 subjects), Contact Dermatitis primarily due to electrocardiogram 
(ECG) electrodes (5 subjects), and Diarrhea (4 subjects). There was no dose/AE 
relationship. 
In the MAD, 43 subjects experienced 126 individual AEs (123 Grade 1; 3 Grade 2). The 
3 Grade 2 AEs were headache (one related and one unrelated) and back pain (unrelated).
The most frequent AEs were Headache (15 subjects), Contact Dermatitis (8 subjects), 
Dizziness (7 subjects), Contusion (6 subjects), Fatigue (6 subjects), and Back Pain (4 
subjects).
There were no clinically significant abnormal fluctuations or trends in vital signs in the
SAD or MAD cohorts. There were no abnormal clinically significant arrhythmias or QT
prolongations (values >500 ms or increases >60 ms from Baseline) observed for any
participant in the SAD or MAD. A cardiodynamic evaluation of healthy subjects in the
MAD portion of Study 207187 (placebo or GSK3640254 dose range 50 to 320 mg daily
for 14 days) was performed. Serial ECGs were extracted from continuous Holter
monitors at time-matched baseline on Day -1 and for approximately 24 hours post-dose
on Days 1 and 14. In the concentration-QTc analysis, a final model with a treatment
effect-specific intercept reasonably represented the data. The slope of the
concentration-QTc relationship was 0.004 ms per ng/mL (90% confidence interval [CI]:
0.0023 to 0.0048) with a small treatment effect-specific intercept of -0.9 ms (90% CI:
-4.47 to 2.69). The QT effect (ΔΔQTcF) of GSK3640254 could be predicted to be
5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms (90% CI: 2.79 to 10.61) for the 200 mg
(1779 ng/mL) and 320 mg (2154 ng/mL) doses, respectively, on Day 14. Based on this
concentration-QTc analysis, a QTcF effect above 10 ms could be excluded up to
GSK3640254 plasma concentrations of approximately 2000 ng/mL (corresponding to
doses approximately ≤200 mg QD; note, the maximum dose used in Part 1 of this study, 
208132, is 200 mg QD). Finally, there were no laboratory abnormality trends across 
doses that were clinically significant or associated with any symptoms.
Preliminary GSK3640254 PK parameters derived based on nominal sampling times 
following single doses of 1 mg to 700 mg administered after a moderate calorie and fat 
breakfast show GSK3640254 is slowly absorbed with a median Tmax observed between 
3-4.5 hours after dosing with a moderate fat breakfast and slowly eliminated with a mean 
half-life ranging from 22-26 hours.  In general, exposure (maximum observed 
concentration [Cmax] and area under the curve [AUC]) increased in a close-to-dose-
proportional manner from 1 mg to 400 mg with no further increase in exposure at 700 
mg.
Repeat dose preliminary PK parameter following once-daily administration of 50 to 320 
mg QD for 14 days were determined on Day 1 and Day 14 and show a median Tmax 
ranging between 3.8 to 4.3 hours. The mean half-life ranged from approximately 22 to 29 
hours. Overall, there was a trend of a slightly less than dose-proportional increase in 
Cmax and AUC(0-24) from 50 to 320 mg. The exposure on Day 14 was, on average, 1.9 
to 2.3 fold higher than that of Day 1 for Cmax and 2.2 to 2.6 fold higher than Day 1 for 


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AUC(0-24). Detailed summary statistics are available in the Study Synopsis [GSK
Document Number 2018N375461_00].
3.2.3.
Preliminary Safety and PK Data in Study 208131
The FTIH Study 207187 uses a bis-hydrochloride salt capsule formulation of 
GSK3640254, which is not suitable for long term clinical development. 
Study 208131 was a single-center, open-label, 2-period, 2-sequence cross-over design, 
conducted in 14 healthy subjects in the UK, designed to assess the relative bioavailability 
of the formulation planned for Phase 2a (mesylate salt in a capsule) to the FTIH 
formulation (bis-hydrochloride salt in a capsule) administered following a moderate 
calorie and fat meal. All subjects have completed dosing and the blinded preliminary 
safety data from Study 208131 shows a total of 11 AEs (all Grade 1). Two were related: 
Headache. The most common AE was Headache (3 instances). There were three 
Gastrointestinal AEs (Abdominal pain, Bleeding gums, and Flatulence). There were no 
Cardiac or Psychiatric AEs. There were no clinically significant changes in vital signs, 
ECG parameters or safety laboratory parameters.
Preliminary PK results from study 208131 showed that in the presence of a moderate fat 
meal, the relative bioavailability of GSK3640254 following 200 mg GSK3640254 
Mesylate Salt administration relative to 200 mg GSK3640254 Bis Hydrochloride salt 
administration was 107% and 110% based on AUC(0-) and Cmax respectively. Due to 
the similarity in exposure between the Bis-hydrochloride and Mesylate salt capsules, no 
dose adjustment is required for study 208132.
3.2.4.
Justification for Part 2 Treatment Duration and Initiation of cART
Data from Part 1 showed a decline in HIV-1 RNA and reasonable PK profile. There were 
no clinically significant trends in AEs, vital signs, ECG findings, or chemistry or 
haematology laboratory abnormalities across dosing arms. However, some participants 
receiving GSK3640254 had treatment emergent resistance mutations associated with 
maturation inhibitors observed on Day 11 (after 10 days of receiving GSK3640254 
monotherapy). Additionally, no resistance to existing and commercially available classes 
of antiretroviral medications (e.g., reverse transcriptase, protease, integrase) was 
observed at Day 11 as there is no known cross-resistance between maturation inhibitors 
and other classes of ARVs. Genotypic analysis of samples at Clinic Visit 5 (Study Day 8 
or 9) revealed no treatment emergent resistance. As a result, VH made two substantial 
changes to decrease the risk of treatment emergent resistance to participants in study Part 
2: 1) decrease the duration of monotherapy from 10 days to 7 days (based on the interim 
genotypic analysis), and 2) immediately start Investigator-selected cART at the 
completion of monotherapy at the Part 2 primary endpoint (HIV-1 RNA measured on 
Day 8).
3.3.
Benefit/Risk Assessment
Based upon pre-clinical and clinical studies with the prior MI GSK3532795 and the 
current molecule GSK3640254, the major risks are GI intolerability (e.g. abdominal pain
and diarrhoea) and toxicity, prolongation of QTc, neuropsychiatric safety, and treatment 


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emergent resistance to GSK3640254. If present, preclinical GI toxicity findings (e.g. 
single cell parietal cell necrosis) in subjects would be minimal and not be persistent upon 
discontinuation of GSK3640254 after 7 days of dosing. The risk of GI intolerability and 
neuropsychiatric safety is described in Section 3.3.1. The risk for QTc prolongation is 
described below in Section 3.3.1 where one pre-clinical study did show one dog with an 
increased QTc interval when given a single dose of GSK3640254. As described in 
Section 3.2.2, a cardiodynamic analysis of healthy subjects in Study 207187 was 
conducted. A final model from the MAD data showed a QT effect (ΔΔQTcF) of 
GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms (90% 
CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) doses, 
respectively, on Day 14. Based on this concentration-QTc analysis, a QTcF effect above 
10 ms could be excluded up to GSK3640254 plasma concentrations of approximately 
2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, 200 mg QD was 
the maximum dose used in Part 1 of this study 208132). Importantly, there were no 
abnormal clinically significant arrhythmias or QTc prolongations (values >500 ms or 
increases >60 ms from Baseline) in Study 207187. This study contains specific cardiac 
exclusion criteria, has ECG monitoring (at Tmax once GSK3640254 attains steady state 
concentration), and has QTcF based stopping criteria.
To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability, QTc prolongation, and neuropsychiatric safety), this clinical trial will
include participants who will receive clinical, laboratory, and ECG assessments during 
their participation in the trial. The protocol will also include a psychological assessment
(C-SSRS) to be administered by the investigator or a clinician (or qualified designee) at 
screening and the end of the trial. Finally, daily AE enquiry will also include a question 
as to a participant’s mental health and mood. Participants with any pre-existing 
psychiatric condition or positive (abnormal) response on the C-SSRS confirmed by the 
investigator/ qualified designee will be excluded (and urgent evaluation by a psychiatrist 
will be arranged).
VH has assessed this study for any risks that may be posed to participants taking part. 
The proposed risk assessment and management plan for the study has been developed in 
accordance with the tenets of European Medicines Agency (EMEA) guidance on 
strategies to identify and mitigate risks for clinical trials with investigational medicinal 
products (EMEA/CHMP/SWP/28367/XX).
More detailed information about the known and expected benefits and risks and
reasonably expected adverse events of GSK3640254 may be found in the most current 
version of the Investigator’s Brochure [GSK Document Number 2018N379610_00].


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3640254]
Cardiovascular (QT prolongation)
Pre-clinically, GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and Ltype calcium 
channel currents recorded from HEK 293 cells stably 
transfected with cDNA 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 one dog given 17 mg/kg. 
Later, there were no GSK3640254-related effects on 
ECG parameters in dogs given up to 25 mg/kg/day for 
4 weeks.
In the first time in human study 207187, no
participant exhibited QTc change from baseline
>60 ms or QTc >500 ms. As described in
Section 3.2.2, in the concentration-QTc analysis, a 
QTcF effect above 10 ms could be excluded up to 
GSK3640254 plasma concentrations of
approximately 2000 ng/mL (corresponding to
doses approximately ≤200 mg QD).
Protocol exclusion criteria based on screening 
ECG parameters and cardiac medical history
(see Section 6.2).
Participants will have ECG monitoring during the 
course of the study (see SOA table) with QTc 
stopping criteria (see Section 8.1.2).
Gastrointestinal intolerability and toxicity
Clinical signs indicative of gastrointestinal intolerability 
(sporadic vomiting and abnormal faeces 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 
Protocol exclusion criterion based on pre-existing 
GI pathology or baseline GI signs/symptoms
(see Section 6.2)
Participants will undergo continuous evaluation 
for adverse events during their participation in 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
were present in preclinical species. These findings 
were reversible. Finally, GI intolerability (predominately 
abdominal pain and diarrhea) was seen with a 
structurally related compound GSK3532795 which was 
evaluated through Phase 2b dosing.
The rates of GI AEs from the FTIH and RBA clinical 
trials (described above) are summarized in their 
respective synopses and the current Investigator 
Brochure.
the trial; there are clinical stopping
criteria based upon intensity of treatment-
emergent AEs (see Section 8.1.3). Finally, a GI
toxicity evaluation and monitoring plan is
available to guide the principal investigator (PI)
should GI AEs emerge (see Section 9.4.6).
Neurologic/psychiatric safety
Two psychiatric SAEs in previous MI GSK3532795 
clinical program (acute psychosis, homicidal/suicidal
ideation) at supratherapeutic doses were seen in 
healthy participants in TQT study.
From a Neurologic and Psychiatric AE summary and 
PK/PD analysis for GSK3532795 across all studies 
mild G1 headache and G1 sleep abnormalities were 
the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing dose 
(based on TQT and P2b studies). No exposure-
response relationship seen for select neurologic and 
psychiatric AEs (based on TQT and P2b studies) CNS 
penetration data for GSK3532795 and GSK3640254 in 
rats demonstrate a similarly low brain 
distribution/penetration.
The rates of Neurologic and Psychiatric AEs from the 
Protocol exclusion criterion based on any 
preexisting psychiatric condition (including 
results of psychological assessment) for patients.
Participants will have psychological assessment 
via a clinician (or qualified designee) 
administered C-SSRS in the study and will be 
included given no positive (abnormal) response. 
Continuous evaluation for adverse events during 
their participation in the trial including daily direct 
AE enquiry; 
The C-SSRS will also be administered after the 
treatment phase of the study. In the event of a 
positive (abnormal) response confirmed by the 
investigator, the patient will discontinue from the 
trial and the Principal Investigator/ Sub-
Investigator (PI/SI) will arrange for urgent 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
FTIH and RBA clinical trials (described above) are 
summarized in their respective synopses and the 
current Investigator’s Brochure.
specialist psychiatric evaluation and 
management.
Guidance for the PI on the management of 
emergent psychiatric symptoms are available 
(see Section 9.4.5)
Finally, there are clinical stopping criteria based 
upon intensity of treatment-emergent psychiatric 
AEs (see Section 8.1.3).
HIV-1 Infection/Patient population
HIV Resistance to GSK3640254
HIV-1 genotypic and phenotypic changes due to 
GSK3640254 monotherapy.
Data from Part 1 showed a decline in HIV-1 RNA and 
reasonable PK profile. However, some participants 
receiving GSK3640254 had treatment emergent 
resistance mutations associated with maturation 
inhibitors observed on or after Day 11 (after 10 days of 
receiving GSK3640254 monotherapy). Additionally, no 
resistance to existing and commercially available 
classes of antiretroviral medications (e.g., reverse 
transcriptase, protease, integrase) was observed at 
Day 11 as there is no known cross-resistance between 
maturation inhibitors and other classes of ARVs. 
Genotypic analysis of samples at Clinic Visit 5 (Study 
Day 8 or 9) revealed no treatment emergent 
resistance.
Dosing is limited to 10 days of monotherapy in 
Part 1 to reduce the risk of emergent drug 
resistance, and additionally limited to 7 days of 
monotherapy in Part 2 to further reduce the risk 
of emergent MI drug resistance based on the 
genotypic analysis of the interim samples from 
Part 1. There are no commercially 
available/approved MIs nor is there evidence of 
cross-class resistance (e.g. protease inhibitors)
therefore dosing with GSK3640254 will not 
interfere with selection of a cART regimen at the 
completion of the entire study (for Part 1) or the 
completion of the monotherapy portion of the 
study (Part 2).
Strict adherence to protocol criteria around
concurrent meds.


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3.3.2.
Benefit Assessment
This study in HIV-1 infected but otherwise healthy participants is a short-term
monotherapy design. There is no expected longer-term anti-HIV benefit to administration 
of GSK3640254. 
3.3.3.
Overall Benefit:Risk Conclusion
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1
infected but otherwise healthy participants at the proposed GSK3640254 doses, for 10 
days in Part 1 and for 7 days in Part 2, is predicted to be low and manageable. Mean 
exposures at the highest dose studied are not projected to exceed lowest observed adverse 
effect level (LOAEL) values obtained in chronic toxicology studies, further reducing 
potential risk.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1-infected participants 
during 10 days of monotherapy in Part 1 and 
during 7 days of monotherapy in Part 2

Maximum change from baseline (Day 
1) in plasma HIV-1 RNA
Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in Part 1 and over 7 
days in Part 2 in HIV-1 infected participants

GSK3640254 safety and tolerability 
parameters: adverse events (AE); post-
baseline values and changes over time of 
clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 infected 
patients 

GSK3640254 PK parameters at the 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax), 
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
plasma drug concentration-time curve from
pre-dose to the end of the dosing interval at 
steady state (AUC[0-]), Cmax, tmax, pre-dose 
concentration (C0), concentration at end of 
dosing interval (C), apparent terminal phase 
half-life (t1/2), and apparent oral clearance 
(CL/F), if data permit.


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Objectives
Endpoints

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in Part 1 and for 7 
days in Part 2 in HIV-1 infected patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 
GSK3640254 PK parameters following dosing 
for 10 days in Part 1 and following dosing for 7 
days in Part 2

Relationship between Day 1 AUC (0-
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
Exploratory

To assess the development of viral 
resistance (genotypic and phenotypic) over 10 
days in Part 1 and over 7 days in Part 2 and 
correlate with viral response, if appropriate.

Emergence of drug resistance 
mutations, if appropriate

To assess attainment of steady state 
following administration of GSK3640254 for 10 
days in Part 1 and for 7 days in Part 2 in HIV-1 
infected patients.

Steady State: pre-morning dose 
concentrations (C0) on Day 2 through Day 10 
C(Day 11) in Part 1 and on Day 2 through 
Day 7 C(Day 8)

To assess the immunologic effects of 
GSK3640254 when administered over 10 days
in Part 1 and over 7 days in Part 2 in HIV-1 
infected adults

Change from baseline in CD4+ T-cell 
count to Day 11 in Part 1 and to Day 8 in Part 2

To explore the relationship between 
GSK3640254 exposure and safety or 
immunologic parameters, if appropriate

GSK3640254 repeat-dose PK 
parameters: AUC (0-), Cmax, Cwith Day 11 
change from baseline in CD4+ cell count in 
Part 1 and with Day 8 change from baseline in 
CD4+ cell count in Part 2
Note: Other exploratory objectives and endpoints may be specified in the Reporting and Analysis 
Plan (RAP).
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase 2a, global, multicenter, double-blind (Sponsor-unblinded), randomized, 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability, PK and PD of GSK3640254 over 10 days in study Part 1 and over 7 days in 
study Part 2 in ART-naïve HIV-1 infected adults.  


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This study will be conducted in two parts, separated to allow for an informal interim 
analysis performed after Part 1 (see Figure 1 Schematic for Study 208132).  
Part 1 will include approximately 14 randomized participants and will evaluate two active 
doses of GSK3640254 in cohorts of 6 participants each. 

The Part 1 200 mg dose was a well-tolerated dose of GSK3640254 based on the 
prior Phase I study (207187) that is predicted to provide at least 90% of the maximum 
anticipated effect for a maturation inhibitor on HIV-1 RNA reduction in a 10-day study. 
It is anticipated that this dose will be the highest dose to be tested in this study unless 
actual exposure in this population is lower than seen in healthy volunteers in studies
207187 and 208131. 

The Part 1 10 mg dose will target approximately fifty percent of the maximum 
anticipated effect on HIV-1 RNA reduction.
Part 1 will also include a cohort of 2 participants who will receive placebo. The 
justification for the use of a placebo control allows for blinded assessment of safety and 
tolerability. Since Investigators and patients will be blinded, any safety event (AE, lab 
abnormality, ECG abnormality, etc) will be evaluated and managed in the same fashion. 
Finally, the use of placebo control does allow for a comparison of antiviral effect 
between GSK3640254 and placebo. 
Part 2 will include approximately 20 randomized participants and will evaluate up to 
three active doses of GSK3640254 (depending upon the data obtained in Part 1) in 
cohorts of 6 participants each. 

Part 2 doses may include one dose lower than the low Part 1 dose, with the 
remaining doses between the range of Part 1 doses; one or two doses in Part 2 may be 
higher than the high dose in Part 1 if exposure in participants is lower than those 
observed from healthy participants in study 207187 and 208131. 
Part 2 will also include a cohort of 2 participants to receive placebo. The justification for 
the use of placebo in Part 2 is the same as Part 1 above.
5.1.1.
Treatment Groups and Duration
5.1.1.1.
Screening Phase
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period in study Part 1 and into a 7-day treatment 
period on study Part 2. Randomization may occur as soon as all Screening procedures 
have been completed and results are available and on file. The 14-day screening period 
may be extended (in some cases) to 28 days to allow receipt of all Screening assessment 
results and to accommodate scheduling.
5.1.1.2.
Treatment Phase and Follow-up Period
Part 1:
Participants will be required to attend 9 in-clinic visits throughout the duration of the 
study in Part 1.  Participant and Investigators will design a patient-centric visit schedule 


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based on the optionality presented in the Part 1 Schedule of Assessments (SOA; Section 
2) to accommodate the 9 required visits over the (maximum) 24-day study period, and 
such that no visit interval exceeds more than 3 days.
Part 2:
Participants will be required to attend 7 in-clinic visits throughout the duration of the 
study in Part 2.  Participant and Investigators will design a patient-centric visit schedule 
based on the optionality presented in the Part 2 Schedule of Assessments (SOA; Section 
2) to accommodate the 7 required visits over the (maximum) 12-day study period, and 
such that no visit interval exceeds more than 3 days.
Treatment Phase: Day 1 – Day 10 in Part 1 and Day 1 – Day 7 in Part 2:  
On Day 1, an appropriate number of bottles of study treatments will be dispensed with 
supply sufficient to cover the entire treatment period.  The blinded bottles will contain 
capsules of either the active dose or placebo.  Each bottle will indicate dosing 
instructions.  Participants will bring the bottles of study treatments to each visit, so that 
they can be administered after the study procedures have been performed.
Participants will report to the clinic for visits in the morning of the days selected for each 
of the 5 visits in the treatment phase.  Participants will arrive each day, with their study 
treatment container(s) and prior to administration of the morning dose, for safety and lab 
assessments, including ECGs and blood draws, as described in the SOA. Participants will 
be given morning doses in the clinic at each visit. On days when an in-clinic visit is not 
required, doses can be self-administered, and during observation by a site staff member 
using various forms of video calling (when at all possible and locally permitted) such as 
FaceTime, Skype, WhatsApp.
Two, serial, intensive blood PK sample collections will be done on Clinic Visit 1 and on 
Clinic Visit 5 (up to 24 hours post-morning dose).  Participants will be required to fast for 
at least 8 hours [overnight] prior to the morning check-in for the intensive PK sampling 
visits. Participants will be required to stay in the clinic until all specified assessments are 
completed (12 hours post-dose). Participants will be required to return to the clinic the 
following morning to allow for the blood sampling at the 24-hr time point.
Study treatments should be administered near the same time each morning, within a 2-hr 
window.
Each dose of study medication will be taken with approximately 240 mL (8 ounces) of 
water following ingestion of a moderate calorie and fat meal (i.e. at least 400 calories, 
with at least 120 calories from fat), that is required to be completed within 30 minutes 
just prior to dosing. A moderate calorie and fat breakfast is planned to be similar to the 
following (with additional meal suggestions in will be included in the Study Reference 
Manual [SRM]): 

2 slices of bread

10 g of butter

20 gr of jam


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
15 g of cheese

175 mL of apple juice
Follow-up Visits
Part 1:
Follow-up Visits Day 11-17 and Final Follow-up Visit Day 18-24
Participants should not start other medicines and will not start ARVs during the post-
dosing follow-up period until after the final follow-up visit has been completed.
Participants will return to the clinic in the post-dosing period for 4 visits (Visits 6-9).  

Three visits will be performed within the 7 days immediately following the dosing 
period for PK and measurement of assessments as shown in the SOA (Section 2).  

A final follow-up visit, to be performed approximately 8-14 days after the last 
dose, will be primarily for safety (e.g., to follow any AEs to resolution).
If a participant is unable to return to the clinic for any reason site staff are encouraged to 
contact the participant for assessment of adverse events.
Part 2:
Follow-up Visit Day 8 and Final Follow-up Visit Day 10-12
Participants should start Investigator-selected, prescribed and provided cART
immediately in the post-dosing period on Day 8, after the blood collection is performed.  
Participants will return to the clinic in the post-dosing period for 2 visits (Visits 6 and 7).  

One visit will be performed on the day immediately following the dosing period 
for PK and measurement of assessments as shown in the SOA (Section 2).  

A final follow-up visit, to be performed approximately 3-5 days after the last 
dose, will be primarily for safety (e.g., to follow any AEs to resolution). 
If a participant is unable to return to the clinic for any reason site staff are encouraged to 
contact the participant for assessment of adverse events.


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Schematic for Study 208132
1.
Mesylate Dose equivalent to 10 and 200 mg once daily bis-HCL
2.
Part 1 safety/PK/viral load data will be evaluated at interim, prior to initiating other cohorts in Part 2, 
which are planned to run in a parallel, randomized fashion.
3.
Part 2 doses are an illustration of the projected doses per cohort. The actual doses for each cohort are 
subject to modification based upon safety, PK and antiviral activity data from Part 1.
5.2.
Number of Participants
A total of approximately 34 participants will be randomized into the trial. Approximately 
14 participants will be randomized in Part 1 of the study, and approximately 20 
participants will be randomized in Part 2 of the study.  Six participants will be enrolled in 
each of the active dose cohorts and 2 participants will be enrolled in each of the placebo 
cohorts.
Additional participants/cohorts may be enrolled to allow for evaluation of additional dose 
levels as appropriate.
If participants prematurely discontinue the study, additional participants may be 
randomized and assigned to the same cohort in consultation with the Investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if the participant has completed 
all phases of the study including the last scheduled procedures shown in the SOA.
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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5.4.
Scientific Rationale for Study Design
Antiviral potency of a novel HIV drug is typically established in a short-course
monotherapy study in HIV infected participants. There is precedent for this across a
number of classes of ART drugs.
Understanding the uncertainties over the inherent potency of GSK3640254 in inhibiting 
the HIV maturation process is a key objective for the GSK3640254 program. This two-
part, adaptive design will allow an early understanding of the potential of GSK3640254, 
while not exposing HIV-infected participants to longer courses of what may be 
suboptimal or redundant doses and possible development of resistance. The two-part 
design will allow for an interim evaluation of the data to refine the doses to be studied in 
Part 2, as needed, therefore ensuring that the doses are adequate to characterize the dose-
exposure-relationship for GSK3640254.
All doses of GSK3640254 in this study will be administered in the fed state, with dosing
occurring within 30 minutes of completing a moderate fat meal (i.e. at least 400 calories, 
at least 120 calories from fat). Data with a previous MI, GSK3532795, demonstrated that 
food was necessary to achieve dose proportional PK and target efficacious 
concentrations. Given the structural similarities, including solubility limitations, between 
GSK3532795 and GSK3640254, current clinical studies evaluated the safety, tolerability, 
and PK of GSK3640254 after administration of a moderate fat meal. 
In Study 207187 (SAD/MAD), doses up to 320mg QD for 14 days were evaluated in a 
repeated dose cohort. The dose of 320 mg QD is potentially 4 times the minimally 
anticipated effective dose of 80 mg predicted based on the emerging PK in healthy 
volunteers and the target trough concentration based on virology data. As described in 
Section 3.2.2, the current Investigator’s Brochure, and the Study 207187 synopsis, doses 
up to 320 mg QD for 14 days were generally well tolerated. Doses up to exposure seen at 
200 mg QD in healthy volunteers will be used in this study of HIV-1 infected patients to 
understand the relationship between GSK3640254 exposures and efficacy, duration of 
response, and development of genotypic and phenotypic changes.
5.5.
Dose Justification
The doses to be used in this study have been defined to adequately described the dose-
exposure-response of GSK3640254 in treatment-naïve HIV patients. The doses were 
selected as to approximately provide a median effect of 30, 50, 75, 90 and 95% of the 
maximum anticipated effect on HIV-1 RNA for an MI drug in a 7-day or 10-day study.
5.5.1.
Dose Justification for Part 1
Historical information from the 10-day POC study conducted with the prior MI 
compound, GSK3532795, was obtained. In that study, a simple effect, at the maximum 
(Emax) model described the relationship between the individual maximum viral load 
decrease and the individual inhibitory quotient (IQ). The IQ was computed by dividing 
the steady-state trough concentration by the individual protein binding adjusted EC90 
(PBAEC90). The IQ providing 50% of the maximum effect was 1.93.  


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Based on the FTIH study for GSK3640254, the pharmacokinetics of GSK3640254 were 
described by a two-compartment model with between subject variabilities on the 
elimination clearance, the central volume of distribution and the absorption rate constant. 
The population PK model of GSK3640254, including parameter uncertainty, was 
integrated with the PK/ Pharmacodynamic (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%). It was assumed 
that the PK of GSK3640254 in treatment-naïve HIV patients will be similar to that seen 
in healthy participants. One thousand trials with 6 participants per dose level were 
simulated to generate, for each individual, the anticipated percent of maximum effect. 
Simulations were then summarized by computing the median percent of maximum effect 
for each dose and trial and then further computing the median and 95% prediction 
interval around the median for each dose across the trials. The simulations are 
summarized in Table 1.
Table 1
Predicted median and 95% prediction interval for median percent of 
maximum effect for different doses (1000 trials with N=6 per dose 
level)
Dose (mg)
2.5th Percentile
Median
97.5th Percentile
5
14.2
31.4
53.5
10
24.8
47.6
69.7
15
33
57.4
77.5
20
39.4
64.1
82.1
25
44.4
69
85.1
30
48.5
72.7
87.2
40
55.5
78
90.1
80
71.1
87.6
94.8
100
75.4
89.8
95.8
200
85.9
94.6
97.8
Based on these simulations and on similar relative bioavailability between the Bis-
hydrochloride salt (used in the 207187 FTIH study) and mesylate salt capsules shown in 
study 208131, Part 1 doses will be 10 mg and 200 mg to respectively approximately 
provide 50% and 95% of maximum effect. 
5.5.2.
Dose Justification for Part 2
It is predicted that Part 2 doses would be 5 mg, 40 mg, and 100 mg to respectively 
provide approximately 30%, 75% and 90% of maximum effect but these doses and target 


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effects will be evaluated at the end of Part 1. An evaluation and unblinded interim 
analysis of GSK3640254 safety, tolerability, PK and antiviral activity will occur after all
participants of Part 1 complete their Day 12 visit. The detailed decision rules are 
illustrated in Section 10.3.1.
Doses higher than 200 mg QD may be explored in Part 2, in the case that the overall PK 
exposure is lower in HIV infected participants relative to healthy participants. The higher 
dose(s) would be designed to not exceed the exposure seen in healthy participants at 
200 mg QD.
Predicted steady-state exposures for 200 mg QD 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 gastrointestinal 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 LOAEL exposures, the lowest 
exposures where minimal, reversible effects on parietal and/or chief cells were identified, 
and mean IQ values for different GSK3640254 doses are presented in Table 2.
Table 2
Predicted Mean Steady-State GSK3640254 Cmax, AUC(0-24), C24, 
and IQ, Following Repeated Dose Administration with Fold Cover to 
rat and dog LOAEL
Doses
(mg)
Cmax, 
ng/mL1
AUC(0-
24), 
ng.h/mL
C24, 
ng/mL
IQ2
Fold cover 
rat:human 
Cmax3
Fold cover   
rat:human
AUC(0-24)
Fold cover  
dog:human 
Cmax3
Fold cover   
dog:human
AUC(0-24)
5 
61
937
30
1.59
64.7
65.2
68.1
78.3
10 
113
1736
56
2.94
34.9
35.2
36.7
42.2
40 
389
5962
193
10.1
10.2
10.2
10.7
12.3
100 
879
13475
436
22.8
4.5
4.5
4.7
5.4
200 
1629
24972
809
42.3
2.4
2.4
2.6
2.9
1.
Predicted mean values based on linear regression analyses of preliminary Day 14 data in Study 207187
available by 01-June-2018.
2.
Mean IQs derived from predicted mean C24/ mean PBAEC90 of 19.1 ng/mL. The PBAEC90 for the triple 
variant is approximately 1.9-fold higher or 36.7 ng/mL. 
3.
A NOAEL was achieved in 1-month study in rats given 10mg/kg/day (AUC(0-24) of 22400 ng.h/mL and 
Cmax of 2370 ng/mL on Day 28). Lowest LOAEL exposure was in 1-month study in rats given 30 mg/kg/day (AUC (0-
24) of 61100 ng.h/mL and Cmax of 3950 ng/mL on Day 28). The LOAEL in 1-month study in dogs was 1 mg/kg/day 
(AUC (0-24) of 73300 ng.h/mL and Cmax of 4160 ng/mL on Day 28). 
C24 = trough concentration at the end of the dosing interval, IQ= inhibitory quotient.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Repeat testing of certain lab parameters within a single Screening period is allowed as 
indicated in the following sections.  Participants may be screened twice.


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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are healthy (other than HIV infection) as determined by the 
Investigator or medically qualified designee based on a medical evaluation including 
medical history, laboratory tests, and cardiac monitoring.   
3.
Screening CD4+ T-cell count 350 cells/mm3 
4.
Documented HIV infection and Screening plasma HIV-1 RNA 5000 copies/mL. 
A single repeat of this test is allowed within a single Screening period to determine 
eligibility.
5.
Treatment-naïve: No ARVs (in combination or monotherapy) received after the 
diagnosis of HIV-1 infection. 
Weight
6.
Body weight 50.0 kg (110 lbs.) for men and 45.0 kg (99 lbs) for women and 
body mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive).
Sex
7.
Male or female:
a.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in 
Appendix 5.
Informed Consent
8.
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and stated in the protocol.
Other
9.
For participants enrolled in France: a participant will be eligible for inclusion 
in this study only if either affiliated to or a beneficiary of a social security category. 
10.
Participant must be willing and able to start cART on Study Day 8 (except in the 
case of early termination, clinically relevant AE/SAE, lab abnormality, the withdrawal of 
consent, lost to follow-up, etc., where circumstances could dictate otherwise).


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6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to starting study treatment
2.
Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment AND positive on reflex to Hepatitis C RNA
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled only if a confirmatory negative Hepatitis C RNA test is obtained (central lab 
will automatically reflex to HCV RNA on positive HCVAb)
3.
Alanine aminotransferase (ALT) >2 x upper limit of normal (ULN). A single 
repeat of ALT is allowed within a single Screening period to determine eligibility.
4.
Bilirubin >1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
5.
Subjects with primary HIV infection, evidenced by acute retroviral syndrome 
(e.g., fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) 
documented viremia without antibody production and/or evidence of recent (within 3 
months) documented seroconversion.
6.
Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones); 
7.
A pre-existing condition interfering with normal gastrointestinal anatomy or 
motility (e.g., gastroesophageal reflux disease [GERD], gastric ulcers, gastritis), hepatic 
and/or renal function, that could interfere with the absorption, metabolism, and/or 
excretion of the study drugs or render the subject unable to take oral study treatment.
8.
Any acute laboratory abnormality at screen which, in the opinion of the 
investigator, should preclude participation in the study of an investigational compound. 
9.
Any Grade 2-4 laboratory abnormality at Screen, with the exception of creatine 
phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, etc), 
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 lab abnormality is allowed within a single 
Screening period to determine eligibility.
10.
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.
11.
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 


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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 ViiV Medical Monitor.
12.
Any pre-existing physical or other psychiatric condition (including alcohol or 
drug abuse), which, in the opinion of the investigator (with or without psychiatric 
evaluation), could interfere with the participant’s ability to comply with the dosing 
schedule and protocol evaluations or which might compromise the safety of the 
participant.
13.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
Prior/Concomitant Therapy
14.
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
Prior/Concurrent Clinical Study Experience
15.
The participant has participated in a clinical trial and has received an 
investigational product within the 30 days prior to the first dosing day in the current 
study.
Diagnostic assessments
16.
Any positive (abnormal) response confirmed by the investigator on a Screening 
clinician- (or qualified designee-) administered C-SSRS.
17.
Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening. A 
positive screen for marijuana is not exclusionary, though if positive for THC, see Section 
6.3.2 for guidance to be given to the participant.
18.
Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.
19.
Exposure to more than four new investigational drugs or vaccines within 12 
months prior to the first dosing day.
20.
Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 
days of study drug administration or anticipated need for such treatment within the study.
21.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell 
carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, 
anal or penile intraepithelial neoplasia; or other localized malignancies require agreement 
between the investigator and the study medical monitor for inclusion of the subject prior 
to randomization.
Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, 
interferons) or any agent with known anti-HIV activity (such as hydroxyurea or 
foscarnet) within 30 days of study drug administration.
22.
An active Center for Disease Control and Prevention (CDC) Category C disease 
except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.


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23.
Treatment with any vaccine within 30 days prior to receiving study medication.
24.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate1
<45 or >100 bpm
<50 or >100 bpm
PR Interval
<120 or >200 msec
QRS duration
<70 or >110 msec
QTc interval2 (Fridericia’s)
>450 msec
>470 msec
1.
A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by ECG or vitals within 30 
minutes to verify eligibility.
2.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF). It is 
either machine read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 208132 will be Fridericia’s formula.
25.
Any significant arrhythmia or ECG finding (eg prior myocardial infarction, 
sinoatrial pauses, bundle branch block, or conduction abnormality) which, in the opinion 
of the Investigator OR ViiV Medical Monitor, will interfere with the safety for the 
individual participant.
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the IB and supplements, approved product labels, and/or local prescribing 
information for detailed information regarding warnings, precautions, contraindications, 
AEs, drug interactions, and other significant data pertaining to the study drugs.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Each dose of study medication will be taken with approximately 240 mL (8 
ounces) of water following ingestion of a moderate calorie and fat meal (i.e. at least 400 
calories with at least 120 calories from fat), completed within approximately 30 minutes 
just prior to dosing.  Prior to the two serial intensive blood PK collection days, to be done 
on Clinic Visit 1 and on Clinic Visit 5, participants will be required to fast for at least 8
hours [overnight] prior to the morning check-in.

Refrain from excessive consumption of red wine, Seville oranges, grapefruit 
or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 3
days prior to the first dose of study medication until the day after the final dose.
Excessive consumption is defined as more than one glass of wine or juice or one fruit per 
day, in combination.
6.3.2
Alcohol, Tobacco and Marijuana

During the study alcohol consumption will be limited to the following: An 
average weekly intake of <14 drinks for males or <7 drinks for females. One drink is 
equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 
1.5 ounces (45 mL) of 80 proof distilled spirits.
No alcohol will be consumed on the in-clinic Intensive PK days (Clinic Visit 1 and Clinic 
Visit 5), until after the final assessment of the day and release from the clinic. 


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
Only clinically minor to moderate use (as determined by the PI/SI) of tobacco 
products will be allowed during trial participation, with extremely limited use on the in-
clinic Intensive PK days (Clinic Visit 1 and Clinic Visit 5).

Subjects should refrain from the use of marijuana during the treatment period.
6.3.3
Activity
Participants should abstain from strenuous exercise during the treatment period.
6.3.4
Counsel regarding Safe Sex Practices
All study participants should be counselled on safer sexual practices including the use 
and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV 
transmission to an uninfected partner.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study
but are not subsequently randomized. 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 that established screen failure, and 
any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure)
may be rescreened an additional time if, in the opinion of the Investigator, a current 
clinical outlook of the participants seems favorable for study inclusion (and if the 
participant never received study medication in this trial).
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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7.1.
Treatments Administered
Study Treatment Name:
GSK3640254 Mesylate Salt
Placebo to match 
GSK3640254 Mesylate Salt
Dosage formulation:
capsule
capsule
Unit dose 
strength(s)/Dosage level(s):
5mg, 20mg, and 100mg
placebo
Route of Administration 
oral
oral
Dosing instructions:
Each dose of study treatment 
will be taken with 
approximately 240 mL (8 
ounces) of water following 
ingestion of a moderate 
calorie and fat meal (i.e. at 
least 400 calories with at least 
120 calories from fat). 
Each dose of study treatment
will be taken with 
approximately 240 mL (8 
ounces) of water following 
ingestion of a moderate 
calorie and fat meal (i.e. at 
least 400 calories with at least 
120 calories from fat).
Packaging and Labeling
Blinded Study Treatment will 
be provided in high-density 
polyethylene (HDPE) bottles.
Each bottle will be labelled as 
required per country 
requirement.
Blinded Study Treatment will 
be provided in HDPE bottles. 
Each bottle will be labelled as 
required per country 
requirement.
Manufacturer
Shanghai STA 
Pharmaceutical Product Co. 
Ltd (previously named 
as Wuxi AppTec (Shanghai) 
Co. Ltd)
Shanghai STA 
Pharmaceutical Product Co. 
Ltd (previously named 
as Wuxi AppTec (Shanghai) 
Co. Ltd)
7.2.
Dose Modification
Dose modifications, as assigned in each cohort, will not be made.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS).  Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information and directions for the IWRS will be 
provided to each site. 
Study treatments will be dispensed at the study visits indicated in the SOA.
Returned study treatment should not be redispensed to another participant.


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7.4.
Blinding and Interim Analysis
This will be a double-blind study with participants and site staff blinded. The sponsor
will be unblinded (meaning those staff may have access to unblinded data). This early 
phase study of relatively small size will not contain an external Data Monitoring 
Committee (DMC). The ongoing monitoring and informal interim analysis will be 
overseen by an experienced central VH/GSK study team. For the informal interim 
analysis, the VH/GSK study team including physicians, statistician, programmer, study 
leads, virologist and clinical pharmacokinetic staff will have access to unblinded data and 
present data in a blinded fashion when interacting with site staff. Other VH/GSK staff 
will remain blinded unless unblinding becomes necessary.
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a participant’s treatment assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact 
ViiV Healthcare prior to unblinding a participant’s treatment assignment unless this 
could delay emergency treatment of the participant. If a participant’s treatment 
assignment is unblinded ViiV Healthcare must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form (CRF), as applicable.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in
accordance with local regulations and/or VH or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.
1.
The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).


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4.
Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  
6.
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 
VH or GSK.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents.  The dose of 
study treatment 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 
treatment. Study site personnel will examine each participant’s mouth to ensure that the 
study treatment was ingested.

If participants self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed preferably through a visual technology such as Skype, 
FaceTime, WhatsApp or the like, if at all possible and locally permitted.  At a minimum, 
a phone call should be made to each participant daily, through querying the participant 
during the site visits and documented in the source documents and CRF.  If the decision 
is made to utilize a diary cards in this study, a record of the number of study treatment 
capsules dispensed to and taken by each participant via “patient diary” must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF.
7.7.
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 or receives during the study 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.
Acetaminophen/paracetamol at doses of ≤2 grams/day or nonsteroidal anti-inflammatory 
drugs (NSAIDs) are permitted for use any time during the study and their use 
documented in the CRF. Other concomitant medication may be considered on a case by 
case basis by the investigator in consultation with the Medical Monitor if required.


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Concomitant medications (prescription and non-prescription) should be administered
only as medically necessary during the study. Participants must notify their Investigator
of any current or proposed concomitant medication, whether prescribed or over-the 
counter because of the potential for interactions between such treatments and the study 
medications. Concomitant medications that may significantly interact with GSK3640254 
as a perpetrator or a victim such as a strong CYP3A inhibitor (Clarithromycin, 
telithromycin, nefazodone, itraconazole, ketoconazole etc), strong CYP3A inducer (e.g. 
phenobarbital, dexamethasone, carbamazepine, phenytoin, rifampin, rifabutine, St John’s 
wort, etc), or substrate of OATP1B3 (e.g. telmisartan, valsartan, olmesartan, rifampin, 
statins such as atorvastatin, rosuvastatin, pitavastatin) are not permitted.
7.8.
Treatment and Care after the End of the Study
Given the lack of longer term clinical benefit (Section 3.3.2), VH recognizes the balance 
between the need to conduct an early phase monotherapy clinical trial (for the larger and 
long term unmet medical need) and the need for HIV-1 infected treatment naïve patients 
to receive cART as soon as possible after diagnosis. To meet both needs, this trial design 
is efficient in screening (shortest period: 14 days) and treatment/follow-up (shortest 
period: 18 days in study Part 1 and 10 days in study Part 2). A clinical trial commitment 
of as short as ~1 month is expected. After this time, VH expects all participating patients 
to receive local standard of care cART. 
VH recognizes some HIV-1 infected adults may encounter barriers to accessing cART. 
Where it has been determined by the Investigator to be an acceptable option, participants
receiving study treatment will have the option (but are not required) to receive 
reimbursement from the Sponsor for locally marketed ARVs (after the completion of 
dosing and through the study final follow-up visit) for up to a maximum of 90 days. The
selection of ARVs will be investigator-chosen based upon local standard of care.
The investigator is responsible for ensuring that participants will be referred for prompt 
cART initiation after completion of the study, whether or not VH is providing
reimbursement for post-study treatment.
In the case of Part 2, participants will start Investigator selected, prescribed and provided
cART immediately after the completion of the primary endpoint; i.e., specifically to be 
administered in the clinic on Day 8 after the blood collection has been performed.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
These protocol guidelines are in alignment with the Food and Drug Administration 
(FDA) premarketing clinical liver safety guidance.


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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests is required when a participant 
meets one of the conditions outlined in the algorithm:
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = 
upper limit of normal
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7 in Section 12.7.
8.1.2.
QTc Stopping Criteria

The same QTcF correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled. 

The Baseline QTcF should be based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief recording period from the Day 1 pre-dose ECG.  

A randomized participant that develops an on-treatment QTcF >500 msec or an 
increase from baseline QTcF >60 msec should have two repeat unscheduled ECG’s
within 10 minutes. Using these triplicate ECGs, if the average QTcF >500 msec or an 
increase from baseline QTcF >60 msec, the subject will be withdrawn from the study.


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Finally, this subject 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.
8.1.3.
Individual Participant Laboratory Abnormality and AE Stopping 
Criteria
Investigators should make every effort to have a discussion with the Medical Monitor 
before the next dose to help assess if the study treatment should be stopped.
Any clinically significant AE deemed to require discontinuation of investigational 
product
Any Grade 3 or higher rash or Grade 2 rash with evidence of systemic involvement 
Any Grade 3 or higher allergic reaction 
Any Grade 3 or higher Psychiatric AE
New onset suicidal ideation
Any Grade 3 or higher AE related to study medication.
Any Grade 4 AE or laboratory abnormalities (with the exception of an asymptomatic 
grade 4 cholesterol, triglyceride or CPK increase) 
8.1.4.
Temporary Discontinuation
Withdrawal of study treatment requires withdrawal from the study. See Section 8.2.
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons.

A participant who is withdrawn from the study for any reason related to safety (listed 
in Section 8.1.3 or otherwise) will be continued to be followed to assess the outcome of 
the safety event that triggered discontinuation of study drug.

If the participant withdraws consent for disclosure of future information, the sponsor
may retain and continue to use any data collected before such a withdrawal of consent.


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
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records.

Refer to the SOA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.

Termination of the study by VH. Safety data will be reviewed by the Sponsor in-
stream by single case and collectively. If a safety concerns arises, a decision about 
continuation of the study will be made.

Loss of ability to freely provide consent due to treatment of either a psychiatric or
physical (eg, infectious disease) will require withdrawal

Repeat non-adherence by the participant with the requirements of the protocol or
treatment (as determined by Investigator in consultation with the Medical Monitor) will 
require withdrawal.
If a participant withdraws from the study, he/she should complete a follow-up visit 7-14 
days after treatment was stopped (conducted as a Visit 9) in study Part 1, and 3-5 days 
after treatment was stopped (conducted as a Visit 7) in study Part 2.  If a participant is 
unable to return to the clinic for any reason site staff are encouraged to contact the subject 
for assessment of adverse events.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

In-clinic assessments should occur in the following order, prior to administration 
of study treatment, and should be conducted so as to allow the blood draw to occur as 
close as possible to the nominal time:
1. 12-lead ECG


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2. vital signs
3. blood draws

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 sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.

Adherence to the study design requirements, including those specified in the SOA
(Section 2), 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 (eg, 
blood count) and obtained before signing of informed consent form (ICF) may be utilized 
for screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the timeframe defined in the SOA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
9.1.1.
HIV-1 RNA Sampling
Plasma for quantitative HIV-1 RNA will be generated at timepoints listed in the SOA
(Section 2).
An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 40 copies/mL will 
be used. 
Details concerning the handling, labeling and shipping of these samples will be supplied
separately.
9.1.2.
Lymphocyte Subsets by Flow Cytometry
Blood samples will be obtained from each participant for the analysis of lymphocyte 
subsets by flow cytometry at the timepoints listed in the SOA (Section 2).
Details concerning the handling, labeling and shipping of these samples will be supplied
separately.


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9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4. As described in Appendix 
4, intensity of AEs (and lab abnormalities) will be graded using the division of AIDS
(DAIDS) Grading table. 
The investigator and any 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 treatment or the study,
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the final follow-up 
visit at the time points specified in the SOA (Section 2).

All AEs will be collected from the start of treatment until the final follow-up 
visit at the time points specified in the SOA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (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 hours, as indicated in Appendix 4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
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. 
Appropriate questions to ask include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”


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
“Have you experienced any alteration in personality, behavior, mood or any
altered mental status?”
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 12.4) will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment 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 treatment under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
Boards (IRB)/Independent Ethics Committees (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 eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 (Section 12.4) and all deaths, 
whether or not they are considered SAEs, specific Cardiovascular (CV) and Death 
sections of the CRF will be required to be completed. These sections include questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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9.2.6.
Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
treatment and until the end of the pregnancy (delivery or termination).

If a pregnancy is reported, the investigator should inform VH/GSK within 24 hours
of learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of the assigned study treatment greater than the assigned dose
within a 30-hour time period will be considered an overdose.
VH/GSK does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat any overdose. 
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis within 7 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SOA (Section 2).
9.4.1.
Physical Examinations

A physical exam will include, at a minimum, assessments of the skin, heart, 
lungs, and abdomen (liver and spleen)

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Pulse rate, respiratory rate, and blood pressure will be assessed.


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
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.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include, systolic and diastolic blood pressure, and pulse and respiratory rate. 
Three readings of blood pressure and pulse will be taken. The first reading 
should be rejected. The second and third readings should be averaged to give the 
measurement to be recorded in the CRF.
9.4.3.
Electrocardiograms

Triplicate and Single 12-lead ECG will be obtained as outlined in the SOA (see 
Section 2) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals. Refer to Section 8.1.2 for QTcF 
withdrawal criteria and additional QTcF readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SOA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 2 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SOA.

Refer to the SRM for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.


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
All study-required laboratory assessments will be performed by a central 
laboratory.
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time.  Additionally, if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered in the CRF.
9.4.5.
Suicidal Risk Monitoring and Management of Emergent 
Psychiatric Symptoms
GSK3640254 is not a CNS 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 at the end of the treatment phase of the study. In case of positive (abnormal) 
response confirmed by the investigator, the patient will discontinue from the trial and the 
PI/SI will arrange for urgent specialist psychiatric evaluation and management.
As described in Section 8.1.3, new onset suicidal ideation at any time will result in 
immediate discontinuation from the trial and the PI/SI will arrange for urgent specialist 
psychiatric evaluation and management.
The definitions of behavioural suicidal events used in this scale are based on those used 
in the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behaviour, 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 PI/SI. Any pharmacotherapy should be discussed 
with the medical monitor.

Any Grade 3 or 4 Psychiatric AE: As described in Section 8.1.3, 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).
9.4.6.
GI Toxicity Evaluation and Monitoring Plan
Pre-clinical 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 


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the evaluation and management of primarily upper gastrointestinal symptoms (Table 3). 
The Investigator may contact the VH Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the trial.
Table 3
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. 
9.5.
Pharmacokinetics

Whole blood samples of approximately 5 mL will be collected for measurement 
of plasma concentrations of GSK3640254 as specified in the SOA. A maximum of 5
samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor. Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual date and time 
(24-hour clock time) of each sample (as well as each subsequent dose) will be recorded.

Samples will be used to evaluate the PK of GSK3640254. Each plasma sample 
will be divided into aliquots as outlined in the laboratory manual. Samples collected for 
analyses of GSK3640254 plasma concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study.

Once the plasma has been analysed for GSK3640254, any remaining plasma may 
be analysed for other compound-related metabolites and the results reported under a 
separate protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Intensive PK sampling (Clinic Visit 1 and Clinic Visit 5) begins with a morning pre-dose 
sampling, i.e, prior to the administration of the morning dose of the study treatment on 
the day of the visit. The pre-dose sampling should be done approximately 24 hours after 
the morning doses of the study drugs were taken the day prior to the visit. This pre-dose 
blood sampling will include the collection of the other parameters as well.
The subsequent 8 time points include samplings through Hour 12, with a final sample 
collected at Hour 24. The subject will either stay overnight or will return to the clinic so 
that the final sample can be collected at Hour 24.
It is critical to capture the exact date and time of each PK sample collection, even if 
drawn slightly off-schedule. If a sample collection time point is missed/late/not done 
within the specified window and the next collection time point has not yet been reached, 
collect the missed time point, and record the exact time of that collection, then get back 
on track for the next time point/on-time collection.


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Table 4 below lists the sampling schedule to be followed for the assessment of intensive 
pharmacokinetics. Further details of PK blood collection and sample processing will be 
provided in the central clinical laboratory manual.


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Table 4
Intensive Pharmacokinetic Sampling Schedule and Other Activities 
at Clinic Visit 1 and Clinic Visit 5
Time 
(Event)
Window for blood draw
Time 
(Relative to Dosing)
Hour: Min
Clinic Visit 1
And
Clinic Visit 5
morning pre-dose work: ECGs, 
vitals and full blood draw to 
include the pre-dose PK 
collection
Eat Meal. Administer study treatment and start the clock for 
subsequent blood draws.
00:00
1 hr PK blood draw
± 5 minutes
01:00
2 hr ECG and PK blood draw
± 15 minutes
02:00
3 hr PK blood draw
± 15 minutes
03:00
4 hr ECG and PK blood draw
± 15 minutes
04:00
5 hr PK blood draw
± 15 minutes
05:00
6 hr ECG and PK blood draw
± 15 minutes
06:00
8 hr PK blood draw
± 30 minutes
08:00
12 hr PK blood draw
± 2 hours
12:00
Next Day
24 hr (morning pre-dose) PK 
blood draw1, 2
± 2 hours
24:00
Eat Meal and administer study treatment.
1. This 24-hr pre-dose PK blood draw will be done at the same time as the collection for the lab kit on the 
next day.
2.  In study Part 1, if the Visit 5 Intensive PK visit is done on Day 10, this 24-hr PK blood draw will be 
done at the same time as the collection for the lab kit on Day 11.  Otherwise, this 24-hr blood draw is the 
only draw done on Day 9 (if the clinic visit is done on Day 8) or Day 10 (if the clinic visit is done on Day 
9).
9.6.
Pharmacodynamics
See Section 10.3.3. 
9.7.
Genetics
Genetics are evaluated in this study.
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected on 
Day 1 from participants who have consented to participate in the genetics analysis 
component of the study. Participation is optional. Participants who do not wish to 
participate in the genetic research may still participate in the study.


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In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the laboratory 
manual and the SRM.
9.8.
Biomarkers
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide plasma 
for viral genotype and phenotype analysis, at the times listed in the SOA (Section 2).
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately.
Genotypic and phenotypic analyses will be carried out by using Gag/PR and PR/RT 
formats, in which PCR amplification is used to generate HIV cDNA products including 
the Gag and the PR and RT coding regions, respectively. Phenotypic analyses of the 
Gag/PR region will include susceptibility to GSK3640254. Analysis will be done on 
samples collected in study Part 1 on Day 1 and Day 11 initially, and on samples collected 
in study Part 2 on Day 1 and Day 8 initially, with other timepoints analyzed as data 
emerge for viral load response.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
10.1.1.
Sample Size Considerations
The primary objectives of this study are to investigate the safety, tolerability and antiviral 
activity of GSK3640254 over a 10-day treatment period in study Part 1 and over a 7-day 
treatment period in study Part 2. The antiviral activity will be assessed by estimating 
plasma HIV-1 RNA max change from baseline during the study.
The sample size for this study is based primarily on feasibility to provide adequate 
precision for the estimations.
Based on data from the short-term monotherapy study of BMS-955176/GSK3532795
POC (AI468002) study and GSK2838232 POC study, we assumed the maximum change 
from baseline viral load drop (VLD) values on log scale for individual participants from 
the higher dose in Part 1 follow a normal distribution. Therefore, we conducted 1000 trial 


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simulations in Fixed and Adaptive Clinical Trial Simulation (FACTS) software using the 
normal distribution with mean of change from baseline VLD on log scale at 0.5 to 2
copies, SD=0.4, and sample sizes=6 for Part 1 higher dose.
Using Bayesian calculation with non-informative priors for the mean and weakly 
informative priors for the error parameters, Normal (0, 100) for mean and Inverse 
Gamma (0.35, 0.0875) for error parameters, the posterior probability to achieve a 
clinically relevant cut-point of 1.3 log was calculated for each simulated trial, and 
percentage of the trials with posterior probability of mean viral load drop (VLD) at the 
higher dose in Part 1 >1.3 log (given the true mean VLD on log scale) ≥20% was
calculated and are shown below in Table 5.
Table 5
Percentage of the trials with posterior probability>=20% for Part 1 
higher dose using sample size=6
True Mean
VLD on log scale
Posterior Probability ≥20% 
Posterior Probability <20% 
0.5
0.0%
100.0%
0.7
0.1%
99.9%
0.8
0.6%
99.4%
0.9
4.6%
95.4%
1
15.0%
85.0%
1.1
35.9%
64.1%
1.2
60.8%
39.2%
1.3
81.8%
18.2%
1.4
92.4%
7.6%
1.5
97.9%
2.1%
1.6
99.8%
0.2%
1.7
100.0%
0.0%
2
100.0%
0.0%
The precision of the dose response curve (with sample size N=6) is provided in Table 1
(Section 5.5.1).   
10.1.2.
Sample Size Sensitivity
Similar simulations in FACTS were conducted using sample sizes of 8 for Part 1 higher 
dose.  Using Bayesian calculation, the posterior probability to achieve a cut-point 1.3 log
was calculated for each simulated trial, and percentage of the trials with posterior 
probability greater than or equal to 20% was calculated (given the true mean VLD on log 
scale) and are shown below in Table 6.


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Table 6
Percentage of the trials with posterior probability ≥20% for Part 1 
higher dose using sample size=8
True Mean
VLD on log scale
Posterior Probability ≥20% 
Posterior Probability <20% 
0.5
0.0%
100.0%
0.7
0.0%
100.0%
0.8
0.6%
99.4%
0.9
2.5%
97.5%
1
10.2%
89.8%
1.1
27.4%
72.6%
1.2
56.2%
43.8%
1.3
81.3%
18.7%
1.4
93.8%
6.2%
1.5
98.9%
1.1%
1.6
99.8%
0.2%
1.7
100.0%
0.0%
2
100.0%
0.0%
Compared with the results of sample size=6 in Table 5, we only found slightly difference 
for the operation characteristics. It would be sufficient using sample size=6 for the 
interim analysis Go/No Go decision making.
10.1.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
10.2.
Populations for Analyses
Intent to Treat Exposed Population (ITT)
The ITT-Exposed Population is defined as all participants who meet study criteria and are 
enrolled into the study with documented evidence of having received at least 1 dose of 
treatment and at least one post-baseline HIV-1 RNA measurement. This will be the 
primary population for the final efficacy analysis for all active treatment groups.
Per Protocol Population (PP)
The Per Protocol Population is defined as all participants who meet study criteria and are 
enrolled into the study with documented evidence of having received all doses and all 
post-baseline HIV-1 RNA measurement, with exceptions of major protocol deviation. 
Safety Population
The Safety Population is defined as all participants who are enrolled into the study with 
documented evidence of having received at least 1 dose of randomized treatment.
Pharmacokinetic Population
The PK Population will include all participants who receive GSK3640254 and undergo 
plasma PK sampling during the study. Participants for whom a plasma PK sample is 
obtained and assayed will be included in the listing of plasma GSK3640254 


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concentration-time data.  Results from samples collected from a participant with emesis 
occurring within 2 hours of the dose will not be considered as evaluable.
10.3.
Statistical Analyses
10.3.1.
Interim Analysis
An informal unblinded interim analysis of preliminary safety, tolerability, PK and 
antiviral activity will occur after participants of Part 1 complete their Day 12 visit. If the
review of Part 1 highest dose shows that exposures are similar or higher than observed 
with 200 mg QD in healthy participants, this dose will be the highest dose in this study 
and only in this case, the Bayesian posterior probability (based on Part 1 higher dose 
data) that the log10 mean VLD from baseline is greater than a cut-point=1.3 log will be 
calculated for the Go/No Go decision for Part 2: 

If the probability is less than 20%, the trial will not move forward into Part 2 (No 
Go decision). 

Otherwise, the study team will review the whole Part 1 data in order to make a 
dose selection decision for the subsequent Part 2 cohorts
The study team will review the safety, tolerability, PK and antiviral activity data in order 
to confirm the dose selection for Part 2 cohorts. If the exposure to GSK3640254 200mg 
(Part 1 higher dose) looks similar or higher to those obtained with 200 mg QD in healthy 
volunteers in prior studies, and the effect observed at the Part 1 low dose is as anticipated, 
the Part 2 doses will be as initially planned as described in Section 5.5.2. If the exposure 
to GSK3640254 200mg are significantly lower than what anticipated (e.g. lower by at 
least 25%), the new highest dose predicted to provide a 200 mg equivalent exposure will 
be estimated and proposed for Part 2. The team will evaluate and possibly run the same 
Bayesian criteria to test the projected new highest dose VL drop in the interim analysis. If 
the effect observed with the Part 1 low dose is not as anticipated, the PK/PD model may 
be refined, and the Part 2 target effects and doses may be updated.  
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by visit. The analyses will be done for both PP and ITT exposed 
population if two populations are not the same. 
10.3.2.
Primary Analyses
The final analysis will be performed after the completion of the study and final datasets 
authorization. Data will be listed and summarized according to GSK reporting standards, 
where applicable. Listings will be sorted by participant, period, day, and time, noting 
treatment; summaries will be presented by treatment, visit/day, and time. Unless stated 
otherwise, descriptive summaries will include n, mean, standard deviation (SD), 
coefficient of variation (%CV), median, minimum, and maximum, geometric mean with 
associated 95% confidence interval (CI), and %CVb for continuous variables, whereas 
and percent will be used as summary statistics for categorical variables. Baseline or pre-
dose assessment is the last available assessment prior to time of the first dose unless it is 
specified otherwise. If there are multiple assessments collected on the same scheduled 
time, the average of these assessments will be used. For tabulated safety summaries, only 


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the scheduled assessments will be included in the summary tables. Version 9.1 or higher 
of the SAS system will be used to analyze the data as well as to generate tables, figures, 
and listings. Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
10.3.2.1.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards and data will be in Clinical Data 
Interchange Standards Consortium (CDISC) format. No formal statistical analysis of the 
safety data will be conducted. 
10.3.2.2.
Efficacy Analyses
Both the PP and ITT Populations will be used for all efficacy analyses if there are 
dropouts.  Plasma HIV-1 RNA max change and change from baseline during the study 
will be calculated for each participant and on each assessment visit/day.
Plasma HIV-1 RNA will be listed by treatment, participant, and assessment visit/day and 
summarized by treatment and assessment visit along with change from baseline.
Plots of mean and median plasma HIV-1 RNA actual and change from baseline data will 
be generated by treatment and assessment visit.

Plasma HIV-1 RNA change from baseline to the nadir (maximum change from 
baseline) will be calculated for each participant and summarized by treatment.
Together, the data from Parts 1 and 2 will investigate the complete dose-exposure-
response curve and the impact of lower doses/exposures on potential development of 
resistance.
10.3.2.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GSK. Plasma GSK3640254 concentration-time 
data will be analyzed by non-compartmental methods with WinNonlin Version 6.1 or 
higher. 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, as data permit:
Plasma GSK3640254 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
area under the plasma concentration time curve from zero to 24 AUC(0-24), 
maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), concentration at 24 hours post dose (C24), absorption lag 
time (tlag)
PART 1:
Day 91
AUC(0-), Cmax, tmax, pre-dose concentration (C0), concentration at end of 
dosing interval (C), half-life (t1/2), apparent oral clearance (CL/F).


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and PART 2:
Day 7
Results based on samples collected from a participant with emesis within 6 hours of 
dosing will not be considered as evaluable.
All PK data will be stored in the R&D archives, GSK.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GSK. Details of the statistical analyses will be provided in the RAP. 
An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK3640254 PK parameters, with the exception of 
Tmax and Tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK3640254 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 91 in study Part 1 and Day 7 in study Part 2 [AUC(0-τ) and Cmax] 
will be assessed using a power model if multiple dose levels are assessed. The power 
model will be fitted by restricted maximum likelihood (REML) using statistical analysis 
software (SAS) Proc Mixed. A fixed effects power model will be used. The mean slope 
will be estimated from the power model with the corresponding 90% CI.
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 91 with Day 1 PK for each dose in Part 1 and 
comparisons of Day 7 with Day 1 PK for each dose in Part 2 will be used for the 
accumulation ratio (R) evaluation. Pre-dose concentrations between Visit 4 and 6 will be 
used for steady-state assessment. 
10.3.3.
Secondary Analyses
10.3.3.1.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various PK parameters (e.g., AUC, Cmax, Cτ, etc.) and PD 
measures (e.g., maximum log10 reduction from baseline in plasma HIV-1 RNA or safety 
parameters) will be explored using various models including Emax. The relationship 
between dose and PD measures will also be explored. 
Details of the PK/PD exploratory analyses will be provided in the RAP.
10.3.3.2.
Viral Genotyping and Phenotyping Analyses
Viral genotypic/phenotypic data will be listed and descriptive summaries will be 
provided. Details of the analyses will be provided in the clinical virology report.


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11.
REFERENCES
Bristol-Myers Squibb Document Number 930109388, 1.0; BMS-TMF-3548385 1.0.  
Clinical Study Report: A Randomized, Double-Blind, Double-Dummy, Positive-
Controlled, Crossover Study to Determine Electrocardiographic Effects of BMS-955176 
in Healthy Subjects, 13-JAN-2017
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10.
GSK Document Number 2016N302783_00. Clinical Study Report: A Phase 2b 
Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy and 
Dose-response of BMS-955176/GSK3532795, Given on a Backbone of 
Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults – Week 24 Interim 
Analysis, 21-JUN-2017
GSK Document Number 2018N375454_00. Clinical Pharmacology Synopsis. A single 
centre, 2-period, randomized, open-label Phase 1 study to assess the relative 
bioavailability of a mesylate salt capsule of GSK3640254 compared to a hydrochloride 
salt capsule in healthy participants. September 2018.
GSK Document Number 2018N375461_00. Clinical Pharmacology Synopsis. A Double-
Blind (Sponsor Unblinded), Randomized, Placebo- Controlled, Single and Repeated Dose 
Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of 
GSK3640254 in Healthy Participants. September 2018.
GSK Document Number 2018N379610_00. Clinical Investigator's Brochure for 
GSK3640254, September 2018
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
International Antiviral Society (IAS)–USA ART Treatment of Adult HIV Infection: 2015 
Recommendations of the International Antiviral Society-USA Panel. Wensing AM et al. 
2015 update of the drug resistance mutations in HIV-1. Topics in Antiviral Medicine 
October/November 2015: 23(4). Available at: 
http://www.iasusa.org/sites/default/files/tam/23-4-132.pdf. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et.al
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
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].


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ART
Anti-retroviral therapy
ARV
Anti-retroviral
AUC(0-)
Area under the curve (Area under the plasma 
drug concentration-time curve from pre-dose to 
the end of the dosing interval at steady state) 
AUC(0-24)
Area under the plasma concentration time curve 
from zero to 24
β-HCG
Human chorionic gonadotropin
BID
Twice daily
BMI
Body mass index
BMS
Bristol-Myers Squibb
cART
Combination anti-retroviral therapy
C0
Concentration, pre-dose
C24
Concentration, 24 hours post-dose
CAp24
Capsid protein 24
CD4
Cluster of designation 4
CD8
Cluster of designation 8
CDC
Center for Disease Control and Prevention
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
CIB
Clinical Investigator's Brochure 


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CIOMS
Council for International Organizations of 
Medical Sciences
CL/F
Apparent oral clearance 
CMV
Cytomegalovirus
Cmax
Maximum observed concentration 
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase
CRF
Case report form
CSR
Clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
Ct
Concentration at end of dosing interval
CV
Cardiovascular
CVb
Between-participant coefficient of variation
DAIDS
Division of AIDS
DNA
Deoxyribonucleic acid
EC90
Effective concentration
ECG
Electrocardiogram 
Emax
Effect, at the maximum
EMEA
European Medicines Agency
FACTS
Fixed and Adaptive Clinical Trial Simulation
FDA
Food and Drug Administration 
FSH
Follicle Stimulating Hormone
FTIH
First-time-in-human
Gag
Group-specific antigen


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GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GERD
Gastroesophageal reflux disease
GI
Gastrointestinal
GSK
GlaxoSmithKline 
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HCV Ab
Hepatitis C antibody
HDPE
High-density polyethylene
HDL
High density lipoprotein
HIV-1
Human immunodeficiency virus-1
HRT
Hormonal replacement therapy
ICF
Informed consent form 
IEC
Independent Ethics Committee 
INR
International normalized ration
IQ
Inhibitory quotient
IRB
Institutional Review Board 
IRT
Interactive Response Technology
ITT
Intent to treat
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
IVRS/IWRS
Interactive Voice/Web Response System
LDL
Low density lipoprotein


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LOAEL
Lowest observed adverse effect level
LLOD
Lower limit of detection
MAD
Multiple ascending dose
MedRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MI
Maturation inhibitors
MOA
Mechanisms of action
MSDS
Material Safety Data Sheet 
msec
Milliseconds
NOAEL
No-observed-adverse-effect-level
NSAIDS
Nonsteroidal anti-inflammatory drugs
PBAEC90
Protein binding adjusted concentration
PBO
Placebo
PCR
Polymerase chain reaction
PD
Pharmacodynamic 
PI
Principal Investigator 
PK
Pharmacokinetic 
POC
Proof of Concept
PGX
Pharmacogenetics
PP
Per protocol
PPL
Physician Product Lead
QD
Once daily
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by 
Fridericia’s formula


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R
Accumulation ratio
RAP
Reporting and Analysis Plan
RBC
Red blood cells
REML
Restricted Maximum Likelihood
RNA
Ribonucleic Acid
SAD
Single ascending dose
SAE
Serious Adverse Event 
SAS
Statistical Analysis Software
SD
Standard deviation 
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SI
Sub-Investigator
SOA
Schedule of activities
SOC
System Organ Class
SP1
Spacer peptide 1
SRM
Study Reference Manual 
SRT
Safety Review Team
SUSAR
Suspected unexpected serious adverse 
reactions
t1/2
Apparent terminal phase half-life
tlag
Absorption lag time
tmax
Time of occurrence of Cmax 
TN
Treatment naïve
ULN
Upper limit of normal 
VH
ViiV Healthcare


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VLD
Viral load drop
WBC
White blood cells
WoCBP
Woman of Childbearing Potential 
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
NONE
DAIDS
FaceTime
MedDRA
Phoenix
SAS
SKYPE
WhatsApp
WonNonlin


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study treatment decision or response evaluation, the results must be 
entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
%Reticulocytes
White blood cells (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cells (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Amylase and 
Lipase
Creatinine
Sodium, 
Bicarbonate, and 
Chloride
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(nonfasting**)
**will be fasting 
on days when 
fasting lipids are 
collected.
Calcium, 
Magnesium, and 
Phosphate
Alkaline 
phosphatase
Fasting Lipid
Panel
(Cholesterol,
Triglycerides,
High density 
lipoprotein [HDL],
low density 
lipoprotein [LDL])


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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (if needed to determine
women of non-childbearing potential)

Urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed)2

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody [HCVAb], with reflex to HCV RNA if positive).

PCR (HIV-1 diagnostic PCR)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

All study-required laboratory assessments will be performed by a 
central laboratory
The results of each test may be entered into the CRF.
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 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies 
of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded or the participant has 
undergone emergency unblinding.


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12.3.
Appendix 3: Study Governance Considerations
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, Investigator Brochure, and other 
relevant documents (eg, 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
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.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 


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Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Committees Structure
The Safety Review Team (SRT) is a VH/GSK cross-functional team reviewing all 
available safety data related to the project, including in-stream data from this study, in an 
ongoing manner. The SRT is an internal VH/GSK requirement put in place to ensure 
holistic evaluation of the safety profile of an investigational product with systematic, 
periodic and documented reviews of available safety data, with the appropriate 
communication and escalation of new findings that have the potential to impact patient
safety.


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Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
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 ViiV Healthcare site or other 
mutually-agreeable location.

ViiV Healthcare 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.

ViiV Healthcare will provide the investigator with the randomization codes for 
their site only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with ViiV Healthcare
Policy.
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 (eg, 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. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

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 


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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. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the 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.

Definition of what constitutes source data can be found in the Study Reference 
Manual (SRM).
Study and Site Closure
ViiV Healthcare 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 ViiV Healthcare. Study sites will 
be closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study-site closure visit has been 
performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

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 treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, 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 treatment 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 
treatment 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
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.


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
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
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 (eg, 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:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been 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 fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 


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functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
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 should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording 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 


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medical records to VH/GSK in lieu of completion of the VH/GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by VH/GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to VH/GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the DAIDS grading table, Version 2.1, March 2017
https://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf and 
assign it to 1 of the following categories:

Mild: no or minimal interference with usual social & functional activities

Moderate: greater than minimal interference with usual social & functional 
activities

Severe: inability to perform usual social & functional activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe.

Life Threatening: inability to perform basic self-care functions
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 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 treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.


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
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to VH/GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to VH/GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by VH/GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide VH/GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information.
Reporting of SAE to VH/GSK
SAE Reporting to VH/GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to VH/GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 


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taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) 
or to the Medical Monitor by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to VH/GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment.
Pregnancy Testing
Women of Childbearing Potential are excluded from trial participation.  
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to VH/GSK
within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will be 


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forwarded to VH/GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to VH/GSK
as described in Appendix 4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
treatment or be withdrawn from the study.


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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the 
disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis

DNA samples will be used for research related to GSK3640254 or HIV and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) related 
to GSK3640254 or study treatments of this drug class, and HIV. Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome [or analysis of the entire genome] (as appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3640254 or study treatments of this class. The results of 
genetic analyses may be reported in the clinical study report or in a separate study 
summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3640254 (or study treatments of 
this class) or HIV continues but no longer than 15 years after the last subject last visit or 
other period as per local requirements.


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and International normalized ratio (INR)>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to VH/GSK within 24 
hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline (see 
MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
VH/GSK Medical Governance approval is granted 
(see below)  

If restart/rechallenge not allowed per 
protocol or not granted, permanently discontinue 
study treatment and continue participant in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, within 5 
days after last dose5

Serum creatine phosphokinase 
(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 the concomitant 
medications report form including 


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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24-72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
acetaminophen, herbal remedies, other 
over the counter medications.

Record alcohol use on the liver 
event alcohol intake case report form (CRF) 
page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, 
magnetic resonance, or computerised 
tomography) and /or liver biopsy to evaluate 
liver disease; complete Liver Imaging and/or 
Liver Biopsy CRF pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.  


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12.8.
Appendix 8: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March
2017
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the hyperlink here to the DAIDS Grading Table.
Alternatively, paste this into your browser: https://rsc.tech-res.com/docs/default-
source/safety/daidsgradingcorrecetedv21.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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12.9.
Appendix 9: CDC Classification for HIV-1 Infection (2014)

Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-
lymphocyte percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-lymphocyte 
percentage should only be considered if the count is missing.

HIV infection, stage 0

Indicates early HIV infection, inferred from a negative or indeterminate HIV test 
result within 180 days of a positive result. The criteria for stage 0 supersede and are 
independent of criteria used for other stages.

HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.

HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.

HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).

Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte 
count of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes of 
>14%. 

HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.

Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary 


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
Cryptococcosis, extrapulmonary 

Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
oesophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary 

Isosporiasis, chronic intestinal (>1 month's duration) 

Kaposi's sarcoma 

Lymphoma, Burkitt's (or equivalent term) 

Lymphoma, immunoblastic (or equivalent term) 

Lymphoma, primary, of brain 

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary 

Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis jirovecii pneumonia 

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy 

Salmonella septicaemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month 

Wasting syndrome attributed to HIV.


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12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 (28-Sep-2018)
Overall Rationale for the Amendment: The original version of the protocol was not 
submitted to any health authority (HA) worldwide. Key elements of the original protocol 
design were discussed with the United States Food and Drug Administration (US FDA)
in the context of pre-Investigational New Drug (IND) feedback (i.e. scientific advice). To 
this end, the overall design, duration, and sample population remain the same. However, 
minor changes were made to exclusion criteria, patient monitoring, and reasons for 
discontinuation to enhance the safety of trial participants. Finally, other administrative 
changes and updates were made (e.g. succinct results from two Phase 1 clinical trials in 
healthy volunteers).


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Section # and 
Name
Description of Change
Brief Rationale
Section 1, 
Synopsis, 
Rationale
Updated text to reflect the most 
current information regarding the 
first-time-in-human (FTIH) 207187 
study.
Updated information is now available.
Section 1, 
Synopsis, Overall 
Design
Provided a justification for the use 
of placebo in the study.
For completeness.
Section 1, 
Synopsis, 
Treatment Groups 
and Duration
Inserted the caveat of local 
permissibility to the suggestion 
that observed dosing may be 
achieved via various forms of 
video calling technology.
Acknowledging there may be cases 
where this method may not be locally 
allowed.
Section 2.2, Part 
1 and Part 2 
Treatment, Post-
Dosing and 
Follow-up Periods
Redesigned the format of the 
entire table.
For clarity regarding procedures to be 
done at the in-clinic visits versus the 
visits done via video/phone.
To footnote 3: Inserted the caveat 
of local permissibility for the 
suggestion that observed dosing 
may be achieved via various 
forms of video calling.
Acknowledging there may be cases 
where this method may not be locally 
allowed.
Inserted new footnotes 7 and 9
For clarity regarding the pharmacokinetic 
(PK) visit relative to visit optionality.
Regarding Single, Pre-dose PK 
and Intensive PK (and new 
footnote 7): Removed the 
collection need for single, pre-
dose PK sample on Day 2, and 
added a footnote of consideration 
for collection the single, pre-dose 
PK samples on Day 11.
Removed redundancy, as the Day 1, 24-
hr PK sample is the same as the Day 2, 
single, pre-dose collection.  This could 
hold true as well for the Day 11 single, 
pre-dose PK collection if the Intensive 
PK event occurs on Day 10.
Section 3.2, 
Background
Updated reference information 
with the most current document 
identification
Updated information is now available.
Section 3.2.2, 
Preliminary Safety 
and PK Data in 
Study 207187
Preliminary Safety and PK Data in 
Study 207187 updated/added
Updated information is now available.


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Section # and 
Name
Description of Change
Brief Rationale
Section 3.2.3, 
Preliminary Safety 
and PK Data in 
Study 208131
Preliminary Safety and PK Data in 
Study 208131 updated/added
Updated information is now available.
Section 3.3, 
Benefit/Risk 
Assessment
Minor text adjustments, and 
updated information for reference 
documents 
Updated information is now available.
Section 3.3.1, 
Risk Assessment
Cardiovascular category: Added 
information about new corrected 
QT (QTc) Stopping criteria
Strengthened conservative measures for 
patient safety.
Gastrointestinal intolerability and 
toxicity category: Added text 
directing the reader to the 
Investigator’s Brochure (IB) for 
summaries of rates of 
gastrointestinal (GI) adverse 
events (AEs), and other minor text 
adjustments.
Current information from the FTIH 
207187 and RBA 208131 studies is 
available.
Neurologic/psychiatric safety 
category: Added text directing the 
reader to the IB for summaries of 
rates of Neurologic and 
Psychiatric AEs, and other minor 
text adjustments
Current information from the FTIH 
207187 and RBA 208131 studies is 
available, and referred to new guidance 
for the management of emergent 
psychiatric symptoms.
Human immunodeficiency virus 
(HIV) Resistance to GSK3640254 
category: provided information to 
indicate there is no cross-class 
resistance.
Provided information to indicate
participation in this trial will not interfere 
with the selection of a combination 
antiretroviral therapy (cART) regimen at 
the completion of the study.
Section 3.3.3, 
Overall 
Benefit:Risk 
Conclusion
Outdated information for study 
207187 was removed.
Updated information is now available.
Section 5.1, 
Overall Design
Expanded the existing justification 
for the use of placebo in Part 1 
and in Part 2
Clarity.
Section 5.1.1.2, 
Treatment Phase 
Inserted the caveat of local 
permissibility for the suggestion 
Acknowledging there may be cases 
where this method may not be locally 


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Section # and 
Name
Description of Change
Brief Rationale
and Follow-up 
Period, Treatment 
Phase Day 1 –
Day 10
that observed dosing may be 
achieved via various forms of 
video calling.
allowed.
Section 5.1.1.2, 
Treatment Phase 
and Follow-up 
Period, Follow-up 
Visits Day 11-17 
and Final Follow-
up Visit Day 18-24
Text modifications regarding the 
start of medications in the post-
dosing period.
Clarification/Correction.
Section 5.4, 
Scientific 
Rationale for 
Study Design
Preliminary Safety and PK Data in 
Study 207187 updated/added, 
and other minor text adjustments.
Updated information is now available.
Section 6.2, 
Exclusion Criteria, 
#8
Extended exclusion criterion for 
laboratory abnormalities from just 
Grade 4 to Grade 2-4, and 
included lipid abnormalities as 
exceptions.
Strengthened conservative measures for 
patient safety.
Section 6.2, 
Exclusion Criteria, 
#24
Reduced the exclusionary values 
for both PR interval and QRS 
duration.
Strengthened conservative measures for 
patient safety.
Section 7.1, 
Treatment 
Administration
Added descriptive information for 
the placebo
Clarity needed to ensure it is understood 
that the placebo will look exactly like any 
one of the active dose capsules of 
GSK3650254 
Changed manufacturer from Wuxi 
to Shanghai STA Pharmaceutical 
Product Co.
STA is a subsidiary of Wuxi, and is the 
location to where the manufacture has 
been transferred.
Section 7.4, 
Blinding
Modified the title due to the 
addition of text explaining the role 
of the study team in the interim 
analysis in lieu of the inclusion of 
a data monitoring committee 
(DMC). 
For clarity.
Section 7.6, 
Inserted the caveat of local 
Acknowledging there may be cases 


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Section # and 
Name
Description of Change
Brief Rationale
Treatment 
Compliance
permissibility for the suggestion 
that observed dosing may be 
achieved via various forms of 
video calling.
where this method may not be locally 
allowed.
Section 7.8, 
Treatment and 
Care after the End 
of the Study
More formally describe the post 
dosing treatment 
expectations/goals for participants
For clarity.
Section 8.1.2, 
QTc Stopping 
Criteria
Added new QTc Stopping Criteria
Strengthened conservative measures for 
patient safety.
Section 8.1.3, 
Individual 
Participant 
Laboratory 
Abnormality and 
AE Stopping 
Criteria
Added new stopping criteria for 
psychiatric AEs, and for related 
AEs.
Strengthened conservative measures for 
patient safety.
Section 9.4.5, 
Suicidal Risk 
Monitoring
Added new guidance for the 
management of emergent suicidal 
and non-suicidal psychiatric AEs.
Strengthened conservative measures for 
patient safety.
Section 9.4.6, GI 
Toxicity 
Evaluation and 
Management, 
Footnote a to the 
table
Adjusted the grading and 
relatedness of GI AEs that will 
now require discontinuation and 
not just a consideration of 
discontinuation.
Strengthened conservative measures for 
patient safety.
Section 9.5, 
Pharmacokinetics
Removed the 0 hr, 00:00 
references in the text associated 
with the pre-dose blood sampling 
and attached those to the actual 
dosing time.
Clarification/Correction
Section 9.5, 
Pharmacokinetics, 
Table 4
Removed the 0 hr, 00:00 
references in the table associated 
with the pre-dose blood sampling 
and attached those to the actual 
dosing time. Added footnotes 
regarding the 24-hr PK blood 
draw to be consistent with new 
Clarification/Correction


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Section # and 
Name
Description of Change
Brief Rationale
footnotes in Section 2.2.
Section 9.7, 
Genetics
Changed the genetics blood 
sampling volume from 10 mL to 6 
mL
Correction.
Section 11, 
References
Updated with the most current 
documents available and that 
were used to amend portions of 
this protocol.
Updated information is now available.
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore not summarized 
Amendment 2 10-JAN-2019
Overall Rationale for the Amendment: Feedback from a Health Authority has provided 
greater specificity and clarification to existing exclusion criteria on psychiatric disease. 
Additionally, we have clarified that patients who are recently infected with HIV-1 should 
be excluded. Next, the human PK data available from Study 207187 (SAD/MAD) 
resulted in the removal of contraceptive requirements of male participants and any 
pregnancy monitoring requirements of female partners (of male participants). Further 
clarification on prohibited concomitant medications was provided. Finally, minor 
changes/clarifications were made to patient monitoring and reasons for discontinuation. 
Individually and in combination, all of these changes will not have a significant impact 
on the safety of clinical trial participants.


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Section # and Name
Description of Change
Brief Rationale
Section 2.2, Part 1 and Part 
2 Treatment, Post-Dosing 
and Follow-up Periods
Corrected some ECG 
collections during the post-
dosing phase to indicate those 
that are not done as a pre-
dose sampling
Correction
Section 2.2, Part 1 and Part 
2 Treatment, Post-Dosing 
and Follow-up Periods
Section 9.5, Table 4 
footnote #2
Corrected some PK samples 
collections during the post-
dosing phase to indicate those 
that are not done as a pre-
dose sampling
For clarity
Section 6.1, Inclusion 
Criteria, #7
Section 9.2.6, Pregnancy
Section 12.5, Appendix 5, 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Removed contraceptive 
requirements and any 
pregnancy reporting 
requirements for female 
partners of male participants.
Preclinical data shows that 
GSK3640254 is not 
genotoxic, and though the 
teratogenicity is unknown, 
data suggests toxicity to 
sperm or embryo at 
therapeutic levels unlikely. 
Thus, there is no impact on 
the risk/benefit assessment.
Section 6.2, Exclusion 
Criteria
Added additional exclusion 
criterion on patients with 
recent HIV-1 infection.
This exclusion criterion 
provides further 
clarification on excluding 
patients with recent HIV-1 
infection who are not 
appropriate for 
participation in a clinical 
trial.
Section 6.2, Exclusion 
Criteria
Added greater specificity and 
clarification to the existing 
psychiatric exclusion criteria 
to directly address a history of 
psychoses or other psychiatric 
conditions that may be 
associated with a higher risk 
of psychosis
Prior versions of the 
protocol did contain 
psychiatric exclusion 
criteria. However, the 
further specificity and 
clarification will exclude 
patients with psychiatric 
disease who are not 
appropriate for 
participation in a clinical 
trial.
Section 6.3.4, Counsel 
regarding Safe Sex 
Practices
Added text to describe the 
content of counselling that 
should occur with participants
Counselling on safe sex 
practices leads to decreases 
in HIV-1 transmission.
Section 7.7, Concomitant 
Added clarification on 
prohibited concomitant 
Concomitant medications 


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Section # and Name
Description of Change
Brief Rationale
Therapy
medications
may have an interaction 
(as victim or perpetrator) 
with GSK3640254
Section 8.2, Withdrawal 
from the Study
Inserted new 2nd bullet to 
indicate that patients who are 
withdrawn from the study for 
reasons of safety should 
continue to be followed to 
assess the outcome of the 
safety event that triggered 
discontinuation of study drug.
For clarity
Section 12.2, Appendix 2, 
Clinical Laboratory Tests, 
Table 7
Inserted Amylase and Lipase 
tests to the Clinical Chemistry 
output
An improved safety 
monitoring for pancreas 
pathology complementing 
the pre-existing Lipase
Other administrative 
changes
Minor editorial and document 
formatting revisions
Minor, therefore not 
summarized
Amendment 03  26-AUG-2019
Summary of Changes
Synopsis, Objectives and Endpoints
PREVIOUS TEXT
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1 infected TN participants 
during 10 days of monotherapy

Maximum change from baseline (Day 
1) in plasma HIV-1 ribonucleic acid (RNA)
Key Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in HIV-1 infected 
TN participants

GSK3640254 safety and tolerability 
parameters: adverse events (AE); post-
baseline values and changes over time of 
clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in HIV-1 

GSK3640254 PK parameters at the 


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Objectives
Endpoints
infected patients 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax), 
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
curve (Area under the plasma drug 
concentration-time curve from pre-dose to the 
end of the dosing interval at steady state (AUC 
[0-]), Cmax, tmax, pre-dose concentration 
(C0), concentration at end of dosing interval 
(C), apparent terminal phase half-life (t1/2), 
and apparent oral clearance (CL/F), if data 
permit.

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in HIV-1 infected 
patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 
GSK3640254 PK parameters following dosing 
for 10 days

Relationship between Day 1 AUC (0-
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
REVISED TEXT
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1 infected TN participants 
during 10 days of monotherapy in Part 1 and 
during 7 days of monotherapy in Part 2

Maximum change from baseline (Day 
1) in plasma HIV-1 ribonucleic acid (RNA)
Key Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in Part 1 and over 
7 days in Part 2 in HIV-1 infected TN 

GSK3640254 safety and tolerability 
parameters: adverse events (AE); post-
baseline values and changes over time of 
clinical laboratory evaluations, vital signs, and 


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Objectives
Endpoints
participants
electrocardiogram (ECG) parameters

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 infected 
patients 

GSK3640254 PK parameters at the 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax), 
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
curve (Area under the plasma drug 
concentration-time curve from pre-dose to the 
end of the dosing interval at steady state (AUC 
[0-]), Cmax, tmax, pre-dose concentration 
(C0), concentration at end of dosing interval 
(C), apparent terminal phase half-life (t1/2), 
and apparent oral clearance (CL/F), if data 
permit.

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in Part 1 and for 7 
days in Part 2 in HIV-1 infected patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 
GSK3640254 PK parameters following dosing 
for 10 days in Part 1 and for 7 days in Part 2

Relationship between Day 1 AUC (0-
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
Synopsis, Overall Design (paragraphs 1 and 7, and Figure 1)
PREVIOUS TEXT
Paragraph 1:
This is a Phase 2a, global, multicenter, randomized, double-blind (Sponsor-unblinded), 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability and PK/ pharmacodynamics (PD) of GSK3640254 over 10 days in ART-
naïve HIV-1 infected adults, who are termed “participants” in rest of this protocol.  
Paragraph 7: 
In both Part 1 and Part 2, following a screening visit, qualified participants will be 
randomized within 14 days (up to 28 days in some cases) into one of the treatment arms, 


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each consisting of a 10-day treatment and minimum of 8 visits over 17 days. Then 
participants will receive follow-up evaluations during approximately 1-2 weeks following 
the last dose
Figure 1: 208132 Study Schematic
REVISED TEXT
Paragraph 1:
This is a Phase 2a, global, multicenter, randomized, double-blind (Sponsor-unblinded), 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability and PK/ pharmacodynamics (PD) of GSK3640254 over 10 days in study 
Part 1 and over 7 days in study Part 2 in ART-naïve HIV-1 infected adults who are 
termed “participants” in rest of this protocol.  
Paragraph 7:
In both study Part 1 and Part 2, following a screening visit, qualified participants will be 
randomized within 14 days (up to 28 days in some cases) into one of the treatment arms, 
each consisting of a 10-day treatment and minimum of 8 visits over 17 days. Then 
participants will receive follow-up evaluations during approximately 1-2 weeks following 
the last dose.
In study Part 2, following a screening visit, qualified participants will be
randomized within 14 days (up to 28 days in some cases) into one of the treatment 
arms, each consisting of a 7-day treatment and minimum of 6 visits over 8 days. 
Then participants will receive follow-up evaluations during approximately 3-5 days 
following the last dose.


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Figure 1: 208132 Study Schematic
Synopsis, Treatment Groups and Duration, paragraphs 2-3, and paragraph 
7 and onward
PREVIOUS TEXT  
Paragraphs 2-3:
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period. The 14-day screening period may be 
extended to 28 days in some cases to allow receipt of all screening results and/or to 
accommodate scheduling. 
A qualified participant will be randomized into the treatment phase of the study and will 
administer study treatments, once daily, from Day 1 through Day 10. On Day 1, an 
appropriate number of bottles will be dispensed, with a supply sufficient to cover the 
entire 10-day treatment period.  The blinded bottles will contain capsules of either the 
active dose or placebo.  Dosing instructions will be indicated on each bottle.  Participants 
will bring the bottles of study treatments to each visit, so that study treatment can be 
administered in the clinic after the study procedures have been performed.
REVISED TEXT
Paragraphs 2-3:
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period in Part 1 and into a 7-day treatment 
period in Part 2. The 14-day screening period may be extended to 28 days in some cases 
to allow receipt of all screening results and/or to accommodate scheduling. 


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A qualified participant will be randomized into the treatment phase of the study and will 
administer study treatments, once daily, from Day 1 through Day 10 in Part 1 and from 
Day 1 through Day 7 in Part 2. On Day 1, an appropriate number of bottles will be 
dispensed, with a supply sufficient to cover the entire 10-day treatment period.  The 
blinded bottles will contain capsules of either the active dose or placebo.  Dosing 
instructions will be indicated on each bottle.  Participants will bring the bottles of study 
treatments to each visit, so that study treatment can be administered in the clinic after the 
study procedures have been performed.
PREVIOUS TEXT
Paragraph 7 and onward:
Participants will then enter the post-dosing period. There are 4 in-clinic visits in the post-
dosing period: 3 visits for PK and other assessments during the 7 days immediately 
following the last dose, and a final follow-up visit primarily for safety (e.g., to follow any 
AEs to resolution) approximately 8-14 days after the last dose, as shown in the Schedule 
of Activities (SOA, Section 2). Participants should not start other medicines and will not 
start ARVs during the post-dosing period until they have completed the final follow-up 
visit.  
In the shortest course, a participant can be screened/qualified, treated and assessed for all 
the planned visits (including the final follow-up visit) in approximately 30 days (if, for 
example, only 10-14 days are needed for the screening period and the final follow-up 
visit is performed on Day 18).  
In the longest course, a participant can be screened/qualified, treated and assessed for all 
the planned visits (including the final follow-up visit) in 52 days (if, for example, 28 days 
are needed for the screening period and the final follow-up visit is performed on Day 24).
REVISED TEXT 
Paragraph 7 and onward:
Participants will then enter the post-dosing period:
Study Part 1: 
There are 4 in-clinic visits in the Part 1 post-dosing period: 3 visits for PK and 
other assessments during the 7 days immediately following the last dose, and a 
final follow-up visit primarily for safety (e.g., to follow any AEs to resolution) 
approximately 8-14 days after the last dose, as shown in the Part 1 Schedule of 
Activities (SOA, Section 2). In Part 1, participants should not start other 
medicines and will not start ARVs during the post-dosing period until they have 
completed the final follow-up visit.  
In the shortest course for Part 1, a participant can be screened/qualified, treated 
and assessed for all the planned visits (including the final follow-up visit) in 
approximately 30 days (if, for example, only 10-14 days are needed for the 
screening period and the final follow-up visit is performed on Day 18).  In the 
longest course for Part 1, a participant can be screened/qualified, treated and 
assessed for all the planned visits (including the final follow-up visit) in 52 days 


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(if, for example, 28 days are needed for the screening period and the final follow-
up visit is performed on Day 24).
Study Part 2: 
There are 2 in-clinic visits in the Part 2 post-dosing period: 1 visit for PK and 
other assessments on the day immediately following the last dose, and a final 
follow-up visit primarily for safety (e.g., to follow any AEs to resolution) 3-5 
days after the last dose, as shown in the Part 2 Schedule of Activities (SOA, 
Section 2).
In Part 2, participants will start Investigator-selected, prescribed and 
provided cART immediately following the completion of the primary 
endpoint, i.e., the measurement of HIV-1 RNA on Day 8.
In the shortest course for Part 2, a participant can be screened/qualified, 
treated and assessed for all the planned visits (including the final follow up 
visit) in approximately 24 days (if, for example, only 10-14 days are needed 
for the screening period and the final follow-up visit is performed on Day 10.  
In the longest course, a participant can be screened/qualified, treated and 
assessed for all the planned visits (including the final follow-up visit) in 40 
days (if, for example, 28 days are needed for the screening period and the 
final follow-up visit is performed on Day 12).


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Section 2.2, Part 1 and Part 2 Treatment, Post-Dosing and Follow-up Periods
PREVIOUS TEXT
A single table existed. No specific table existed for Part 2.
Previous Table Notes:
1.
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration.
2.
The study requires 9 in-clinic visits.  Flexibility is offered for Visits 3, 4, 5, 8 and 9.  The visit schedule for each participant should be pre-
planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the treatment period can be 
greater than 3 days.
3.
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not in the 
clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al.
4.
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen).
5.
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 11 samples, with other visits tested as appropriate.
6.
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study completion, they 
will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response (excluding any human genetic 
testing)
7.
If the Intensive PK day occurs on Day 10, do not collect the Day 11 pre-dose PK sample (as it is redundant with the 24-hr PK collection 
(completing the sample set started on Day 10).
8.
Intensive Plasma PK samples will be collected as outlined in Table 4 in Section 9.5
9.
If Day 8 or 9 is the Clinic Visit 5 to include the Intensive PK collection, the participant must return the following day for the 24-hr PK 
collection, meal and dosing.  The assessments to be done as indicated on what is a “virtual visit day” should be captured as a virtual visit, even if 
the questions are asked in the clinic.
10. Log in to RAMOS on Day 1 to randomize the participant and to receive blinded study treatment.  Subsequently log-in to RAMOS for 
study treatment supply as needed. If a participant is discontinued from the study early, log in to RAMOS to record the discontinuation
REVISED TEXT
In this amendment, the existing single table was given a label of Study Part 1:


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A second table specific to study Part 2 was inserted and labelled as Study Part 2:  The footnotes from Study Part 1 table were modified 
and inserted for Study Part 2 as shown below.
Study Part 2:
Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Clinical 
Assessments
Outpatient Visit2
X
X
X
X
X
X
X
Video/Phone Call
X
X
Verify Inclusion/
Exclusion Criteria
X
Medical/medicatio
n/drug/alcohol 
history
X
Prior Anti-retroviral 
(ARV) Check
X
CDC Classification
X
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
HIV-associated 
conditions 
assessments3
X
X
X
X
X
X
X
X
X
Adverse event 
(AE)/SAE 
assessment3
X
X
X
X
X
X
X
X
X
Concomitant 
medication 
review3
X
X
X
X
X
X
X
X
X
Weight, BMI and 
Physical exam4 
X
Vital Signs
X
X
X
X
X
C-SSRS 
Administration          
(Since Last Visit
form)
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Clinical 
Procedures
12-lead ECG 
(triplicate reading, 
done pre-dose; 
single readings at 
PK draws 2hr, 4hr, 
and 6hr)
X
12-lead ECG
(single reading, 
done pre-dose at 
Visits 2 and 3)
X
X
X
12-lead ECG 
(single reading 
done pre-dose and 
at PK draws 2hr, 
4hr, and 6hr)
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Pharmacogenetics 
(PGX) Collection 
(if consented)
X
Hematology/Chem
istry/Urine
X
X
X
X
X
X
X
Fasting Lipid 
Panel
(approximately 8 
hrs)
X
X
X
Lymphocyte T-cell 
subsets (CD4, 
CD8)
X
X
Plasma for HIV-1 
genotype/phenoty
pe5
X
X
X
X
X
X
Plasma for 
storage6
X
X
X
X
X
X
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
HIV-1 RNA
X
X
X
X
X
X
X
Single, 
Pharmacokinetic 
(PK) sample done 
pre-dose 
X
X
Intensive PK 
sampling(to 
include the 24hr 
samples drawn the 
next day)
X
X
Observed dosing 
with GSK3640254
/placebo3
X
X
X
X
X
X
X


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Procedure1
Treatment Period 
Day 1 – Day 7
Post-Dosing 
Follow Up Period
Final Follow-
up
Day 1
Day 2
Day 3, 4
Choose one day for the 
Clinic Visit 3. 
The other day will be a 
virtual event.
Day 5, 6
Choose one day for the   
Clinic Visit 4. 
The other day 
will be a virtual event.
Day 7
Day 8
Day 10, 11 or 
12
Clinic 
Visit 1
Clinic 
Visit 2
Clinic 
Visit 3
Virtual
Clinic
Visit 4
Virtual
Clinic 
Visit 5
Clinic 
Visit 6
Clinic           
Visit 7
Observed dosing 
with Investigator-
selected, 
prescribed and 
provided CART, 
and eCRF 
completion
X
IWRS (RAMOS) 
activity8
X


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1
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration.
2
The study requires 9 7 in-clinic visits.  Flexibility is offered for Visits 3, 4, 5, 8 and 9 7.  The visit schedule for each participant 
should be pre-planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the 
treatment period can be greater than 3 days.
3
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not 
in the clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al.
4
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen).
5
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 11 8 samples, with other visits tested as appropriate.
6
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be 
used when needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study 
completion, they will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response 
(excluding any human genetic testing)
7.
If the Intensive PK day occurs on Day 10, do not collect the Day 11 pre-dose PK sample (as it is redundant with the 24-hr PK 
collection (completing the sample set started on Day 10).
7
Intensive Plasma PK samples will be collected as outlined in Table 4 in Section 9.5
9.
If Day 8 or 9 is the Clinic Visit 5 to include the Intensive PK collection, the participant must return the following day for the 24-
hr PK collection, meal and dosing.  The assessments to be done as indicated on what is a “virtual visit day” should be captured as a virtual 
visit, even if the questions are asked in the clinic.
8
Log in to RAMOS on Day 1 to randomize the participant and to receive dispense blinded study treatment.  Subsequently log-
in to RAMOS for study treatment supply as needed. If a participant is discontinued from the study early, log in to RAMOS to record the 
discontinuation.


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Section 3.1, Study Rationale
PREVIOUS TEXT
The proposed Study 208132 is a proof of concept (POC), randomized double blind 
(Sponsor-unblinded) study to characterize antiviral activity, safety/tolerability, PK, and 
the relationship between PK and antiviral activity of GSK3640254 given once daily 
(QD), administered across a range of doses over 10 days in HIV-1 infected treatment-
naïve adults.  To minimize the number of participants exposed to suboptimal or 
redundant doses, a two-part, adaptive and dose-ranging design is applied in this study.
This two-part, adaptive design will allow an early understanding of the potential of 
GSK3640254, while not exposing HIV-infected participants to longer courses and 
possible development of resistance.  Data from this study will be utilized to select doses 
for further studies in Phase 2b.
REVISED TEXT
The proposed Study 208132 is a proof of concept (POC), randomized double blind 
(Sponsor-unblinded) study to characterize antiviral activity, safety/tolerability, PK, and 
the relationship between PK and antiviral activity of GSK3640254 given once daily 
(QD), administered across a range of doses over 10 days in study Part 1 and over 7 
days in study Part 2 in HIV-1 infected treatment-naïve adults.  To minimize the number 
of participants exposed to suboptimal or redundant doses, a two-part, adaptive and dose-
ranging design is applied in this study. This two-part, adaptive design will allow an early 
understanding of the potential of GSK3640254, while not exposing HIV-infected 
participants to longer courses and possible development of resistance.  Data from this 
study will be utilized to select doses for further studies in Phase 2b.
Section 3.2.2, Preliminary Safety and PK Data in Study 20718, Paragraph 6
PREVIOUS TEXT
There were no clinically significant abnormal fluctuations or trends in vital signs in the 
SAD or MAD cohorts. There were no abnormal clinically significant arrhythmias or QT 
prolongations (values >500 msec or increases >60 msec from Baseline) observed for any 
participant in the SAD or MAD. There were no laboratory abnormality trends across 
doses that were clinically significant or associated with any symptoms.
REVISED TEXT
There were no clinically significant abnormal fluctuations or trends in vital signs in 
the SAD or MAD cohorts. There were no abnormal clinically significant
arrhythmias or QT prolongations (values >500 ms or increases >60 ms from 
Baseline) observed for any participant in the SAD or MAD. A cardiodynamic 
evaluation of healthy subjects in the MAD portion of Study 207187 (placebo or 
GSK3640254 dose range 50 to 320 mg daily for 14 days) was performed. Serial 
ECGs were extracted from continuous Holter monitors at time-matched baseline on 
Day -1 and for approximately 24 hours post-dose on Days 1 and 14. In the 
concentration-QTc analysis, a final model with a treatment effect-specific intercept 
reasonably represented the data. The slope of the concentration-QTc relationship 


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was 0.004 ms per ng/mL (90% confidence interval [CI]: 0.0023 to 0.0048) with a 
small treatment effect-specific intercept of -0.9 ms (90% CI: -4.47 to 2.69). The QT 
effect (ΔΔQTcF) of GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 
9.10) and 6.70 ms (90% CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg 
(2154 ng/mL) doses, respectively, on Day 14. Based on this concentration-QTc 
analysis, a QTcF effect above 10 ms could be excluded up to GSK3640254 plasma 
concentrations of approximately 2000 ng/mL (corresponding to doses approximately 
≤200 mg QD; note, the maximum dose used in Part 1 of this study, 208132, is 200 mg 
QD). Finally, there were no laboratory abnormality trends across doses that were 
clinically significant or associated with any symptoms.
Section 3.2.4, Justification for Part 2 Treatment Duration and Initiation of 
cART
PREVIOUS TEXT
No previous text.
REVISED TEXT
Data from Part 1 showed a decline in HIV-1 RNA and reasonable PK profile. There 
were no clinically significant trends in AEs, vital signs, ECG findings, or chemistry 
or haematology laboratory abnormalities across dosing arms. However, some 
participants receiving GSK3640254 had treatment emergent resistance mutations 
associated with maturation inhibitors observed on Day 11 (after 10 days of receiving 
GSK3640254 monotherapy). Additionally, no resistance to existing and 
commercially available classes of antiretroviral medications (e.g., reverse 
transcriptase, protease, integrase) was observed at Day 11 as there is no known 
cross-resistance between maturation inhibitors and other classes of ARVs. 
Genotypic analysis of samples at Clinic Visit 5 (Study Day 8 or 9) revealed no 
treatment emergent resistance. As a result, VH made two substantial changes to 
decrease the risk of treatment emergent resistance to participants in study Part 2: 1) 
decrease the duration of monotherapy from 10 days to 7 days (based on the interim 
genotypic analysis), and 2) immediately start Investigator-selected cART at the 
completion of monotherapy at the Part 2 primary endpoint (HIV-1 RNA measured 
on Day 8).
Section 3.3, Benefit/Risk Assessment, Paragraph 1
PREVIOUS TEXT
Based upon pre-clinical and clinical studies with the prior MI GSK3532795, the major 
risks are GI intolerability (e.g. abdominal pain and diarrhoea), prolongation of QTc, and 
neuropsychiatric safety. The risk of GI intolerability and neuropsychiatric safety is 
described in Section 3.3.1. The risk for QTc prolongation is described below in Section 
3.3.1 where one pre-clinical study did show one dog with an increased QTc interval when 
given a single dose of GSK3640254.


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REVISED TEXT
Based upon pre-clinical and clinical studies with the prior MI GSK3532795, the major 
risks are GI intolerability (e.g. abdominal pain and diarrhoea) and toxicity, prolongation 
of QTc, and neuropsychiatric safety, and treatment emergent resistance to 
GSK3640254. If present, preclinical GI toxicity findings (e.g. single cell parietal cell 
necrosis) in subjects would be minimal and not be persistent upon discontinuation 
of GSK3640254 after 7 days of dosing. The risk of GI intolerability and 
neuropsychiatric safety is described in Section 3.3.1. The risk for QTc prolongation is 
described below in Section 3.3.1 where one pre-clinical study did show one dog with an 
increased QTc interval when given a single dose of GSK3640254. As described in 
Section 3.2.2, a cardiodynamic analysis of healthy subjects in Study 207187 was 
conducted. A final model from the MAD data showed a QT effect (ΔΔQTcF) of 
GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms 
(90% CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) 
doses, respectively, on Day 14. Based on this concentration-QTc analysis, a QTcF 
effect above 10 ms could be excluded up to GSK3640254 plasma concentrations of 
approximately 2000 ng/mL (corresponding to doses approximately ≤200 mg QD; 
note, 200 mg QD was the maximum dose used in Part 1 of this study 208132). 
Importantly, there were no abnormal clinically significant arrhythmias or QTc 
prolongations (values >500 ms or increases >60 ms from Baseline) in Study 207187. 
This study contains specific cardiac exclusion criteria, has ECG monitoring (at 
Tmax once GSK3640254 attains steady state concentration), and has QTcF based 
stopping criteria.


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Section 3.3.1, Risk Assessment
PREVIOUS TEXT
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3640254]
Cardiovascular (QT prolongation)
Pre-clinically, GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and Ltype calcium 
channel currents recorded from HEK 293 cells stably 
transfected with cDNA 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 one 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 ongoing FTIH 208187 study, no participants to 
date have exhibited QTc change from baseline >60 
msec or QTc > 500 msec.
Protocol exclusion criteria based on screening 
ECG parameters and cardiac medical history
(see Section 6.2).
Participants will have ECG monitoring during the 
course of the study (see SOA table) with QTc 
stopping criteria (see Section 8.1.2).
Gastrointestinal intolerability and toxicity
Clinical signs indicative of gastrointestinal intolerability 
(sporadic vomiting and abnormal faeces 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 
Protocol exclusion criterion based on pre-existing 
GI pathology or baseline GI signs/symptoms
(see Section 6.2)
Participants will undergo continuous evaluation 
for adverse events during their participation in 
the trial; there are clinical stopping


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
were reversible. Finally, GI intolerability (predominately 
abdominal pain and diarrhea) was seen with a 
structurally related compound GSK3532795 which was 
evaluated through Phase 2b dosing.
The rates of GI AEs from the FTIH and RBA clinical 
trials (described above) are summarized in their 
respective synopses and the current Investigator 
Brochure.
criteria based upon intensity of treatment-
emergent AEs (see Section 8.1.3). Finally, a GI 
toxicity evaluation and monitoring plan is
available to guide the principal investigator (PI)
should GI AEs emerge (see Section 9.4.6).
Neurologic/psychiatric safety
Two psychiatric SAEs in previous MI GSK3532795 
clinical program (acute psychosis, homicidal/suicidal
ideation) at supratherapeutic doses were seen in 
healthy participants in TQT study.
From a Neurologic and Psychiatric AE summary and 
PK/PD analysis for GSK3532795 across all studies 
mild G1 headache and G1 sleep abnormalities were 
the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing dose 
(based on TQT and P2b studies). No exposure-
response relationship seen for select neurologic and 
psychiatric AEs (based on TQT and P2b studies) CNS 
penetration data for GSK3532795 and GSK3640254 in 
rats demonstrate a similarly low brain 
distribution/penetration.
The rates of Neurologic and Psychiatric AEs from the 
FTIH and RBA clinical trials (described above) are 
Protocol exclusion criterion based on any 
preexisting psychiatric condition (including 
results of psychological assessment) for patients.
Participants will have psychological assessment 
via a clinician (or qualified designee) 
administered C-SSRS in the study and will be 
included given no positive (abnormal) response. 
Continuous evaluation for adverse events during 
their participation in the trial including daily direct 
AE enquiry; 
The C-SSRS will also be administered after the 
treatment phase of the study. In the event of a 
positive (abnormal) response confirmed by the 
investigator, the patient will discontinue from the 
trial and the Principal Investigator/ Sub-
Investigator (PI/SI) will arrange for urgent 
specialist psychiatric evaluation and 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
summarized in their respective synopses and the 
current Investigator’s Brochure.
management.
Guidance for the PI on the management of 
emergent psychiatric symptoms are available 
(see Section 9.4.5)
Finally, there are clinical stopping criteria based 
upon intensity of treatment-emergent psychiatric 
AEs (see Section 8.1.3).
HIV-1 Infection/Patient population
HIV Resistance to GSK3640254
HIV-1 genotypic and phenotypic changes due to 
GSK3640254 monotherapy
Dosing is limited to 10 days of monotherapy to 
reduce the risk of emergent drug resistance.
There are no commercially available/approved 
MIs nor is there evidence of cross-class 
resistance (e.g. protease inhibitors) therefore 
dosing with GSK3640254 will not interfere with 
selection of a cART regimen at the completion of 
the study.
Strict adherence to protocol criteria around
concurrent meds.


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REVISED TEXT
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3640254]
Cardiovascular (QT prolongation)
Pre-clinically, GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and Ltype calcium 
channel currents recorded from HEK 293 cells stably 
transfected with cDNA 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 one 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 ongoing FTIH 208187 study, no participants to 
date have exhibited QTc change from baseline >60 
msec or QTc > 500 msec.
In the first time in human study 207187, no
participant exhibited QTc change from baseline >60 
ms or QTc >500 ms. As described in Section 3.2.2, 
in the concentration-QTc analysis, a QTcF effect 
above 10 ms could be excluded up to GSK3640254 
plasma concentrations of approximately 2000 
ng/mL (corresponding to doses approximately 
≤200 mg QD).
Protocol exclusion criteria based on screening 
ECG parameters and cardiac medical history
(see Section 6.2).
Participants will have ECG monitoring during the 
course of the study (see SOA table) with QTc 
stopping criteria (see Section 8.1.2).
Gastrointestinal intolerability and toxicity
Clinical signs indicative of gastrointestinal intolerability 
(sporadic vomiting and abnormal faeces beginning on 
Day 1 and continuing
Protocol exclusion criterion based on pre-existing 
GI pathology or baseline GI signs/symptoms
(see Section 6.2)


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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. Finally, GI intolerability (predominately 
abdominal pain and diarrhea) was seen with a 
structurally related compound GSK3532795 which was 
evaluated through Phase 2b dosing.
The rates of GI AEs from the FTIH and RBA clinical 
trials (described above) are summarized in their 
respective synopses and the current Investigator 
Brochure.
Participants will undergo continuous evaluation 
for adverse events during their participation in 
the trial; there are clinical stopping
criteria based upon intensity of treatment-
emergent AEs (see Section 8.1.3). Finally, a GI 
toxicity evaluation and monitoring plan is
available to guide the principal investigator (PI)
should GI AEs emerge (see Section 9.4.6).
Neurologic/psychiatric safety
Two psychiatric SAEs in previous MI GSK3532795 
clinical program (acute psychosis, homicidal/suicidal
ideation) at supratherapeutic doses were seen in 
healthy participants in TQT study.
From a Neurologic and Psychiatric AE summary and 
PK/PD analysis for GSK3532795 across all studies 
mild G1 headache and G1 sleep abnormalities were 
the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing dose 
(based on TQT and P2b studies). No exposure-
response relationship seen for select neurologic and 
psychiatric AEs (based on TQT and P2b studies) CNS 
penetration data for GSK3532795 and GSK3640254 in 
rats demonstrate a similarly low brain 
Protocol exclusion criterion based on any 
preexisting psychiatric condition (including 
results of psychological assessment) for patients.
Participants will have psychological assessment 
via a clinician (or qualified designee) 
administered C-SSRS in the study and will be 
included given no positive (abnormal) response. 
Continuous evaluation for adverse events during 
their participation in the trial including daily direct 
AE enquiry; 
The C-SSRS will also be administered after the 
treatment phase of the study. In the event of a 
positive (abnormal) response confirmed by the 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
distribution/penetration.
The rates of Neurologic and Psychiatric AEs from the 
FTIH and RBA clinical trials (described above) are 
summarized in their respective synopses and the 
current Investigator’s Brochure.
investigator, the patient will discontinue from the 
trial and the Principal Investigator/ Sub-
Investigator (PI/SI) will arrange for urgent 
specialist psychiatric evaluation and 
management.
Guidance for the PI on the management of 
emergent psychiatric symptoms are available 
(see Section 9.4.5)
Finally, there are clinical stopping criteria based 
upon intensity of treatment-emergent psychiatric 
AEs (see Section 8.1.3).
HIV-1 Infection/Patient population
HIV Resistance to GSK3640254
HIV-1 genotypic and phenotypic changes due to 
GSK3640254 monotherapy.
Data from Part 1 showed a decline in HIV-1 RNA 
and reasonable PK profile. However, some 
participants receiving GSK3640254 had treatment 
emergent resistance mutations associated with 
maturation inhibitors observed on Day 11 (after 10 
days of receiving GSK3640254 monotherapy). 
Additionally, no resistance to existing and 
commercially available classes of antiretroviral 
medications (e.g., reverse transcriptase, protease, 
integrase) was observed at Day 11 as there is no 
known cross-resistance between maturation 
inhibitors and other classes of ARVs. Genotypic 
Dosing is limited to 10 days of monotherapy in 
Part 1 to reduce the risk of emergent drug 
resistance, and additionally limited to 7 days 
of monotherapy in Part 2 to further reduce 
the risk of emergent MI drug resistance 
based on the genotypic analysis of the 
interim samples from Part 1. There are no 
commercially available/approved MIs nor is there 
evidence of cross-class resistance (e.g. protease 
inhibitors) therefore dosing with GSK3640254
will not interfere with selection of a cART 
regimen at the completion of the entire study 
(for Part 1) or the completion of the 
monotherapy portion of the study (Part 2).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
analysis of samples at Clinic Visit 5 (Study Day 8 or 
9) revealed no treatment emergent resistance.
Strict adherence to protocol criteria around
concurrent meds.


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Section 3.3.2, Benefit Assessment
PREVIOUS TEXT
This study in HIV-1 infected but otherwise healthy participants is a 10-day monotherapy
design. There is no expected longer term anti-HIV benefit to administration of 
GSK3640254. 
REVISED TEXT
This study in HIV-1 infected but otherwise healthy participants is a 10-day short term
monotherapy design. There is no expected longer-term anti-HIV benefit to administration 
of GSK3640254. 
Section 3.3.3, Overall Benefit:Risk Conclusion
PREVIOUS TEXT
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1
infected but otherwise healthy participants at the proposed GSK3640254 doses for 10 
days is predicted to be low and manageable. Mean exposures at the highest dose studied 
are not projected to exceed lowest observed adverse effect level (LOAEL) values 
obtained in chronic toxicology studies, further reducing potential risk.
REVISED TEXT
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1
infected but otherwise healthy participants at the proposed GSK3640254 doses, for 10 
days in Part 1 and for 7 days in Part 2, is predicted to be low and manageable. Mean 
exposures at the highest dose studied are not projected to exceed lowest observed adverse 
effect level (LOAEL) values obtained in chronic toxicology studies, further reducing 
potential risk.
Section 4, OBJECTIVES AND ENDPOINTS
PREVIOUS TEXT
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1-infected participants 
during 10 days of monotherapy

Maximum change from baseline (Day 
1) in plasma HIV-1 RNA
Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in HIV-1 infected 
participants

GSK3640254 safety and tolerability 
parameters: adverse events(AE); post-baseline 
values and changes over time of clinical 
laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters


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Objectives
Endpoints

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in HIV-1 
infected patients 

GSK3640254 PK parameters at the 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax),
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
plasma drug concentration-time curve from 
pre-dose to the end of the dosing interval at 
steady state (AUC[0-]), Cmax, tmax, pre-dose 
concentration (C0), concentration at end of 
dosing interval (C), apparent terminal phase 
half-life (t1/2), and apparent oral clearance 
(CL/F), if data permit.

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in HIV-1 infected 
patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 
GSK3640254 PK parameters following dosing 
for 10 days

Relationship between Day 1 AUC (0-
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
Exploratory

To assess the development of viral 
resistance (genotypic and phenotypic) over 10 
days and correlate with viral response, if
appropriate.

Emergence of drug resistance 
mutations, if appropriate

To assess attainment of steady state 
following administration of GSK3640254 for 10 
days in HIV-1 infected patients.

Steady State: pre-morning dose 
concentrations (C0) on Day 2 through Day 10 
C(Day 11)

To assess the immunologic effects of 
GSK3640254 when administered over 10 days 
in HIV-1 infected adults

Change from baseline in CD4+ T-cell 
count to Day 11

To explore the relationship between 
GSK3640254 exposure and safety or 
immunologic parameters, if appropriate

GSK3640254 repeat-dose PK 
parameters: AUC (0-), Cmax, Cwith Day 11 
change from baseline in CD4+ cell count


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Objectives
Endpoints
Note: Other exploratory objectives and endpoints may be specified in the Reporting and Analysis 
Plan (RAP).
REVISED TEXT
Objectives
Endpoints
Primary

To evaluate the antiviral activity of 
GSK3640254 in HIV-1-infected participants 
during 10 days of monotherapy in Part 1 and 
during 7 days of monotherapy in Part 2

Maximum change from baseline (Day 
1) in plasma HIV-1 RNA
Secondary

To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in Part 1 and over 
7 days in Part 2 in HIV-1 infected participants

GSK3640254 safety and tolerability 
parameters: adverse events (AE); post-
baseline values and changes over time of 
clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters

To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 infected 
patients 

GSK3640254 PK parameters at the 
following dose administration:
Day 1: area under the plasma concentration 
time curve from zero to 24 (AUC [0-24]), 
maximum observed concentration (Cmax), time 
to maximum observed concentration (tmax), 
concentration at 24 hours post dose (C24), 
absorption lag time (tlag) 
Following repeat administration: Area under the 
plasma drug concentration-time curve from 
pre-dose to the end of the dosing interval at 
steady state (AUC[0-]), Cmax, tmax, pre-dose 
concentration (C0), concentration at end of 
dosing interval (C), apparent terminal phase 
half-life (t1/2), and apparent oral clearance 
(CL/F), if data permit.

To explore the relationship between 
GSK3640254 exposure and change in plasma 
HIV-1 RNA

GSK3640254 repeat-dose PK 
parameters AUC(0-), Cmax, Cwith maximum 
HIV-1 RNA change from baseline

To estimate GSK3640254 
accumulation following administration of 
GSK3640254 for 10 days in Part 1 and for 7 
days in Part 2 in HIV-1 infected patients.

Accumulation: GSK3640254 PK 
accumulation ratios (R): repeat -dose AUC (0-
), Cmax, and Ccompared to Day 1 AUC (0-
24), Cmax, C24, respectively

To examine dose proportionality of 

Relationship between Day 1 AUC (0-


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Objectives
Endpoints
GSK3640254 PK parameters following dosing 
for 10 days in Part 1 and following dosing for 
7 days in Part 2
24), Cmax, C24, and repeat-dose AUC (0-), 
Cmax and Cand GSK3640254 dose levels
Exploratory

To assess the development of viral 
resistance (genotypic and phenotypic) over 10 
days in Part 1 and over 7 days in Part 2 and 
correlate with viral response, if appropriate.

Emergence of drug resistance 
mutations, if appropriate

To assess attainment of steady state 
following administration of GSK3640254 for 10 
days in Part 1 and for 7 days in Part 2 in HIV-
1 infected patients.

Steady State: pre-morning dose 
concentrations (C0) on Day 2 through Day 10 
C(Day 11) in Part 1 and on Day 2 through 
Day 7 C(Day 8)

To assess the immunologic effects of 
GSK3640254 when administered over 10 days
in Part 1 and over 7 days in Part 2 in HIV-1 
infected adults

Change from baseline in CD4+ T-cell 
count to Day 11 in Part 1 and to Day 8 in Part 
2

To explore the relationship between 
GSK3640254 exposure and safety or 
immunologic parameters, if appropriate

GSK3640254 repeat-dose PK 
parameters: AUC (0-), Cmax, Cwith Day 11 
change from baseline in CD4+ cell count in 
Part 1 and with Day 8 change from baseline 
in CD4+ cell count in Part 2
Note: Other exploratory objectives and endpoints may be specified in the Reporting and Analysis 
Plan (RAP).
Section 5.1, Overall Design, Paragraph 1
PREVIOUS TEXT
This is a Phase 2a, global, multicenter, double-blind (Sponsor-unblinded), randomized, 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability, PK and PD of GSK3640254 over 10 days in ART-naïve HIV-1 infected 
adults.  
REVISED TEXT
This is a Phase 2a, global, multicenter, double-blind (Sponsor-unblinded), randomized, 
placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, safety, 
tolerability, PK and PD of GSK3640254 over 10 days in study Part 1 and over 7 days 
in study Part 2 in ART-naïve HIV-1 infected adults.  
Section 5.1.1.1, Screening Phase
PREVIOUS TEXT
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period. Randomization may occur as soon as all 


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Screening procedures have been completed and results are available and on file. The 14-
day screening period may be extended (in some cases) to 28 days to allow receipt of all 
Screening assessment results and to accommodate scheduling.
REVISED TEXT
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period in study Part 1 and into a 7-day 
treatment period on study Part 2. Randomization may occur as soon as all Screening 
procedures have been completed and results are available and on file. The 14-day 
screening period may be extended (in some cases) to 28 days to allow receipt of all 
Screening assessment results and to accommodate scheduling.
Section 5.1.1.2, Treatment Phase and Follow-up Phase
PREVIOUS TEXT
Participants will be required to attend 9 in-clinic visits throughout the duration of the 
study.  Participant and Investigators will design a patient-centric visit schedule based on 
the optionality presented in the Schedule of Assessments (SOA; Section 2) to 
accommodate the 9 required visits over the (maximum) 24-day study period, and such 
that no visit interval exceeds more than 3 days.
Treatment Phase: Day 1 – Day 10
On Day 1, an appropriate number of bottles of study treatments will be dispensed with 
supply sufficient to cover the entire 10-day treatment period.  The blinded bottles will 
contain capsules of either the active dose or placebo.  Each bottle will indicate dosing 
instructions.  Participants will bring the bottles of study treatments to each visit, so that 
they can be administered after the study procedures have been performed.
Participants will report to the clinic for visits in the morning of the days selected for each 
of the 5 visits in the treatment phase.  Participants will arrive each day, with their study 
treatment container(s) and prior to administration of the morning dose, for safety and lab 
assessments, including ECGs and blood draws, as described in the SOA. Participants will 
be given morning doses in the clinic at each visit. On days when an in-clinic visit is not 
required, doses can be self-administered, and during observation by a site staff member 
using various forms of video calling (when at all possible and locally permitted) such as 
FaceTime, Skype, WhatsApp.
Two, serial, intensive blood PK sample collections will be done on Day 1, Clinic Visit 1
and on Day 9±1, Clinic Visit 5 (up to 24 hours post-morning dose).  Participants will be 
required to fast for at least 8 hours [overnight] prior to the morning check-in for the 
intensive PK sampling visits. Participants will be required to stay in the clinic on Days 1 
and 9±1 until all specified assessments are completed (12 hours post-dose). Participants 
will be required to return to the clinic the following morning to allow for the blood 
sampling at the 24-hr time point.
Study treatments should be administered near the same time each morning, within a 2-hr 
window.


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Each dose of study medication will be taken with approximately 240 mL (8 ounces) of 
water following ingestion of a moderate calorie and fat meal (i.e. at least 400 calories, 
with at least 120 calories from fat), that is required to be completed within 30 minutes 
just prior to dosing. A moderate calorie and fat breakfast is planned to be similar to the 
following (with additional meal suggestions in will be included in the Study Reference 
Manual [SRM]): 

2 slices of bread

10 g of butter

20 gr of jam 

15 g of cheese

175 mL of apple juice
Follow-up Visits Day 11-17 and Final Follow-up Visit Day 18-24
Participants should not start other medicines and will not start ARVs during the post-
dosing follow-up period until after the final follow-up visit has been completed.
Participants will return to the clinic in the post-dosing period for 4 visits (Visits 6-9).  

Three visits will be performed within the 7 days immediately following the dosing 
period for PK and measurement of assessments as shown in the SOA (Section 2).  

A final follow-up visit, to be performed approximately 8-14 days after the last 
dose, will be primarily for safety (e.g., to follow any AEs to resolution). 
If a participant is unable to return to the clinic for any reason site staff are encouraged to 
contact the participant for assessment of adverse events.
208132 Study Schematic


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REVISED TEXT
Part 1: 
Participants will be required to attend 9 in-clinic visits throughout the duration of the 
study in Part 1.  Participant and Investigators will design a patient-centric visit schedule 
based on the optionality presented in the Part 1 Schedule of Assessments (SOA; Section 
2) to accommodate the 9 required visits over the (maximum) 24-day study period, and 
such that no visit interval exceeds more than 3 days.
Part 2: 
Participants will be required to attend 7 in-clinic visits throughout the duration of 
the study in Part 2.  Participant and Investigators will design a patient-centric visit 
schedule based on the optionality presented in the Part 2 Schedule of Assessments 
(SOA; Section 2) to accommodate the 7 required visits over the (maximum) 12-day 
study period, and such that no visit interval exceeds more than 3 days.
Treatment Phase: Day 1 – Day 10 in Part 1 and Day 1 – Day 7 in Part 2:  
On Day 1, an appropriate number of bottles of study treatments will be dispensed with 
supply sufficient to cover the entire 10-day treatment period.  The blinded bottles will 
contain capsules of either the active dose or placebo.  Each bottle will indicate dosing 
instructions.  Participants will bring the bottles of study treatments to each visit, so that 
they can be administered after the study procedures have been performed.
Participants will report to the clinic for visits in the morning of the days selected for each 
of the 5 visits in the treatment phase.  Participants will arrive each day, with their study 
treatment container(s) and prior to administration of the morning dose, for safety and lab 
assessments, including ECGs and blood draws, as described in the SOA. Participants will 
be given morning doses in the clinic at each visit. On days when an in-clinic visit is not 
required, doses can be self-administered, and during observation by a site staff member 
using various forms of video calling (when at all possible and locally permitted) such as 
FaceTime, Skype, WhatsApp.
Two, serial, intensive blood PK sample collections will be done on Day 1, Clinic Visit 1
and on Day 9±1, Clinic Visit 5 (up to 24 hours post-morning dose).  Participants will be 
required to fast for at least 8 hours [overnight] prior to the morning check-in for the 
intensive PK sampling visits. Participants will be required to stay in the clinic on Days 1 
and 9±1 until all specified assessments are completed (12 hours post-dose). Participants 
will be required to return to the clinic the following morning to allow for the blood 
sampling at the 24-hr time point.
Study treatments should be administered near the same time each morning, within a 2-hr 
window.
Each dose of study medication will be taken with approximately 240 mL (8 ounces) of 
water following ingestion of a moderate calorie and fat meal (i.e. at least 400 calories, 
with at least 120 calories from fat), that is required to be completed within 30 minutes 
just prior to dosing. A moderate calorie and fat breakfast is planned to be similar to the 


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following (with additional meal suggestions in will be included in the Study Reference 
Manual [SRM]): 

2 slices of bread

10 g of butter

20 gr of jam 

15 g of cheese

175 mL of apple juice
Follow-up Visits
Part 1:
Follow-up Visits Day 11-17 and Final Follow-up Visit Day 18-24
Participants should not start other medicines and will not start ARVs during the post-
dosing follow-up period until after the final follow-up visit has been completed.
Participants will return to the clinic in the post-dosing period for 4 visits (Visits 6-9).  

Three visits will be performed within the 7 days immediately following the dosing 
period for PK and measurement of assessments as shown in the SOA (Section 2).  

A final follow-up visit, to be performed approximately 8-14 days after the last 
dose, will be primarily for safety (e.g., to follow any AEs to resolution). 
If a participant is unable to return to the clinic for any reason site staff are encouraged to 
contact the participant for assessment of adverse events.
Part 2:
Follow-up Visit Day 8 and Final Follow-up Visit Day 10-12
Participants should start Investigator-selected, prescribed and provided cART
immediately in the post-dosing period on Day 8, after the blood collection is 
performed.  
Participants will return to the clinic in the post-dosing period for 2 visits (Visits 6 
and 7).  

One visit will be performed on the day immediately following the dosing 
period for PK and measurement of assessments as shown in the SOA (Section 2).  

A final follow-up visit, to be performed approximately 3-5 days after the last 
dose, will be primarily for safety (e.g., to follow any AEs to resolution). 
If a participant is unable to return to the clinic for any reason site staff are 
encouraged to contact the participant for assessment of adverse events.


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208132 Study Schematic
Section 5.5, Dose Justification
PREVIOUS TEXT
The doses to be used in this study have been defined to adequately described the dose-
exposure-response of GSK3640254 in treatment-naïve HIV patients. The doses were 
selected as to approximately provide a median effect of 30, 50, 75, 90 and 95% of the 
maximum anticipated effect on HIV-1 RNA for an MI drug in a 10-day study.
REVISED TEXT
The doses to be used in this study have been defined to adequately described the dose-
exposure-response of GSK3640254 in treatment-naïve HIV patients. The doses were 
selected as to approximately provide a median effect of 30, 50, 75, 90 and 95% of the 
maximum anticipated effect on HIV-1 RNA for an MI drug in a 7-day or 10-day study.
Section 6.1, Inclusion Criteria
PREVIOUS TEXT
None
REVISED TEXT


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10. Participant must be willing and able to start cART on Study Day 8 (except in the 
case of early termination, clinically relevant AE/SAE, lab abnormality, the 
withdrawal of consent, lost to follow-up, etc., where circumstances could dictate 
otherwise)
Section 6.3.1, Meals and Dietary Restrictions, 1st Bullet
PREVIOUS TEXT

Each dose of study medication will be taken with approximately 240 mL (8 
ounces) of water following ingestion of a moderate calorie and fat meal (i.e. at least 
400 calories with at least 120 calories from fat), completed within approximately 30 
minutes just prior to dosing.  Prior to the two serial intensive blood PK collection 
days, to be done on Day 1 and on Day 9±1, participants will be required to fast for at 
least 8 hours [overnight] prior to the morning check-in.
REVISED TEXT

Each dose of study medication will be taken with approximately 240 mL (8 
ounces) of water following ingestion of a moderate calorie and fat meal (i.e. at least 
400 calories with at least 120 calories from fat), completed within approximately 30 
minutes just prior to dosing.  Prior to the two serial intensive blood PK collection 
days, to be done on Day 1Clinic Visit 1 and on Day 9±1Clinic Visit 5, participants 
will be required to fast for at least 8 hours [overnight] prior to the morning check-in.
Section 6.3.2, Alcohol, Tobacco and Marijuana
PREVIOUS TEXT

During the study alcohol consumption will be limited to the following: An 
average weekly intake of <14 drinks for males or <7 drinks for females. One drink is 
equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 
1.5 ounces (45 mL) of 80 proof distilled spirits.
No alcohol will be consumed on the in-clinic Intensive PK days (Day 1, Clinic Visit 1 
and Day 9 ± 1, Clinic Visit 5), until after the final assessment of the day and release from 
the clinic. 

Only clinically minor to moderate use (as determined by the PI/SI) of tobacco 
products will be allowed during trial participation, with extremely limited use on the in-
clinic Intensive PK days, (Day 1, Clinic Visit 1 and Day 9 ± 1, Clinic Visit 5).

Subjects should refrain from the use of marijuana during the 10-day treatment 
period.
REVISED TEXT

During the study alcohol consumption will be limited to the following: An 
average weekly intake of <14 drinks for males or <7 drinks for females. One drink is 


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equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 
1.5 ounces (45 mL) of 80 proof distilled spirits.
No alcohol will be consumed on the in-clinic Intensive PK days (Day 1, Clinic Visit 1 
and Day 9 ± 1, Clinic Visit 5), until after the final assessment of the day and release from 
the clinic. 

Only clinically minor to moderate use (as determined by the PI/SI) of tobacco 
products will be allowed during trial participation, with extremely limited use on the in-
clinic Intensive PK days, (Day 1, Clinic Visit 1 and Day 9 ± 1, Clinic Visit 5).

Subjects should refrain from the use of marijuana during the 10-day treatment 
period.
Section 6.3.3, Activity
PREVIOUS TEXT
Participants should abstain from strenuous exercise during the 10-day treatment period.
REVISED TEXT
Participants should abstain from strenuous exercise during the 10-day treatment period.
Section 7.8, Treatment and Care after the End of the Study
PREVIOUS TEXT
Given the lack of longer term clinical benefit (Section 3.3.2), VH recognizes the balance 
between the need to conduct an early phase monotherapy clinical trial (for the larger and 
long term unmet medical need) and the need for HIV-1 infected treatment naïve patients 
to receive cART as soon as possible after diagnosis. To meet both needs, this trial design 
is efficient in screening (shortest period: 14 days) and treatment/follow-up (shortest 
period: 18 days). A clinical trial commitment of as short as ~1 month is expected. After 
this time, VH expects all participating patients to receive local standard of care cART. 
VH recognizes some HIV-1 infected adults may encounter barriers to accessing cART. 
Where it has been determined by the Investigator to be an acceptable option, participants
receiving study treatment will have the option (but are not required) to receive 
reimbursement from the Sponsor for locally marketed ARVs (after the completion of 10 
days of dosing and through the study final follow-up visit) for up to a maximum of 90 
days. The selection of ARVs will be investigator-chosen based upon local standard of 
care.
The investigator is responsible for ensuring that participants will be referred for prompt 
cART initiation after completion of the study, whether or not VH is providing
reimbursement for post-study treatment.
REVISED TEXT
Given the lack of longer term clinical benefit (Section 3.3.2), VH recognizes the balance 
between the need to conduct an early phase monotherapy clinical trial (for the larger and 
long term unmet medical need) and the need for HIV-1 infected treatment naïve patients 
to receive cART as soon as possible after diagnosis. To meet both needs, this trial design 


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is efficient in screening (shortest period: 14 days) and treatment/follow-up (shortest 
period: 18 days in study Part 1 and 10 days in study Part 2). A clinical trial 
commitment of as short as ~1 month is expected. After this time, VH expects all 
participating patients to receive local standard of care cART. 
VH recognizes some HIV-1 infected adults may encounter barriers to accessing cART. 
Where it has been determined by the Investigator to be an acceptable option, participants
receiving study treatment will have the option (but are not required) to receive 
reimbursement from the Sponsor for locally marketed ARVs (after the completion of 10 
days of dosing and through the study final follow-up visit) for up to a maximum of 90 
days. The selection of ARVs will be investigator-chosen based upon local standard of 
care.
The investigator is responsible for ensuring that participants will be referred for prompt 
cART initiation after completion of the study, whether or not VH is providing
reimbursement for post-study treatment.
In the case of Part 2, participants will start Investigator selected, prescribed and 
provided cART immediately after the completion of the primary endpoint; i.e., 
specifically to be administered in the clinic on Day 8 after the blood collection has 
been performed.
Section 8.2, Withdrawal from the Study, final paragraph
PREVIOUS TEXT
If a participant withdraws from the study, he/she should complete a follow-up visit 7-14 
days after treatment was stopped (Visit 9).  If a participant is unable to return to the clinic 
for any reason site staff are encouraged to contact the subject for assessment of adverse 
events.
REVISED TEXT
If a participant withdraws from the study, he/she should complete a follow-up visit 7-14 
days after treatment was stopped (conducted as a Visit 9) in study Part 1, and 3-5 days 
after treatment was stopped (conducted as a Visit 7) in study Part 2.  If a participant 
is unable to return to the clinic for any reason site staff are encouraged to contact the 
subject for assessment of adverse events.
Section 9.5, Pharmacokinetics, 2nd paragraph after bullets
PREVIOUS TEXT
Intensive PK sampling (Day 1, Clinic Visit 1 and Day 9±1, Clinic Visit 5) begins with a 
morning pre-dose sampling, i.e, prior to the administration of the morning dose of the 
study treatment on the day of the visit. The pre-dose sampling should be done 
approximately 24 hours after the morning doses of the study drugs were taken the day 
prior to the visit. This pre-dose blood sampling will include the collection of the other 
parameters as well.
REVISED TEXT


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Intensive PK sampling (Day 1, Clinic Visit 1 and Day 9±1, Clinic Visit 5) begins with a 
morning pre-dose sampling, i.e, prior to the administration of the morning dose of the 
study treatment on the day of the visit. The pre-dose sampling should be done 
approximately 24 hours after the morning doses of the study drugs were taken the day 
prior to the visit. This pre-dose blood sampling will include the collection of the other 
parameters as well.
Section 9.5, Pharmacokinetics, Table 4
PREVIOUS TEXT
Table 8
Intensive Pharmacokinetic Sampling Schedule and Other Activities 
at Day 1, Clinic Visit 1 and Day 9±1, Clinic Visit 5
Time 
(Event)
Window for blood draw
Time 
(Relative to Dosing)
Hour: Min
Day 1, Clinic Visit 1
And
Day 9±1, Clinic 
Visit 5
morning pre-dose work: ECGs, 
vitals and full blood draw to 
include the pre-dose PK 
collection
Eat Meal. Administer study treatment and start the clock for 
subsequent blood draws.
00:00
1 hr PK blood draw
± 5 minutes
01:00
2 hr ECG and PK blood draw
± 15 minutes
02:00
3 hr PK blood draw
± 15 minutes
03:00
4 hr ECG and PK blood draw
± 15 minutes
04:00
5 hr PK blood draw
± 15 minutes
05:00
6 hr ECG and PK blood draw
± 15 minutes
06:00
8 hr PK blood draw
± 30 minutes
08:00
12 hr PK blood draw
± 2 hours
12:00
Next Day
24 hr (morning pre-dose) PK 
blood draw1, 2
± 2 hours
24:00
Eat Meal and administer study treatment.
1. This 24-hr pre-dose PK blood draw will be done at the same time as the collection for the lab kit on Day 
2, Visit 2.


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2.  If the Visit 5 Intensive PK visit is done on Day 10, this 24-hr PK blood draw will be done at the same 
time as the collection for the lab kit on Day 11.  Otherwise, this 24-hr blood draw is the only draw done on 
Day 9 (if the clinic visit is done on Day 8) or Day 10 (if the clinic visit is done on Day 9).
REVISED TEXT
Table 9
Intensive Pharmacokinetic Sampling Schedule and Other Activities 
at Day 1, Clinic Visit 1 and Day 9±1, Clinic Visit 5
Time 
(Event)
Window for blood draw
Time 
(Relative to Dosing)
Hour: Min
Day 1, Clinic Visit 1
And
Day 9±1, Clinic 
Visit 5
morning pre-dose work: ECGs, 
vitals and full blood draw to 
include the pre-dose PK 
collection
Eat Meal. Administer study treatment and start the clock for 
subsequent blood draws.
00:00
1 hr PK blood draw
± 5 minutes
01:00
2 hr ECG and PK blood draw
± 15 minutes
02:00
3 hr PK blood draw
± 15 minutes
03:00
4 hr ECG and PK blood draw
± 15 minutes
04:00
5 hr PK blood draw
± 15 minutes
05:00
6 hr ECG and PK blood draw
± 15 minutes
06:00
8 hr PK blood draw
± 30 minutes
08:00
12 hr PK blood draw
± 2 hours
12:00
Next Day
24 hr (morning pre-dose) PK 
blood draw1, 2
± 2 hours
24:00
Eat Meal and administer study treatment.
1. This 24-hr pre-dose PK blood draw will be done at the same time as the collection for the lab kit on Day 
2, Visit 2.the next day.
2.  In study Part 1, if If the Visit 5 Intensive PK visit is done on Day 10, this 24-hr PK blood draw will be 
done at the same time as the collection for the lab kit on Day 11.  Otherwise, this 24-hr blood draw is the 
only draw done on Day 9 (if the clinic visit is done on Day 8) or Day 10 (if the clinic visit is done on Day 
9).
Section 9.8, Biomarkers, 2nd paragraph
PREVIOUS TEXT


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Genotypic and phenotypic analyses will be carried out by using Gag/PR and PR/RT 
formats, in which PCR amplification is used to generate HIV cDNA products including 
the Gag and the PR and RT coding regions, respectively. Phenotypic analyses of the 
Gag/PR region will include susceptibility to GSK3640254. Analysis will be done on Day 
1 and Day 11 samples initially, with other timepoints analyzed as data emerge for viral 
load response.
REVISED TEXT
Genotypic and phenotypic analyses will be carried out by using Gag/PR and PR/RT 
formats, in which PCR amplification is used to generate HIV cDNA products including 
the Gag and the PR and RT coding regions, respectively. Phenotypic analyses of the 
Gag/PR region will include susceptibility to GSK3640254. Analysis will be done on 
samples collected in study Part 1 on Day 1 and Day 11 samples initially, and on 
samples collected in study Part 2 on Day 1 and Day 8 initially, with other timepoints 
analyzed as data emerge for viral load response.
Section 10.1.1, Sample Size Considerations, 1st paragraph
PREVIOUS TEXT
The primary objectives of this study are to investigate the safety, tolerability and antiviral 
activity of GSK3640254 over a 10-day treatment period. The antiviral activity will be 
assessed by estimating plasma HIV-1 RNA max change from baseline during the study
REVISED TEXT
The primary objectives of this study are to investigate the safety, tolerability and antiviral 
activity of GSK3640254 over a 10-day treatment period in study Part 1 and over a 7-
day treatment period in study Part 2. The antiviral activity will be assessed by 
estimating plasma HIV-1 RNA max change from baseline during the study
Section 10.3.2.3, Pharmacokinetic Analysis
PREVIOUS TEXT
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GSK. Plasma GSK3640254 concentration-time 
data will be analyzed by non-compartmental methods with WinNonlin Version 6.1 or 
higher. 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, as data permit:
Plasma GSK3640254 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
area under the plasma concentration time curve from zero to 24 AUC(0-24), 
maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), concentration at 24 hours post dose (C24), absorption lag 
time (tlag)
PART 1:
Day 91
AUC(0-), Cmax, tmax, pre-dose concentration (C0), concentration at end of 
dosing interval (C), half-life (t1/2), apparent oral clearance (CL/F).


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Results based on samples collected from a participant with emesis within 6 hours of 
dosing will not be considered as evaluable.
All PK data will be stored in the R&D archives, GSK.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GSK. Details of the statistical analyses will be provided in the RAP. 
An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK3640254 PK parameters, with the exception of 
Tmax and Tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK3640254 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 91 [AUC(0-τ) and Cmax] will be assessed using a power model if 
multiple dose levels are assessed. The power model will be fitted by restricted maximum 
likelihood (REML) using statistical analysis software (SAS) Proc Mixed. A fixed effects 
power model will be used. The mean slope will be estimated from the power model with 
the corresponding 90% CI.
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 91 with Day 1 PK for each dose will be used for 
the accumulation ratio (R) evaluation. Pre-dose concentrations between Visit 4 and 6 will 
be used for steady-state assessment. 
REVISED TEXT
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GSK. Plasma GSK3640254 concentration-time 
data will be analyzed by non-compartmental methods with WinNonlin Version 6.1 or 
higher. 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, as data permit:
Plasma GSK3640254 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
area under the plasma concentration time curve from zero to 24 AUC(0-24), 
maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), concentration at 24 hours post dose (C24), absorption lag 
time (tlag)
PART 1:
Day 91
and PART 
2:
Day 7
AUC(0-), Cmax, tmax, pre-dose concentration (C0), concentration at end of 
dosing interval (C), half-life (t1/2), apparent oral clearance (CL/F).


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Results based on samples collected from a participant with emesis within 6 hours of 
dosing will not be considered as evaluable.
All PK data will be stored in the R&D archives, GSK.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GSK. Details of the statistical analyses will be provided in the RAP. 
An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK3640254 PK parameters, with the exception of 
Tmax and Tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK3640254 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 91 in study Part 1 and Day 7 in study Part 2 [AUC(0-τ) and 
Cmax] will be assessed using a power model if multiple dose levels are assessed. The 
power model will be fitted by restricted maximum likelihood (REML) using statistical 
analysis software (SAS) Proc Mixed. A fixed effects power model will be used. The 
mean slope will be estimated from the power model with the corresponding 90% CI.
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 91 with Day 1 PK for each dose in Part 1 and 
comparisons of Day 7 with Day 1 PK for each dose in Part 2 will be used for the 
accumulation ratio (R) evaluation. Pre-dose concentrations between Visit 4 and 6 will be 
used for steady-state assessment. 
Section 12.2, Appendix 2: Clinical Laboratory Tests, Table 7, Under Clinical 
Chemistry, Glucose
PREVIOUS TEXT
Glucose (nonfasting)
REVISED TEXT
Glucose (non-fasting**)
**will be fasting on days when fasting lipids are collected.

SAP_001.pdf: 
Statistical Analysis Plan 
Official Title of Study: Reporting and Analysis Plan for A Randomized, Double-Blind (Sponsor-unblinded), 
Placebo-Controlled, Adaptive Trial to Investigate the Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in HIV-1 Infected Treatment-Naïve Adults 
 
NCT ID: NCT03784079 
Other Identifiers: 208132 
Date of Document: 06Feb2020 
 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208132 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A Randomized, Double-
Blind (Sponsor-unblinded), Placebo-Controlled, Adaptive 
Trial to Investigate the Antiviral Effect, Safety, Tolerability 
and Pharmacokinetics of GSK3640254 in HIV-1 Infected 
Treatment-Naïve Adults 
Compound Number  : GSK3640254 
Effective Date  
: 06-FEB-2020 
 
Description: 
 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 208132. 
 
This RAP is intended to describe the safety, tolerability, pharmacokinetic, and 
antiviral analyses required for the study.  
 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
Approver 
Date 
06-FEB-2020 
Principal Statistician (Infectious Disease, Clinical Statistics)  
 
06-FEB-2020 
Programming Manager (Biostatistics, Clinical Programming) 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
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The GlaxoSmithKline group of companies 
 
208132 
 
2 
 
RAP Team Reviewer 
Clinical Development Manager (Clinical Development, ViiV Healthcare) 
Physician Product Lead (Clinical Development, ViiV Healthcare) 
Clinical Development Manager (Infectious Disease, CPSSO) 
Director (Clinical Pharmacology Modelling and Simulation) 
 
Clinical Development Investigator (Clinical Virology) 
Medical Advisor (SMG Pharma Safety)  
Data Manager (Infectious Disease, Data Management) 
Clinical Statistics and Clinical Programming Line Approvals: 
(Method: eMail approval due to the shifting to Veeva Vault, go through Veeva Vault 
e-Signature afterwards) 
Approver 
Date 
06-FEB-2020 
Statistics Leader (Infectious Disease, Clinical Statistics)  
06-FEB-2020 
Manager Programming (Biostatistics, Clinical Programming)  
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design ................................................................................................ 8 
2.4. 
Statistical Hypotheses / Statistical Analyses ................................................. 9 
3. 
PLANNED ANALYSES .......................................................................................... 10 
3.1. 
Interim Analyses ......................................................................................... 10 
3.2. 
Final Analyses ............................................................................................ 10 
4. 
ANALYSIS POPULATIONS ................................................................................... 11 
4.1. 
Protocol Deviations ..................................................................................... 12 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 13 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 13 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Multicentre Studies ..................................................................................... 14 
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 14 
6. 
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Overview of Planned Study Population Analyses ........................................ 15 
6.2. 
Display Details ............................................................................................ 15 
6.2.1. 
Subject Disposition ...................................................................... 15 
6.2.2. 
Protocol Deviations ...................................................................... 15 
6.2.3. 
Populations analysed ................................................................... 15 
6.2.4. 
Demography ................................................................................ 16 
6.2.5. 
Medical Conditions and Medications ............................................ 16 
6.2.5.1. 
Medical Conditions ..................................................... 16 
6.2.5.2. 
Medications ................................................................ 16 
6.2.6. 
Exposure and Treatment Compliance .......................................... 16 
7. 
EFFICACY ANALYSES .......................................................................................... 18 
7.1. 
Primary Efficacy Analyses .......................................................................... 18 
7.1.1. 
Endpoint / Variables ..................................................................... 18 
7.1.2. 
Summary Measure ...................................................................... 18 
7.1.3. 
Statistical Analyses / Methods ..................................................... 18 
7.1.3.1. 
Statistical Methodology Specification .......................... 19 
7.2. 
Secondary Efficacy Analyses ...................................................................... 19 
7.2.1. 
Endpoint / Variables ..................................................................... 19 
7.2.2. 
Summary Measure ...................................................................... 19 
7.2.3. 
Statistical Analyses / Methods ..................................................... 20 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 20 
7.3.1. 
Immunology ................................................................................. 20 
7.3.1.1. 
Endpoint / Variables ................................................... 20 
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7.3.1.2. 
Summary Measure ..................................................... 20 
7.3.1.3. 
Statistical Analyses / Methods .................................... 20 
7.3.1.4. 
Statistical Methodology Specification .......................... 21 
8. 
SAFETY ANALYSES ............................................................................................. 22 
8.1. 
Adverse Events Analyses ........................................................................... 22 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 22 
8.3. 
Clinical Laboratory Analyses ....................................................................... 23 
8.4. 
Other Safety Analyses ................................................................................ 25 
8.4.1. 
Electrocardiograms ...................................................................... 25 
8.4.2. 
Vital Signs .................................................................................... 26 
8.4.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................... 26 
8.4.4. 
Combination anti-retroviral therapy (cART) .................................. 26 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 27 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 27 
9.1.1. 
Endpoint / Variables ..................................................................... 27 
9.1.1.1. 
Drug Concentration Measures .................................... 27 
9.1.1.2. 
Derived Pharmacokinetic Parameters......................... 27 
9.1.2. 
Summary Measure ...................................................................... 28 
9.1.3. 
Population of Interest ................................................................... 28 
9.1.4. 
Statistical Analyses / Methods ..................................................... 28 
9.1.4.1. 
Dose proportionality .................................................... 29 
9.1.4.1.1. 
Statistical Methodology 
Specification ........................................... 29 
9.1.4.2. 
Steady State ............................................................... 30 
9.1.4.2.1. 
Statistical Methodology 
Specification ........................................... 30 
10. PHARMACODYNAMIC ANALYSES....................................................................... 31 
10.1. 
Primary Pharmacodynamic Analyses .......................................................... 31 
10.1.1. 
Endpoint / Variables ..................................................................... 31 
10.1.2. 
Summary Measure ...................................................................... 31 
10.1.3. 
Population of Interest ................................................................... 31 
10.1.4. 
Statistical Analyses / Methods ..................................................... 31 
10.1.4.1. Statistical Methodology Specification .......................... 32 
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 33 
11.1. 
PK/PD Analyses of HIV-1 RNA ................................................................... 33 
11.1.1. 
Statistical Analyses / Methods ..................................................... 33 
11.1.2. 
Population of Interest ................................................................... 33 
11.2. 
Concentration-QTcF Analyses .................................................................... 34 
12. REFERENCES ....................................................................................................... 35 
13. APPENDICES ........................................................................................................ 37 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 37 
13.1.1. 
Exclusions from Per Protocol Population ..................................... 37 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 38 
13.3. 
Appendix 3: Assessment Windows ............................................................. 51 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 51 
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13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 54 
13.4.1. 
Study Phases .............................................................................. 54 
13.4.1.1. Study Phases for Concomitant Medication ................. 54 
13.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 54 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 55 
13.5.1. 
Reporting Process ....................................................................... 55 
13.5.2. 
Reporting Standards .................................................................... 55 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 56 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 57 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 59 
13.7.1. 
Premature Withdrawals ................................................................ 59 
13.7.2. 
Handling of Missing Data ............................................................. 59 
13.7.2.1. Handling of Missing and Partial Dates ........................ 59 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 61 
13.9. 
Appendix 9: Biomarker Analyses ................................................................ 63 
13.9.1. 
Viral Genotyping and Phenotyping ............................................... 63 
13.9.2. 
Genetics ...................................................................................... 63 
13.10. Appendix 10: Abbreviations & Trade Marks ................................................ 64 
13.10.1. Abbreviations ............................................................................... 64 
13.10.2. Trademarks ................................................................................. 65 
13.11. Appendix 11: List of Data Displays.............................................................. 66 
13.11.1. Data Display Numbering .............................................................. 66 
13.11.2. Mock Example Shell Referencing ................................................ 66 
13.11.3. Deliverables ................................................................................. 66 
13.11.4. Study Population Tables .............................................................. 67 
13.11.5. Efficacy Tables ............................................................................ 70 
13.11.6. Efficacy Figures ........................................................................... 74 
13.11.7. Safety Tables ............................................................................... 75 
13.11.8. Safety Figures ............................................................................. 80 
13.11.9. Pharmacokinetic Tables ............................................................... 81 
13.11.10. Pharmacokinetic Figures ............................................................. 83 
13.11.11. Pharmacodynamic Tables ........................................................... 85 
13.11.12. Pharmacodynamic Figures .......................................................... 85 
13.11.13. Pharmacokinetic / Pharmacodynamic Tables .............................. 86 
13.11.14. Pharmacokinetic / Pharmacodynamic Figures ............................. 86 
13.11.15. ICH Listings ................................................................................. 87 
13.11.16. Non-ICH Listings .......................................................................... 91 
13.12. Appendix 12: Example Mock Shells for Data Displays ................................ 94 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the end of analyses 
to be included in the Clinical Study Report for Protocol. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 26/AUG/2019 Version: 208132/03). 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
 
To evaluate the antiviral activity of 
GSK3640254 in HIV-1 infected 
Treatment-Naïve(TN) participants 
during 10 days of monotherapy in Part 
1 and during 7 days of monotherapy 
in Part 2 
 
Maximum change from baseline (Day 1) in plasma HIV-1 
ribonucleic acid (RNA) 
Secondary Objectives 
Secondary Endpoints 
 
To assess the safety and tolerability of 
GSK3640254 when administered as 
monotherapy over 10 days in Part 1 
and over 7 days in Part 2 in HIV-1 
infected TN participants 
 
GSK3640254 safety and tolerability parameters: adverse 
events (AE) ; post-baseline values and changes over time 
of clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters 
 
To characterize the pharmacokinetics 
of GSK3640254 dosing for 10 days in 
Part 1 and for 7 days in Part 2 in HIV-
1 infected patients 
 
GSK3640254 PK parameters at the following dose 
administration: 
Day 1: area under the plasma concentration time curve 
from zero to 24 (AUC[0-24]), maximum observed 
concentration (Cmax), time to maximum observed 
concentration (tmax), concentration at 24 hours post dose 
(C24), absorption lag time (tlag).  
Following repeat administration: Area under the curve 
(Area under the plasma drug concentration-time curve 
from pre-dose to the end of the dosing interval at steady 
state (AUC[0-]), Cmax, tmax, pre-dose concentration 
(C0), concentration at end of dosing interval (C), 
apparent terminal phase half-life (t1/2), and apparent oral 
clearance (CL/F), if data permit. 
 
To explore the relationship between 
GSK3640254 exposure and change in 
plasma HIV-1 RNA 
 
GSK3640254 repeat-dose PK parameters AUC(0-), 
Cmax, C with maximum HIV-1 RNA change from 
baseline 
 
To estimate GSK3640254 
accumulation following administration 
of GSK3640254 for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 
infected patients 
 
Accumulation: GSK3640254 PK accumulation ratios (R): 
repeat -dose AUC (0-), Cmax, and C compared to Day 
1 AUC (0-24), Cmax, C24, respectively 
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Objectives 
Endpoints 
 
To examine dose proportionality of 
GSK3640254 PK parameters 
following dosing for 10 days in Part 1 
and for 7 days in Part 2 
 
Relationship between Day 1 AUC (0-24), Cmax, C24, and 
repeat-dose AUC (0-), Cmax and C and GSK3640254 
dose levels 
Exploratory Objectives 
Exploratory Endpoints 
 
To assess the development of viral 
resistance (genotypic and phenotypic) 
over 10 days in Part 1 and over 7 days 
in Part 2 and correlate with viral 
response, if appropriate. 
 
Emergence of drug resistance mutations, if appropriate 
 
To assess attainment of steady state 
following administration of 
GSK3640254 for 10 days in Part 1 
and for 7 days in Part 2 in HIV-1 
infected patients. 
 
Steady State: pre-morning dose concentrations (C0) on 
Day 2 through Day 10 C (Day 11) in Part 1 and on Day 2 
through Day 7 C (Day 8) 
 
To assess the immunologic effects of 
GSK3640254 when administered over 
10 days in Part 1 and 7 days in Part 2 
in HIV-1 infected adults 
 
Change from baseline in CD4+ T-cell count to Day 11 in 
Part 1 and to Day 8 in Part 2 
 
To explore the relationship between 
GSK3640254 exposure and safety or 
immunologic parameters, if 
appropriate 
 
GSK3640254 repeat-dose PK parameters: AUC (0-), 
Cmax, C with Day 11 change from baseline in CD4+ cell 
count in Part 1 and with Day 8 change from baseline in 
CD4+ cell count in Part 2 
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
 
This is a Phase 2a, global, multicentre, randomized, double-blind (Sponsor-
unblinded), placebo-controlled, adaptive clinical trial to evaluate the antiviral effect, 
safety, tolerability and PK/ pharmacodynamics (PD) of GSK3640254 over 10 days in 
study Part 1 and over 7 days in study Part 2 in ART naïve HIV-1 infected adults, who 
are termed “participants” in the study. 
 
All participants will be screened for eligibility before being randomized, preferably 
within 14 days, into a 10-day treatment period in Part 1 and into a 7-day treatment in 
Part 2. The 14-day screening period may be extended to 28 days in some cases to 
allow receipt of all screening results and/or to accommodate scheduling. 
Dosing 
 
Part 1 will include approximately 14 randomized participants and will evaluate two 
active doses of GSK3640254, 200 mg once daily or 10 mg once daily, in cohorts of 6 
participants each for 10 days. A cohort of 2 participants will be randomized to receive 
placebo for 10 days. 
 
Part 2 will include approximately 20 randomized participants and will evaluate three 
active doses of GSK3640254, 140/80/40 mg once daily, in cohorts of 6 participants 
each for 7 days. A cohort of 2 participants will be randomized to receive placebo for 7 
days. 
Time & 
Events 
 
See Appendix 2: Schedule of Activities for additional details of activities 
Treatment 
Assignment 
 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). 
Interim 
Analysis 
 
An informal unblinded interim analysis of preliminary safety, tolerability, PK and 
antiviral activity occurred after participants of Part 1 completed their Day 12 visit. 
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2.4. 
Statistical Hypotheses / Statistical Analyses 
Study 208132 is a proof of concept (POC), randomized double blind (Sponsor-unblinded) 
study to characterize antiviral activity, safety/tolerability, PK, and the relationship 
between PK and antiviral activity of GSK3640254 given once daily (QD), administered 
across a range of doses over 10 days in Part 1 and over 7 days in Part 2 in HIV-1 infected 
treatment naïve adults. No formal hypotheses will be tested. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
An informal unblinded interim analysis of preliminary safety, tolerability, PK and 
antiviral activity occurred after participants of Part 1 complete their Day 12 visit. The 
analysis was accomplished following criterion defined in protocol Section 10.3.1.  
Based on the results of the interim analysis, the dose levels for Part B were determined to 
be 140 mg, 80 mg, and 40 mg GSK3640254. Details of the Interim analysis displays are 
presented in Appendix 11: List of Data Displays. The main statistical results are included 
in the ICPSR [GlaxoSmithKline Document Number 2019N405148_01. Study 208132]. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
 
All participants who were screened for eligibility 
 
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 population as they did not 
enter the study. 
 
Study Population 
Randomized  
 
 
All participants who were randomly assigned to 
treatment in the study. 
 
This population will be based on the treatment the 
participant was randomized to. 
 
Study Population 
Safety 
 
All randomized participants who received at least one 
dose of study treatment. 
 
This population will be analysed based on the treatment 
the participant actually received. 
 
Study Population 
 
Safety 
Intent-To-Treat 
Exposed (ITT) 
 
All randomized participants who meet the study criteria 
and are enrolled into the study with documented 
evidence of having received at least one dose of 
treatment and at least one post-baseline HIV-1 RNA 
measurement. 
 
This will be the primary population for the final efficacy 
analysis for all active treatment groups. 
 
This population will be based on the treatment the 
participant was randomized to. 
 
Efficacy 
Per-Protocol  
(PP) 
 
all participants who meet study criteria and are 
enrolled into the study with documented evidence of 
having received all doses and all post-baseline HIV-1 
RNA measurement. 
 
Protocol deviations that would exclude participants from 
the PP population are defined in Section 4.1 (Protocol 
Deviations) and Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol 
Population). 
 
The PP set will not be analysed if no participants drop 
out of ITT population. 
 
Efficacy 
 
Pharmacokinetic 
(PK) 
 
The PK Population will include all participants who 
receive GSK3640254 and undergo plasma PK sampling 
during the study. Participants for whom a plasma PK 
sample is obtained and assayed will be included in the 
listing of plasma GSK3640254 concentration-time data. 
Results from samples collected from a participant with 
emesis occurring within 2 hours of the dose will not be 
considered as evaluable.  
 
PK 
Pharmacokinetic/ 
Pharmacodynamic 
(PK/PD) 
 
Participants who meet criteria for Per-Protocol and 
Pharmacokinetic Population analysis sets and who 
undergo PD sampling during the study. 
 
Pharmacokinetic/ 
Pharmacodynamic 
Refer to Appendix 11: List of Data Displays which details the population used for each display. 
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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 
summarised and listed. 
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population). 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP) [04 Nov 2019 
Version 2]. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Part 1 Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF 
D1 
GSK3640254 10 mg 
GSK 10 mg 
1 
D2 
GSK3640254 200 mg 
GSK 200 mg 
2 
P 
Placebo 
Part 1 Placebo 
3 
 
Part 2 Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF 
D3 
GSK3640254 Dose 3 
GSK 40 mg 
4 
D4 
GSK3640254 Dose 4 
GSK 80 mg 
5 
D5 
GSK3640254 Dose 5 
GSK 140 mg 
6 
P 
Placebo 
Part 2 Placebo 
7 
 
Data collected from protocol planned visits (ex. Lab, ECG, vital signs and PK etc.) will 
be analysed and reported separately for each part of the study, unless otherwise specified. 
Data collected from unplanned visits (ex. Adverse events, concomitant medications etc) 
or collected only once in study i.e. study population(ex. Demography , medical history 
etc.) will be reported two parts in single output. Unless otherwise indicated (in statistical 
models), randomized placebo participants from Parts 1 and 2 will always be treated as 
two groups for summaries tables. Besides, overall column will be added in all summary 
output. 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment 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. 
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Parameter 
Study Assessments Considered as Baseline 
Baseline Used 
in Data Display 
Screening 
Day 1 (Pre-Dose) 
Efficacy 
All efficacy endpoints 
X 
X 
Day 1 
Safety 
All laboratory, vital signs and 
ECG measurement endpoints 
X 
X 
Day 1 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3. 
Multicentre Studies 
Data will be summarised for all centres combined.  
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
13.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population 
13.2 
Appendix 2: Schedule of Activities 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.4.1 
Appendix 5: Data Display Standards & Handling Conventions 
13.5.1 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.8 
Appendix 8: Values of Potential Clinical Importance 
13.9 
Appendix 9: Biomarker Analyses 
13.10 
Appendix 10: Abbreviations & Trade Marks 
13.11 
Appendix 11: List of Data Displays 
13.12 
Appendix 12: Example Mock Shells for Data Displays 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the ITT population, unless otherwise 
specified. The study population analysis will include part 1 and part 2 together in one 
display (Part 1 placebo and Part 2 placebo displayed separately).  
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
medical history and exposure and treatment compliance will be based on GSK Core Data 
Standards. Details of the planned displays are presented in Appendix 11: List of Data 
Displays. 
6.2. 
Display Details 
6.2.1. 
Subject Disposition 
The disposition table will consist of all intent-to-treat participants   
The number and percentage of participants who failed screening and were, therefore, not 
enrolled into the study, overall and by reason, will be summarized. A listing of the screen 
failure record for all participants who failed screening, including the reasons for screen 
failure will be presented.  
Reasons for study treatment discontinuation will be summarized by treatment group and 
overall.  A by-subject listing of reasons for study withdrawal, a by-subject listing of 
reasons for study treatment discontinuation, and a by-subject listing of planned and actual 
treatment received will be produced.  
The number and percentage of participants at each visit will be summarized for each 
treatment group and overall.  
6.2.2. 
Protocol Deviations 
Please refer to Section 4.1 for details.  
Inclusion and exclusion criteria deviations will be listed.  
6.2.3. 
Populations analysed 
The number of participants who were enrolled into the study, and the number of 
participants within each analysis population (screened, enrolled, randomized, ITT, Per 
Protocol, Safety, PK and PK/PD) will be summarized for each treatment group and 
overall.  
The number and percentage of participants will be summarized by centre for each 
treatment group and overall.  
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Participants excluded from any population, including participants excluded from the Per 
Protocol population, will be listed. 
6.2.4. 
Demography 
The demographic and baseline characteristics age, sex, race, ethnicity, height, weight, 
BMI, and baseline CDC HIV-1 classification will be summarized by treatment group and 
overall for the safety population. The count, mean, standard deviation, median, minimum, 
and maximum value will be computed for age, BMI, height, and weight. A separate 
summary will be provided for age ranges.  
A by-subject listing of demographic and baseline characteristics will also be produced.  
Summaries of race and racial combinations will be produced for each treatment group 
and overall.  A listing of race by subject will also be produced. 
6.2.5. 
Medical Conditions and Medications 
6.2.5.1. 
Medical Conditions 
The number and percentage of participants with each past and current medical condition 
will be summarized for each treatment group and overall. Past conditions are those 
reported as ‘past’ and current conditions are those reported as ‘current’ at screening.  
Past and current conditions will be reported separately. Medical conditions will be 
summarised by category according to eCRF. By-subject listings of past and current 
medical conditions will also be produced. 
A by-subject listing for HIV associated conditions will be produced. 
6.2.5.2. 
Medications 
For reporting purposes, medications will be classified as prior, concomitant using the 
associated start and stop dates recorded in the eCRF and relative to the first and last dose 
dates of investigational product (IP) (see Appendix 4). Medications will be coded using 
the GSK Drug coding dictionary (current version at the time of DBF). 
Concomitant and prior medications will be summarised by GSK-Drug Anatomical 
Therapeutic Chemical (ATC) classification level 1 (body system) and ingredient. Drugs 
that are composed of a combination of ingredients will be displayed according to the 
ATC classifications of the ingredients, not of the combination.  
The relationship between ATC level 1, ingredients and verbatim text for all medications 
in the study will be listed. 
6.2.6. 
Exposure and Treatment Compliance 
The complete dosing experience will be listed for all participants. The total duration of 
exposure (number of days on study drug), average daily dose, and cumulative dose will 
be summarized by treatment group. 
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For participants who completed the 10-day treatment period in Part 1 and 7-day treatment 
period in Part 2 of the study, the expected number of doses is 10 for Part 1 and 7 for Part 
2.  For participants who permanently discontinued the study treatment and/or withdrew 
from the study, the expected number of doses during the treatment period will be 
calculated using “Days on study drug” where “Days on study drug” is Last Dose Date – 
First Dose Date +1.  
A summary of study medication compliance will be produced by treatment group: >0-
<100%, 100%, >100%. The compliance will be calculated for the whole study treatment 
period as the percentage of cumulative dose [100*(actual cumulative dose) / (expected 
cumulative dose for the participant’s treatment duration)].   
For participants who completed the 10-day treatment period in Part 1 or 7-day treatment 
period in Part 2, the expected cumulative dose of GSK3640254 taken during the 
treatment period would be planned dose*10 days or planned dose*7 days.  E.g.   For 
participants who received 200 mg GSK3640254 in Part 1, the expected cumulative dose 
is 2,000 mg GSK3640254 (the 200 mg of IP is comprised of two 100 mg capsules of 
GSK3640254 administered daily over the 10-day treatment period). 
 
For participants who permanently discontinued study treatment or withdrew early from 
the study, the expected cumulative dose of GSK3640254 taken during the treatment 
period would be the planned dose*(Last Dose Date – First Dose Date + 1). 
 
The actual cumulative dose of GSK3640254 for all participants is the sum of all doses, in 
mg, of study drug consumed for the duration of the study. (Approach for handling 
missing treatment stopping dates is discussed in Section 13.7.2) 
 
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7. 
EFFICACY ANALYSES 
Efficacy data will be listed and summarized according to GSK reporting standards, where 
applicable. Unless specified, efficacy tables will be reported separately for Part 1 and Part 
2. Listings will be paginated by part, sorted by participant, day, and time, noting 
treatment; Descriptive statistics (n, mean, median, SD, min and max) will be calculated 
for continuous data and n and percentages will be calculated for categorical data. 
Both the ITT and PP populations will be used for all efficacy analyses when there are 
participants excluded from the PP population. If there are no exclusions (i.e., if the PP 
and ITT population do not differ), then only the ITT population will be used for all 
efficacy analyses. 
For summary tables, Plasma HIV-1 RNA values below lower limit of detection (LLOD = 
50 copies/mL), will be imputed to 49 copies/mL. Otherwise, for listings, it will be listed 
as collected. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
 Change from baseline to the nadir (maximum change from baseline) in Plasma HIV-1 
RNA 
 Change from baseline to Visit 6 (Day 11 in Part 1 and Day 8 in Part 2) in Plasma 
HIV-1 RNA 
7.1.2. 
Summary Measure 
 Mean rate of maximum change from baseline to the nadir 
 Mean rate of change from baseline to Visit 6 (Day 11 in Part 1 and Day 8 in Part 2) 
7.1.3. 
Statistical Analyses / Methods 
Statistical models will be fitted separately for Part 1 and Part 2. 
Plasma HIV-1 RNA maximum change from baseline (on original scale and log10 scale) 
and time to nadir will be calculated for each subject and summarized by treatment for 
each part. 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
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7.1.3.1. 
Statistical Methodology Specification 
Endpoint / Variables  
 
Change from baseline to the nadir in Plasma HIV-1 RNA (on log10 scale) 
 
Change from baseline to Visit 6 (Day 11 in Part 1 and Day 8 in Part 2) in Plasma HIV-1 RNA (on log10 
scale) 
Model Specification 
 
Plasma HIV-1 RNA change from baseline (on log10 scale) to nadir and change from baseline to Visit 6 
(Day 11 in Part 1 or Day 8 in Part 2) (on log10 scale) will be fitted in a mixed-effects linear model by 
treatment, with baseline plasma HIV-1 RNA (on log10 scale) and visit fitted as fixed effects and subject 
fitted as a random effect. 
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
 
Statistical analysis for maximum change from baseline to the nadir and change from baseline will be 
presented in tabular format. The linear model will be used to estimate slope, intercept and a 90% CI of 
the slope. The model will be fitted for Part 1 and Part 2 data respectively. 
Example SAS Code: 
proc mixed data=dataset; 
class dose visit subjid; 
model chgRNA = baseRNA visit dose; 
random subjid / type=un solution; 
run; 
Sensitivity and Supportive Analyses 
Both ITT and PP population will be used for the above analyses if PP population is differed from ITT 
population.  
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
 Plasma HIV-1 RNA and log10 Plasma HIV-1 RNA on each assessment visit 
 Change from baseline of plasma HIV-1 RNA and log10 plasma HIV-1 RNA on each 
assessment visit 
 Proportion of participants with plasma HIV-1 RNA <400 copies/mL and < 50 
copies/mL 
 Proportion of participants with plasma HIV-1 RNA change from baseline > 1.5 log10 
copies/mL decrease 
7.2.2. 
Summary Measure 
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum, 
and maximum for continuous variables, whereas n and percent will be used as summary 
statistics for categorical variables. 
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7.2.3. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment visit and 
summarized by treatment and assessment visit along with change from baseline. 
A plot of mean and median log10 plasma HIV-1 RNA and change from baseline data will 
be generated by treatment and assessment visit. 
7.3. 
Exploratory Efficacy Analyses 
7.3.1. 
Immunology 
7.3.1.1. 
Endpoint / Variables 
 CD4+ and CD8+ T-cell count at each assessment visit along with change from 
baseline 
 
7.3.1.2. 
Summary Measure 
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum, 
and maximum for continuous variables, whereas n and percent will be used as summary 
statistics for categorical variables. 
In addition, mean rate of change for CD4+ T-cell count change from baseline to Visit 6 
(Day 11 in Part 1 and Day 8 in Part 2) will be calculated based on the following linear 
mixed model. 
7.3.1.3. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.3.1will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
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7.3.1.4. 
Statistical Methodology Specification 
Endpoint / Variables 
 
Change from baseline in CD4+ T-cell count to Visit 6 (Day 11 in Part 1 and Day 8 in Part 2) (on log10 
scale) 
Model Specification 
 
Change from baseline to Visit 6 (Day 11 in Part or Day 8 in Part 2) in CD4+ T-cell count (on log10 scale) 
will be fitted in a mixed-effects linear model by treatment, with baseline CD4+ (on log10 scale) and 
VISIT fitted as fixed effects and subject fitted as a random effect. 
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
 
Statistical analysis for change from baseline will be presented in tabular format. The linear model will be 
used to estimate slope, intercept and a 90% CI of the slope. The model will be fitted for Part 1 and Part 
2 data respectively. 
Example SAS Code: 
proc mixed data=dataset 
class dose visit subjid; 
model chgCD4 = baseCD4 visit dose; 
random subjid / type=un solution; 
run; 
Sensitivity and Supportive Analyses 
Both ITT and PP population will be used for the above analyses if PP population is differed from ITT 
population. 
 
7.3.2. Clinical Virology 
If virology data is available and up to analysis standards by DBF, viral genotypic and 
phenotypic data will be listed by treatment group, subject, and assessment day as in 
Appendix 11: List of Data Displays and will be based on GSK data standards and 
statistical principles. If virology data is not available by DBF, a separate virology 
analysis report will be generated. 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards and data will be in Clinical Data 
Interchange Standards Consortium (CDISC) format. No formal statistical analysis of the 
safety data will be conducted. 
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays. The AE analysis 
will include part 1 and part 2 in one display (Part 1 placebo and Part 2 placebo displayed 
separately) for summary tables and listings. 
The following summaries will be provided: 
 Adverse events overview 
 All adverse events by SOC and PT and all adverse events by maximum grade and 
SOC and PT 
 Drug related adverse events by SOC and PT and drug related adverse events by 
maximum grade and SOC and PT 
 Serious Adverse Events by SOC and PT (Number of Participants and Occurrences) 
 Adverse events leading to withdrawal from study/permanent discontinuation of study 
treatment 
 Common (>= 5%) adverse events by overall frequency 
 Common (>= 5%) non-serious adverse events (Number of Subjects and Occurrences) 
The following listings will be provided: 
 All adverse events 
 Subject numbers for individual AEs 
 Serious adverse events 
 Drug related adverse events 
 Adverse events leading to withdrawal from study/permanent discontinuation of study 
treatment 
 Fatal serious adverse events 
 Non-fatal serious adverse events 
8.2. 
Adverse Events of Special Interest Analyses 
At the end of the study, all Cardiac System Organ Class / Preferred Terms, seizure, and 
syncope (regardless of Grade/Relationship), will be summarized by treatment. A listing 
will also be provided accordingly. 
Gastrointestinal intolerability/toxicity AEs of special interest will be defined within three 
narrow sub-SMQs [Gastrointestinal nonspecific symptoms and therapeutic procedures 
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SMQ; Gastrointestinal nonspecific dysfunction SMQ; Gastrointestinal nonspecific 
inflammation (SMQ) plus a selection of relevant broad preferred terms from the 
Gastrointestinal non-specific symptoms and therapeutic procedures SMQ.  
Psychiatric AEs of special interest will be defined within the following: Sub-SMQ 
'Suicide/self-injury' (SMQ) from parent SMQ of 'Depression and Suicide/Self 
Injury'. Only narrow terms from the sub-SMQ selected. 
Sub-SMQ 'Depression (excluding suicide and self-injury)' (SMQ) from parent 
SMQ of 'Depression and Suicide/Self Injury'. Only narrow terms from the sub-
SMQ selected. 
All preferred terms from HLGT 'Manic and Bipolar mood disorders and 
disturbances' under SOC 'Psychiatric disorders'. 
narrow terms from SMQ 'Psychosis and psychotic disorders' selected. 
All preferred terms from HLGT 'Anxiety disorders and symptoms', under SOC 
'Psychiatric disorders'. 
All preferred terms from HLGT 'Sleep Disorders and Disturbances' and HLGT '
 
Sleep disturbances (include subtypes)' 
Nervous system disorders AEs of special interest will be defined within the following:  
Four HLGTs under Nervous System Disorders SOC: "Headaches"; "Mental 
impairment disorders"; "Neurological disorders" and "Seizures" 
8.3. 
Clinical Laboratory Analyses 
Unless specified, clinical laboratory tables will be reported separately for Part 1 and Part 
2. Corresponding listings will be paginated by part, sorted by participant, day, and time, 
noting treatment. 
Haematology and clinical chemistry parameters collected are listed below. 
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Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
Mean corpuscular 
volume (MCV) 
Mean corpuscular 
haemoglobin (MCH) 
%Reticulocytes 
White blood cells (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cells (RBC) 
Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Amylase and 
Lipase 
Sodium, 
Bicarbonate, and 
Chloride 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
(nonfasting) 
Calcium, 
Magnesium, and 
Phosphate 
Alkaline 
phosphatase 
Fasting Lipid 
Panel 
(Cholesterol, 
Triglycerides, 
High density 
lipoprotein [HDL], 
low density 
lipoprotein [LDL]) 
Routine 
Urinalysis 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
 
Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
 
Follicle-stimulating hormone and estradiol (if needed to determine 
women of non-childbearing potential) 
 
Urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed)2 
 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody [HCVAb], with reflex to HCV RNA if positive). 
 
PCR (HIV-1 diagnostic PCR) 
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Laboratory 
Assessments 
Parameters 
 
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
 
All study-required laboratory assessments will be performed by a 
central laboratory 
The results of each test may be entered into the CRF. 
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 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies 
of hepatic impairment or cirrhosis). 
2. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
 
Laboratory values, treatment emergent toxicities, and change from baseline for 
haematology, clinical chemistry, and liver function parameters will be summarized by 
visit and by treatment group. Laboratory values for haematology, clinical chemistry, liver 
function, and urinalysis will also be listed by subject. In addition, the number and 
percentage of participants with on-treatment laboratory abnormalities worsened from 
baseline by maximum grade will be reported for haematology, clinical chemistry. The 
participants with laboratory values of potential clinical importance will be summarised 
and listed (potential clinical importance criteria are specified in Section 13.8). The details 
of the planned displays are in Appendix 11: List of Data Displays. 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs, vital signs and 
Hepatobiliary will be based on GSK Core Data Standards, unless otherwise specified. 
Similar as clinical laboratory analysis, tables for other safety analyses will be reported 
separately for Part 1 and Part 2. Corresponding listings will be paginated by part, sorted 
by participant, day, and time, noting treatment. The details of the planned displays are 
presented in Appendix 11: List of Data Displays. 
8.4.1. 
Electrocardiograms 
ECG is collected triplicates at certain visits and for those visits average values will be 
reported in summary tables and triplicate readings will be listed in listings. A summary of 
the number and percentage of participants with ECG findings will be displayed by 
treatment. For abnormal ECG findings, the most recent one will be used if there’s 
multiple records in the same visit. Additionally, summary statistics of change from 
baseline in ECG values will be presented. Maximum QTc values and maximum increase 
in QTc values post-baseline relate to baseline will be summarized by category. Mean 
(95% CI) change from baseline in QTcB-interval and QTcF interval will be plotted by 
time and treatment. All ECG Values for Participants with a Value of Potential Clinical 
Importance will be listed (potential clinical importance criteria are specified in Appendix 
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8: Values of Potential Clinical Importance). QTc interval data for subjects with QTc 
measurement > 500msec or increase from baseline > 60msec will also be listed. 
8.4.2. 
Vital Signs 
Vital sign parameter (systolic blood pressure, diastolic blood pressure, pulse rate and heart 
rate) change from baseline at every assessed time point will be summarized (n, mean, 
standard deviation, median, minimum, and maximum). The number of subjects with worst 
case vital sign results relative to normal range criteria which are post-baseline relative to 
baseline will be summarized by test and category.  A by-subject listing of vital signs for all 
participants with potential clinical importance will be produced. Potential clinical importance 
criteria are specified in Appendix 8: Values of Potential Clinical Importance.  
8.4.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Summaries of Columbia Suicide Severity Rating Scale (CSSRS) will be produce for each 
treatment group in Part 1 and Part 2. 
8.4.4. 
Combination anti-retroviral therapy (cART) 
In Part 2 of the study, participant must be willing and able to start cART on Study Day 8. 
Summary and listing of cART medication will be produced accordingly.  
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9. 
PHARMACOKINETIC ANALYSES 
Unless specified, pharmacokinetic analyses tables will be reported separately for Part 1 
and Part 2. Listings will be paginated by part, sorted by participant, day, time, and noting 
treatment. 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
9.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic) 
9.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin Version 6.1 or higher. All calculations of non-compartmental parameters will 
be based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits. 
Parameter 
Parameter Description 
Visit 1 (Day 1) 
AUC(0-24) 
Area under the concentration-time curve from time zero to the concentration at 24-hour 
post dose. AUC will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
C24 
Concentration at 24 hours post dose 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
tlag 
absorption lag time 
Visit 5 (Day 8, 9 or 10 for Part 1 and Day 7 for Part 2) 
AUC(0-) 
Area under the concentration-time curve over the dosing interval. AUC will be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal 
rule for each decremental trapezoid. 
C0 
Concentration at pre-dose 
C 
Concentration at the end of the dosing interval 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
λz 
The slope of the apparent terminal phase 
t½ 
Apparent terminal half-life will be calculated as:  
t½ = ln2 / λz 
CL/F 
Apparent oral clearance will be calculated as: 
CL/F = Dose / AUC(0-) 
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Parameter 
Parameter Description 
R_AUC 
The accumulation ratio of AUC will be calculated as: will be calculated as:  
R_AUC = AUC(0-) Visit 5 / AUC(0-24) Visit 1 
R_Cmax 
The accumulation ratio of Cmax will be calculated as: will be calculated as:  
R_Cmax = Cmax Visit 5 / Cmax Visit 1 
R_C 
The accumulation ratio of C will be calculated as: will be calculated as:  
R_C = C Visit 5 / C24 Visit 1 
NOTES: 
 
Additional parameters may be included as required. 
 
9.1.2. 
Summary Measure 
For each of these parameters, except tmax, tmin, and tlag, the following summary 
statistics will be calculated for each active treatment group: median, maximum, 
minimum, arithmetic mean, standard deviation, coefficient of variation on arithmetic 
mean, geometric mean, coefficient of variation on geometric mean, 95% confidence 
interval for the geometric mean and standard deviation of logarithmically transformed 
data.  For tmax, tmin, and tlag, median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
9.1.3. 
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
9.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
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9.1.4.1. 
Dose proportionality 
9.1.4.1.1. 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). The statistical 
model will be fitted for Part 1 and Part 2 combined data. 
Endpoint / Variables 
 
Plasma primary PK endpoints on log10 scale include  
Day 1: AUC(0-24), Cmax and C24; 
Day 8/9/10 in Part 1 and Day 7 in Part 2: AUC(0-) and Cmax and C.  
Model Specification 
 
To assess the dose proportionality of plasma GSK3640254, PK parameters on log10 scale from Day1 
[AUC(0-24) , Cmax and C24] and Day 8/9/10 for Part 1 or Day 7 for Part 2 [AUC(0-), Cmax and C] 
will be assessed using a power model if multiple dose levels are assessed. The power model will be 
fitted by restricted maximum likelihood (REML) using SAS Proc Mixed. A fixed effects power model will 
be used. The mean slope will be estimated from the power model with the corresponding 90% CI, 
separately for Day 1 and Day 8/9/10 for Part 1 or Day 7 for Part 2.  
 
Additionally, if power model does not show dose proportionality, dose proportionality may be assessed 
by pair-wise analysis of variance(ANOVA) using the SAS Mixed model procedure. A reference dose of 
10 mg will be used and the other doses would be treated as test dose. PK parameters will be 
normalized to the reference dose and then log-transformed prior to the analysis. Point estimates and 
90% confidence intervals for AUC and Cmax will be reported to 4 decimal places with no rounding. An 
example of SAS code is also included here for the ANOVA approach. 
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
 
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. 
 
Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance structure. 
Model Results Presentation 
Statistical analysis for dose proportionality from Day 1 [AUC(0-24) , Cmax and C24] and Day 8/9/10 in Part 
1 and Day 7 in Part 2 [AUC(0-), Cmax and C] will be presented in tabular format, respectively. The linear 
model will be used to provide a slope, intercept and a 90% CI of the slope. 
Example SAS Code for power model:   
PROC MIXED;  
MODEL LNPKPARM=LNDOSE /SOLUTION CL ALPHA=0.1;  
ODS OUTPUT SOLUTIONF=SOLUTION1(RENAME=(ESTIMATE=EST STDERR=SE));  
RUN;  
 
Example SAS Code for ANOVA model:  
ODS output solutionf=stat;  
Proc Mixed; 
class treatment; /* treatments are different dose groups */ 
model logdnPKvar = treatment/ddfm=kr; 
lsmeans treatment; /* assuming one ref and four test treatments */ 
estimate 'test1 vs ref' treatment -1 1 0 0 0 /cl alpha=0.1; 
estimate 'test2 vs ref' treatment -1 0 1 0 0/cl alpha=0.1; 
run; 
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9.1.4.2. 
Steady State 
9.1.4.2.1. 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). Statistical model 
will be fitted for Part 1 and Part 2 respectively. 
Endpoint / Variables 
 
Plasma primary PK endpoints include  
Visit 2 to visit 6 Pre-dose concentrations C0 and visit 5 C 
 
Model Specification 
 
To assess the achievement of steady state with the pre-dose concentrations between Visit 2~6 for each 
treatment. A linear mixed model using Day as fixed effects and subject as a random effect on the ln-
transformed pre-dose values will be performed evaluating whether steady state was achieved using 
Helmert transformation approach. The comparison will begin with Visit 2~6 then Visit 3~6, etc. The 
estimate and 90% CI of the slope for the day will be presented for the comparison(s).  
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
 Statistical analysis of steady state will be analyze using Helmert transformation approach.  
Model Results Presentation 
Code will be separated for Part 1 and Part 2 due to the different study design of the two parts. 
Example SAS Code for Part 1: 
PROC MIXED; 
BY TREATMENT; 
WHERE (DAY IN (2,3,4,5,6,7,8,9,10,11)); 
CLASS SUBJECT; 
MODEL LOGCTAU = DAY/CL ALPHA=0.1 SOLUTION; 
RANDOM INTERCEPT/SUBJECT=SUBJECT TYPE=UN; 
RUN; 
 
 
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10. 
PHARMACODYNAMIC ANALYSES 
10.1. 
Primary Pharmacodynamic Analyses 
Relationships between dose and PD measures (maximum change (in Day 1 to Day 8) in 
log10 plasma HIV-1 RNA from baseline) will be explored with an Emax and linear 
models. Part 1 and Part 2 doses combined in the model fitting. Model selection will be 
based on Akaike Information Criteria (AIC) value, where model with the lowest AIC 
value will be considered the best model.   
10.1.1. 
Endpoint / Variables 
 Log10 Maximum change from baseline to Day 8 and change from baseline to Day 
8 in plasma HIV-1 RNA 
10.1.2. 
Summary Measure 
 Parameter estimates for Emax, ED50 and variance along with their standard error, 
and 95% CI 
10.1.3. 
Population of Interest 
The primary pharmacodynamics analyses will be based on the PP population, unless 
otherwise specified. 
10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.  
Descriptive Summary tables are separated for Part 1 and Part 2 while the summary table 
for statistical modelling results are combined for two Parts.  
In endpoint descriptive summary tables, the maximum change from baseline includes all 
visits while in model fitting it only includes visits from baseline to Day 8 in HIV-1 RNA 
for both parts. 
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10.1.4.1. 
Statistical Methodology Specification 
Model Specification 
 
To model the dose-response relationship, a frequentist simplified Emax model is planned.  This model 
assumes the following form:  
 
 
 
Where: 
 
ΔVL is the change from baseline, defined as Log10 Maximum change from baseline to Day 8 and 
change from baseline to Day 8 (both parts) in plasma HIV-1 RNA on log10 scale. 
 
Emax is the maximum response 
 
ED50 is the dose that attains the 50% of the maximal effect ε is a random error assumed to be 
normally distributed with mean zero and constant variance (σ2) 
The observed maximum change from baseline in Plasma HIV-1 RNA will be used as the response 
variable in the Emax model.   
 
The derived data from this Emax model (estimates Emax, ED50 and Variance along with their standard 
error, and 95% CI) will be tabulated and a dose-response curve will also be produced. 
 
 
If problems are encountered Emax model or if the Emax shape is a poor fit for the data and a linear 
relationship looks plausible across the dose range, then a linear model will be considered of the form:  
 
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
 The statistical model will use doses from both parts for model fitting. 
 
The derived data from this Emax model (estimates Emax, ED50 and Variance along with their standard 
error, and 95% CI) will be tabulated and an exposure-response curve will also be produced.  
 
Example SAS Code:  
PROC NLMIXED;  
PARMS E0 = EST EMAX = EST ED50 = EST S2E = SE;  
BOUNDS E0>0 EMAX>0 ED50>0 S2E>0;  
PRED = E0 +(EMAX-E0)/(1+(ED50/DOSE));  
MODEL RESPONSE ~ NORMAL (PRED, S2E);  
PREDICT PRED OUT=DOSE;  
RUN;  
 
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11. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
11.1. 
PK/PD Analyses of HIV-1 RNA 
11.1.1. 
Statistical Analyses / Methods 
Scatter plots of plasma HIV-1 RNA change from baseline to Day 8 vs. plasma 
GSK3640254 PK parameters (AUC(0-), Cmax and C) will be generated separately for 
each active treatment. The Pearson’s correlations between plasma HIV-1 RNA change 
from baseline to Day 8 and plasma GSK3640254 PK parameters will be summarized by 
treatment and overall. 
Relationships between various PK parameters (AUC(0-), Cmax and C) and PD 
measures (Log10 maximum change from baseline to Day 8 in plasma RNA and Log10 
change from baseline to Day 8 in plasma HIV-1 RNA) will be explored with various 
Emax models. Model selection will be based on Akaike Information Criteria (AIC) value, 
where model with the lowest AIC value will be considered the best model.   
11.1.2. 
Population of Interest 
The primary pharmacodynamics analyses will be based on the PK/PD population, unless 
otherwise specified. Part 1 Day 9~11 HIV RNA are excluded to fulfil the same dosing 
days and be used in one statistical model. 
11.1.3. 
Statistical Methodology Specification 
Endpoint / Variables 
 
Log10 maximum change from baseline to day 8 in plasma RNA, Log10 change from baseline to Day 8 
in plasma HIV-1 RNA relative to the PK parameters (AUC(0-τ), Cmax and Cτ) Day 8/9/10 from Part 1 
and Day 7 from Part 2 
Model Specification 
 
To model the exposure-response relationship, a frequentist three-parameter Emax model is planned.  
This model assumes the following form 
 
 
Where: 
 
ΔVL is the log10 maximum viral load change from baseline to day 8 or change to Day 8 in plasma HIV-1 
RNA  
 
E0 is the baseline response 
 
Emax is the maximum response 
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 
EC50 is the corresponding exposure/PK parameter value that attains the 50% of the maximal effect 
 
PK is the PK parameter 
 
ε is a random error assumed to be normally distributed with mean zero and constant variance (σ2) 
 
If problems are encountered Emax model or if the Emax shape is a poor fit for the data and a linear 
relationship looks plausible across the dose range, then a linear model will be considered of the form:  
 
Model Checking & Diagnostics 
 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
 
The derived data from this Emax model (estimates E0, Emax, EC50 and Variance along with their 
standard error, and 95% CI) will be tabulated and an exposure-response curve will also be produced. If 
E0 turns out as not significant, the reduced Emax model without baseline E0 will be selected as the 
final model. 
Example SAS Code:  
PROC NLMIXED;  
PARMS E0 = EST EMAX = EST EC50 = EST S2E = SE;  
BOUNDS E0>0 EMAX>0 EC50>0 S2E>0;  
PRED = E0 +(EMAX-E0)/(1+(EC50/PARAM));  
MODEL RESPONSE ~ NORMAL (PRED, S2E);  
PREDICT PRED OUT=DOSE;  
RUN;  
11.2. 
Concentration-QTcF Analyses 
For each ECG assessment, the individual subject’s QTcF change from baseline will be 
calculated and will be merged with time-matched PK concentration values, when 
available. QTcF change from baseline (y-axis) to Day 8 for all doses in Part 1 and Part 2 
will be plotted against the PK concentration data (x-axis) with a linear regression overlay. 
The placebo arms from Part 1 and Part 2 would be combined as one group (with PK 
concentration value as 0) and included in the figure. 
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12. 
REFERENCES 
Bristol-Myers Squibb Document Number 930109388, 1.0; BMS-TMF-3548385 1.0.  
Clinical Study Report: A Randomized, Double-Blind, Double-Dummy, Positive-
Controlled, Crossover Study to Determine Electrocardiographic Effects of BMS-955176 
in Healthy Participants, 13-JAN-2017 
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10. 
GlaxoSmithKline Document Number 2019N405148_01. A Randomized, Double-Blind 
(Sponsor-unblinded), Placebo-Controlled, Adaptive Trial to Investigate the Antiviral 
Effect, Safety, Tolerability and Pharmacokinetics of GSK3640254 in HIV-1 Infected 
Treatment-Naïve Adults – Part 1, Interim Analysis. Effective Date: 26-AUG-2019 
GSK Document Number 2016N302783_00. Clinical Study Report: A Phase 2b 
Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy and 
Dose-response of BMS-955176/GSK3532795, Given on a Backbone of 
Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults – Week 24 Interim 
Analysis, 21-JUN-2017 
GSK Document Number 2018N375454_00. Clinical Pharmacology Synopsis. A single 
centre, 2-period, randomized, open-label Phase 1 study to assess the relative 
bioavailability of a mesylate salt capsule of GSK3640254 compared to a hydrochloride 
salt capsule in healthy participants. September 2018. 
GSK Document Number 2018N375461_00. Clinical Pharmacology Synopsis. A Double-
Blind (Sponsor Unblinded), Randomized, Placebo- Controlled, Single and Repeated Dose 
Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of 
GSK3640254 in Healthy Participants. September 2018. 
GSK Document Number 2018N379610_00. Clinical Investigator's Brochure for 
GSK3640254, September 2018 
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill 
International Antiviral Society (IAS)–USA ART Treatment of Adult HIV Infection: 2015 
Recommendations of the International Antiviral Society-USA Panel. Wensing AM et al. 
2015 update of the drug resistance mutations in HIV-1. Topics in Antiviral Medicine 
October/November 2015: 23(4). Available at: 
http://www.iasusa.org/sites/default/files/tam/23-4-132.pdf.  
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et.al 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
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FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035–1043.] 
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]. 
 
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13. 
APPENDICES 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
13.1.1. 
Exclusions from Per Protocol Population 
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population: 
Number 
Exclusion Description 
1 
Participant who deviated from any inclusion/exclusion criteria 
2 
Participant who did not receive correct treatment which the participant was randomized to 
3 
Participant who have missed at least one dose of GSK3640254 
4 
Participant who did not have Visit 6 HIV-RNA measurement 
5 
Not withdrawn after meeting the following stopping criteria 
 
Liver chemistry stopping criteria 
 
QTc stopping criteria 
 
Stopping criteria based on Laboratory Abnormality and Adverse Event 
6 
Informed Consent 
 
Study-specific assessments conducted prior to obtaining proper consent. 
7 
Study visits performed out of window  
 
Consecutive participant study visits performed out of window 
 
Multiple study visits performed out of window by various Participants (Trending) 
8 
Incorrect study treatment  
 
Unresolved IP accountability discrepancy 
 
IP storage guidelines not followed 
 
IP incorrectly administered 
 
IP accountability not done 
9 
Lack of PI oversight 
10 
Participant Used prohibited medication  
11 
Participant became pregnant while on study 
12 
Safety assessments not performed when clinically relevant 
 
Central safety lab samples not collected and/or not properly sent to Q2 when 
clinically relevant 
 
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13.2. 
Appendix 2: Schedule of Activities 
Study Part 1: 
 
Procedure1 
Treatment Period  
Day 1 – Day 10 
Post-Dosing Follow Up Period 
Day 11 – 17 
Final 
Follow-up 
Day 18-24 
Day 1 
Day 2 
Day 3, 4 
Choose one day for 
the Clinic Visit 3.  
The other day will 
be a virtual event. 
Day 5, 6, 7 
Choose one day for the   
Clinic Visit 4.  
The other days  
will be virtual events. 
Day 8, 9, 10 
Choose one day for the    
Clinic Visit 5.  
The other days  
will be virtual events. 
Day 11 
Day 12 
Day 13, 14, 
15, 16 or 17 
Day 18, 19, 
20, 21, 22, 
23 or 24 
 
Clinic 
Visit 1 
Clinic 
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Virtual 
Clinic  
Visit 5 
Virtual 
Virtual 
Clinic 
Visit 6 
Clinic 
Visit 7 
Clinic    
Visit 8 
Clinic    
Visit 9 
Clinical 
Assessments 
 
 
Outpatient Visit2 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Video/Phone Call 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
Verify Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medicatio
n/drug/alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Anti-retroviral 
(ARV) Check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDC Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Procedure1 
Treatment Period  
Day 1 – Day 10 
Post-Dosing Follow Up Period 
Day 11 – 17 
Final 
Follow-up 
Day 18-24 
Day 1 
Day 2 
Day 3, 4 
Choose one day for 
the Clinic Visit 3.  
The other day will 
be a virtual event. 
Day 5, 6, 7 
Choose one day for the   
Clinic Visit 4.  
The other days  
will be virtual events. 
Day 8, 9, 10 
Choose one day for the    
Clinic Visit 5.  
The other days  
will be virtual events. 
Day 11 
Day 12 
Day 13, 14, 
15, 16 or 17 
Day 18, 19, 
20, 21, 22, 
23 or 24 
 
Clinic 
Visit 1 
Clinic 
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Virtual 
Clinic  
Visit 5 
Virtual 
Virtual 
Clinic 
Visit 6 
Clinic 
Visit 7 
Clinic    
Visit 8 
Clinic    
Visit 9 
HIV-associated 
conditions 
assessments3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
(AE)/SAE 
assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication review3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, BMI and 
Physical exam4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
C-SSRS 
Administration     
(Since Last Visit 
form) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
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Procedure1 
Treatment Period  
Day 1 – Day 10 
Post-Dosing Follow Up Period 
Day 11 – 17 
Final 
Follow-up 
Day 18-24 
Day 1 
Day 2 
Day 3, 4 
Choose one day for 
the Clinic Visit 3.  
The other day will 
be a virtual event. 
Day 5, 6, 7 
Choose one day for the   
Clinic Visit 4.  
The other days  
will be virtual events. 
Day 8, 9, 10 
Choose one day for the    
Clinic Visit 5.  
The other days  
will be virtual events. 
Day 11 
Day 12 
Day 13, 14, 
15, 16 or 17 
Day 18, 19, 
20, 21, 22, 
23 or 24 
 
Clinic 
Visit 1 
Clinic 
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Virtual 
Clinic  
Visit 5 
Virtual 
Virtual 
Clinic 
Visit 6 
Clinic 
Visit 7 
Clinic    
Visit 8 
Clinic    
Visit 9 
Clinical 
Procedures 
 
 
12-lead ECG 
(triplicate reading, 
pre-dose; single 
readings at PK 
draws 2hr, 4hr, 
and 6hr) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
(single reading, 
pre-dose at Visits 
2 and 3) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
(single reading 
pre-dose and at 
PK draws 2hr, 4hr, 
and 6hr) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pharmacogenetics 
(PGX) Collection   
(if consented) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure1 
Treatment Period  
Day 1 – Day 10 
Post-Dosing Follow Up Period 
Day 11 – 17 
Final 
Follow-up 
Day 18-24 
Day 1 
Day 2 
Day 3, 4 
Choose one day for 
the Clinic Visit 3.  
The other day will 
be a virtual event. 
Day 5, 6, 7 
Choose one day for the   
Clinic Visit 4.  
The other days  
will be virtual events. 
Day 8, 9, 10 
Choose one day for the    
Clinic Visit 5.  
The other days  
will be virtual events. 
Day 11 
Day 12 
Day 13, 14, 
15, 16 or 17 
Day 18, 19, 
20, 21, 22, 
23 or 24 
 
Clinic 
Visit 1 
Clinic 
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Virtual 
Clinic  
Visit 5 
Virtual 
Virtual 
Clinic 
Visit 6 
Clinic 
Visit 7 
Clinic    
Visit 8 
Clinic    
Visit 9 
Hematology/Chem
istry/Urine 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fasting Lipid 
Panel 
(approximately 8 
hrs) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Lymphocyte T-cell 
subsets (CD4, 
CD8) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Plasma for HIV-1 
genotype/phenoty
pe5 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Plasma for 
storage6 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
HIV-1 RNA 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
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Procedure1 
Treatment Period  
Day 1 – Day 10 
Post-Dosing Follow Up Period 
Day 11 – 17 
Final 
Follow-up 
Day 18-24 
Day 1 
Day 2 
Day 3, 4 
Choose one day for 
the Clinic Visit 3.  
The other day will 
be a virtual event. 
Day 5, 6, 7 
Choose one day for the   
Clinic Visit 4.  
The other days  
will be virtual events. 
Day 8, 9, 10 
Choose one day for the    
Clinic Visit 5.  
The other days  
will be virtual events. 
Day 11 
Day 12 
Day 13, 14, 
15, 16 or 17 
Day 18, 19, 
20, 21, 22, 
23 or 24 
 
Clinic 
Visit 1 
Clinic 
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Virtual 
Clinic  
Visit 5 
Virtual 
Virtual 
Clinic 
Visit 6 
Clinic 
Visit 7 
Clinic    
Visit 8 
Clinic    
Visit 9 
Single, 
Pharmacokinetic 
(PK) sample (pre-
dose at Visits 3 
and 4) 
 
 
X 
 
X 
 
 
 
 
 
X7 
X 
X 
 
Intensive PK 
sampling8 (with 
sample at 24hr 
time point the next 
morning) 
X 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
Observed dosing 
with 
GSK3640254/plac
ebo3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
IWRS (RAMOS) 
activity10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. 
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration. 
2. 
The study requires 9 in-clinic visits.  Flexibility is offered for Visits 3, 4, 5, 8 and 9.  The visit schedule for each participant should be 
pre-planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the treatment 
period can be greater than 3 days. 
3. 
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not in the 
clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al. 
4. 
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen). 
5. 
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 11 samples, with other visits tested as appropriate. 
6. 
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study completion, 
they will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response (excluding any human 
genetic testing) 
7. 
If the Intensive PK day occurs on Day 10, do not collect the Day 11 pre-dose PK sample (as it is redundant with the 24-hr PK collection 
(completing the sample set started on Day 10). 
8. 
Intensive Plasma PK samples will be collected as outlined in Protocol Table 4 in Section 9.5 
9. 
If Day 8 or 9 is the Clinic Visit 5 to include the Intensive PK collection, the participant must return the following day for the 24-hr PK 
collection, meal and dosing.  The assessments to be done as indicated on what is a “virtual visit day” should be captured as a virtual visit, 
even if the questions are asked in the clinic. 
10. 
Log in to RAMOS on Day 1 to randomize the participant and to receive blinded study treatment.  Subsequently log-in to RAMOS for 
study treatment supply as needed. If a participant is discontinued from the study early, log in to RAMOS to record the discontinuation. 
 
 
The timing and number of planned study assessments, including safety, efficacy, pharmacokinetic, pharmacodynamic/biomarker assessments 
may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring.  
 
Any changes in the timing or addition of time points for any planned study assessments 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 IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the ICF. 
 
 
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Study Part 2: 
 
Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
Clinical 
Assessments 
 
Outpatient Visit2 
X 
X 
X 
 
X 
 
X 
X 
X 
Video/Phone Call 
 
 
 
X 
 
X 
 
 
 
Verify Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Medical/medicatio
n/drug/alcohol 
history 
X 
 
 
 
 
 
 
 
 
Prior Anti-retroviral 
(ARV) Check 
X 
 
 
 
 
 
 
 
 
CDC Classification 
X 
 
 
 
 
 
 
 
X 
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Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
HIV-associated 
conditions 
assessments3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
(AE)/SAE 
assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication  
review3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, BMI and 
Physical exam4  
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
 
 
X 
 
X 
C-SSRS 
Administration     
(Since Last Visit 
form) 
 
 
 
 
 
 
 
X 
 
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Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
Clinical 
Procedures 
 
12-lead ECG 
(triplicate reading, 
done pre-dose; 
single readings at 
PK draws 2hr, 4hr, 
and 6hr) 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
(single reading, 
done pre-dose at 
Visits 2 and 3) 
 
X 
X 
 
 
 
 
 
X 
12-lead ECG 
(single reading 
done pre-dose and 
at PK draws 2hr, 
4hr, and 6hr) 
 
 
 
 
 
 
X 
 
 
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Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
Pharmacogenetics 
(PGX) Collection 
(if consented) 
X 
 
 
 
 
 
 
 
 
Hematology/Chem
istry/Urine 
X 
X 
X 
 
X 
 
X 
X 
X 
Fasting Lipid 
Panel 
(approximately 8 
hrs) 
X 
 
 
 
 
 
 
X 
X 
Lymphocyte T-cell 
subsets (CD4, 
CD8) 
X 
 
 
 
 
 
 
X 
 
Plasma for HIV-1 
genotype/phenoty
pe5 
X 
X 
X 
 
X 
 
X 
X 
 
Plasma for 
storage6 
X 
X 
X 
 
X 
 
X 
X 
X 
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Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
HIV-1 RNA 
X 
X 
X 
 
X 
 
X 
X 
X 
Single, 
Pharmacokinetic 
(PK) sample done 
pre-dose  
 
 
X 
 
X 
 
 
 
 
Intensive PK 
sampling (to 
include the 24hr 
samples drawn the 
next day) 
X 
 
 
 
 
 
X 
  
 
Observed dosing 
with GSK3640254 
/placebo3 
X 
X 
X 
X 
X 
X 
X 
 
 
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Procedure1 
Treatment Period  
Day 1 – Day 7 
Post-Dosing 
Follow Up Period 
 
Final Follow-
up 
Day 1 
Day 2 
Day 3, 4 
Choose one day for the 
Clinic Visit 3.  
The other day will be a 
virtual event. 
Day 5, 6 
Choose one day for the   
Clinic Visit 4.  
The other day  
will be a virtual event. 
 
Day 7 
 
Day 8 
Day 10, 11 or 
12 
 
Clinic  
Visit 1 
Clinic  
Visit 2 
Clinic  
Visit 3 
Virtual 
Clinic 
Visit 4 
Virtual 
Clinic  
Visit 5 
Clinic  
Visit 6 
Clinic     
Visit 7 
Observed dosing 
with Investigator-
selected, 
prescribed and 
provided CART, 
and eCRF 
completion 
 
 
 
 
 
 
 
X 
 
IWRS (RAMOS) 
activity8 
X 
 
 
 
 
 
 
 
 
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1. 
Procedures should be performed in the following order:  ECG, Vitals, Blood Draws, followed by dose administration. 
2. 
The study requires 7 in-clinic visits.  Flexibility is offered for Visits 3, 4 and 7.  The visit schedule for each participant should be pre-
planned to be sure weekend, work schedules and clinic hours are appropriately considered.  No visit interval during the treatment period 
can be greater than 3 days. 
3. 
These assessments must be conducted with a participant during each day indicated, to include the days when the participant is not in the 
clinic.  This can be done in via phone, preferably via a visual method (as locally permitted) of Skype, Facetime, WhatsApp, et. al. 
4. 
Physical Exam will include, at a minimum, assessments of the Skin, Heart, Lungs, and Abdomen (liver and spleen). 
5. 
Genotypic/Phenotypic testing will be conducted on Day 1 and Day 8 samples, with other visits tested as appropriate. 
6. 
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where quantity is insufficient for testing. In the event samples are not used by study completion, 
they will be utilized for additional research on ARV resistance and/or HIV-1 disease biology/host immune response (excluding any human 
genetic testing) 
7. 
Intensive Plasma PK samples will be collected as outlined in Protocol Table 4 in Section 9.5 
8. 
Log in to RAMOS on Day 1 to dispense blinded study treatment.  Subsequently log-in to RAMOS for study treatment supply as needed. If 
a participant is discontinued from the study early, log in to RAMOS to record the discontinuation. 
 
 
The timing and number of planned study assessments, including safety, efficacy, pharmacokinetic, pharmacodynamic/biomarker assessments 
may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring.  
 
Any changes in the timing or addition of time points for any planned study assessments 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 IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the ICF
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13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
Analyses will be presented by scheduled visits as collected in the CRF.  The following 
table presents protocol defined assessment windows. 
Part 1 
Analysis Set 
/ Domain 
Parameter 
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Safety and 
Efficacy 
All 
14 - 28 days prior to first 
dose 
28 days prior 
to first dose 
Day -1 
Screen 
Efficacy 
HIV-1 RNA, 
HIV-1 
genotype / 
phenotype 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 5, 6, or 7 
Day 5 
Day 7 
Visit 4 
Day 8, 9, or 10 
Day 8 
Day 10 
Visit 5 
Day 11 
Day 11 
Day 11 
Visit 6 
Day 12 
Day 12 
Day 12 
Visit 7 
Day 13, 14, 15, 16, or 17 
Day 13 
Day 17 
Visit 8 
Days 18 to final follow up 
visit day 
Day 18 
final follow 
up visit day  
Follow-up 
CD4 and CD8 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 11 
Day 11 
Day 11 
Visit 6 
Safety 
Laboratory: 
Chemistry/ 
Haematology/ 
Urinalysis 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 5, 6, or 7 
Day 5 
Day 7 
Visit 4 
Day 8, 9, or 10 
Day 8 
Day 10 
Visit 5 
Day 11 
Day 11 
Day 11 
Visit 6 
Days 18 to final follow up 
visit day 
Day 18 
final follow 
up visit day  
Follow-up 
Fasting Lipid 
Panel 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 11 
Day 11 
Day 11 
Visit 6 
Days 18 to final follow up 
visit day 
Day 18 
final follow 
up visit day 
Follow-up 
ECG 
Day 11 
Day 1 
Day 1 
Visit 1 
Day 22 
Day 2 
Day 2 
Visit 2 
Day 3 or 42 
Day 3 
Day 4 
Visit 3 
Day 8, 9, or 103 
Day 8 
Day 10 
Visit 5 
Days 18 to final follow up 
visit day2 
Day 18 
final follow 
up visit day 
Follow-up 
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Analysis Set 
/ Domain 
Parameter 
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Vital Signs 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 8, 9, or 10 
Day 8 
Day 10 
Visit 5 
Days 18 to final follow up 
visit day 
Day 18 
final follow 
up visit day 
Follow-up 
NOTES: 
1 12-lead ECG (triplicate reading, pre-dose; single readings at PK draws 2hr, 4hr, and 6hr) 
2 12-lead ECG (single reading, pre-dose) 
3 12-lead ECG (single reading pre-dose and at PK draws 2hr, 4hr, and 6hr) 
Part 2 
Analysis Set 
/ Domain 
Parameter 
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Safety and 
Efficacy 
All 
14 - 28 days prior to first 
dose 
28 days prior 
to first dose 
Day -1 
Screen 
Efficacy 
HIV-1 RNA, 
HIV-1 
genotype / 
phenotype 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 5 or 6 
Day 5 
Day 6 
Visit 4 
Day 7 
Day 7 
Day 7 
Visit 5 
Day 8 
Day 8 
Day 8 
Visit 6 
Days 10 to final follow up 
visit day  
Day 10 
final follow 
up visit day 
Visit 7 
CD4 and CD8 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 8 
Day 8 
Day 8 
Visit 6 
Safety 
Laboratory: 
Chemistry/ 
Haematology/ 
Urinalysis 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 5 or 6 
Day 5 
Day 6 
Visit 4 
Day 7 
Day 7 
Day 7 
Visit 5 
Day 8 
Day 8 
Day 8 
Visit 6 
Days 10 to final follow up 
visit day 
Day 10 
final follow 
up visit day 
Visit 7 
Fasting Lipid 
Panel 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 8 
Day 8 
Day 8 
Visit 6 
Days 10 to final follow up 
visit day 
Day 10 
final follow 
up visit day 
Visit 7 
ECG 
Day 11 
Day 1 
Day 1 
Visit 1 
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Analysis Set 
/ Domain 
Parameter 
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Day 22 
Day 2 
Day 2 
Visit 2 
Day 3 or 42 
Day 3 
Day 4 
Visit 3 
Day 73 
Day 7 
Day 7 
Visit 5 
Days 10 to final follow up 
visit day 
Day 10 
final follow 
up visit day 
Visit 7 
Vital Signs 
Day 1 
Day 1 
Day 1 
Visit 1 
Day 2 
Day 2 
Day 2 
Visit 2 
Day 3 or 4 
Day 3 
Day 4 
Visit 3 
Day 7 
Day 7 
Day 7 
Visit 5 
Days 10 to final follow up 
visit day 
Day 10 
final follow 
up visit day 
Visit 7 
NOTES: 
1 12-lead ECG (triplicate reading, pre-dose; single readings at PK draws 2hr, 4hr, and 6hr) 
2 12-lead ECG (single reading, pre-dose) 
3 12-lead ECG (single reading pre-dose and at PK draws 2hr, 4hr, and 6hr) 
 
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13.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
13.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop date of the study treatment. 
Study Phase 
Definition 
Screening Period  
Day -28 to Day -1 
Treatment Period 
Day 1 to Day 10 / study treatment stop date in Part 1 and Day 1 to Day 7 / study 
treatment stop date in Part 2 
Follow-up Period 
Study treatment stop date + 1 to Day 24 in Part 1 and study treatment stop date + 1 
to Day 12 in Part 2 
 
13.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
13.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment Emergent 
Study Treatment Start Date ≤ AE Start Date ≤ Final Follow-up Visit. 
NOTES:  
 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
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13.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
13.5.1. 
Reporting Process 
Software 
 
The currently supported versions of SAS software 9.4 or higher will be used. 
Reporting Area 
HARP Server 
:\\us1salx00259.corpnet2.com 
HARP Compound 
:\arwork\gsk3640254\mid208132\final_01 
Analysis Datasets  
 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1.  
Generation of RTF Files 
RTF files will be generated for Tables, one RTF file per item. Listings will be generated in 
L10 format, and Figures will be generated in PDF format.  
 
 
13.5.2. 
Reporting Standards 
General 
 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
Formats 
 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated. 
 
Numeric data will be reported at the precision collected on the eCRF. 
 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
 
Reporting for tables, figures and formal statistical analyses: 
o Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
 
Reporting for Data Listings:  
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the participant’s listings.  
Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables and/or figures. 
 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
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Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
13.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to PK 
One document (Standards for the Transfer and Reporting of PK Data using 
HARP).   
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
PK/PD file (CSV format) for the PK/PD analysis will be created according to the 
data specification detailed in Section 13.9 Pharmacokinetic/Pharmacodynamic 
Dataset Specification. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Programmer: R_AUC, R_Cmax, 
R_C 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to Standards for Handling NQ Impacted PK Parameters. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
 
Units for PK 
Parameters 
ug/mL for PK parameters;  
Original units (ng/mL) for listings, summary tables and figures of concentration-time 
data 
 
 
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13.6. 
Appendix 6: Derived and Transformed Data 
13.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
 
Triplicate 12-lead ECGs will be recorded at each study-specified visit. Mean of the measurements will 
be calculated and used in any derivation of summary statistics but if listed, all data will be presented. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
 
Calculated as the number of days from First Dose Date: 
 
Ref Date = Missing              → Study Day = Missing  
 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
13.6.2. 
Study Population 
Demographics 
Age 
Due to local privacy regulations, only the year of birth is recorded in the eCRF. The following algorithm 
will be used for imputation: 
 
All dates of birth will be imputed using the 30th day of June. 
Completely missing dates of birth will remain as missing, with no imputation applied.  Consequently, the 
age of the participant will not be calculated and will remain missing. In listings of demographic data, the 
year of birth as entered will be displayed. 
Body Mass Index (BMI) 
 
Calculated as Weight (kg) / [Height (m)]2 
 
13.6.3. 
Efficacy 
 Efficacy Parameters 
Plasma HIV-1 RNA 
 
If there are two values within a time window, the latest value will be used for summaries and analyses 
CD4+ T-cell 
 
If there are two values within a time window, the average value will be used for summaries and 
analyses 
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13.6.4. 
Safety 
ECG Parameters 
RR Interval 
 
IF RR interval (msec) is not provided directly, then RR can be derived as: 
[1] If QTcB is machine read & QTcF is not provided, then: 
 
[2] If QTcF is machine read and QTcB is not provided, then:  
 
 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected 
value THEN do not derive. 
Corrected QT Intervals 
 
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fredericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements. 
 
IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:  
 
 
 
Laboratory Parameters 
 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the number of significant digits in the observed values will be used to determine how 
much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
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13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 
Participant study completion (i.e. as specified in the protocol) was defined as a 
participant who has completed all phases of the study including the follow-up visit.  
 
Withdrawn participants may be replaced in the study. 
 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
13.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Exposure 
 If study treatment stop date is missing, then for the purposes of calculating 
exposure, it will be imputed using the date of last visit or the recorded date of 
withdrawal/completion whichever is earlier. 
 Partially Missing Stop Day: Last day of the month or last month of the year will 
be used, unless this is after the date of last visit or the recorded date of 
withdrawal/completion; in this case the earliest of the two dates will be used. 
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
13.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
 
Completely missing start or end dates will remain missing, with no imputation applied. 
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Element 
Reporting Detail 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
 
The recorded partial date will be displayed in listings. 
 
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13.8. 
Appendix 8: Values of Potential Clinical Importance 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
 
Low Flag (< 
x) 
High Flag 
(>x) 
 
Hematocrit  
Ratio of 
1 
Male 
 
0.54 
 
Female 
 
0.54 
 
∆ from BL 
↓0.075 
 
 
Hemoglobin  
g/L 
 
Male 
 
180 
 
Female 
 
180 
 
∆ from BL 
↓25 
 
 
Lymphocytes  
x109/ L 
 
0.8 
 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
 
Platelet Count  
x109/ L 
 
100 
550 
 
White Blood Cell Count 
(WBC) 
x109/ L 
 
3 
12 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Comments
Low Flag (< 
x) 
High Flag 
(>x) 
 
Bicarbonates 
mmol/L 
 
18 
32 
 
BUN 
mmol/L 
 
 
9 
 
Calcium 
mmol/L 
 
2 
2.75 
Chloride 
mmol/L 
 
98 
107 
 
Creatinine 
µmol/L 
∆ from BL 
 
44.2 
 
Glucose 
mmol/L 
 
3 
11 
Potassium 
mmol/L 
 
3 
5.5 
 
Sodium 
mmol/L 
 
130 
150 
 
Total Protein 
g/L 
∆ from BL 
-15 
15 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
 
ALT/SGPT  
U/L 
High 
 2x ULN 

AST/SGOT  
U/L 
High 
 2x ULN 

AlkPhos  
U/L 
High 
 2x ULN 

Total Bilirubin  
µmol/L 
High 
 1.5xULN 

 
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ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
PR Interval 
msec 
< 120 
> 200 
QRS Duration 
msec 
< 60 
> 120 
QT Interval 
msec 
< 320 
> 450 
QTc Interval (Bazett) 
msec 
< 320 
> 450 
QTc Interval (Fridericia) 
msec  
< 320 
> 450 
RR Interval 
msec 
< 600 
> 1200 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 140 
Diastolic Blood Pressure 
mmHg 
< 45 
> 90 
Heart Rate 
bpm 
< 40 
> 100 
 
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13.9. 
Appendix 9: Biomarker Analyses 
13.9.1. 
Viral Genotyping and Phenotyping 
Whole venous blood samples will be obtained from each participant to provide plasma 
for viral genotype and phenotype analysis, at the times listed in the Time and Events 
Table in Appendix 2. Details concerning the handling, labelling and shipping of these 
samples will be supplied separately. 
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using 
their GAG/PR, PR/RT, and IN formats, in which PCR amplification is used to generate 
HIV cDNA products including the Gag,  the PR and RT, and IN coding regions, 
respectively. Phenotypic analyses of the GAG/PR region will include susceptibility to 
GSK3640254. Analysis will be done on Day 1 and Day 11 samples in Part 1 and Day 1 
and Day 8 samples in Part 2. In the case of rebound HIV-1 viral load, analysis will be 
completed on samples corresponding to time point of rebound occurrence.  
13.9.2. 
Genetics 
Information regarding genetic research is included in Appendix 6, Section 12.6 of 
protocol Amendment 2 (Dated: 10/JAN/2019). 
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13.10. 
Appendix 10: Abbreviations & Trade Marks 
13.10.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
AIDS 
Auto immunodeficiency syndrome 
A&R 
Analysis and Reporting  
ALT 
Alanine aminotransferase 
ART 
Antiretroviral therapy 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
AUC(0-τ) 
Area under the plasma concentration time curve over the dosing interval 
AUC(0-24) 
Area under the plasma concentration time curve from time zero to the concentration at 
24 hours post dose 
A&R 
Analysis and Reporting  
Bpm 
beats per minute 
BIL 
Bilirubin 
C0 
Concentration at pre-dose 
Cτ 
Concentration at the end of the dosing interval 
C24 
Concentration at 24 hours post dose 
cART 
Combination anti-retroviral therapy 
CDISC 
Clinical Data Interchange Standards Consortium 
CL/F 
Apparent oral clearance 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DOB 
Date of Birth 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
g 
gram 
GSK 
GlaxoSmithKline 
GUI 
Graphical User Interface 
H 
Hour(s) 
HIV 
Human Immunodeficiency Virus 
Kg 
Kilogram 
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Abbreviation 
Description 
λz 
The slope of the apparent terminal phase 
L 
Litre 
LOC 
Last Observation Carries Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
mg 
milligrams 
MMRM 
Mixed Model Repeated Measures 
ng/mL 
Nanogram per millilitre 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
R_AUC 
The accumulation ratio of AUC from Day 10 to Day 1 in Part 1 or Day 7 to Day 1 in Part 
2 
R_Cmax 
The accumulation ratio of Cmax from Day 10 to Day 1 in Part 1 or Day 7 to Day 1 in 
Part 2 
R_Cτ 
The accumulation ratio of Cτ from Day 10 to Day 1 in Part 1 or Day 7 to Day 1 in Part 2 
RAP 
Reporting & Analysis Plan 
Rsq 
The correlation coefficient of the slope of the terminal phase 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
t½ 
Apparent terminal half-life 
tlag 
Absorption lag time 
tmax 
Time to reach Cmax 
TFL 
Tables, Figures & Listings  
U 
Units 
LLOD 
Lower limit of detection 
13.10.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
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13.11. 
Appendix 11: List of Data Displays 
13.11.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.19 
Not applicable 
Efficacy 
2.1 to 2.32 
2.1 to 2.6 
Safety 
3.1 to 3.57 
3.1 to 3.2 
Pharmacokinetic 
4.1 to 4.13 
4.1 to 4.12 
Population Pharmacokinetic (PopPK) 
Not applicable 
Not applicable 
Pharmacodynamic 
5.1 
5.1 
Pharmacokinetic / Pharmacodynamic 
6.1 
6.1 to 6.3 
Section 
Listings 
ICH Listings 
1 to 31 
Other Listings 
32~56 
 
13.11.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PKPD_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
13.11.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
HL 
Headline report 
SAC [1] 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
 
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13.11.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Participant Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Status and Reason for Study Withdrawal 
ICH E3, FDAAA, EudraCT 
HL, SAC 
1.2. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
SAC 
1.3. 
Safety 
ES4 
Summary of Subject Disposition 
ICH E3  
SAC 
1.4. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC 
Protocol Deviation 
1.5. 
Safety 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
1.6. 
Safety 
DV1A 
Summary of Deviations Leading to Exclusions from Per Protocol 
Population 
 
SAC 
1.7. 
Safety 
IE1 
Summary of Inclusion/Exclusion Criteria Deviations 
 
SAC 
Population Analysed 
1.8. 
All Screened 
SP1 
Summary of Study Populations  
IDSL 
SAC 
1.9. 
Safety 
SP2 
Summary of Exclusions from the Per Protocol Population 
IDSL 
SAC 
1.10. 
Safety 
NS1 
Summary of Number of Subjects by Centre 
IDSL/EudraCT/Clinical Operations 
SAC 
Demographic and Baseline Characteristics 
1.11. 
Safety 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
HL, SAC 
1.12. 
Safety 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.13. 
Safety 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.2 
Summary of Race and Racial 
Combinations 
SAC 
Prior and Concomitant Medications 
1.14. 
Safety 
MH1 
Summary of Past Medical Conditions 
ICH E3 
Categories of medical conditions 
will be sorted in descending order of 
“Total” incidence, and medical 
conditions within each category will 
be sorted in descending order of 
“Total” incidence. If the “Total” 
incidence for any two or more 
medical conditions is equal, then 
they will be presented in 
alphabetical order.  
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.15. 
Safety 
MH1 
Summary of Current Medical Conditions 
ICH E3 
Categories of medical conditions 
will be sorted in descending order of 
“Total” incidence, and medical 
conditions within each category will 
be sorted in descending order of 
“Total” incidence. If the “Total” 
incidence for any two or more 
medical conditions is equal, then 
they will be presented in 
alphabetical order. 
SAC 
1.16. 
Safety 
CM1 
Summary of Prior Concomitant Medications ATC Level 1 by 
Ingredient 
ICH E3 
Medications will be sorted in 
descending order of “Total” 
incidence for the ATC level 1 and in 
descending order of total incidence 
for the ingredient within each ATC 
level. If the total incidence of for any 
two or more ingredients is equal, 
the events will be presented in 
alphabetical order. 
See GSK IDSL “CONCOMITANT 
MEDICATIONS STATISTICAL 
DISPLAY STANDARDS” (Version 
12), Section 1.1.1 
SAC 
1.17. 
Safety 
CM1 
Summary of Current Concomitant Medications ATC Level 1 by 
Ingredient 
ICH E3 
Same as Table 1.16 notes 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure and Treatment Compliance 
1.18. 
Safety 
COMP1 
Summary of Study Treatment Overall Compliance 
 
SAC 
1.19. 
Safety 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
HL, SAC 
 
13.11.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Plasma HIV-1 RNA (ITT) 
2.1.  
ITT 
EFF_T1 
Summary of Plasma HIV-1 RNA – Part 1 
On original and log10 scale 
SAC 
2.2.  
ITT 
EFF_T1 
Summary of Plasma HIV-1 RNA – Part 2 
On original and log10 scale 
SAC 
2.3.  
ITT 
EFF_T2 
Summary of Change from Baseline to Nadir and Change from 
Baseline to Visit 6 (Day 11) in Plasma HIV-1 RNA – Part 1 
On original and log10 scale 
SAC 
2.4.  
ITT 
EFF_T2 
Summary of Change from Baseline to Nadir and Change from 
Baseline to Visit 6 (Day 8) in Plasma HIV-1 RNA – Part 2 
On original and log10 scale 
SAC 
2.5.  
ITT 
EFF_T2 
Summary of Time to Nadir in Plasma HIV-1 RNA – Part 1 
 
SAC 
2.6.  
ITT 
EFF_T2 
Summary of Time to Nadir in Plasma HIV-1 RNA – Part 2 
 
SAC 
2.7.  
ITT 
EFF_T3 
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Change 
from baseline to Visit 6 (Day 11) and Maximum Change by 
Treatment – Part 1 
On log10 scale 
SAC 
2.8.  
ITT 
EFF_T3 
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Change 
from baseline to Visit 6 (Day 8) and Maximum Change by 
Treatment – Part 2 
On log10 scale 
SAC 
2.9.  
ITT 
EFF_T4 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
<400 and < 50 copies/mL – Part 1 
By visit and by treatment 
SAC 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.10. 
ITT 
EFF_T4 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
<400 and < 50 copies/mL – Part 2 
By visit and by treatment 
SAC 
2.11. 
ITT 
EFF_T5 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease -Part 1 
By visit and by treatment 
SAC 
2.12. 
ITT 
EFF_T5 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease -Part 2 
By visit and by treatment 
SAC 
Immunology (ITT) 
2.13. 
ITT 
EFF_T6 
Summary of CD4+ and CD8+ and Change from Baseline by 
Visit – Part 1 
Please include both absolute CD4 
count and CD4 percentage, Same 
to CD8 
SAC 
2.14. 
ITT 
EFF_T6 
Summary of CD4+ and CD8+ and Change from Baseline by 
Visit – Part 2 
Please include both absolute CD4 
count and CD4 percentage, same to 
CD8 
SAC 
2.15. 
ITT 
EFF_T3 
Summary of Modelled CD4+ Cell Count Mean Rate of Change 
from baseline to Visit 6 (Day 11) by Treatment – Part 1 
On log10 scale 
SAC 
2.16. 
ITT 
EFF_T3 
Summary of Modelled CD4+ Cell Count Mean Rate of Change 
from baseline to Visit 6 (Day 8) by Treatment – Part 2 
On log10 scale 
SAC 
Plasma HIV-1 RNA (PP) 
2.17. 
PP 
EFF_T1 
Summary of Plasma HIV-1 RNA – Pat 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.18. 
PP 
EFF_T1 
Summary of Plasma HIV-1 RNA – Pat 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.19. 
PP 
EFF_T2 
Summary of Change from Baseline to Visit 6 (Day 11) and 
Maximum Decline from Baseline in plasma HIV-1 RNA – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.20. 
PP 
EFF_T2 
Summary of Change from Baseline to Visit 6 (Day 8) and 
Maximum Decline from Baseline in plasma HIV-1 RNA – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.21. 
PP 
EFF_T2 
Summary of Time to Nadir in Plasma HIV-1 RNA – Part 1 
 
SAC 
2.22. 
PP 
EFF_T2 
Summary of Time to Nadir in Plasma HIV-1 RNA – Part 2 
 
SAC 
2.23. 
PP 
EFF_T2 
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Change 
from baseline to Visit 6 (Day 11) and Maximum Change by 
Treatment – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.24. 
PP 
EFF_T3 
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Change 
from baseline to Visit 6 (Day 8) and Maximum Change by 
Treatment – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.25. 
PP 
EFF_T4 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
<400 and < 50 copies/mL – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.26. 
PP 
EFF_T4 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
<400 and < 50 copies/mL – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.27. 
PP 
EFF_T5 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.28. 
PP 
EFF_T5 
Summary of Proportion of Participants with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
Immunology (PP) 
2.29. 
PP 
EFF_T6 
Summary of CD4+ Cell Count and Change from Baseline by 
Visit – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.30. 
PP 
EFF_T6 
Summary of CD4+ Cell Count and Change from Baseline by 
Visit – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.31. 
PP 
EFF_T3 
Summary of Modelled CD4+ Cell Count Mean Rate of Change 
from baseline to Visit 6 (Day 11) by Treatment – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.32. 
PP 
EFF_T3 
Summary of Modelled CD4+ Cell Count Mean Rate of Change 
from baseline to Visit 6 (Day 8) by Treatment – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
 
 
 
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13.11.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Plasma HIV-1 RNA 
2.1.  
ITT 
EFF_F1 
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment – Part 1 
Overlay all treatment groups together. 
95% CI will also be provided based on 
T-distribution. 
HL, SAC 
2.2.  
ITT 
EFF_F1 
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment – Part 2 
Overlay all treatment groups together. 
95% CI will also be provided based on 
T-distribution. 
HL, SAC 
2.3.  
ITT 
PK24 
Plot of Individual Change from Baseline (Day 1) in Plasma HIV-1 
RNA by Treatment and Day – Part 1 
Present individual change from 
baseline profile on same plot. Use 
different legend to denote the 
treatment arms. Day used for x axis. 
SAC 
2.4.  
PP 
EFF_F1 
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment – Part 1 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.5.  
PP 
EFF_F1 
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment – Part 2 
To be generated if there are 
participants excluded from the Per 
Protocol population 
SAC 
2.6.  
PP 
PK24 
Plot of Individual Change from Baseline (Day 1) in Plasma HIV-1 
RNA by Treatment and Day – Part 2 
Present individual change from 
baseline profile on same plot. Use 
different legend to denote the 
treatment arms. Day used for x axis. 
SAC 
 
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13.11.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE13 
Adverse Events Overview 
 
SAC 
3.2.  
Safety 
AE1 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
HL, SAC 
3.3.  
Safety 
AE5B 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.4.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Preferred 
Term 
ICH E3 
SAC 
3.5.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
Preferred Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT 
SAC 
3.6.  
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
ICH E3 
HL, SAC 
3.7.  
Safety 
AE5B 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.8.  
Safety  
AE1  
Summary of Adverse Events of Special Interest  
  
SAC  
Serious and Other Significant Adverse Events 
3.9.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
SAC 
3.10. 
Safety 
AE1 
 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term 
IDSL 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Chemistry  
3.11. 
Safety 
LB1 
Summary of Clinical Chemistry Data by Visit – Part 1 
ICH E3 
SAC 
3.12. 
Safety 
LB1 
Summary of Clinical Chemistry Data by Visit – Part 2 
ICH E3 
SAC 
3.13. 
Safety 
LB1 
Summary of Changes from Baseline in Clinical Chemistry Data 
by Visit – Part 1 
ICH E3 
. 
SAC 
3.14. 
Safety 
LB1 
Summary of Changes from Baseline in Clinical Chemistry Data 
by Visit – Part 2 
ICH E3 
. 
SAC 
3.15. 
Safety 
LB18 
Summary of Worst-Case Chemistry Grade Shifts from Baseline 
Grade – Part 1 
ICH E3 
Display only worst case post 
baseline visits. 
HL, SAC 
3.16. 
Safety 
LB18 
Summary of Worst-Case Chemistry Grade Shifts from Baseline 
Grade – Part 2 
ICH E3 
Display only worst case post 
baseline visits. 
HL, SAC 
3.17. 
Safety 
LB17 
Summary of Chemistry Laboratory Abnormalities of Potential 
Clinical Importance – Part 1 
 
SAC 
3.18. 
Safety 
LB17 
Summary of Chemistry Laboratory Abnormalities of Potential 
Clinical Importance – Part 2 
 
SAC 
3.19. 
Safety 
SAFE_T1 
Summary of Treatment Emergent Clinical Chemistry Toxicities – 
Part 1 
Exclude Liver tests(AST, ALT , ALP, 
TBIL) 
SAC 
3.20. 
Safety 
SAFE_T1 
Summary of Treatment Emergent Clinical Chemistry Toxicities – 
Part 2 
Exclude Liver tests(AST, ALT , ALP, 
TBIL) 
SAC 
Laboratory: Haematology 
3.21. 
Safety 
LB1 
Summary of Haematology Data by Visit – Part 1 
ICH E3 
SAC 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.22. 
Safety 
LB1 
Summary of Haematology Data by Visit – Part 2 
ICH E3 
SAC 
3.23. 
Safety 
LB1 
Summary of Changes from Baseline in Haematology by Visit – 
Part 1 
ICH E3 
SAC 
3.24. 
Safety 
LB1 
Summary of Changes from Baseline in Haematology by Visit – 
Part 2 
ICH E3 
SAC 
3.25. 
Safety 
LB18 
Summary of Worst-Case Haematology Grade Shifts from 
Baseline Grade – Part 1 
ICH E3 
HL, SAC 
3.26. 
Safety 
LB18 
Summary of Worst-Case Haematology Grade Shifts from 
Baseline Grade – Part 2 
ICH E3 
HL, SAC 
3.27. 
Safety 
LB17 
Summary of Haematology Laboratory Abnormalities of Potential 
Clinical Importance – Part 1 
 
 
3.28. 
Safety 
LB17 
Summary of Haematology Laboratory Abnormalities of Potential 
Clinical Importance – Part 2 
 
 
3.29. 
Safety 
SAFE_T1 
Summary of Treatment Emergent Haematology Toxicities – Part 
1 
 
SAC 
3.30. 
Safety 
SAFE_T1 
Summary of Treatment Emergent Haematology Toxicities – Part 
2 
 
SAC 
Laboratory: Urinalysis 
3.31. 
Safety 
LB1 
Summary of Urine Concentration Data by Visit – Part 1 
ICH E3 
SAC 
3.32. 
Safety 
LB1 
Summary of Urine Concentration Data by Visit – Part 2 
ICH E3 
SAC 
3.33. 
Safety 
LB1 
Summary of Changes from Baseline in Urine Concentration by 
Visit – Part 1 
ICH E3 
SAC 
3.34. 
Safety 
LB1 
Summary of Changes from Baseline in Urine Concentration by 
Visit – Part 2 
ICH E3 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.35. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline – Part 1 
ICH E3 
 
SAC 
3.36. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline – Part 2 
ICH E3 
 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.37. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 1 
IDSL 
SAC 
3.38. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 2 
IDSL 
SAC 
3.39. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities – Part 1 
IDSL 
SAC 
3.40. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities – Part 2 
IDSL 
SAC 
3.41. 
Safety 
SAFE_T2 
Summary of Treatment Emergent Liver Toxicities – Part 1 
 
SAC 
3.42. 
Safety 
SAFE_T2 
Summary of Treatment Emergent Liver Toxicities – Part 2 
 
SAC 
ECG 
3.43. 
Safety 
EG1 
Summary of ECG Findings – Part 1 
IDSL 
HL. SAC 
3.44. 
Safety 
EG1 
Summary of ECG Findings – Part 2 
IDSL 
HL. SAC 
3.45. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit – 
Part 1 
IDSL 
SAC 
3.46. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit – 
Part 2 
IDSL 
SAC 
3.47. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 1 
IDSL  
SAC 
3.48. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 2 
IDSL  
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.49. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category – Part 1 
IDSL  
SAC 
3.50. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category – Part 2 
IDSL  
SAC 
3.51. 
Safety 
ING111207, 
Table 10.30 
Listing of QTc Interval Data for Subjects with QTc Measurement 
> 500msec or Increase from Baseline > 60msec- Part 1 and 2 
For subjects with QTcB or QTcF 
measurement > 500msec or 
increase from baseline > 60msec, 
list QTcB and QTcF data (both 
value and change from baseline) at 
all time points, and flag the values > 
500msec and increases > 60msec 
SAC 
Vital Signs 
3.52. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 1 
ICH E3 
SAC 
3.53. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 2 
ICH E3 
SAC 
3.54. 
Safety 
VS3 
Summary of Worst-Case Vital Signs Relative to Normal Range 
Post-Baseline Relative to Baseline – Part 1 
IDSL 
SAC 
3.55. 
Safety 
VS3 
Summary of Worst-Case Vital Signs Relative to Normal Range 
Post-Baseline Relative to Baseline – Part 2 
IDSL 
SAC 
C-SSRS 
3.56. 
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation or Behaviour Data 
IDSL. Part 1 and Part 2 in one 
table. 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
cART 
3.57. 
Safety 
CM1 
Summary of cART Medications ATC Categories by Ingredient – 
Part 2 
IDSL. Part 2 only. 
SAC 
13.11.8. 
Safety Figures 
Safety : Figures 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
3.1.  
Safety 
SAFE_F1 
Plot of Mean (95% CI) Change from Baseline in QTc Interval by 
Treatment and Time – Part 1 
For both QTcB-interval and QTcF 
interval 
SAC  
3.2.  
Safety 
SAFE_F1 
Plot of Mean (95% CI) Change from Baseline in QTc Interval by 
Treatment and Time – Part 2 
For both QTcB-interval and QTcF 
interval 
SAC  
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13.11.9. 
Pharmacokinetic Tables 
 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
4.1.  
PK 
PK01 
Summary of Plasma GSK3640254 Pharmacokinetic 
Concentration-Time Data – Part 1 
 
SAC 
4.2.  
PK 
PK01 
Summary of Plasma GSK3640254 Pharmacokinetic 
Concentration-Time Data – Part 2 
 
SAC 
PK Derived Parameters 
4.3.  
PK 
PKPL1P 
Listing of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by Treatment - Visit 1 – Part 1  
Parameters with units  
SAC 
4.4.  
PK 
PKPL1P 
Listing of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by Treatment - Visit 1 – Part 2  
Parameters with units  
SAC 
4.5.  
PK 
PKPL1P 
Listing of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by Treatment – Visit 5 – Part 1 
Parameters with units  
SAC 
4.6.  
PK 
PKPL1P 
Listing of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by Treatment – Visit 5 – Part 2 
Parameters with units  
SAC 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.7.  
PK 
PKPT2 
Summary Statistics of Derived Plasma GSK3640254 
Pharmacokinetic Parameters by Treatment and Visit – Part 1 
Parameters with units  
SAC 
4.8.  
PK 
PKPT2 
Summary Statistics of Derived Plasma GSK3640254 
Pharmacokinetic Parameters by Treatment and Visit – Part 2 
Parameters with units  
SAC 
4.9.  
PK 
PKPT4 
Summary Statistics of Log-Transformed Derived Plasma 
GSK3640254 Pharmacokinetic Parameters and Visit -Part 1 
Parameters with units  
SAC 
4.10. 
PK 
PKPT4 
Summary Statistics of Log-Transformed Derived Plasma 
GSK3640254 Pharmacokinetic Parameters and Visit -Part 2 
Parameters with units  
SAC 
4.11. 
PK 
PK_T1 
Assessment of Dose Proportionality of GSK3640254 by Days 
Part 1 and Part 2 doses all included 
in the statistical mode.  
Day 1: AUC(0-24), Cmax and C24; 
Day 8:  AUC(0-tau) and Cmax and 
C-tau. 
SAC 
4.12. 
PK 
PK_T2 
Assessment of Plasma GSK3640254 Steady State 
Concentrations – Part 1 
Pre-dose concentration values for 
Visit 2~6 
SAC 
4.13. 
PK 
PK_T2 
Assessment of Plasma GSK3640254 Steady State 
Concentrations – Part 2 
Pre-dose concentration values for 
Visit 2~6 
SAC 
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13.11.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
4.1.  
PK 
PKCF1P 
Individual Plasma GSK3640254 Concentration-Time Plot by 
Visit (Linear and Semi-Log)  
Present individual Visit 1 and Visit 5 
profile on same plot. Paginate by 
Subject and Part 
SAC 
4.2.  
PK 
PK26 
Individual Plasma GSK3640254 Trough Concentration-Time Plot 
(Linear and Semi-Log)  
Present Pre-dose and 24 hr time 
points only. Paginate by Subject 
and Part 
SAC 
Mean/Median Concentration Plots 
4.3.  
PK 
PKCF2 
Mean Plasma GSK3640254 Concentration-Time Plots by 
Treatment and Visit (Linear and Semi-Log) – Part 1 
Paginate by Visit 
SAC 
4.4.  
PK 
PKCF2 
Mean Plasma GSK3640254 Concentration-Time Plots by 
Treatment and Visit (Linear and Semi-Log) – Part 2 
Paginate by Visit 
SAC 
4.5.  
PK 
PK27 
Mean Plasma GSK3640254 Trough Concentration-Time Plots 
by Treatment (Linear and Semi-Log) – Part 1 
Pre-dose and 24 hr time points only. 
Time scale by Visit 
SAC 
4.6.  
PK 
PK27 
Mean Plasma GSK3640254 Trough Concentration-Time Plots 
by Treatment (Linear and Semi-Log) – Part 2 
Pre-dose and 24 hr time points only. 
Time scale by Visit 
SAC 
4.7.  
PK 
PKCF3 
Median Plasma GSK3640254 Concentration-Time Plots by 
Treatment and Visit (Linear and Semi-Log) – Part 1 
Paginate by Visit 
SAC 
4.8.  
PK 
PKCF3 
Median Plasma GSK3640254 Concentration-Time Plots by 
Treatment and Visit (Linear and Semi-Log) – Part 2 
Paginate by Visit 
SAC 
4.9.  
PK 
PK27 
Median Plasma GSK3640254 Trough Concentration-Time Plots 
by Treatment (Linear and Semi-Log) – Part 1 
Pre-dose and 24 hr time points only. 
Time scale by Visit 
SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.10. 
PK 
PK27 
Median Plasma GSK3640254 Trough Concentration-Time Plots 
by Treatment (Linear and Semi-Log) – Part 2 
Pre-dose and 24 hr time points only. 
Time scale by Visit 
SAC 
PK Parameter Plots 
4.11. 
PK 
PK28 
Individual and Geometric Mean (95% CI) of Plasma PK 
Parameters versus Dose by Visit – Part 1 
Paginate by Parameter and Visit. 
Present overlay of individual 
parameters with Geometric mean 
and 95%CI for parameters and 
results for Table 4.4 for regression 
line 
SAC 
4.12. 
PK 
PK28 
Individual and Geometric Mean (95% CI) of Plasma PK 
Parameters versus Dose by Visit – Part 2 
Paginate by Parameter and Visit. 
Present overlay of individual 
parameters with Geometric mean 
and 95%CI for parameters and 
results for Table 4.4 for regression 
line 
SAC 
 
 
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13.11.11. Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PD Linear and Emax Models 
5.1.  
PP 
PD_T1 
Summary of Estimates from Dose-Response Model 
Only include visits from Day 1 to 
Day 8 for the HIV-RNA change. 
Part 1 and Part 2 doses all included 
in the statistical mode.  
SAC 
 
13.11.12. Pharmacodynamic Figures 
 Pharmacodynamic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK/PD – RNA Change from Baseline 
5.1 
PP 
PK28 
Scatter Plot of HIV RNA Maximum Decline from Baseline versus 
Dose 
Only include visits from Day 1 to 
Day 8 for the HIV-RNA change. 
Part 1 and Part 2 doses in one plot. 
SAC 
 
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13.11.13. Pharmacokinetic / Pharmacodynamic Tables 
Pharmacokinetic / Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
6.1.  
PK/PD 
PK28 
Summary of Estimates from Exposure Response Model 
Part 1 and Part 2 doses all included 
in the statistical mode.  
SAC 
 
13.11.14. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK/PD – RNA Change from Baseline 
6.1.  
PK/PD 
PK28 
Scatter Plot of Day 8 HIV RNA Change from Baseline versus 
Plasma PK Parameters 
Present Day 8 HIV RNA Change 
from Baseline vs AUC(0-τ), Cmax 
and Cτ, for all doses in Part 1 and 
Part 2 
SAC 
6.2.  
PK/PD 
PK28 
Scatter Plot of HIV RNA Maximum Change from Baseline to day 
8 versus Plasma PK Parameters 
Maximum change from baseline to 
day 8 HIV RNA vs AUC(0-τ), Cmax 
and Cτ, for all doses in Part 1 and 
Part 2 
SAC 
PK/PD – QTcF Change from Baseline 
6.3.  
PK/PD 
PK28 
Scatter Plot of QTcF Change from Baseline versus Time-
matched PK Concentration 
Placebo group included with PK 
concentration value as 0.  
Day 1 to Day 8 in Part 1 and Part 2. 
SAC 
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13.11.15. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Participant Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
SAC 
2.  
ITT 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
HL, SAC 
3.  
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC 
4.  
ITT 
BL1 
Listing of Participants for Whom the Treatment Blind was Broken ICH E3 
SAC 
5.  
ITT 
TA1 
Listing of Planned and Actual Treatments 
IDSL. 
SAC 
Protocol Deviations 
6.  
ITT 
DV2 
Listing of Important Protocol Deviations  
ICH E3, add one flag for denoting the 
protocol deviation leading to exclusion 
from PP population.  
SAC 
7.  
ITT 
IE3 
Listing of Inclusion/Exclusion Criteria Deviations 
ICH E3 
SAC 
Populations Analysed 
8.  
ITT 
SP3 
Listing of Participants Excluded from Any Population 
ICH E3 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Demographic and Baseline Characteristics 
9.  
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Age, sex, race, ethnicity, height, 
weight, and BMI. 
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.1 
Summary of Demographic 
Characteristics 
SAC 
10.  
ITT 
DM9 
Listing of Race and Racial Combinations 
ICH E3  
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.2 
Summary of Race and Racial 
Combinations 
SAC 
Prior and Concomitant Medications 
11.  
Safety 
CP_CM3 
Listing of Prior Concomitant Medications 
IDSL 
SAC 
12.  
Safety 
CP_CM3 
Listing of Current Concomitant Medications 
IDSL 
SAC 
Exposure and Treatment Compliance 
13.  
Safety 
EX3 
Listing of Exposure Data 
ICH E3 
SAC 
Adverse Events 
14.  
Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
HL, SAC 
15.  
Safety 
AE7 
Listing of Participant Numbers for Individual Adverse Events 
ICH E3 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
16.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC 
Serious and Other Significant Adverse Events 
17.  
Safety 
AE8 
Listing of Serious Adverse Events  
 
HL, SAC 
18.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC 
19.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC 
20.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC 
21.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
HL, SAC 
22.  
Safety  
AE8  
Listing of Cardiovascular Adverse Events of Special Interest  
 
SAC 
Hepatobiliary (Liver) 
23.  
Safety 
MH2 
Listing of Medical Conditions for Participants with Liver Stopping 
Events 
IDSL 
SAC 
24.  
Safety 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events 
IDSL 
SAC 
All Laboratory 
25.  
Safety 
LB5 
Listing of Clinical Chemistry Laboratory Data for Participants 
with Any Value of Potential Clinical Importance 
ICH E3 
SAC 
26.  
Safety 
LB5 
Listing of Haematology Laboratory Data for Participants with Any 
Value of Potential Clinical Importance 
ICH E3 
SAC 
27.  
Safety 
LB5 
Listing of Liver Function Laboratory Data for Participants with 
Any Value of Potential Clinical Importance 
ICH E3 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
28.  
Safety 
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
HL, SAC 
29.  
Safety 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding 
IDSL 
HL, SAC 
Vital Signs 
30.  
Safety 
VS5 
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
HL, SAC 
cART 
31.  
Safety 
CM2 
Listing of cART Medications – Part 2 
IDSL, for Part 2 only 
SAC 
 
 
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13.11.16. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Populations Analysed 
32.  
All Screened 
POP_L1 
Listing of Study Populations 
 
SAC 
Demography & Disease Characteristics at Screening 
33.  
ITT 
POP_L2 
Listing of Cardiovascular Risk Assessment 
 
SAC 
34.  
ITT 
POP_L3 
Listing of HIV Risk Factors 
 
SAC 
Medical Condition & Concomitant Medications 
35.  
ITT 
MH2 
Listing of Current and Past Medical Conditions 
 
SAC 
36.  
ITT 
POP_L4 
Listing of HIV Associated Conditions 
 
SAC 
37.  
ITT 
CM6 
Listing Relationship Between ATC Level 1, Ingredients and 
Verbatim Text 
 
SAC 
Adverse Event 
38.  
Safety  
AE8  
Listing of Drug Related Adverse Events  
 
SAC 
Laboratory Values 
39.  
Safety  
LB5  
Listing of Clinical Chemistry Data  
Exclude Liver tests(AST, ALT , ALP, 
TBIL) 
SAC  
40.  
Safety 
LB5 
Listing of Haematology Data 
 
SAC 
41.  
Safety  
LB5  
Listing of Liver Function Data  
 
SAC  
42.  
Safety  
UR2A 
Listing of Urinalysis Data  
 
SAC  
Efficacy 
43.  
ITT 
EFF_L1 
Listing of Plasma HIV-1 RNA 
 
SAC  
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
44.  
ITT 
EFF_L2 
Listing of CD4+ T-cell counts 
Please include both absolute CD4 
count and CD4 percentage.  
SAC  
45.  
ITT 
EFF_L2 
Listing of CD8+ T-cell counts 
Please include both absolute CD8 
count and CD8 percentage. 
SAC  
Virology 
46.  
ITT 
VR_L1 
Listing of Viral Genotypic Data 
 
SAC  
47.  
ITT 
VR_L2 
Listing of Viral Phenotypic Data 
 
SAC  
Pharmacokinetic 
48.  
PK 
PKCL1P 
Listing of Plasma GSK3640254 Concentrations (ng/mL) by 
Treatment 
List all the concentration data 
including unscheduled. Repeat for 
all treatments. 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Statistical Output 
49.  
ITT 
 
Statistical Output Listing of Modelled Plasma HIV-1 RNA 
Maximum Change by Treatment 
 
SAC 
50.  
ITT 
 
Statistical Output Listing of Modelled Plasma HIV-1 RNA Mean 
Rate of Change by Treatment 
 
SAC 
51.  
PP 
 
Statistical Output Listing of Modelled Plasma HIV-1 RNA 
Maximum Change by Treatment 
 
SAC 
52.  
PP 
 
Statistical Output Listing of Modelled Plasma HIV-1 RNA Mean 
Rate of Change by Treatment 
 
SAC 
53.  
PK 
 
Statistical Output Listing of Assessment of Dose Proportionality 
of GSK3640254 by Day 
 
SAC 
54.  
PK 
 
Statistical Output Listing of Assessment of Plasma GSK3640254 
Steady State Concentrations 
 
SAC 
55.  
PP 
 
Statistical Output Listing of Summary of Estimates from Dose-
Response Model 
 
SAC 
56.  
PK/PD 
 
Statistical Output Listing of Summary of Estimates from 
Exposure Response Model 
 
SAC 
 
 
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13.12. 
Appendix 12: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 
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208132 | Statistical Analysis Plan  RAP 11 Mar 2020 | TMF-1612790 | 2.0
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