Conditions: HIV Infections
Keywords: 2-period Pharmacokinetics FTIH GSK3640254 healthy subject bioavailability
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 14
Healthy volunteers: yes

Brief summary:
This is a first time in human (FTIH), 2-period study, to assess the relative bioavailability of a mesylate salt capsule of GSK3640254, compared to a bis- hydrochloride salt capsule of GSK3640254, in healthy subjects, administered following a moderate calorie and fat meal. The subjects will be randomized to 2 sequences, Regimen AB or Regimen BA. For Regimen AB: The Regimen A, which will include oral administration of GSK3640254 bis-hydrochloride Capsule 200 milligram (mg) (reference), which will be administered, in Period 1 and Regimen B will include GSK3640254 Mesylate salt capsule (test), 200 mg, which will be administered in Period 2. For the regimen BA, the regimen B, will be administered, in Period 1 and regimen A, in Period 2. Each of the regimens will be given orally as 2 capsules in the morning, as per randomization sequence. There will be a minimum washout of 7 days between each dose of study treatment. A total, of 14 subjects, are planned to be enrolled in the study. The maximum duration of the study from screening to follow-up is approximately 7 weeks.

Detailed description:

Arms:
arm 1: The subjects in this arm will receive an oral administration of 200 mg, as 2 GSK3640254 bis-hydrochloride salt Capsules(reference), as single oral dose, on the morning of Day 1 during Period 1 of the study. This will be followed by an oral administration of 200 mg, as 2 GSK3640254 Mesylate salt capsule (test), as single oral dose, on the morning of Day 1, during Period 2 of the study. The drug will be administered following a moderate calorie and fat meal. There will be a minimum washout of 7 days between each dose of study treatment. arm 2: The subjects in this arm will receive an oral administration of 200 mg as 2 GSK3640254 Mesylate salt capsule (test), as single oral dose, on the morning of Day 1 during Period 1 of the study. This will be followed by an oral administration of 200 mg, as 2 GSK3640254 bis-hydrochloride salt Capsule, 100 mg (reference), as single oral dose, on the morning of Day 1 during Period 2, of the study. The drug, will be administered following a moderate calorie and fat meal. There will be a minimum washout of 7 days between each dose of study treatment.

Interventions: intervention 1: GSK3640254 bis-hydrochloride salt capsule intervention 2: GSK3640254 Mesylate Salt Capsule
Intervention descriptions: intervention 1: Administered orally (as single dose) on morning of Day 1, as 2 capsules of 100 mg following a moderate calorie and fat meal during Period 1 and Period 2, at the specified sequence, as per study. intervention 2: Administered orally (as single dose) on morning of Day 1, as 2 capsules of , 100 mg following a moderate calorie and fat meal during Period 1 and Period 2, at the specified sequence, as per study.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: 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
Protocol Number: 208131 (QCL118221)
Short Title: A study to compare the relative bioavailability of two different formulations 
of GSK3640254
Compound Number:
GSK3640254
Sponsor Name and Legal Registered Address: 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information:
 DO, MPH
(USA)
Regulatory Agency Identifying Number(s): EudraCT Number 2018-001175-21
Approval Date: 13-APR-2018
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................7
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................17
3.3.3.
Overall Benefit:Risk Conclusion...................................................17
4.
OBJECTIVES AND ENDPOINTS...........................................................................17
5.
STUDY DESIGN ....................................................................................................17
5.1.
Overall Design ............................................................................................17
5.2.
Number of Participants ................................................................19
5.3.
Participant and Study Completion...............................................................19
5.4.
Scientific Rationale for Study Design ..........................................................19
5.5.
Dose Justification........................................................................................20
6.
STUDY POPULATION...........................................................................................20
6.1.
Inclusion Criteria.........................................................................................21
6.2.
Exclusion Criteria........................................................................................21
6.3.
Lifestyle Restrictions...................................................................................24
6.3.1.
Meals and Dietary Restrictions ....................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................24
6.3.3.
Activity .........................................................................................25
6.4.
Screen Failures...........................................................................................25
7.
TREATMENTS.......................................................................................................25
7.1.
Treatments Administered............................................................................26
7.2.
Dose Modification .......................................................................................26
7.3.
Method of Treatment Assignment ...............................................................26
7.4.
Blinding.......................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability..............................................27
7.6.
Treatment Compliance................................................................................28
7.7.
Concomitant Therapy..................................................................................28
7.8.
Treatment after the End of the Study ..........................................................28
8.
DISCONTINUATION CRITERIA.............................................................................28
8.1.
Discontinuation of Study Treatment ............................................................28
8.1.1.
Liver Chemistry Stopping Criteria ................................................29
8.1.2.
QTc Stopping Criteria ..................................................................30
8.1.3.
Individual Safety Stopping Criteria ...............................................30
8.1.4.
Temporary Discontinuation ..........................................................31
8.1.5.
Rechallenge.................................................................................31
8.1.5.1.
Study Treatment Restart or Rechallenge....................31
8.2.
Withdrawal from the Study..........................................................................31


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8.3.
Lost to Follow Up........................................................................................32
8.4.
Study Stopping Criteria...............................................................................32
8.5.
Study Termination.......................................................................................33
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
9.1.
Efficacy Assessments.................................................................................34
9.2.
Adverse Events...........................................................................................34
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................34
9.2.2.
Method of Detecting AEs and SAEs.............................................35
9.2.3.
Follow-up of AEs and SAEs.........................................................35
9.2.4.
Regulatory Reporting Requirements for SAEs .............................35
9.2.5.
Pregnancy ...................................................................................36
9.3.
Treatment of Overdose...............................................................................36
9.4.
Safety Assessments ...................................................................................36
9.4.1.
Physical Examinations.................................................................36
9.4.2.
Vital Signs....................................................................................37
9.4.3.
Electrocardiograms......................................................................37
9.4.4.
Clinical Safety Laboratory Assessments ......................................38
9.4.5.
Suicidal Risk Monitoring...............................................................39
9.5.
Pharmacokinetics .......................................................................................39
9.6.
Pharmacodynamics ....................................................................................40
9.7.
Genetics .....................................................................................................40
9.8.
Biomarkers .................................................................................................40
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................40
10. STATISTICAL CONSIDERATIONS........................................................................40
10.1.
Sample Size Determination ........................................................................40
10.2.
Populations for Analyses ............................................................................40
10.3.
Statistical Analyses.....................................................................................41
10.3.1.
Pharmacokinetic Analyses...........................................................41
10.3.2.
Safety Analyses...........................................................................42
10.3.3.
Interim Analyses ..........................................................................42
11. REFERENCES.......................................................................................................43
12. APPENDICES........................................................................................................44
12.1.
Appendix 1: Abbreviations and Trademarks................................................44
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................46
12.3.
Appendix 3: Study Governance Considerations..........................................48
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................53
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................59
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................63
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................65


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1.
SYNOPSIS
Protocol Title: 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 bis-
hydrochloride salt capsule in healthy participants
Short Title: A study to compare the relative bioavailability of two different formulations 
of GSK3640254
Rationale: A First Time in Human (FTIH) study is in progress and has used the bis-
hydrochloride salt immediate release capsule formulation of GSK3640254 administered 
following a moderate calorie and fat meal. However, the bis-hydrochloride salt 
formulation is not suitable for long term clinical development as it is susceptible to 
humidity. A mesylate salt capsule formulation of GSK3640254 has been generated for 
later phase development and commercialization. The aim of this relative bioavailability 
study is to compare the exposure of the mesylate salt capsule formulation of 
GSK3640254 (mentioned as GSK3640254 Mesylate Salt Capsule in regimens) with that 
of the bis-hydrochloride salt capsule formulation (mentioned as GSK3640254 Capsule in 
regimens) administered following a moderate calorie and fat meal.
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the pharmacokinetic (PK)
profiles of GSK3640254 following 
administration of the mesylate salt
capsule relative to that of the bis-
hydrochloride salt capsule (reference) in 
healthy participants

GSK3640254 area under the curve from 
time zero to infinity (AUC(0-∞)), AUC(0-tlast),  
maximum observed concentration (Cmax), 
Time to Cmax (Tmax), Concentration at 24 
hours post-dose (C24h), relative 
bioavailability (Frel) based on AUC and 
Cmax
Secondary

To provide additional information of the 
safety and tolerability of single doses of 
GSK3640254 in healthy participants

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and/or other safety biomarkers
Overall Design:
This is a Phase 1 study and will be conducted at a single centre. This study will include 
2 treatment periods, during which each of the open-label treatments will be administered 
to each of the 2 treatment groups. It is planned to enroll 14 healthy participants.


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Number of Participants:
Fourteen participants will be enrolled such that sufficient data will be available for at 
least 12 evaluable participants. An evaluable participant is a participant who has received 
both Regimens A and B, and has safety and PK data up to 72 hours post-dose.
Up to 7 replacement participants may be enrolled. The maximum number of participants 
that may be dosed is 21.
Treatment Groups and Duration:
Participants will receive a single oral dose of each study treatment (Regimens A and B) 
during each of the 2 inpatient periods, in a sequence of administration to be assigned via
the randomization: AB or BA.

Treatment Group AB: Regimen A is administered in Period 1, Regimen B is 
administered in Period 2.

Treatment Group BA: Regimen B is administered in Period 1, Regimen A is 
administered in Period 2.
Regimens:

Regimen A: An oral dose of 200 mg as 2 x 100 mg GSK3640254 Capsule, 100 mg
(reference) following g a moderate fat meal.

Regimen B: An oral dose of 200 mg as 2 x 100 mg GSK3640254 Mesylate Salt 
Capsule, 100 mg (test) following a moderate fat meal.
Participants will receive the formulations in the morning after a moderate-fat breakfast 
(approximately 600 calories with approximately 30% of the calories from fat).
Each participant will be enrolled in the study for approximately 7 weeks, dependent on 
screening and washout duration between periods. Participation will include a screening 
evaluation within 28 days of first study treatment administration and 2 separate inpatient 
periods. Participants will be admitted to the clinic in the morning of the day before dosing 
(i.e. Day -1) for Periods 1 and 2, and in the evening of Day -1 for Period 2. Each inpatient 
period will consist of 4 days (Period 1, morning admission on Day -1) or 3 days (Period 
2, evening admission on Day -1) and 3 nights followed by a return visit 72 hours post-
dose.
There will be a minimum washout of 7 days between each dose of study treatment.
A follow-up visit will occur 7 to 10 days after the last dose of study treatment.


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2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities are presented in Table 1. The time points for the PK blood 
sample collection, and ECG and vital sign assessments are presented in Table 2.
The competent authority (CA) and ethics committee (EC) will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will 
be approved by the CA and the EC before implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances, the following will apply to post-dose time points:
The order of assessments will be:
ECGs
Vital 
signs
PK blood 
sampling
(nominal 
time)
Other assessments 
eg physical exams
Electrocardiograms will be taken prior to vital signs when both measurements are 
scheduled at the same time point. Other assessments, e.g. physical examinations etc, will 
be performed within the required time windows. All safety assessments will be timed and 
performed relative to the start of dosing.


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Table 1
Schedule of Activities
Procedure
Screening 
(up to 28 days 
before Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days post last 
dose) or Early 
Discontinuation 
Notes
–1
1
2
3
4
Outpatient visit
X
X
X
Inpatient stay
X1
X
X
X2
1.
Admission in the morning
2.
Furlough from unit after 
assessments
Informed consent
X
Inclusion and exclusion criteria
X
X3
3.
Recheck clinical status at 
admission of Period 1
Demography
X
Full physical examination including height 
and weight4
X
4.
See Section 9.4.1 for systems to 
be examined
Columbia Suicide Severity Rating Scale 
(CSSRS)
X
Brief physical examination
X5
X5
X
5.
Pre-dose and 48 h post-dose
See Section 9.4.1 for systems to 
be examined
Medical history (includes substance 
usage)6
X
6.
Substances: Drugs, alcohol, 
tobacco and caffeine
Urine pregnancy test7
X
X
X
7.
All female participants
Follicle stimulating hormone (FSH)8
X
8.
As needed in women to confirm 
postmenopausal status
HIV, Hepatitis B and C screening
X
Urine drug screen
X
X


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Procedure
Screening 
(up to 28 days 
before Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days post last 
dose) or Early 
Discontinuation 
Notes
–1
1
2
3
4
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments (haematology, 
clinical chemistry and urinalysis)
X
X9
X9
X
9.
48 h post-dose
Allowable windows in Section 9.4.4
12-lead ECG
X
X
X10
X10
X10
X
10. Time points in Table 2
Allowable windows in Section 9.4.3
Vital signs
X
X
X11
X11
X11
X
11. Time points in Table 2
Allowable windows in Section 9.4.2
Randomization
X12
12. Pre-dose Period 1 only
Study treatment
X
AE review
X
===========================
X
SAE review
X
X
===========================
X
Concomitant medication review
X
===========================
X
PK blood sample collection13
===========================
13. Time points in Table 2


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Table 2
Pharmacokinetic Blood Sampling Collection, ECG ad Vital Sign Times
Treatment Periods 1 and 2
Time (h)
Pre-dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
36
48
72
Dosing 
X
PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-
lead ECG
(repeat 
allowed)
X
X
X
X
X
X
Single set of 
Vital signs
X
X
X
X
X
X


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3.
INTRODUCTION
GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI); this novel class of 
anti-human immunodeficiency virus (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. 
3.1.
Study Rationale
A First Time in Human (FTIH) study is in progress and has used the bis-hydrochloride 
salt immediate release capsule formulation of GSK3640254 administered following a 
moderate calorie and fat meal. However, the bis-hydrochloride salt formulation is not 
suitable for long term clinical development as it is susceptible to humidity. A mesylate 
salt capsule formulation of GSK3640254 has been identified for later phase development
and commercialization. The aim of this relative bioavailability study is to compare the 
exposure of the mesylate salt capsule formulation of GSK3640254 with that of the bis-
hydrochloride salt capsule formulation administered following a moderate calorie and fat 
meal.
3.2.
Background
Current therapy for HIV-infected individuals consists of a combination of approved 
antiretroviral (ARV) agents. More than twenty medicines are currently approved for 
HIV-1 infection, either as single agents, fixed-dose combinations or single-tablet 
regimens, the latter two containing 2 to 4 approved agents. Given the challenges inherent 
with the lifetime dosing of daily medications, there remains a need for new ARV agents 
that combine an optimal safety, tolerability and efficacy profile with a convenient dosing 
schedule. Significant toxicities have been described with each ARV agent in current use, 
and data continue to accumulate on the long-term clinical consequences of chronic ARV 
therapy [Centers for Disease Control and Prevention, 2015; Claessens, 2003; Collins, 
2006; The DAD Study Group, 2007]. New ARV agents that offer an improved 
tolerability and safety profile are needed.
Despite the availability of different classes of ARV agents providing a variety of 
treatment options, treatment failure continues to occur as a result of high transmitted drug 
resistance, drug-associated toxicity and tolerability problems, and poor adherence to 
medication regimens. Although prevalence rates of drug resistance are falling in Western 
Europe, ~80% of HIV-infected patients who have received ARV therapy have resistance 
to at least one class of ARV [De Luca, 2013]. Additionally, the prevalence of transmitted 
resistance to at least one ARV is ~10-17% in resource-rich regions, such as Europe 
[WHO, 2012]. Unfortunately, resistance mutations selected by one ARV agent often 
confer resistance to multiple drugs in the same class, significantly limiting future 
therapeutic options. Later regimens often lack the convenience and tolerability of firstline 
drugs, which in turn exacerbates non-adherence. Thus, there is a continuing need for new 
classes of ARV drugs capable of providing potent, durable antiviral activity to a broad 
population of HIV-infected patients, with no cross-resistance to current agents, a 
relatively high barrier to the development of resistance on its own, and activity across 
diverse HIV-1 subtypes.


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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 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 HIV capsid protein p24 and spacer peptide 1. Blockage at 
this step results in the release of immature non-infectious virus particles. GSK3640254 
has excellent potency and a broad pangenotypic spectrum in vitro. Laboratory studies 
confirm that GSK3640254 is an MI with a mechanism of action distinct from current 
ARVs, suggesting little if any risk of cross-resistance to current therapeutic agents.
As of 4 April 2018, the First Time in Human (FTIH) study is ongoing. It includes: 1) a 
single ascending dose (SAD) portion with doses of 1 mg to 700 mg (completed) and 2) a 
14-day multiple ascending dose (MAD) portion (ongoing with 50 mg and 100 mg QD 
cohorts completed). The pharmacokinetics of GSK3640254 administered as a single dose 
following a moderate calorie/fat breakfast is characterized by a slow absorption with 
maximum concentration observed on average 3 to 4 hours after dosing. GSK3640254 is 
also slowly eliminated with an average half-life around 23 hours. Cmax and AUC tended 
to increase in a dose proportional manner from 1 mg to 400 mg with a less than dose 
proportional increase from 400 mg to 700 mg. 
To support future toxicology studies to be conducted with the mesylate salt, single dose 
PK studies were conducted in male rats (doses of 10, 30 and 100 mg/kg) and male dogs 
(0.2, 1 and 5 mg/kg) with the mesylate salt. PK data were compared back to other PK 
studies conducted with the bis-hydrochloride salt. While the mesylate salt provided 
similar exposure as the bis-hydrochloride salt in dogs, the mesylate salt provided 
approximately a 75% increase in Cmax and AUC at the dose of 10 mg/kg with a smaller 
improvement of around 30% at the dose of 100 mg/kg in rats.    
A detailed description of the chemistry, and the nonclinical pharmacology, 
pharmacokinetic and toxicology studies of GSK3640254 is provided in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2016N294821_00].
3.3.
Benefit/Risk Assessment
GSK3640254 is currently being studied in a Phase 1 SAD/MAD clinical trial in healthy 
participants to evaluate the safety, tolerability, and PK. The SAD portion of the study 
evaluating single doses ranging from 1 to 700 mg has been completed with preliminary 
data showing no major clinical safety or tolerability finding.
Until additional clinical safety information for GSK3640254 is available, precautions will 
be taken that are based on non-clinical safety assessment of GSK3640254 and reported 
clinical experiences of a previous, structurally similar maturation inhibitor
(GSK3532795), in healthy and HIV-1 infected participants. Specifically, this previous 
maturation inhibitor (GSK3532795) was not progressed beyond Phase 2b clinical trials 
because of Grade 1-2 gastrointestinal intolerability (diarrhoea, abdominal pain) and 
treatment emergent resistance to study medications. In addition, two serious adverse 
events (SAEs; acute psychosis and suicidal/homicidal ideation) led to the early 


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termination of a Phase 1 Thorough QT (TQT) study in healthy participants at 
supratherapeutic doses.
Nonclinical findings with GSK3640254 have indicated the following potential risks for 
the clinical program: gastrointestinal (GI) intolerability/microscopic GI changes, cardiac 
conduction abnormalities (prolonged QT interval), hepatic injury (single cell necrosis), 
and renal changes (eosinophilic intracytoplasmatic inclusion bodies).
Until further preclinical studies on the effects of GSK3640254 on the reproductive 
system are available, it will be assumed that GSK3640254 has the potential to impair 
male and female fertility.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3640254 may be found in the Investigator’s 
Brochure.
ViiV Healthcare 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 FTIH clinical trials with 
investigational medicinal products (EMEA/CHMP/SWP/28367/07). 


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3.3.1.
Risk Assessment
Potential risks of the IP (GSK3640254) are detailed below
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3640254
GI intolerability/toxicity
Non-clinical data:
In a 14-day dose-range-finding study in rats, a 
non-tolerated dose of 300 mg/kg/day produced 
GI clinical signs and microscopic changes in the 
stomach and small intestine that were not seen 
at lower doses. These included minimal 
ulceration in the glandular stomach, minimal to 
moderate enterocyte vacuolation (lipid) in the 
duodenum, and minimal epithelial hyperplasia in 
the jejunum.
At tolerated doses, GI clinical signs occurred in 
rats (unformed faeces) at 100 mg/kg/day and 
dogs (sporadic vomiting and unformed, liquid or 
mucoid faeces) at ≥1 mg/kg/day.
At tolerated doses, reversible dose-responsive 
microscopic changes were observed in the
stomachs of rats and dogs.
Participant selection:

Participants with a clinically significant
history of or current GI disorders will not be 
eligible to participate in this study
Participant monitoring:

Participants will be monitored for GI-related 
AEs
Cardiac conduction abnormalities (prolonged QT 
interval)
Non-clinical data:
GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and L-type 
calcium channel currents with moderate potency. 
ECG changes attributed to GSK3640254 in 
telemeterized dogs at doses of 12.5 and 17 
Participant selection:

Participants with a history of or current 
cardiovascular disorders will not be eligible 
to participate in this study

Participants with a QT interval corrected for 
heart rate according to Fridericia’s formula


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
mg/kg consisted of increased rate-corrected QT 
interval from 3.5 to 6 hours post-dose (~ 9 msec) 
and during the overnight period (~ 6 msec). 
These QT effects were primarily limited to one 
dog given 17 mg/kg (≤20 msec increase), with a 
plasma concentration of 7.96 µg/mL 8 hours 
after dosing. 
The no observed adverse effect level (NOAEL) in 
the study was 12.5 mg/kg, which produced 
similar systemic exposures (8.79 µg/mL 5 hours 
after dose).
There were no GSK3640254-related effects on 
ECG parameters evaluated in the definitive 
general toxicity study in conscious restrained 
dogs given multiple doses of up to 25 mg/kg/day 
for 4 weeks.
(QTcF) >450 msec at screening will not be 
eligible for this study
Participant monitoring:

Participants will be monitored for cardiac-
related AEs

ECGs will be monitored throughout the study
Neurologic/psychiatric safety
Clinical data:
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 Grade 1 headache and 
Grade 1 sleep abnormalities were the 
predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing 
dose (based on TQT and P2b studies). No 
exposure-response relationship was seen for 
Participant selection:

Participants with a history of psychiatric
disease requiring pharmacologic treatment in 
the last 5 years, any history of suicidal 
ideation (ever) or any clinically significant 
psychiatric history per investigator 
judgement will be excluded from the study

Protocol exclusion criterion based 
assessment using the CSSRS):

Participants will undergo physical exams and 
continuous evaluation for adverse events 
during their participation in the trial.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
select neurologic and psychiatric AEs (based on 
TQT and P2b studies) 
Non-Clinical Data
CNS penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low 
brain distribution/penetration 
Potential risks of study procedures are detailed below
Study Procedures
Cannulation 
During cannulation more than one attempt may 
be needed to insert the cannula in a vein of a 
participant and it is possible that bruising and/or 
inflammation may be experienced at the site of 
cannulation.

A vein assessment will be conducted at 
screening to ensure only volunteers with 
veins suitable for multiple venepuncture and 
cannulation are enrolled.

Cannulation and venepuncture will only be 
performed by staff who are trained in these 
procedures
Electrocardiograms
Electrocardiogram stickers on the participants’ 
chests and limbs may cause some local irritation 
and may be uncomfortable to remove.

Participants will be closely monitored to 
ensure any local irritation does not persist.

2.5% hydrocortisone cream will be included 
in the list of permitted medication to relieve 
irritation from ECG leads.


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3.3.2.
Benefit Assessment
There is no intended direct health benefit to the participants in this study. 
3.3.3.
Overall Benefit:Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the emerging clinical profile of GSK3640254 in the FTIH study, and 
the planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 are low, evaluable, and manageable.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the PK profiles of GSK3640254 
following administration of the mesylate salt 
capsule relative to that of the bis-
hydrochloride salt capsule (reference) in 
healthy participants

GSK3640254 area under the curve from
time zero to infinity (AUC(0-∞)), AUC(0-tlast), 
maximum observed concentration (Cmax), 
Time to Cmax (Tmax), Concentration at 24 
hours post-dose (C24h), relative 
bioavailability (Frel) based on AUC and 
Cmax
Secondary

To provide additional information of the 
safety and tolerability of single doses of 
GSK3640254 in healthy participants

AEs, clinical laboratory values, vital signs, 
ECGs, and/or other safety biomarkers
5.
STUDY DESIGN
5.1.
Overall Design
This is a single centre, 2-period, randomized, open-label Phase 1 study. It is planned to 
enroll 14 healthy participants. It is planned to study 2 regimens (A and B) during 
2 periods (1 and 2).
The following regimens will be administered during each period in the study:

Regimen A: An oral dose of 200 mg as 2 x GSK3640254 Capsule, 100 mg
(reference) following a moderate fat meal. 

Regimen B: An oral dose of 200 mg as 2 x GSK3640254 Mesylate Salt Capsule, 
100 mg (test) following a moderate fat meal.
Each participant will receive each of the regimens (Regimens A and B) in a sequence 
during Period 1 and Period 2 as determined by the randomization:


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
Randomized to AB: Regimen A administered in Period 1, followed by Regimen B 
in Period 2

Randomized to BA: Regimen B administered in Period 1, followed by Regimen A 
in Period 2
Participants will receive a single oral dose of study treatment during each inpatient 
period. Participants will receive the formulations in the morning after a moderate-fat 
breakfast (approximately 600 calories with approximately 30% of the calories from fat).
Study Outline:
Period 1: Participants will be admitted to the clinical unit on the morning of the day 
before study treatment administration (Day -1) for Period 1. Participants will receive a 
single oral dose of the assigned study treatment regimen on Day 1 and will remain on site 
until 48 hours post-dose, and then return to the clinical unit for a 72 hours PK sample, 
vital signs and ECGs. 
There will be a minimum washout of 7 days between each dose of study treatment. 
Period 2: Participants will be admitted to the clinical unit on the morning of the day 
before study treatment administration (Day -1) for Period 2. Participants will receive a 
single oral dose of the assigned study treatment regimen on Day 1 and will remain on site 
until 48 hours post-dose, and then return to the clinical unit for a 72 hours PK sample, 
vital signs and ECGs. 
Follow up: A Follow-up visit will be conducted 7 to10 days after the last dose of study 
treatment.
The estimated maximum duration of the study from screening until follow-up for each 
participant is approximately 7 weeks.
Figure 1
Study Design
Treatment 
Sequence
Period 1:
Period 2:
Follow-up 
visit
AB
(N = 7)
Regimen A
200 mg as 2 x 
GSK3640254 Capsule, 
100 mg (reference)
fed (moderate fat meal)
Regimen B
200 mg as 2 x 
GSK3640254 Mesylate 
Salt Capsule, 100 mg (test)
fed (moderate fat meal)
7 to 10 
days after 
last dose
BA
(N = 7)
Regimen B
200 mg as 2 x 
GSK3640254 Mesylate 
Salt Capsule, 100 mg
(test)
fed (moderate fat meal)
Regimen A
200 mg as 2 x
GSK3640254 Capsule, 
100 mg (reference) fed 
(moderate fat meal)


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5.2.
Number of Participants
Fourteen participants will be enrolled such that sufficient data will be available for
at least 12 evaluable participants. An evaluable participant is a participant who has 
received both Regimens A and B, and has safety and PK data up to 72 hours post-dose.
Up to 7 replacement participants may be enrolled. The maximum number of participants 
that may be dosed is 21.
Participants withdrawn by the investigator due to a moderate AE at least possibly related 
to study treatment will not be replaced. If participants prematurely discontinue the study 
for other reasons, additional replacement participants may be recruited at the discretion of 
the Sponsor in consultation with the investigator. Replacement participants are 
individuals who have met inclusion into the study but have not been dosed at the 
discretion of the PI.
Replacement participants will receive both Regimens A and B, and will receive them in 
the same order as planned for the original participant and the minimum washout period of 
7 days between dosing will be respected.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the last scheduled procedure shown in the SoA (i.e. the 
follow-up visit).
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
The current bis-hydrochloride salt capsule formulation of GSK3640254 that has been 
used in the FTIH study is not suitable for long term development due to its susceptibility 
to humidity; therefore, a mesylate salt capsule formulation has been generated for future 
development. This is a bridging study to assess the relative bioavailability of the mesylate 
salt capsule formulation compared with the bis-hydrochloride salt capsule formulation. 
All doses of GSK3640254 in this study will be administered in the fed state, with dosing 
occurring within 5 minutes of completing a moderate calorie/fat meal, similar to the 
FTIH study and the future proof of concept study planned in HIV-infected participants. 
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, 
administration of GSK3640254 with food is expected to enhance its bioavailability. The 
impact of food on exposures to GSK3640254 will be assessed in a future Phase 1 study in 
healthy participants during clinical development.


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A 2-period, 2-sequence crossover design has been selected as recommended by the 
European Medicines Agency (EMA) guidance on bioavailability and bioequivalence 
studies. In addition, participants will be randomized to treatment sequence to avoid any 
potential period effects. The study is open-label as the primary objective is to assess the 
PK and there are no concerns about introducing bias. The washout period of at least 
7 days between each dose of study treatment is considered sufficient to avoid any 
carryover effect between treatment periods, based on the average preliminary half-life of 
GSK3640254 of 23 hours observed in the first time in human study.
As this is a Phase 1 study, the most relevant population is healthy participants which 
allows characterisation of safety, tolerability and PK in a homogenous population without 
potential biases from a patient population. The EMA recommends including participants 
aged 18 years and older with normal weight, who are non-smokers, without a history of 
alcohol or drug abuse. The latter criteria are proposed to avoid interaction on drug 
metabolism and to avoid non-compliance. Therefore, this study will enroll healthy male 
and female participants aged between 18 to 55 years of age.
The study treatment has been shown in vitro to bind progesterone receptor, and only 
preliminary animal reproductive studies have been conducted; therefore, only women of 
nonchildbearing potential will be eligible for inclusion in this study. 
5.5.
Dose Justification
To date, single oral doses of 1, 3, 10, 30, 100, 200, 400 and 700 mg have been 
administered to healthy participants in the fed state. Preliminary data show these dose 
levels have been well tolerated with no SAEs reported. The majority of AEs reported 
were mild in severity and unrelated to study treatment. 
Emerging PK data suggest that the anticipated effective daily dose range is between 
80 mg and 360 mg based on the bis-hydrochloride salt capsule data. Based on an 
improved solubility of the mesylate salt formulation in simulated gastric fluid and the 
emerging animal PK data with the mesylate salt, it is possible that the extent of 
absorption of the mesylate salt formulation could be up to 2-fold higher than the bis-
hydrochloride salt formulation. 
Therefore, taking all of these factors into consideration, single oral doses of 200 mg have 
been selected for this study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Quotient Sciences must have a full medical history from each participant’s general 
practitioner (GP) within the last 12 months, prior to enrollment in the study. 
Participants will be recruited from the Quotient Sciences panel or by direct advertising to 
the public. 


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Before participants are admitted to the clinic, The Over Volunteering Prevention System 
(TOPS) will be checked to ensure that each participant has not participated in a study at 
another site within at least 3 months of the dosing date.
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 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ≥50 kg for men and ≥ 45 kg for women, and body mass index (BMI) 
within the range 19.0 to 32.0 kg/m2 (inclusive).
Sex
4.
Male or female 
a. Male participants:
A male participant must adhere to the contraception requirements as detailed in 
Appendix 5 of this protocol during the treatment period and for at least 95 days after 
the last dose of study treatment and refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Appendix 5
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
Inclusion criteria 2 will also be assessed at admission/pre-dose.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:


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Medical Conditions
1.
History of or current cardiovascular, respiratory, hepatic, renal, GI, endocrine, 
haematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the 
study treatment; or interfering with the interpretation of data.
2.
History of clinically significant psychiatric disorders as judged by the investigator.  
Psychiatric disorder requiring pharmacologic treatment in the last 5 years.
3.
Any positive (abnormal) response confirmed by the investigator on a screening 
clinician (or qualified designee) administered CSSRS.
4.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
5.
History of GI surgery (with exception of appendectomy).
6.
History of Cholecystectomy
7.
Any history of GI ulceration (oesophageal, stomach, duodenal).
8.
Any history of GI symptoms requiring treatment in the last 3 months.
9.
History of unexplained vaginal bleeding, endometrial hyperplasia with atypia or 
endometrial carcinoma.
10. Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator. Hayfever is allowed unless it is active.
11. ALT >1.5x ULN.
12. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).
13. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome).
14. Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome. 
15. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 or >100 bpm
<50 or >100 bpm
PR interval
<120 or >220 msec
QRS duration
<70 or >120 msec
QTcF interval
>450 msec
Note: A heart rate from 100 to 110 bpm can be re-checked by ECG or vital signs within 30 minutes to verify 
eligibility.
16.
Evidence of previous myocardial infarction (does not include ST segment changes 
associated with re-polarization). 


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17. Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome). 
18. Sinus Pauses >3 seconds. 
19. Any significant arrhythmia which, in the opinion of the Investigator OR GSK/ViiV 
Medical Monitor, will interfere with the safety for the individual participant. 
20. Non-sustained or sustained ventricular tachycardia (³3 consecutive ventricular 
ectopic beats). 
Prior/Concomitant Therapy
21. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) prior to dosing 
(paracetamol/acetaminophen [up to 2 g per day] and 2.5% Hydrocortisone [for 
ECG lead contact dermatitis] is permitted any time during the study).
Prior/Concurrent Clinical Study Experience
22. Participation in the study would result in loss of blood or blood products in excess 
of 500 mL within a 56 day period; therefore donation or loss of greater than 400 
mL of blood within the previous 3 months.
23. Current enrollment or past participation within the last 3 months before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research.
24. Participants who have previously been enrolled in this study. 
Diagnostic assessments
25. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis 
C antibody test result at screening or within 3 months prior to first dose. 
26. Confirmed positive pre-study drug/alcohol screen.
27. Positive HIV antibody test.
28. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
5 years.
Other Exclusions
29. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >21 units for males or >14 units for females. One unit is 
equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer or 1 (25 mL) measure of 
spirits. One glass (125 mL) of wine is equivalent to 1.5 to 2 units, depending on 
type)
30. Current use or history of regular use of tobacco- or nicotine-containing products 
within 6 months prior to screening. A confirmed carbon monoxide breath test 
reading of greater than 10 ppm.


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31. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
32. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
33. Participants who do not have the ability to swallow size 00 capsules.
34. Participants who are study site employees, or immediate family members of a study 
site or sponsor employee.
Exclusion criteria 1, 11, 12, 15, 17, 18, 19, 20, 21, and 26, from the list above will be re-
assessed at admission/pre-dose Period 1.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from Seville 
oranges and grapefruit derivatives for 24 hours before admission to each study 
period until after collection of the final PK sample in that period.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK 
sample in that period.

Participants will be required to fast for at least 8 hours prior to dosing on Day 1 of 
each period. On the morning of Day 1, participants will be provided with a moderate 
calorie/fat breakfast. The breakfast will be consumed over a maximum period of 
25 min, with dosing occurring approximately 30 min after the start of breakfast. 
Participants will be encouraged to eat their meal evenly over the 25 min period. It is 
acknowledged that some participants will take less time to eat, but dosing will still 
occur approximately 30 min after the start of breakfast. Lunch will be provided 
approximately 4 hours after dosing, an evening meal will be provided approximately 
10 hours after dosing and an evening snack will be provided approximately 14 hours 
after dosing. Participants will consume at least 80% of the breakfast in order to be 
eligible for dosing in each period. The start and stop time of the meal will be 
recorded in the source documents and where less than 100% of the meal has been 
consumed, the percentage consumed will be recorded in the source documents.

Other than liquid provided with breakfast and dosing, participants will refrain from 
drinking for 1 hour prior to dosing until 1 hour after dosing.

Water will be allowed ad libitum from 1 hour post-dose. Decaffeinated fluid will be 
allowed from 4 hours post-dose.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for
24 hours before admission until after collection of the final PK sample in that period.


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
Participants will abstain from alcohol for 24 hours before screening. During each 
dosing session, participants will abstain from alcohol from 24 hours before 
admission until after collection of the final PK sample in that period. 

Current smokers or users of other tobacco products will not be enrolled in this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before screening and 
then from 72 hours before admission until discharge from the study. Participants may 
participate in light recreational activities during studies (eg, watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the investigator if the reasons for the screening 
failure are expected to be temporary. Rescreened participants will be assigned a new 
screening number and will be re-consented.
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
Regimen
A
B
Study Treatment 
Name:
GSK3640254 Capsule, 100 mg
GSK3640254 Mesylate Salt 
Capsule, 100 mg
Dosage formulation:
Bis-Hydrochloride salt formulation 
capsule
Mesylate salt formulation
capsule
Unit dose 
strength(s)/Dosage 
level(s):
100 mg / 200 mg
100 mg / 200 mg
Route of 
Administration 
Oral
Oral
Dosing instructions:
2 capsules, on the morning of 
Day 1 following a moderate fat 
meal. Capsules will be 
administered with 240 mL water.
2 capsules, on the morning of 
Day 1 following a moderate fat 
meal. Capsules will be 
administered with 240 mL water.
Packaging and 
Labelling
Study Treatment will be provided in HDPE containers with 
polypropylene screw cap lids. Each HDPE container will be labelled as 
required per country requirement.
Manufacturer
GSK
Quotient
7.2.
Dose Modification
No dose modification is permitted in this study. If a participant does not tolerate the dose 
administered, then the participant will be withdrawn from the study.
7.3.
Method of Treatment Assignment
This is an open-label, randomized study, therefore a randomization schedule will be 
produced. 
Participants will be randomized immediately before administration of the first dose in 
Period 1.
On the morning of Day 1 of Period 1, participants will be assigned a unique number 
(randomization number) in ascending numerical order at the study site. The 
randomization number encodes the participant’s assignment to one of the two treatment 
sequences of the study (Table 3), according to the randomization schedule generated 
prior to the study by the Statistics Department at GSK, using validated internal software.


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Participant randomization numbers will be allocated to treatment sequence in a 1:1 ratio. 
The allocation will be balanced with 7 participants receiving each treatment sequence. 
Each participant will be dispensed study treatment, labelled with his/her unique 
randomization number, throughout the study.
Table 3
Treatment Sequences
Treatment 
Sequence
N
Period 1
Period 2
AB
7
Regimen A
Regimen B
BA
7
Regimen B
Regimen A
Regimen A: 200 mg as 2 x 100 mg GSK3640254 Capsule, 100mg (reference)
Regimen B: 200 mg as 2 x 100 mg GSK3640254 Mesylate Salt Capsule, 100 mg (test)
A treatment allocation list will be produced prior to dosing using the randomization 
schedule and will be retained in the investigator site file (ISF).
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
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).
4.
Further guidance and information for the final disposition of unused study 
treatment are provided in the technical agreement.
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 GSK.


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7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

Participants will be dosed at the site, and 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 and 
hands to ensure that the study treatment was ingested.
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 in the case report form (CRF)
along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor will be contacted if there are any questions regarding concomitant 
or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol/Acetaminophen, at doses of 2 grams/day and 2.5% Hydrocortisone (for 
EKG lead contact dermatitis), is permitted for use any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the Medical Monitor (if appropriate) if required to treat AEs.
7.8.
Treatment after the End of the Study
There is no treatment after the end of the study. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant will be withdrawn from the study at any time: 

At his or her own request


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
At the discretion of the Investigator or the Sponsor for safety (including lab 
abnormalities or intercurrent illness), psychiatric, compliance, or administrative 
reasons. 

Any SAE.

Termination of the study by GSK/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) illness

Repeat non-adherence by the participant with the requirements of the protocol or 
treatment (as determined by Investigator in consultation with the Medical 
Monitor)
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
If a participant withdraws from the study, he/she must complete a follow-up visit.
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. Discontinuation of study 
treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is in the 
best interest of the participant.


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
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, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7.
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. The formula to be used in 
this study is Fridericia’s formula (i.e. QTcF). This formula may not be changed or 
substituted once the participant has been enrolled.

The QTc will be based on single electrocardiograms. 

ECGs will be repeated if a participant has QTcF> 450 msec or > 30 msec increase 
from pre-dose in QTcF. 
A participant that meets either bulleted criterion below based on the average of repeated 
ECG readings will be withdrawn from study treatment.  

QTcF >500 msec

Change from baseline (pre-dose Day 1) of QTcF >60 msec
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 Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is related to investigational product.

The participant becomes pregnant.


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
The participant initiates treatment with any prohibited medications.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.
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.
8.1.4.
Temporary Discontinuation
If a participant is not dosed when planned in a particular period (eg in case of unexpected 
personal circumstances or AEs that occur between treatment periods), they may be dosed 
at a later date (if a participant cannot re-attend within 28 days, they will be considered 
withdrawn), provided the following criteria are met: 

The AE has resolved or stabilized.

The AE preventing dosing was not considered related to the study treatment.

The participant has not met any individual stopping criteria.

It is considered safe to continue to dose in the opinion of the investigator.
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria or any other 
withdrawal 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, 
behavioural, compliance or administrative reasons. If a participant withdraws 
from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records. The reason for 
withdrawal will be documented in the CRF.

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.

A participant may be withdrawn at the Sponsor’s request, for reasons such as 
significant protocol deviations or participant safety concern (and after discussion 
with the Investigator).

If a participant is withdrawn from study treatment, this participant is also 
considered to be withdrawn from the study following completion of follow-up 
assessments.

Participants will be withdrawn if the study is terminated.

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.


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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 will 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 
will be documented in the participant’s CRF.

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. 
8.4.
Study Stopping Criteria
The study will be halted, and the risk to other participants evaluated, if any of the 
following criteria are met: 

Two participants experience an AE of Grade 3 intensity assessed as related to 
GSK3640254, by the principle investigator (PI).

One participant experiences an AE of Grade 4 intensity assessed as related to 
GSK3640254, by the PI 

If greater than 25% of participants within the same period receiving 
GSK3640254 have a ≥ Grade 3 intensity AE or laboratory abnormality (with the 
exception of asymptomatic changes in lipid panel) or a ≥ Grade 2 intensity rash 
with concurrent fever, transaminase elevation or eosinophilia. 

There is one Serious Adverse Event (SAE) or death assessed as related to 
GSK3640254, by the PI. 

Two participants with confirmed QTcF ≥500 msec within the same period 

Two participants with clinically significant, in the opinion of the PI, arrhythmias 
within the same period 

Relatedness will be determined by the investigator. If the study is halted, a 
temporary halt will be submitted to the MHRA and EC in the form of a 
substantial amendment. The study may be resumed or terminated; however, it 
will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC. Of note, the intensity of AEs will be 
determined using DAIDS criteria (see Section 12.4 for further details) 


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8.5.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA 
and EC. The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is terminated, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons if applicable, will also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the principal 
investigator (PI) or sponsor must notify the EC and MHRA by letter outlining the reasons 
for abandonment of the trial.
Once exposure to GSK3640254 has begun, the study will be completed as planned unless 
the following criteria are satisfied that require a temporary halt or early termination of the 
study.

The occurrence of serious or severe AE(s), as defined in Appendix 4, if 
considered to be related to study treatment.

New information regarding the safety of the study treatment that indicates a 
change in the risk/benefit profile for the compound, such that the risk/benefit is 
no longer acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the 
ability to achieve the primary study objectives or compromises participant 
safety.
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 3.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination.
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor.  
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns will be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant will continue or discontinue 
study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.


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
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 or by 
generic screening (eg, blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in the 
SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
550 mL in a 4-week period.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 48 hours post-dose providing that:
−
No AEs have been reported during the study visit
−
The participant responds positively when asked “How are you feeling?”
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorization of the investigator or appropriately 
qualified delegate.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Section 12.4 . The intensity of AEs (and 
lab abnormalities) will be graded using the DAIDS Grading table. While the study 
population will consist of HIV-1 seronegative healthy volunteers, the DAIDS criteria will 
be used in later clinical trials (Phase 2a and beyond); additionally, the DAIDS criteria are 
have a more conservative grading scale relative to others (eg. CTCAE v 4.0). Thus, 
participant safety evaluation and monitoring will be more conservative.
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 follow-up visit at the 
time points specified in the SoA (Section 2).


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
All AEs will be collected from the start of treatment until the 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 CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 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. 
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 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.


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
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.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of
male participants will be collected after the start of study treatment and until 90 days 
after the last dose.

If a pregnancy is reported, the investigator will inform ViiV/GSK within 24 hours of
learning of the pregnancy and will follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than that intended in this study will be 
considered an overdose.
There is no specific antidote for overdose with GSK3640254. The investigator will use
clinical judgment to treat any overdose.
In the event of an overdose, the investigator will:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 can no longer be detected systemically (at least 72 hours after the last 
dose of GSK3640254).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor at 2, 4 
and 6 hours post dose (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.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI and neurological systems. Height and 
weight will also be measured and recorded.


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
A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators will pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate.

The acceptable deviations from the nominal vital signs measurement time points 
are:
−
The pre-dose vital signs measurements will be taken ≤2 hours before 
dosing.
−
≥0.5 to 4 hours post-dose vital signs measurement will be taken within ± 5 
minutes of the nominal post-dose sampling time
−
>5 to 12 hours post-dose vital signs measurement will be taken within 
± 10 minutes of the nominal post-dose sampling time 
−
>12 hours post-dose vital signs measurement will be taken within ± 30 
min of the nominal post-dose sampling time if participants are resident in 
the clinic
−
For the return visit, vital signs measurements will be taken ± 2 hours from 
the nominal return visit time point.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline 
(pre-dose Day 1), must be reported as an AE. 
9.4.3.
Electrocardiograms

A single 12-lead ECG will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

As noted in Section 8.1.2 , ECGs will be repeated if a participant has QTcF> 
450 msec or > 30 msec increase from pre-dose in QTcF. If the ECG is repeated, 
the QTc will be based on averaged QTc values of repeated ECGs obtained 
Baseline QTc for the assessment of the withdrawal criteria will be the mean 
pre-dose QTcF of the relevant treatment period.

The acceptable deviations from the nominal ECG measurement time points are:
−
The pre-dose ECG measurements will be taken ≤ 2 hours before dosing


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−
Post-dose ECG measurements will be taken ± 15 minutes from the 
nominal post-dose time point.
−
For the return visit, ECG measurements will be taken ± 2 hours from the 
nominal return visit time point.

ECGs are to be measured after participant has been in a semi-supine position 
after approximately 5 minutes rest.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline 
(pre-dose Day 1), will be reported as an AE.
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. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast of at least 8 hours.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
−
The pre-dose blood sample will be taken ≤2 hours before dosing
−
Post-dose blood samples will be taken ± 1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal
during participation in the study or within 7 days after the last dose of study 
treatment will 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 will 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.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 


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management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
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 CSSRS 
administered by a clinician (or qualified designee); any positive (abnormal) response 
confirmed by the investigator, will exclude them from participating. In the case of 
positive (abnormal) response confirmed by the investigator, the PI/Sub-investigator 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 Severity Rating Scale (C-SSRS; v4.1, 28 Apr 2010) [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. 
9.5.
Pharmacokinetics

Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK3640254 as specified in the SoA (see Section 2).
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

The first 0.5 mL of blood withdrawn via cannula will be discarded.

Processing, storage and shipping procedures are provided in the SRM or 
equivalent.

The acceptable deviations from the nominal post-dose blood sampling times are 
as follows:
−
The pre-dose blood sample will be taken ≤1 hour before dosing. 
−
≥0.5 to 4 hours post-dose samples will be taken within ± 5 minutes of the 
nominal post-dose sampling time
−
>5 to 12 hours post-dose samples will be taken within ± 10 minutes of the 
nominal post-dose sampling time 
−
>12 hours post-dose samples will be taken within ± 30 min of the nominal 
post-dose sampling time if participants are resident in the clinic
−
The return visit (72 hours post-dose) sample will be taken within ± 2 hours 
of the nominal sampling time

Samples will be used to evaluate the PK of GSK3640254. Samples collected for 
analyses of GSK3640254 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.


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
Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained.

Once the plasma has been analyzed for GSK3640254 any remaining plasma may 
be analyzed for other compound-related metabolites and the results reported under 
a separate protocol.

Plasma analysis will be performed by PPD. Concentrations of GSK3640254 will 
be determined in plasma using the current approved bioanalytical methodology. 
Raw data will be archived at the Bioanalytical site as detailed in the SRM or 
equivalent.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
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
No formal sample size calculation has been made; however, based on experience from 
previous similar studies, 14 participants enrolled to achieve a minimum of 12 evaluable 
participants is considered sufficient.
Based on the emerging single-dose PK data from the FTIH study, the within-participant 
variability was 31.6% for Cmax and 36.8% for AUC(0-inf). Assuming a within-
participant coefficient of variation (CVw) of 37% for Cmax and AUC(0-inf), and a 
sample size of 12 participants, it is estimated that the half width of the 90% confidence 
interval for the treatment difference on log-scale will be within 26% of the point 
estimate. If the point estimate of the ratio of geometric means is 1, then 90% confidence 
interval will be approximately (0.77,1.30) on the original scale.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:


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Population
Description
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
Participants in the ‘Safety Population’ for whom a PK sample was 
obtained and analysed and will be the population for reporting of PK 
data.
10.3.
Statistical Analyses
10.3.1.
Pharmacokinetic Analyses
No statistical hypotheses will be tested. All PK analyses will be performed on the PK 
Population. 
Plasma GSK3640254 concentration-time data will be analysed by non-compartmental 
methods.  
The plasma concentration-time data for each of the regimens will be used to determine 
the following PK parameters, as data permit: 

maximum observed plasma concentration (Cmax).

time to Cmax (Tmax).

the elapsed time from dosing at which GSK3640254 was first quantifiable in a 
concentration vs time profile (Tlag).

time from dosing at which GSK3640254 was last quantifiable in a concentration vs 
time profile (Tlast).

observed plasma concentration at Tlast (Clast).

observed concentration at 24 hours post-dose (C24h).

area under the plasma concentration vs time curve (AUC(0-tlast) and AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point
(AUC%extrap).

oral clearance, the apparent volume of plasma cleared of GSK3640254 per unit time 
following extravascular dosing (Cl/F)

the apparent volume of distribution following extravascular dosing (Vd/F)

terminal half-life (t1/2).

Lambda-z


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
relative bioavailability (Frel) of the GSK3640254 Mesylate Salt Capsule formulation
(test) vs the GSK3640254 Capsule formulation (reference) based on AUC(0-inf) (or 
AUC(0-tlast) if AUC(0-inf) can’t be derived) and Cmax.
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI and %CVb (100 * √ (exp(SD2) -1)) will be provided, 
where the SD is the standard deviation of log-transformed data.
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoint is the comparison of the GSK3640254
Mesylate Salt Capsule formulation (test) with the GSK3640254 Capsule 
formulation (reference). 
Log transformed AUC(0-inf), (AUC(0-tlast), if AUC(0-inf) cannot be derived), 
and Cmax values for GSK3640254 will be subjected to mixed effects 
modelling, including terms for period and treatment as fixed effects and 
participant as a random effect. The point estimate and associated 90% 
confidence interval (CIs) will be constructed for the difference, test 
treatment (B) – reference treatment (A). The point estimate and 
associated 90% CI will then be back-transformed to provide a point 
estimate and 90% CI for the ratio test/reference on the original scale. 
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
The safety endpoints will be summarized descriptively, and no formal statistical 
analysis will be conducted.
The Reporting and Analysis Plan will detail the content of the safety tables, figures and 
listings to be generated. 
10.3.3.
Interim Analyses
No formal statistical analyses or interim analyses are planned.


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11.
REFERENCES
Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United 
States and dependent areas. HIV Surveillance Report, 2014; vol. 26. Available at: 
http://www.cdc.gov/hiv/library/reports/surveillance/. Published November 2015. 
Accessed 20 June 2016.
Claessens YE. Bench-to-bedside review: Severe lactic acidosis in HIV patients treated 
with nucleoside analogue reverse transcriptase inhibitors. Crit Care. 2003;7(3):226-232.
Collins S. D:A:D study shows that PIs rather than NNRTIs drive the previously reported 
cardiovascular risk of combination antiretroviral therapy. HIV Treatment Bulletin 2006; 
7(3). Available at: http://www.ibase.info/v7/htb7-3/dad.html. Accessed 12 November 
2009.
De Luca A, Dunn D, Zazzi M, et al. Declining prevalence of HIV-1 drug resistance in 
antiretroviral treatment-exposed individuals in Western Europe. JID. 2013; 207: 1216-20.
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events corrected version 2.1 July 2017.  (available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables).
GlaxoSmithKline Document Number 2016N294821_00. GSK3640254 Investigator’s 
Brochure, Version 01. Effective Date Expected: 10 May 2017.
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.
The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial 
infarction. N Engl J Med. 2007;356 (17): 1723-1735.
WHO. HIV resistance report-2012. Available at: 
http://apps.who.int/iris/bitstream/10665/75183/1/9789241503938_eng.pdf Published July 
2012. Accessed: 20 June 2016.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse Event
ALT
Alanine Aminotransferase
ARV
Antiretroviral
AUC(0-inf)
Area under the concentration-time curve from time 
zero (pre-dose) extrapolated to infinite time
AUC(0-tlast)
Area under the concentration-time curve from zero 
to time of last sample taken
BMI
Body Mass Index
C24h
Concentration at 24 hour post-dose
CA
Competent authority
CI
Confidence Interval
Cmax
Maximum observed concentration
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
DAIDS
Division of Acquired Immunodeficiency Syndrome
EC
Ethics Committee
ECG
Electrocardiogram
EMA
European Medicines Agency
Frel
Relative bioavailability
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
Gag
Group-specific Antigen
GCP
Good Clinical Practice
GI
gastrointestinal
GP
General Practitioner
HBcAb
hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
investigator site file
MAD
Multiple Ascending Dose
MI
Maturation Inhibitor
MSDS
Material Safety Data Sheet
PK
Pharmacokinetics
PI
Principal investigator
QTcF
QT interval corrected for heart rate according to 
Fridericia’s formula


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SAD
Single Ascending Dose
SAEs
Serious Adverse Events
SD
Standard Deviation
SoA
Schedule of Activities 
SUSAR
Suspected Unexpected Serious Adverse Reactions
TOPS
The Over Volunteering Prevention System
TQT
Thorough QT
ULN
Upper Limit of Normal
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
NONE 


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed at The Doctors Laboratory, with 
the exception of routine urinalysis, urine pregnancy test, urine drug screen, 
alcohol and carbon monoxide breath tests. These tests will be performed on-site.

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.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study will be repeated until the values 
return to normal or baseline. If such values do not return to normal within a 
period judged reasonable by the Investigator, the etiology will be identified and 
the sponsor notified.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
Mean Corpuscular 
Volume (MCV)
Mean Corpuscular 
Haemoglobin (MCH)
Mean Corpuscular 
Haemoglobin
Concentration (MCHC)
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin (direct 
only if total is 
elevated)
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Chloride
Bicarbonate
Routine 
Urinalysis

Specific gravity


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Laboratory 
Assessments
Parameters

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes by dipstick

Microscopic examination (if blood, leukocytes, nitrites or protein is 
abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in postmenopausal 
women only)

Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Alcohol breath test

Carbon monoxide breath test

Urine human chorionic gonadotropin (hCG) pregnancy test (for all women)

Serology (HIV 1 and 2 antibodies, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)
The results of each test must 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 6. 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.


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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 substantial amendments to the protocol will require IEC/IRB and local 
regulatory 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 SUSARs or other significant safety findings that 
occur on the study as required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Protocol Amendments

After the protocol has been submitted to the MHRA and/or EC, any amendment 
must be agreed by the investigator after discussion with the sponsor and will be 
formally documented.

All substantial amendments will be submitted to the MHRA and/or EC for an 
opinion as required by current regulations.

If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled 
participants and must be provided to additional participants prior to their entry
into the study.


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Protocol Deviations

The study must be conducted in accordance with the Clinical Protocol. Should a 
protocol deviation occur, it must be promptly assessed in order to decide 
whether any of these non-compliances will be reported to the MHRA as a 
serious breach of GCP and the Clinical Protocol.

Protocol waivers are not acceptable.

Deviations from the protocol will be recorded in the source workbook as noted 
by the clinical staff. If necessary, the sponsor will be informed of the deviation.

Any protocol deviations assessed as major will be discussed with the sponsor in 
order to determine if the withdrawal criteria stated in Section 8 have been met.
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

Participants will be provided with a written explanation of the study at least one 
day before the screening visit.

The investigator or his/her representative will explain the nature of the study, its 
purpose, expected duration and the benefits and risks involved in study 
participation to the participant and answer all questions regarding the study. 
Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that 
carry out clinical studies in the local area. 

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 local regulations, ICH 
guidelines, and the IRB/IEC. 

The CRF 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.


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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 and by inspectors from regulatory authorities.
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. 

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Following completion of the study, a clinical study report will be prepared. 

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 and will be made available to the EC/MHRA within 1 year of 
the declaration of the end of trial.
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. 


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
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
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.

A study-specific source documentation list will be finalized by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data will be considered source data for this study.
Declaration of the End of the Study

The definition of the end of the study is defined as the last visit of the last 
participant (eg follow-up assessment). Any changes to this definition will be 
notified as a substantial amendment.

The EC and MHRA will be notified in writing of the conclusion of the study 
within 90 days of the end of the study, or within 15 days if the study is 
terminated early, clearly explaining the reasons for the termination.
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.


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study 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 will be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (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 


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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 
will 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, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment will 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 


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other outcomes listed in the above definition. These events will 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 an Adverse Drug Reaction (ADR)
An ADR is defined as an untoward medical occurrence that, at any dose:

Where a causal relationship with study treatment is at least a reasonable possibility 
(possibly related or related)
Definition of a SUSAR
A SUSAR is defined as any untoward medical occurrence that, at any dose:

Is believed to be related to study treatment and is both unexpected (ie the nature or 
severity is not expected from the information provided in the Investigator’s 
Brochure) and serious. SUSARs are subject to expedited reporting to the MHRA, 
European Medicines Agency (EMA), EC (see Appendix 7)
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 (ie the 
date and time of onset, a description of the AE, severity, duration, actions taken, 
outcome and an investigator’s current opinion on the relationship between the study 
treatment and the event).

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.


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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during using the DAIDS grading table (http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf) and assign it to 1 of the 
following categories: Events):

Grade 1, Mild: no or minimal interference with usual social & functional activities.

Grade 2, Moderate: greater than minimal interference with usual social & functional 
activities.

Grade 3, 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.

Grade 4, Life Threatening: inability to perform basic self-care functions

Grade 5, Death
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.

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 GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

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 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Communication Plan.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 


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telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Communication Plan.


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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. 
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 5 when having 
penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame 


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
Refrain from donating sperm for duration of study and for 90 days after study 
completion or from last dose
Female participants
Female participants who are not of childbearing potential do not need to use any methods 
of contraception.
Female participants of childbearing potential are not eligible to participate in this study. 
Female participants will not participate in egg donation from dosing, for the duration of 
the study and for at least 28 days after the last dose of study treatment.
Table 5
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 


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Pregnancy Testing

Urine pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using 
the SureScreen Diagnostics test in accordance with instructions provided in its 
package insert at screening and admission to each study period
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal 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 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. 


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Any female participant who becomes pregnant while participating will be withdrawn 
from the study.


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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 2 days of 
last dose4 

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 paracetamol/acetaminophen, 
herbal remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:


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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

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 computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation will be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
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
References
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.


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12.7.
Appendix 7: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of a study treatment or that 
would be sufficient to consider changes in the study treatments administration or in the 
overall conduct of the study, for instance:

an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

new events related to the conduct of the study or the development of the study 
treatments and likely to affect the safety of the participants, such as:
−
an SAE which could be associated with the study procedures and which could 
modify the conduct of the study
−
a major safety finding from a newly completed animal study (such as 
carcinogenicity)
−
any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same study treatments in another country by the same 
sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures will be followed.
Fatal or life-threatening SUSARs
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility will be delegated to the 
pharmacovigilance provider, GSK/ViiV.
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.


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Any additional relevant information will be sent within 8 days of the report.
Other SUSARs
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility will be delegated to the pharmacovigilance provider, 
GSK/ViiV.
The investigator is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.
Any additional relevant information will be sent within 8 days of the report.
Urgent Safety Measures
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Sciences may take urgent safety measures before 
informing the sponsor, but the sponsor must be informed immediately after the hazard 
has resolved. 
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC.
Reporting of Urgent Safety Issues
Quotient Sciences is required to inform the appropriate competent authorities and the EC 
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.


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TITLE PAGE
Protocol Title: 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
Protocol Number: 208131 (QCL118221) / 01
Short Title: A study to compare the relative bioavailability of two different formulations 
of GSK3640254
Compound Number:
GSK3640254
Sponsor Name and Legal Registered Address: 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information:
 DO, MPH
(USA)
Regulatory Agency Identifying Number(s): EudraCT Number 2018-001175-21
Approval Date: 29-MAY-2018
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
29-MAY-2018
Original Protocol
13-APR-2018
Amendment 1 29-May-2018
Overall Rationale for the Amendment: The purpose of Amendment 1 is: 1) to further 
enhance neuropsychiatric safety monitoring by assessing subjects using the Columbia 
Suicide Severity Rating Scale during the study and at the end of the study, and 2) to align 
recommendations on Male contraception and sperm donation with the ongoing First Time 
in Human (FTIH) clinical trial (207187).


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Section # and 
Name
Description of Change
Brief Rationale
Section 2, 
Schedule of 
Activities
Subjects will be evaluated 
using the Columbia Suicide 
Severity Rating Scale (CSSRS) 
on Day 3 (of both Period 1 and 
2)
More frequent monitoring further 
enhances subject monitoring of 
neuropsychiatric AEs (e.g. 
suicidality) during the trial and at the 
end of the trial.
Section 3.3.1. 
Risk 
Assessment
Participants will be assessed 
for CSSRS during study and at 
end of study as additional 
mitigation of the 
neurologic/psychiatric safety 
risk.
This change further enhances the 
evaluation and management of 
neuropsychiatric AEs (e.g. 
suicidality).
Section 6.1, 
Inclusion 
Criteria
Male subjects must agree to 
use contraception as detailed in 
Appendix 5 during the 
treatment period and for at 
least 14 weeks following the 
last dose. In addition, male 
participants must refrain from 
donating sperm during this 
period.
This change aligns recommendations 
on Male contraception and sperm 
donation with the ongoing FTIH 
clinical trial (207187)
Section 8.1, 
Discontinuation 
of Study 
Treatment
A subject will be withdrawn 
from the trial for the 
emergence of any positive 
(abnormal) response confirmed 
by the investigator on a 
clinician (or qualified 
designee) administered CSSRS 
on Day 3 (Period 1 or 2)
This change further enhances 
management of treatment emergent 
neuropsychiatric AEs (e.g. 
suicidality) during the trial and at the 
end of the trial.
Section 9.4.5, 
Suicidal Risk 
Monitoring
A positive (abnormal) response 
to the CSSRS confirmed by the 
investigator will result in the 
PI/SI arranging for urgent 
specialist psychiatric 
evaluation and management.
This change further enhances the 
evaluation and management of 
neuropsychiatric AEs (e.g. 
suicidality).
Appendix 5, 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Male subjects must refrain 
from donating sperm for 
duration of study and for 14 
weeks after study completion 
or from last dose.
This change aligns recommendations 
on Male contraception and sperm 
donation with the ongoing FTIH 
clinical trial (207187)


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................14
3.3.1.
Risk Assessment .........................................................................16
3.3.2.
Benefit Assessment.....................................................................19
3.3.3.
Overall Benefit:Risk Conclusion...................................................19
4.
OBJECTIVES AND ENDPOINTS...........................................................................19
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ................................................................21
5.3.
Participant and Study Completion...............................................................21
5.4.
Scientific Rationale for Study Design ..........................................................21
5.5.
Dose Justification........................................................................................22
6.
STUDY POPULATION...........................................................................................22
6.1.
Inclusion Criteria.........................................................................................23
6.2.
Exclusion Criteria........................................................................................23
6.3.
Lifestyle Restrictions...................................................................................26
6.3.1.
Meals and Dietary Restrictions ....................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................26
6.3.3.
Activity .........................................................................................27
6.4.
Screen Failures...........................................................................................27
7.
TREATMENTS.......................................................................................................27
7.1.
Treatments Administered............................................................................28
7.2.
Dose Modification .......................................................................................28
7.3.
Method of Treatment Assignment ...............................................................28
7.4.
Blinding.......................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability..............................................29
7.6.
Treatment Compliance................................................................................30
7.7.
Concomitant Therapy..................................................................................30
7.8.
Treatment after the End of the Study ..........................................................30
8.
DISCONTINUATION CRITERIA.............................................................................30
8.1.
Discontinuation of Study Treatment ............................................................30
8.1.1.
Liver Chemistry Stopping Criteria ................................................31
8.1.2.
QTc Stopping Criteria ..................................................................32
8.1.3.
Individual Safety Stopping Criteria ...............................................32
8.1.4.
Temporary Discontinuation ..........................................................33
8.1.5.
Rechallenge.................................................................................33


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8.1.5.1.
Study Treatment Restart or Rechallenge....................33
8.2.
Withdrawal from the Study..........................................................................33
8.3.
Lost to Follow Up........................................................................................34
8.4.
Study Stopping Criteria...............................................................................34
8.5.
Study Termination.......................................................................................35
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
9.1.
Efficacy Assessments.................................................................................36
9.2.
Adverse Events...........................................................................................36
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................36
9.2.2.
Method of Detecting AEs and SAEs.............................................37
9.2.3.
Follow-up of AEs and SAEs.........................................................37
9.2.4.
Regulatory Reporting Requirements for SAEs .............................37
9.2.5.
Pregnancy ...................................................................................38
9.3.
Treatment of Overdose...............................................................................38
9.4.
Safety Assessments ...................................................................................38
9.4.1.
Physical Examinations.................................................................38
9.4.2.
Vital Signs....................................................................................39
9.4.3.
Electrocardiograms......................................................................39
9.4.4.
Clinical Safety Laboratory Assessments ......................................40
9.4.5.
Suicidal Risk Monitoring...............................................................41
9.5.
Pharmacokinetics .......................................................................................41
9.6.
Pharmacodynamics ....................................................................................42
9.7.
Genetics .....................................................................................................42
9.8.
Biomarkers .................................................................................................42
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................42
10. STATISTICAL CONSIDERATIONS........................................................................42
10.1.
Sample Size Determination ........................................................................42
10.2.
Populations for Analyses ............................................................................43
10.3.
Statistical Analyses.....................................................................................43
10.3.1.
Pharmacokinetic Analyses...........................................................43
10.3.2.
Safety Analyses...........................................................................44
10.3.3.
Interim Analyses ..........................................................................44
11. REFERENCES.......................................................................................................45
12. APPENDICES........................................................................................................46
12.1.
Appendix 1: Abbreviations and Trademarks................................................46
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................48
12.3.
Appendix 3: Study Governance Considerations..........................................50
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................55
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................61
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................65
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................67
12.8.
Appendix 8: Protocol Amendment History...................................................69


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1.
SYNOPSIS
Protocol Title: 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 bis-
hydrochloride salt capsule in healthy participants
Short Title: A study to compare the relative bioavailability of two different formulations 
of GSK3640254
Rationale: A First Time in Human (FTIH) study is in progress and has used the bis-
hydrochloride salt immediate release capsule formulation of GSK3640254 administered 
following a moderate calorie and fat meal. However, the bis-hydrochloride salt 
formulation is not suitable for long term clinical development as it is susceptible to 
humidity. A mesylate salt capsule formulation of GSK3640254 has been generated for 
later phase development and commercialization. The aim of this relative bioavailability 
study is to compare the exposure of the mesylate salt capsule formulation of 
GSK3640254 (mentioned as GSK3640254 Mesylate Salt Capsule in regimens) with that 
of the bis-hydrochloride salt capsule formulation (mentioned as GSK3640254 Capsule in 
regimens) administered following a moderate calorie and fat meal.
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the pharmacokinetic (PK)
profiles of GSK3640254 following 
administration of the mesylate salt
capsule relative to that of the bis-
hydrochloride salt capsule (reference) in 
healthy participants

GSK3640254 area under the curve from 
time zero to infinity (AUC(0-∞)), AUC(0-tlast),  
maximum observed concentration (Cmax), 
Time to Cmax (Tmax), Concentration at 24 
hours post-dose (C24h), relative 
bioavailability (Frel) based on AUC and 
Cmax
Secondary

To provide additional information of the 
safety and tolerability of single doses of 
GSK3640254 in healthy participants

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and/or other safety biomarkers
Overall Design:
This is a Phase 1 study and will be conducted at a single centre. This study will include 
2 treatment periods, during which each of the open-label treatments will be administered 
to each of the 2 treatment groups. It is planned to enroll 14 healthy participants.


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Number of Participants:
Fourteen participants will be enrolled such that sufficient data will be available for at 
least 12 evaluable participants. An evaluable participant is a participant who has received 
both Regimens A and B, and has safety and PK data up to 72 hours post-dose.
Up to 7 replacement participants may be enrolled. The maximum number of participants 
that may be dosed is 21.
Treatment Groups and Duration:
Participants will receive a single oral dose of each study treatment (Regimens A and B) 
during each of the 2 inpatient periods, in a sequence of administration to be assigned via
the randomization: AB or BA.

Treatment Group AB: Regimen A is administered in Period 1, Regimen B is 
administered in Period 2.

Treatment Group BA: Regimen B is administered in Period 1, Regimen A is 
administered in Period 2.
Regimens:

Regimen A: An oral dose of 200 mg as 2 x 100 mg GSK3640254 Capsule, 100 mg
(reference) following g a moderate fat meal.

Regimen B: An oral dose of 200 mg as 2 x 100 mg GSK3640254 Mesylate Salt 
Capsule, 100 mg (test) following a moderate fat meal.
Participants will receive the formulations in the morning after a moderate-fat breakfast 
(approximately 600 calories with approximately 30% of the calories from fat).
Each participant will be enrolled in the study for approximately 7 weeks, dependent on 
screening and washout duration between periods. Participation will include a screening 
evaluation within 28 days of first study treatment administration and 2 separate inpatient 
periods. Participants will be admitted to the clinic in the morning of the day before dosing 
(i.e. Day -1) for Periods 1 and 2, and in the evening of Day -1 for Period 2. Each inpatient 
period will consist of 4 days (Period 1, morning admission on Day -1) or 3 days (Period 
2, evening admission on Day -1) and 3 nights followed by a return visit 72 hours post-
dose.
There will be a minimum washout of 7 days between each dose of study treatment.
A follow-up visit will occur 7 to 10 days after the last dose of study treatment.


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2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities are presented in Table 1. The time points for the PK blood 
sample collection, and ECG and vital sign assessments are presented in Table 2.
The competent authority (CA) and ethics committee (EC) will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will 
be approved by the CA and the EC before implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances, the following will apply to post-dose time points:
The order of assessments will be:
ECGs
Vital 
signs
PK blood 
sampling
(nominal 
time)
Other assessments 
eg physical exams
Electrocardiograms will be taken prior to vital signs when both measurements are 
scheduled at the same time point. Other assessments, e.g. physical examinations etc, will 
be performed within the required time windows. All safety assessments will be timed and 
performed relative to the start of dosing.


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Table 1
Schedule of Activities
Procedure
Screening 
(up to 28 days 
before Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days post last 
dose) or Early 
Discontinuation 
Notes
–1
1
2
3
4
Outpatient visit
X
X
X
Inpatient stay
X1
X
X
X2
1.
Admission in the morning
2.
Furlough from unit after 
assessments
Informed consent
X
Inclusion and exclusion criteria
X
X3
3.
Recheck clinical status at 
admission of Period 1
Demography
X
Full physical examination including height 
and weight4
X
4.
See Section 9.4.1 for systems to 
be examined
Columbia Suicide Severity Rating Scale 
(CSSRS)
X
X
Brief physical examination
X5
X5
X
5.
Pre-dose and 48 h post-dose
See Section 9.4.1 for systems to 
be examined
Medical history (includes substance 
usage)6
X
6.
Substances: Drugs, alcohol, 
tobacco and caffeine
Urine pregnancy test7
X
X
X
7.
All female participants
Follicle stimulating hormone (FSH)8
X
8.
As needed in women to confirm 
postmenopausal status
HIV, Hepatitis B and C screening
X
Urine drug screen
X
X


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Procedure
Screening 
(up to 28 days 
before Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days post last 
dose) or Early 
Discontinuation 
Notes
–1
1
2
3
4
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments (haematology, 
clinical chemistry and urinalysis)
X
X9
X9
X
9.
48 h post-dose
Allowable windows in Section 9.4.4
12-lead ECG
X
X
X10
X10
X10
X
10. Time points in Table 2
Allowable windows in Section 9.4.3
Vital signs
X
X
X11
X11
X11
X
11. Time points in Table 2
Allowable windows in Section 9.4.2
Randomization
X12
12. Pre-dose Period 1 only
Study treatment
X
AE review
X
===========================
X
SAE review
X
X
===========================
X
Concomitant medication review
X
===========================
X
PK blood sample collection13
===========================
13. Time points in Table 2


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Table 2
Pharmacokinetic Blood Sampling Collection, ECG ad Vital Sign Times
Treatment Periods 1 and 2
Time (h)
Pre-dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
36
48
72
Dosing 
X
PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-
lead ECG
(repeat 
allowed)
X
X
X
X
X
X
Single set of 
Vital signs
X
X
X
X
X
X


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3.
INTRODUCTION
GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI); this novel class of 
anti-human immunodeficiency virus (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. 
3.1.
Study Rationale
A First Time in Human (FTIH) study is in progress and has used the bis-hydrochloride 
salt immediate release capsule formulation of GSK3640254 administered following a 
moderate calorie and fat meal. However, the bis-hydrochloride salt formulation is not 
suitable for long term clinical development as it is susceptible to humidity. A mesylate 
salt capsule formulation of GSK3640254 has been identified for later phase development
and commercialization. The aim of this relative bioavailability study is to compare the 
exposure of the mesylate salt capsule formulation of GSK3640254 with that of the bis-
hydrochloride salt capsule formulation administered following a moderate calorie and fat 
meal.
3.2.
Background
Current therapy for HIV-infected individuals consists of a combination of approved 
antiretroviral (ARV) agents. More than twenty medicines are currently approved for 
HIV-1 infection, either as single agents, fixed-dose combinations or single-tablet 
regimens, the latter two containing 2 to 4 approved agents. Given the challenges inherent 
with the lifetime dosing of daily medications, there remains a need for new ARV agents 
that combine an optimal safety, tolerability and efficacy profile with a convenient dosing 
schedule. Significant toxicities have been described with each ARV agent in current use, 
and data continue to accumulate on the long-term clinical consequences of chronic ARV 
therapy [Centers for Disease Control and Prevention, 2015; Claessens, 2003; Collins, 
2006; The DAD Study Group, 2007]. New ARV agents that offer an improved 
tolerability and safety profile are needed.
Despite the availability of different classes of ARV agents providing a variety of 
treatment options, treatment failure continues to occur as a result of high transmitted drug 
resistance, drug-associated toxicity and tolerability problems, and poor adherence to 
medication regimens. Although prevalence rates of drug resistance are falling in Western 
Europe, ~80% of HIV-infected patients who have received ARV therapy have resistance 
to at least one class of ARV [De Luca, 2013]. Additionally, the prevalence of transmitted 
resistance to at least one ARV is ~10-17% in resource-rich regions, such as Europe 
[WHO, 2012]. Unfortunately, resistance mutations selected by one ARV agent often 
confer resistance to multiple drugs in the same class, significantly limiting future 
therapeutic options. Later regimens often lack the convenience and tolerability of firstline 
drugs, which in turn exacerbates non-adherence. Thus, there is a continuing need for new 
classes of ARV drugs capable of providing potent, durable antiviral activity to a broad 
population of HIV-infected patients, with no cross-resistance to current agents, a 
relatively high barrier to the development of resistance on its own, and activity across 
diverse HIV-1 subtypes.


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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 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 HIV capsid protein p24 and spacer peptide 1. Blockage at 
this step results in the release of immature non-infectious virus particles. GSK3640254 
has excellent potency and a broad pangenotypic spectrum in vitro. Laboratory studies 
confirm that GSK3640254 is an MI with a mechanism of action distinct from current 
ARVs, suggesting little if any risk of cross-resistance to current therapeutic agents.
As of 4 April 2018, the First Time in Human (FTIH) study is ongoing. It includes: 1) a 
single ascending dose (SAD) portion with doses of 1 mg to 700 mg (completed) and 2) a 
14-day multiple ascending dose (MAD) portion (ongoing with 50 mg and 100 mg QD 
cohorts completed). The pharmacokinetics of GSK3640254 administered as a single dose 
following a moderate calorie/fat breakfast is characterized by a slow absorption with 
maximum concentration observed on average 3 to 4 hours after dosing. GSK3640254 is 
also slowly eliminated with an average half-life around 23 hours. Cmax and AUC tended 
to increase in a dose proportional manner from 1 mg to 400 mg with a less than dose 
proportional increase from 400 mg to 700 mg. 
To support future toxicology studies to be conducted with the mesylate salt, single dose 
PK studies were conducted in male rats (doses of 10, 30 and 100 mg/kg) and male dogs 
(0.2, 1 and 5 mg/kg) with the mesylate salt. PK data were compared back to other PK 
studies conducted with the bis-hydrochloride salt. While the mesylate salt provided 
similar exposure as the bis-hydrochloride salt in dogs, the mesylate salt provided 
approximately a 75% increase in Cmax and AUC at the dose of 10 mg/kg with a smaller 
improvement of around 30% at the dose of 100 mg/kg in rats.    
A detailed description of the chemistry, and the nonclinical pharmacology, 
pharmacokinetic and toxicology studies of GSK3640254 is provided in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2016N294821_00].
3.3.
Benefit/Risk Assessment
GSK3640254 is currently being studied in a Phase 1 SAD/MAD clinical trial in healthy 
participants to evaluate the safety, tolerability, and PK. The SAD portion of the study 
evaluating single doses ranging from 1 to 700 mg has been completed with preliminary 
data showing no major clinical safety or tolerability finding.
Until additional clinical safety information for GSK3640254 is available, precautions will 
be taken that are based on non-clinical safety assessment of GSK3640254 and reported 
clinical experiences of a previous, structurally similar maturation inhibitor
(GSK3532795), in healthy and HIV-1 infected participants. Specifically, this previous 
maturation inhibitor (GSK3532795) was not progressed beyond Phase 2b clinical trials 
because of Grade 1-2 gastrointestinal intolerability (diarrhoea, abdominal pain) and 
treatment emergent resistance to study medications. In addition, two serious adverse 
events (SAEs; acute psychosis and suicidal/homicidal ideation) led to the early 


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termination of a Phase 1 Thorough QT (TQT) study in healthy participants at 
supratherapeutic doses.
Nonclinical findings with GSK3640254 have indicated the following potential risks for 
the clinical program: gastrointestinal (GI) intolerability/microscopic GI changes, cardiac 
conduction abnormalities (prolonged QT interval), hepatic injury (single cell necrosis), 
and renal changes (eosinophilic intracytoplasmatic inclusion bodies).
Until further preclinical studies on the effects of GSK3640254 on the reproductive 
system are available, it will be assumed that GSK3640254 has the potential to impair 
male and female fertility.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3640254 may be found in the Investigator’s 
Brochure.
ViiV Healthcare 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 FTIH clinical trials with 
investigational medicinal products (EMEA/CHMP/SWP/28367/07). 


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3.3.1.
Risk Assessment
Potential risks of the IP (GSK3640254) are detailed below
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3640254
GI intolerability/toxicity
Non-clinical data:
In a 14-day dose-range-finding study in rats, a 
non-tolerated dose of 300 mg/kg/day produced 
GI clinical signs and microscopic changes in the 
stomach and small intestine that were not seen 
at lower doses. These included minimal 
ulceration in the glandular stomach, minimal to 
moderate enterocyte vacuolation (lipid) in the 
duodenum, and minimal epithelial hyperplasia in 
the jejunum.
At tolerated doses, GI clinical signs occurred in 
rats (unformed faeces) at 100 mg/kg/day and 
dogs (sporadic vomiting and unformed, liquid or
mucoid faeces) at ≥1 mg/kg/day.
At tolerated doses, reversible dose-responsive 
microscopic changes were observed in the
stomachs of rats and dogs.
Participant selection:

Participants with a clinically significant
history of or current GI disorders will not be 
eligible to participate in this study
Participant monitoring:

Participants will be monitored for GI-related 
AEs
Cardiac conduction abnormalities (prolonged QT 
interval)
Non-clinical data:
GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and L-type 
calcium channel currents with moderate potency. 
ECG changes attributed to GSK3640254 in 
telemeterized dogs at doses of 12.5 and 17 
Participant selection:

Participants with a history of or current 
cardiovascular disorders will not be eligible 
to participate in this study

Participants with a QT interval corrected for 
heart rate according to Fridericia’s formula


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
mg/kg consisted of increased rate-corrected QT 
interval from 3.5 to 6 hours post-dose (~ 9 msec) 
and during the overnight period (~ 6 msec). 
These QT effects were primarily limited to one 
dog given 17 mg/kg (≤20 msec increase), with a 
plasma concentration of 7.96 µg/mL 8 hours 
after dosing. 
The no observed adverse effect level (NOAEL) in 
the study was 12.5 mg/kg, which produced 
similar systemic exposures (8.79 µg/mL 5 hours 
after dose).
There were no GSK3640254-related effects on 
ECG parameters evaluated in the definitive 
general toxicity study in conscious restrained 
dogs given multiple doses of up to 25 mg/kg/day 
for 4 weeks.
(QTcF) >450 msec at screening will not be 
eligible for this study
Participant monitoring:

Participants will be monitored for cardiac-
related AEs

ECGs will be monitored throughout the study
Neurologic/psychiatric safety
Clinical data:
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 Grade 1 headache and 
Grade 1 sleep abnormalities were the 
predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing 
dose (based on TQT and P2b studies). No 
exposure-response relationship was seen for 
Participant selection:

Participants with a history of psychiatric 
disease requiring pharmacologic treatment in 
the last 5 years, any history of suicidal 
ideation (ever) or any clinically significant 
psychiatric history per investigator 
judgement will be excluded from the study

Protocol exclusion criterion and monitoring 
(during study and end of study) using 
assessment by the CSSRS. In the event of a 
positive (abnormal) response confirmed by 
the investigator, the participant will 
discontinue from the trial and the PI/Sub-


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
select neurologic and psychiatric AEs (based on 
TQT and P2b studies) 
Non-Clinical Data
CNS penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low 
brain distribution/penetration 
Investigator will arrange for urgent specialist 
psychiatric evaluation and management. 

Participants will undergo physical exams and 
continuous evaluation for adverse events 
during their participation in the trial.
Potential risks of study procedures are detailed below
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Cannulation 
During cannulation more than one attempt may 
be needed to insert the cannula in a vein of a 
participant and it is possible that bruising and/or 
inflammation may be experienced at the site of 
cannulation.

A vein assessment will be conducted at 
screening to ensure only volunteers with 
veins suitable for multiple venepuncture and 
cannulation are enrolled.

Cannulation and venepuncture will only be 
performed by staff who are trained in these 
procedures
Electrocardiograms
Electrocardiogram stickers on the participants’ 
chests and limbs may cause some local irritation 
and may be uncomfortable to remove.

Participants will be closely monitored to 
ensure any local irritation does not persist.

2.5% hydrocortisone cream will be included 
in the list of permitted medication to relieve 
irritation from ECG leads.


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3.3.2.
Benefit Assessment
There is no intended direct health benefit to the participants in this study. 
3.3.3.
Overall Benefit:Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the emerging clinical profile of GSK3640254 in the FTIH study, and 
the planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 are low, evaluable, and manageable.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the PK profiles of GSK3640254 
following administration of the mesylate salt 
capsule relative to that of the bis-
hydrochloride salt capsule (reference) in 
healthy participants

GSK3640254 area under the curve from 
time zero to infinity (AUC(0-∞)), AUC(0-tlast), 
maximum observed concentration (Cmax), 
Time to Cmax (Tmax), Concentration at 24 
hours post-dose (C24h), relative 
bioavailability (Frel) based on AUC and 
Cmax
Secondary

To provide additional information of the 
safety and tolerability of single doses of 
GSK3640254 in healthy participants

AEs, clinical laboratory values, vital signs, 
ECGs, and/or other safety biomarkers
5.
STUDY DESIGN
5.1.
Overall Design
This is a single centre, 2-period, randomized, open-label Phase 1 study. It is planned to
enroll 14 healthy participants. It is planned to study 2 regimens (A and B) during 
2 periods (1 and 2).
The following regimens will be administered during each period in the study:

Regimen A: An oral dose of 200 mg as 2 x GSK3640254 Capsule, 100 mg
(reference) following a moderate fat meal. 

Regimen B: An oral dose of 200 mg as 2 x GSK3640254 Mesylate Salt Capsule, 
100 mg (test) following a moderate fat meal.
Each participant will receive each of the regimens (Regimens A and B) in a sequence 
during Period 1 and Period 2 as determined by the randomization:


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
Randomized to AB: Regimen A administered in Period 1, followed by Regimen B 
in Period 2

Randomized to BA: Regimen B administered in Period 1, followed by Regimen A 
in Period 2
Participants will receive a single oral dose of study treatment during each inpatient 
period. Participants will receive the formulations in the morning after a moderate-fat 
breakfast (approximately 600 calories with approximately 30% of the calories from fat).
Study Outline:
Period 1: Participants will be admitted to the clinical unit on the morning of the day 
before study treatment administration (Day -1) for Period 1. Participants will receive a 
single oral dose of the assigned study treatment regimen on Day 1 and will remain on site 
until 48 hours post-dose, and then return to the clinical unit for a 72 hours PK sample, 
vital signs and ECGs. 
There will be a minimum washout of 7 days between each dose of study treatment. 
Period 2: Participants will be admitted to the clinical unit on the morning of the day 
before study treatment administration (Day -1) for Period 2. Participants will receive a 
single oral dose of the assigned study treatment regimen on Day 1 and will remain on site 
until 48 hours post-dose, and then return to the clinical unit for a 72 hours PK sample, 
vital signs and ECGs. 
Follow up: A Follow-up visit will be conducted 7 to10 days after the last dose of study 
treatment.
The estimated maximum duration of the study from screening until follow-up for each 
participant is approximately 7 weeks.
Figure 1
Study Design
Treatment 
Sequence
Period 1:
Period 2:
Follow-up 
visit
AB
(N = 7)
Regimen A
200 mg as 2 x 
GSK3640254 Capsule, 
100 mg (reference)
fed (moderate fat meal)
Regimen B
200 mg as 2 x 
GSK3640254 Mesylate 
Salt Capsule, 100 mg (test)
fed (moderate fat meal)
7 to 10 
days after 
last dose
BA
(N = 7)
Regimen B
200 mg as 2 x 
GSK3640254 Mesylate 
Salt Capsule, 100 mg
(test)
fed (moderate fat meal)
Regimen A
200 mg as 2 x
GSK3640254 Capsule, 
100 mg (reference) fed 
(moderate fat meal)


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5.2.
Number of Participants
Fourteen participants will be enrolled such that sufficient data will be available for
at least 12 evaluable participants. An evaluable participant is a participant who has 
received both Regimens A and B, and has safety and PK data up to 72 hours post-dose.
Up to 7 replacement participants may be enrolled. The maximum number of participants 
that may be dosed is 21.
Participants withdrawn by the investigator due to a moderate AE at least possibly related 
to study treatment will not be replaced. If participants prematurely discontinue the study 
for other reasons, additional replacement participants may be recruited at the discretion of 
the Sponsor in consultation with the investigator. Replacement participants are 
individuals who have met inclusion into the study but have not been dosed at the 
discretion of the PI.
Replacement participants will receive both Regimens A and B, and will receive them in 
the same order as planned for the original participant and the minimum washout period of 
7 days between dosing will be respected.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the last scheduled procedure shown in the SoA (i.e. the 
follow-up visit).
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
The current bis-hydrochloride salt capsule formulation of GSK3640254 that has been 
used in the FTIH study is not suitable for long term development due to its susceptibility 
to humidity; therefore, a mesylate salt capsule formulation has been generated for future 
development. This is a bridging study to assess the relative bioavailability of the mesylate 
salt capsule formulation compared with the bis-hydrochloride salt capsule formulation. 
All doses of GSK3640254 in this study will be administered in the fed state, with dosing 
occurring within 5 minutes of completing a moderate calorie/fat meal, similar to the 
FTIH study and the future proof of concept study planned in HIV-infected participants. 
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, 
administration of GSK3640254 with food is expected to enhance its bioavailability. The 
impact of food on exposures to GSK3640254 will be assessed in a future Phase 1 study in 
healthy participants during clinical development.


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A 2-period, 2-sequence crossover design has been selected as recommended by the 
European Medicines Agency (EMA) guidance on bioavailability and bioequivalence 
studies. In addition, participants will be randomized to treatment sequence to avoid any 
potential period effects. The study is open-label as the primary objective is to assess the 
PK and there are no concerns about introducing bias. The washout period of at least 
7 days between each dose of study treatment is considered sufficient to avoid any 
carryover effect between treatment periods, based on the average preliminary half-life of 
GSK3640254 of 23 hours observed in the first time in human study.
As this is a Phase 1 study, the most relevant population is healthy participants which 
allows characterisation of safety, tolerability and PK in a homogenous population without 
potential biases from a patient population. The EMA recommends including participants 
aged 18 years and older with normal weight, who are non-smokers, without a history of 
alcohol or drug abuse. The latter criteria are proposed to avoid interaction on drug 
metabolism and to avoid non-compliance. Therefore, this study will enroll healthy male 
and female participants aged between 18 to 55 years of age.
The study treatment has been shown in vitro to bind progesterone receptor, and only 
preliminary animal reproductive studies have been conducted; therefore, only women of 
nonchildbearing potential will be eligible for inclusion in this study. 
5.5.
Dose Justification
To date, single oral doses of 1, 3, 10, 30, 100, 200, 400 and 700 mg have been 
administered to healthy participants in the fed state. Preliminary data show these dose 
levels have been well tolerated with no SAEs reported. The majority of AEs reported 
were mild in severity and unrelated to study treatment. 
Emerging PK data suggest that the anticipated effective daily dose range is between 
80 mg and 360 mg based on the bis-hydrochloride salt capsule data. Based on an 
improved solubility of the mesylate salt formulation in simulated gastric fluid and the 
emerging animal PK data with the mesylate salt, it is possible that the extent of 
absorption of the mesylate salt formulation could be up to 2-fold higher than the bis-
hydrochloride salt formulation. 
Therefore, taking all of these factors into consideration, single oral doses of 200 mg have 
been selected for this study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Quotient Sciences must have a full medical history from each participant’s general 
practitioner (GP) within the last 12 months, prior to enrollment in the study. 
Participants will be recruited from the Quotient Sciences panel or by direct advertising to 
the public. 


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Before participants are admitted to the clinic, The Over Volunteering Prevention System 
(TOPS) will be checked to ensure that each participant has not participated in a study at 
another site within at least 3 months of the dosing date.
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 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ≥50 kg for men and ≥ 45 kg for women, and body mass index (BMI) 
within the range 19.0 to 32.0 kg/m2 (inclusive).
Sex
4.
Male or female 
a. Male participants:
b. A male participant must agree to use contraception as detailed in 12.5 of this 
protocol during the treatment period and for at least 14 weeks following the last 
dose, corresponding to the time needed to eliminate study treatment for potential 
genotoxic and teratogenic study treatments plus an additional 90 days 
(spermatogenesis cycle). In addition, male participants must refrain from 
donating sperm during this period.Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Appendix 5
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
Inclusion criteria 2 will also be assessed at admission/pre-dose.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:


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Medical Conditions
1.
History of or current cardiovascular, respiratory, hepatic, renal, GI, endocrine, 
haematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the 
study treatment; or interfering with the interpretation of data.
2.
History of clinically significant psychiatric disorders as judged by the investigator.  
Psychiatric disorder requiring pharmacologic treatment in the last 5 years.
3.
Any positive (abnormal) response confirmed by the investigator on a screening 
clinician (or qualified designee) administered CSSRS.
4.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
5.
History of GI surgery (with exception of appendectomy).
6.
History of Cholecystectomy
7.
Any history of GI ulceration (oesophageal, stomach, duodenal).
8.
Any history of GI symptoms requiring treatment in the last 3 months.
9.
History of unexplained vaginal bleeding, endometrial hyperplasia with atypia or 
endometrial carcinoma.
10. Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator. Hayfever is allowed unless it is active.
11. ALT >1.5x ULN.
12. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).
13. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome).
14. Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome. 
15. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 or >100 bpm
<50 or >100 bpm
PR interval
<120 or >220 msec
QRS duration
<70 or >120 msec
QTcF interval
>450 msec
Note: A heart rate from 100 to 110 bpm can be re-checked by ECG or vital signs within 30 minutes to verify 
eligibility.
16.
Evidence of previous myocardial infarction (does not include ST segment changes 
associated with re-polarization). 


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17. Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome). 
18. Sinus Pauses >3 seconds. 
19. Any significant arrhythmia which, in the opinion of the Investigator OR GSK/ViiV 
Medical Monitor, will interfere with the safety for the individual participant. 
20. Non-sustained or sustained ventricular tachycardia (³3 consecutive ventricular 
ectopic beats). 
Prior/Concomitant Therapy
21. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) prior to dosing 
(paracetamol/acetaminophen [up to 2 g per day] and 2.5% Hydrocortisone [for 
ECG lead contact dermatitis] is permitted any time during the study).
Prior/Concurrent Clinical Study Experience
22. Participation in the study would result in loss of blood or blood products in excess 
of 500 mL within a 56 day period; therefore donation or loss of greater than 400 
mL of blood within the previous 3 months.
23. Current enrollment or past participation within the last 3 months before signing of 
consent in this or any other clinical study involving an investigational study
treatment or any other type of medical research.
24. Participants who have previously been enrolled in this study. 
Diagnostic assessments
25. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis 
C antibody test result at screening or within 3 months prior to first dose. 
26. Confirmed positive pre-study drug/alcohol screen.
27. Positive HIV antibody test.
28. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
5 years.
Other Exclusions
29. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >21 units for males or >14 units for females. One unit is 
equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer or 1 (25 mL) measure of 
spirits. One glass (125 mL) of wine is equivalent to 1.5 to 2 units, depending on 
type)
30. Current use or history of regular use of tobacco- or nicotine-containing products 
within 6 months prior to screening. A confirmed carbon monoxide breath test 
reading of greater than 10 ppm.


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31. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
32. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
33. Participants who do not have the ability to swallow size 00 capsules.
34. Participants who are study site employees, or immediate family members of a study 
site or sponsor employee.
Exclusion criteria 1, 11, 12, 15, 17, 18, 19, 20, 21, and 26, from the list above will be re-
assessed at admission/pre-dose Period 1.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from Seville 
oranges and grapefruit derivatives for 24 hours before admission to each study 
period until after collection of the final PK sample in that period.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK 
sample in that period.

Participants will be required to fast for at least 8 hours prior to dosing on Day 1 of 
each period. On the morning of Day 1, participants will be provided with a moderate 
calorie/fat breakfast. The breakfast will be consumed over a maximum period of 
25 min, with dosing occurring approximately 30 min after the start of breakfast. 
Participants will be encouraged to eat their meal evenly over the 25 min period. It is
acknowledged that some participants will take less time to eat, but dosing will still 
occur approximately 30 min after the start of breakfast. Lunch will be provided 
approximately 4 hours after dosing, an evening meal will be provided approximately 
10 hours after dosing and an evening snack will be provided approximately 14 hours 
after dosing. Participants will consume at least 80% of the breakfast in order to be 
eligible for dosing in each period. The start and stop time of the meal will be 
recorded in the source documents and where less than 100% of the meal has been 
consumed, the percentage consumed will be recorded in the source documents.

Other than liquid provided with breakfast and dosing, participants will refrain from 
drinking for 1 hour prior to dosing until 1 hour after dosing.

Water will be allowed ad libitum from 1 hour post-dose. Decaffeinated fluid will be 
allowed from 4 hours post-dose.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for
24 hours before admission until after collection of the final PK sample in that period.


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
Participants will abstain from alcohol for 24 hours before screening. During each 
dosing session, participants will abstain from alcohol from 24 hours before 
admission until after collection of the final PK sample in that period. 

Current smokers or users of other tobacco products will not be enrolled in this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before screening and 
then from 72 hours before admission until discharge from the study. Participants may 
participate in light recreational activities during studies (eg, watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the investigator if the reasons for the screening 
failure are expected to be temporary. Rescreened participants will be assigned a new 
screening number and will be re-consented.
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
Regimen
A
B
Study Treatment 
Name:
GSK3640254 Capsule, 100 mg
GSK3640254 Mesylate Salt 
Capsule, 100 mg
Dosage formulation:
Bis-Hydrochloride salt formulation 
capsule
Mesylate salt formulation
capsule
Unit dose 
strength(s)/Dosage 
level(s):
100 mg / 200 mg
100 mg / 200 mg
Route of 
Administration 
Oral
Oral
Dosing instructions:
2 capsules, on the morning of 
Day 1 following a moderate fat 
meal. Capsules will be 
administered with 240 mL water.
2 capsules, on the morning of 
Day 1 following a moderate fat 
meal. Capsules will be 
administered with 240 mL water.
Packaging and 
Labelling
Study Treatment will be provided in HDPE containers with 
polypropylene screw cap lids. Each HDPE container will be labelled as 
required per country requirement.
Manufacturer
GSK
Quotient
7.2.
Dose Modification
No dose modification is permitted in this study. If a participant does not tolerate the dose 
administered, then the participant will be withdrawn from the study.
7.3.
Method of Treatment Assignment
This is an open-label, randomized study, therefore a randomization schedule will be 
produced. 
Participants will be randomized immediately before administration of the first dose in 
Period 1.
On the morning of Day 1 of Period 1, participants will be assigned a unique number 
(randomization number) in ascending numerical order at the study site. The 
randomization number encodes the participant’s assignment to one of the two treatment 
sequences of the study (Table 3), according to the randomization schedule generated 
prior to the study by the Statistics Department at GSK, using validated internal software.


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Participant randomization numbers will be allocated to treatment sequence in a 1:1 ratio. 
The allocation will be balanced with 7 participants receiving each treatment sequence. 
Each participant will be dispensed study treatment, labelled with his/her unique 
randomization number, throughout the study.
Table 3
Treatment Sequences
Treatment 
Sequence
N
Period 1
Period 2
AB
7
Regimen A
Regimen B
BA
7
Regimen B
Regimen A
Regimen A: 200 mg as 2 x 100 mg GSK3640254 Capsule, 100mg (reference)
Regimen B: 200 mg as 2 x 100 mg GSK3640254 Mesylate Salt Capsule, 100 mg (test)
A treatment allocation list will be produced prior to dosing using the randomization 
schedule and will be retained in the investigator site file (ISF).
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
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).
4.
Further guidance and information for the final disposition of unused study 
treatment are provided in the technical agreement.
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 GSK.


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7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

Participants will be dosed at the site, and 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 and 
hands to ensure that the study treatment was ingested.
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 in the case report form (CRF)
along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor will be contacted if there are any questions regarding concomitant 
or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol/Acetaminophen, at doses of 2 grams/day and 2.5% Hydrocortisone (for 
EKG lead contact dermatitis), is permitted for use any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the Medical Monitor (if appropriate) if required to treat AEs.
7.8.
Treatment after the End of the Study
There is no treatment after the end of the study. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant will be withdrawn from the study at any time: 

At his or her own request


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
At the discretion of the Investigator or the Sponsor for safety (including lab 
abnormalities or intercurrent illness), psychiatric, compliance, or administrative 
reasons. 

Any SAE.

Termination of the study by GSK/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) illness

Repeat non-adherence by the participant with the requirements of the protocol or 
treatment (as determined by Investigator in consultation with the Medical 
Monitor)

Emergence of any positive (abnormal) response confirmed by the investigator on 
a clinician (or qualified designee) administered CSSRS on Day 3 (Period 1 or 2).
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
If a participant withdraws from the study, he/she must complete a follow-up visit.
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. Discontinuation of study 
treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is in the 
best interest of the participant.


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
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, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7.
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. The formula to be used in 
this study is Fridericia’s formula (i.e. QTcF). This formula may not be changed or 
substituted once the participant has been enrolled.

The QTc will be based on single electrocardiograms. 

ECGs will be repeated if a participant has QTcF> 450 msec or > 30 msec increase 
from pre-dose in QTcF. 
A participant that meets either bulleted criterion below based on the average of repeated 
ECG readings will be withdrawn from study treatment.  

QTcF >500 msec

Change from baseline (pre-dose Day 1) of QTcF >60 msec
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 Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is related to investigational product.

The participant becomes pregnant.


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
The participant initiates treatment with any prohibited medications.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.
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.
8.1.4.
Temporary Discontinuation
If a participant is not dosed when planned in a particular period (eg in case of unexpected 
personal circumstances or AEs that occur between treatment periods), they may be dosed 
at a later date (if a participant cannot re-attend within 28 days, they will be considered 
withdrawn), provided the following criteria are met: 

The AE has resolved or stabilized.

The AE preventing dosing was not considered related to the study treatment.

The participant has not met any individual stopping criteria.

It is considered safe to continue to dose in the opinion of the investigator.
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria or any other 
withdrawal 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, 
behavioural, compliance or administrative reasons. If a participant withdraws 
from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records. The reason for 
withdrawal will be documented in the CRF.

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.

A participant may be withdrawn at the Sponsor’s request, for reasons such as 
significant protocol deviations or participant safety concern (and after discussion 
with the Investigator).

If a participant is withdrawn from study treatment, this participant is also 
considered to be withdrawn from the study following completion of follow-up 
assessments.

Participants will be withdrawn if the study is terminated.

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.


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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 will 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 
will be documented in the participant’s CRF.

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. 
8.4.
Study Stopping Criteria
The study will be halted, and the risk to other participants evaluated, if any of the 
following criteria are met: 

Two participants experience an AE of Grade 3 intensity assessed as related to 
GSK3640254, by the principle investigator (PI).

One participant experiences an AE of Grade 4 intensity assessed as related to 
GSK3640254, by the PI 

If greater than 25% of participants within the same period receiving 
GSK3640254 have a ≥ Grade 3 intensity AE or laboratory abnormality (with the 
exception of asymptomatic changes in lipid panel) or a ≥ Grade 2 intensity rash 
with concurrent fever, transaminase elevation or eosinophilia.

There is one Serious Adverse Event (SAE) or death assessed as related to 
GSK3640254, by the PI. 

Two participants with confirmed QTcF ≥500 msec within the same period 

Two participants with clinically significant, in the opinion of the PI, arrhythmias 
within the same period 

Relatedness will be determined by the investigator. If the study is halted, a 
temporary halt will be submitted to the MHRA and EC in the form of a 
substantial amendment. The study may be resumed or terminated; however, it 
will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC. Of note, the intensity of AEs will be 
determined using DAIDS criteria (see Section 12.4 for further details) 


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8.5.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA 
and EC. The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is terminated, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons if applicable, will also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the principal 
investigator (PI) or sponsor must notify the EC and MHRA by letter outlining the reasons 
for abandonment of the trial.
Once exposure to GSK3640254 has begun, the study will be completed as planned unless 
the following criteria are satisfied that require a temporary halt or early termination of the 
study.

The occurrence of serious or severe AE(s), as defined in Appendix 4, if 
considered to be related to study treatment.

New information regarding the safety of the study treatment that indicates a 
change in the risk/benefit profile for the compound, such that the risk/benefit is 
no longer acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the 
ability to achieve the primary study objectives or compromises participant 
safety.
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 3.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination.
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor.  
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns will be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant will continue or discontinue 
study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.


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
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 or by 
generic screening (eg, blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in the 
SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
550 mL in a 4-week period.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 48 hours post-dose providing that:
−
No AEs have been reported during the study visit
−
The participant responds positively when asked “How are you feeling?”
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorization of the investigator or appropriately 
qualified delegate.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Section 12.4 . The intensity of AEs (and 
lab abnormalities) will be graded using the DAIDS Grading table. While the study 
population will consist of HIV-1 seronegative healthy volunteers, the DAIDS criteria will 
be used in later clinical trials (Phase 2a and beyond); additionally, the DAIDS criteria are 
have a more conservative grading scale relative to others (eg. CTCAE v 4.0). Thus, 
participant safety evaluation and monitoring will be more conservative.
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 follow-up visit at the 
time points specified in the SoA (Section 2).


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
All AEs will be collected from the start of treatment until the 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 CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 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. 
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 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.


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
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.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 90 days 
after the last dose.

If a pregnancy is reported, the investigator will inform ViiV/GSK within 24 hours of
learning of the pregnancy and will follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than that intended in this study will be 
considered an overdose.
There is no specific antidote for overdose with GSK3640254. The investigator will use
clinical judgment to treat any overdose.
In the event of an overdose, the investigator will:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 can no longer be detected systemically (at least 72 hours after the last 
dose of GSK3640254).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor at 2, 4 
and 6 hours post dose (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.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI and neurological systems. Height and 
weight will also be measured and recorded.


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
A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators will pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate.

The acceptable deviations from the nominal vital signs measurement time points 
are:
−
The pre-dose vital signs measurements will be taken ≤2 hours before 
dosing.
−
≥0.5 to 4 hours post-dose vital signs measurement will be taken within ± 5 
minutes of the nominal post-dose sampling time
−
>5 to 12 hours post-dose vital signs measurement will be taken within 
± 10 minutes of the nominal post-dose sampling time 
−
>12 hours post-dose vital signs measurement will be taken within ± 30 
min of the nominal post-dose sampling time if participants are resident in 
the clinic
−
For the return visit, vital signs measurements will be taken ± 2 hours from 
the nominal return visit time point.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline 
(pre-dose Day 1), must be reported as an AE. 
9.4.3.
Electrocardiograms

A single 12-lead ECG will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

As noted in Section 8.1.2 , ECGs will be repeated if a participant has QTcF> 
450 msec or > 30 msec increase from pre-dose in QTcF. If the ECG is repeated, 
the QTc will be based on averaged QTc values of repeated ECGs obtained 
Baseline QTc for the assessment of the withdrawal criteria will be the mean 
pre-dose QTcF of the relevant treatment period.

The acceptable deviations from the nominal ECG measurement time points are:
−
The pre-dose ECG measurements will be taken ≤ 2 hours before dosing


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−
Post-dose ECG measurements will be taken ± 15 minutes from the 
nominal post-dose time point.
−
For the return visit, ECG measurements will be taken ± 2 hours from the 
nominal return visit time point.

ECGs are to be measured after participant has been in a semi-supine position 
after approximately 5 minutes rest.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline 
(pre-dose Day 1), will be reported as an AE.
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. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast of at least 8 hours.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
−
The pre-dose blood sample will be taken ≤2 hours before dosing
−
Post-dose blood samples will be taken ± 1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal
during participation in the study or within 7 days after the last dose of study 
treatment will 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 will 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.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 


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management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
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 CSSRS 
administered by a clinician (or qualified designee); any positive (abnormal) response 
confirmed by the investigator, will exclude them from participating. Finally, participants 
will also have assessment by the CSSRS on Day 3 (of both Period 1 and 2) (see Section 2
SoA table for details). Any positive (abnormal) response confirmed by the investigator on 
Day 3 (of both Period 1 and 2) will result in their discontinuation. A positive (abnormal) 
response confirmed by the investigator will result in the PI/Sub-Investigator arranging 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 Severity Rating Scale (C-SSRS; v4.1, 28 Apr 2010) [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. 
9.5.
Pharmacokinetics

Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK3640254 as specified in the SoA (see Section 2).
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

The first 0.5 mL of blood withdrawn via cannula will be discarded.

Processing, storage and shipping procedures are provided in the SRM or 
equivalent.

The acceptable deviations from the nominal post-dose blood sampling times are 
as follows:
−
The pre-dose blood sample will be taken ≤1 hour before dosing. 
−
≥0.5 to 4 hours post-dose samples will be taken within ± 5 minutes of the 
nominal post-dose sampling time
−
>5 to 12 hours post-dose samples will be taken within ± 10 minutes of the 
nominal post-dose sampling time 
−
>12 hours post-dose samples will be taken within ± 30 min of the nominal 
post-dose sampling time if participants are resident in the clinic
−
The return visit (72 hours post-dose) sample will be taken within ± 2 hours 
of the nominal sampling time


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
Samples will be used to evaluate the PK of GSK3640254. Samples collected for 
analyses of GSK3640254 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained.

Once the plasma has been analyzed for GSK3640254 any remaining plasma may 
be analyzed for other compound-related metabolites and the results reported under 
a separate protocol.

Plasma analysis will be performed by PPD. Concentrations of GSK3640254 will 
be determined in plasma using the current approved bioanalytical methodology. 
Raw data will be archived at the Bioanalytical site as detailed in the SRM or 
equivalent.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
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
No formal sample size calculation has been made; however, based on experience from 
previous similar studies, 14 participants enrolled to achieve a minimum of 12 evaluable 
participants is considered sufficient.
Based on the emerging single-dose PK data from the FTIH study, the within-participant 
variability was 31.6% for Cmax and 36.8% for AUC(0-inf). Assuming a within-
participant coefficient of variation (CVw) of 37% for Cmax and AUC(0-inf), and a 
sample size of 12 participants, it is estimated that the half width of the 90% confidence 
interval for the treatment difference on log-scale will be within 26% of the point 
estimate. If the point estimate of the ratio of geometric means is 1, then 90% confidence 
interval will be approximately (0.77,1.30) on the original scale.


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10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
Participants in the ‘Safety Population’ for whom a PK sample was 
obtained and analysed and will be the population for reporting of PK 
data.
10.3.
Statistical Analyses
10.3.1.
Pharmacokinetic Analyses
No statistical hypotheses will be tested. All PK analyses will be performed on the PK 
Population. 
Plasma GSK3640254 concentration-time data will be analysed by non-compartmental 
methods.  
The plasma concentration-time data for each of the regimens will be used to determine 
the following PK parameters, as data permit: 

maximum observed plasma concentration (Cmax).

time to Cmax (Tmax).

the elapsed time from dosing at which GSK3640254 was first quantifiable in a 
concentration vs time profile (Tlag).

time from dosing at which GSK3640254 was last quantifiable in a concentration vs 
time profile (Tlast).

observed plasma concentration at Tlast (Clast).

observed concentration at 24 hours post-dose (C24h).

area under the plasma concentration vs time curve (AUC(0-tlast) and AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point
(AUC%extrap).

oral clearance, the apparent volume of plasma cleared of GSK3640254 per unit time 
following extravascular dosing (Cl/F)

the apparent volume of distribution following extravascular dosing (Vd/F)

terminal half-life (t1/2).


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
Lambda-z

relative bioavailability (Frel) of the GSK3640254 Mesylate Salt Capsule formulation
(test) vs the GSK3640254 Capsule formulation (reference) based on AUC(0-inf) (or 
AUC(0-tlast) if AUC(0-inf) can’t be derived) and Cmax.
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI and %CVb (100 * √ (exp(SD2) -1)) will be provided, 
where the SD is the standard deviation of log-transformed data.
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoint is the comparison of the GSK3640254
Mesylate Salt Capsule formulation (test) with the GSK3640254 Capsule 
formulation (reference). 
Log transformed AUC(0-inf), (AUC(0-tlast), if AUC(0-inf) cannot be derived), 
and Cmax values for GSK3640254 will be subjected to mixed effects 
modelling, including terms for period and treatment as fixed effects and 
participant as a random effect. The point estimate and associated 90% 
confidence interval (CIs) will be constructed for the difference, test 
treatment (B) – reference treatment (A). The point estimate and 
associated 90% CI will then be back-transformed to provide a point 
estimate and 90% CI for the ratio test/reference on the original scale. 
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
The safety endpoints will be summarized descriptively, and no formal statistical 
analysis will be conducted.
The Reporting and Analysis Plan will detail the content of the safety tables, figures and 
listings to be generated. 
10.3.3.
Interim Analyses
No formal statistical analyses or interim analyses are planned.


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11.
REFERENCES
Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United 
States and dependent areas. HIV Surveillance Report, 2014; vol. 26. Available at: 
http://www.cdc.gov/hiv/library/reports/surveillance/. Published November 2015. 
Accessed 20 June 2016.
Claessens YE. Bench-to-bedside review: Severe lactic acidosis in HIV patients treated 
with nucleoside analogue reverse transcriptase inhibitors. Crit Care. 2003;7(3):226-232.
Collins S. D:A:D study shows that PIs rather than NNRTIs drive the previously reported 
cardiovascular risk of combination antiretroviral therapy. HIV Treatment Bulletin 2006; 
7(3). Available at: http://www.ibase.info/v7/htb7-3/dad.html. Accessed 12 November 
2009.
De Luca A, Dunn D, Zazzi M, et al. Declining prevalence of HIV-1 drug resistance in 
antiretroviral treatment-exposed individuals in Western Europe. JID. 2013; 207: 1216-20.
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events corrected version 2.1 July 2017.  (available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables).
GlaxoSmithKline Document Number 2016N294821_00. GSK3640254 Investigator’s 
Brochure, Version 01. Effective Date Expected: 10 May 2017.
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.
The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial
infarction. N Engl J Med. 2007;356 (17): 1723-1735.
WHO. HIV resistance report-2012. Available at: 
http://apps.who.int/iris/bitstream/10665/75183/1/9789241503938_eng.pdf Published July 
2012. Accessed: 20 June 2016.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse Event
ALT
Alanine Aminotransferase
ARV
Antiretroviral
AUC(0-inf)
Area under the concentration-time curve from time 
zero (pre-dose) extrapolated to infinite time
AUC(0-tlast)
Area under the concentration-time curve from zero 
to time of last sample taken
BMI
Body Mass Index
C24h
Concentration at 24 hour post-dose
CA
Competent authority
CI
Confidence Interval
Cmax
Maximum observed concentration
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
DAIDS
Division of Acquired Immunodeficiency Syndrome
EC
Ethics Committee
ECG
Electrocardiogram
EMA
European Medicines Agency
Frel
Relative bioavailability
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
Gag
Group-specific Antigen
GCP
Good Clinical Practice
GI
gastrointestinal
GP
General Practitioner
HBcAb
hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
investigator site file
MAD
Multiple Ascending Dose
MI
Maturation Inhibitor
MSDS
Material Safety Data Sheet
PK
Pharmacokinetics
PI
Principal investigator
QTcF
QT interval corrected for heart rate according to 
Fridericia’s formula


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SAD
Single Ascending Dose
SAEs
Serious Adverse Events
SD
Standard Deviation
SoA
Schedule of Activities 
SUSAR
Suspected Unexpected Serious Adverse Reactions
TOPS
The Over Volunteering Prevention System
TQT
Thorough QT
ULN
Upper Limit of Normal
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed at The Doctors Laboratory, with 
the exception of routine urinalysis, urine pregnancy test, urine drug screen, 
alcohol and carbon monoxide breath tests. These tests will be performed on-site.

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.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study will be repeated until the values 
return to normal or baseline. If such values do not return to normal within a 
period judged reasonable by the Investigator, the etiology will be identified and 
the sponsor notified.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
Mean Corpuscular 
Volume (MCV)
Mean Corpuscular 
Haemoglobin (MCH)
Mean Corpuscular 
Haemoglobin
Concentration (MCHC)
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin (direct 
only if total is 
elevated)
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Chloride
Bicarbonate
Routine 
Urinalysis

Specific gravity


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Laboratory 
Assessments
Parameters

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes by dipstick

Microscopic examination (if blood, leukocytes, nitrites or protein is 
abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in postmenopausal 
women only)

Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Alcohol breath test

Carbon monoxide breath test

Urine human chorionic gonadotropin (hCG) pregnancy test (for all women)

Serology (HIV 1 and 2 antibodies, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)
The results of each test must 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 6. 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.


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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 substantial amendments to the protocol will require IEC/IRB and local 
regulatory 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 SUSARs or other significant safety findings that 
occur on the study as required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Protocol Amendments

After the protocol has been submitted to the MHRA and/or EC, any amendment 
must be agreed by the investigator after discussion with the sponsor and will be 
formally documented.

All substantial amendments will be submitted to the MHRA and/or EC for an 
opinion as required by current regulations.

If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled 
participants and must be provided to additional participants prior to their entry 
into the study.


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Protocol Deviations

The study must be conducted in accordance with the Clinical Protocol. Should a 
protocol deviation occur, it must be promptly assessed in order to decide 
whether any of these non-compliances will be reported to the MHRA as a 
serious breach of GCP and the Clinical Protocol.

Protocol waivers are not acceptable.

Deviations from the protocol will be recorded in the source workbook as noted 
by the clinical staff. If necessary, the sponsor will be informed of the deviation.

Any protocol deviations assessed as major will be discussed with the sponsor in 
order to determine if the withdrawal criteria stated in Section 8 have been met.
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

Participants will be provided with a written explanation of the study at least one 
day before the screening visit.

The investigator or his/her representative will explain the nature of the study, its 
purpose, expected duration and the benefits and risks involved in study 
participation to the participant and answer all questions regarding the study. 
Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that 
carry out clinical studies in the local area. 

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 local regulations, ICH 
guidelines, and the IRB/IEC. 

The CRF 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.


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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 and by inspectors from regulatory authorities.
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. 

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Following completion of the study, a clinical study report will be prepared. 

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 and will be made available to the EC/MHRA within 1 year of 
the declaration of the end of trial.
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. 


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
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
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.

A study-specific source documentation list will be finalized by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data will be considered source data for this study.
Declaration of the End of the Study

The definition of the end of the study is defined as the last visit of the last 
participant (eg follow-up assessment). Any changes to this definition will be 
notified as a substantial amendment.

The EC and MHRA will be notified in writing of the conclusion of the study 
within 90 days of the end of the study, or within 15 days if the study is 
terminated early, clearly explaining the reasons for the termination.
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.


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study 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 will be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (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 


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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 
will 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, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment will 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 


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other outcomes listed in the above definition. These events will 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 an Adverse Drug Reaction (ADR)
An ADR is defined as an untoward medical occurrence that, at any dose:

Where a causal relationship with study treatment is at least a reasonable possibility 
(possibly related or related)
Definition of a SUSAR
A SUSAR is defined as any untoward medical occurrence that, at any dose:

Is believed to be related to study treatment and is both unexpected (ie the nature or 
severity is not expected from the information provided in the Investigator’s 
Brochure) and serious. SUSARs are subject to expedited reporting to the MHRA, 
European Medicines Agency (EMA), EC (see Appendix 7)
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 (ie the 
date and time of onset, a description of the AE, severity, duration, actions taken, 
outcome and an investigator’s current opinion on the relationship between the study 
treatment and the event).

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.


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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during using the DAIDS grading table (http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf) and assign it to 1 of the 
following categories: Events):

Grade 1, Mild: no or minimal interference with usual social & functional activities.

Grade 2, Moderate: greater than minimal interference with usual social & functional 
activities.

Grade 3, 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.

Grade 4, Life Threatening: inability to perform basic self-care functions

Grade 5, Death
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.

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 GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

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 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Communication Plan.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 


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telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Communication Plan.


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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. 
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 5 when having 
penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame 


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Refrain from donating sperm for duration of study and for 14 weeks after study 
completion or from last dose.Female participants
Female participants who are not of childbearing potential do not need to use any methods 
of contraception.
Female participants of childbearing potential are not eligible to participate in this study. 
Female participants will not participate in egg donation from dosing, for the duration of 
the study and for at least 28 days after the last dose of study treatment.
Table 5
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 


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Pregnancy Testing

Urine pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using 
the SureScreen Diagnostics test in accordance with instructions provided in its 
package insert at screening and admission to each study period
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal 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 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. 


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Any female participant who becomes pregnant while participating will be withdrawn 
from the study.


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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 2 days of 
last dose4 

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 paracetamol/acetaminophen, 
herbal remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:


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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

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 computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation will be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
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
References
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.


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12.7.
Appendix 7: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of a study treatment or that 
would be sufficient to consider changes in the study treatments administration or in the 
overall conduct of the study, for instance:

an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

new events related to the conduct of the study or the development of the study 
treatments and likely to affect the safety of the participants, such as:
−
an SAE which could be associated with the study procedures and which could 
modify the conduct of the study
−
a major safety finding from a newly completed animal study (such as 
carcinogenicity)
−
any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same study treatments in another country by the same 
sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures will be followed.
Fatal or life-threatening SUSARs
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility will be delegated to the 
pharmacovigilance provider, GSK/ViiV.
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.


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Any additional relevant information will be sent within 8 days of the report.
Other SUSARs
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility will be delegated to the pharmacovigilance provider, 
GSK/ViiV.
The investigator is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.
Any additional relevant information will be sent within 8 days of the report.
Urgent Safety Measures
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Sciences may take urgent safety measures before 
informing the sponsor, but the sponsor must be informed immediately after the hazard 
has resolved. 
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC.
Reporting of Urgent Safety Issues
Quotient Sciences is required to inform the appropriate competent authorities and the EC 
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.


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12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
208131
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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
Compound Number 
:
GSK3640254
Effective Date 
:
21-NOV-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 208131 (QCL118221_01)
RAP Author(s):
Approver
Date
Approval Method
21-NOV-2018
E-Signature
Principal Statistician (Infectious Disease, 
Clinical Statistics)
13-NOV-2018
Review 
Confirmation 
Email
Associate Manager (SPDS India, Clinical 
Programming)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


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2
RAP Team Review Confirmations 
(Method: E-mail)
Date
14-NOV-2018
Clinical Development Manager (Infectious Disease, CPSSO)
13-NOV-2018
Physician Product Lead (Clinical Development, ViiV Healthcare)
14-NOV-2018
Director (Clinical Pharmacology Modelling and Simulation)
13-NOV-2018
Principal Data Manager (Infectious Disease, Data Management)
Clinical Statistics and Clinical Programming Line Approvals:
(Method: Pharma TMF eSignature)
Approver
Date
 
21-NOV-2018
Statistics Leader (Infectious Disease, Clinical Statistics)
On behalf of 
 (Infectious Disease, Senior 
Statistics Director)
21-NOV-2018
Biostatistics and Programming Manager (SPDS India, Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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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 ................................................................................................7
2.4.
Statistical Analyses.......................................................................................7
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................10
5.3.
Multicentre Studies .....................................................................................10
5.4.
Examination of Covariates, Other Strata and Subgroups............................11
5.4.1.
Covariates and Other Strata ........................................................11
5.4.2.
Examination of Subgroups...........................................................11
5.5.
Multiple Comparisons and Multiplicity .........................................................11
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
7.
EFFICACY ANALYSES..........................................................................................12
8.
SAFETY ANALYSES .............................................................................................12
8.1.
Adverse Events Analyses ...........................................................................12
8.2.
Adverse Events of Special Interest Analyses..............................................12
8.3.
Clinical Laboratory Analyses.......................................................................12
8.4.
Other Safety Analyses ................................................................................12
9.
PHARMACOKINETIC ANALYSES.........................................................................13
9.1.
Primary Pharmacokinetic Analyses.............................................................13
9.1.1.
Endpoint / Variables.....................................................................13
9.1.1.1.
Drug Concentration Measures....................................13
9.1.1.2.
Derived Pharmacokinetic Parameters.........................13
9.1.2.
Summary Measure ......................................................................14
9.1.3.
Population of Interest...................................................................14
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................14
9.1.5.
Statistical Analyses / Methods .....................................................14
9.1.5.1.
Statistical Methodology Specification..........................15


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9.2.
Secondary Pharmacokinetic Analyses........................................................16
9.3.
Exploratory Pharmacokinetic Analyses .......................................................16
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................16
11. PHARMACODYNAMIC ANALYSES.......................................................................16
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................16
13. REFERENCES.......................................................................................................17
14. APPENDICES........................................................................................................18
14.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................18
14.1.1.
Exclusions from Per Protocol Population .....................................18
14.2.
Appendix 2: Schedule of Activities ..............................................................19
14.2.1.
Protocol Defined Schedule of Events...........................................19
14.3.
Appendix 3: Assessment Windows .............................................................22
14.3.1.
Definitions of Assessment Windows for Analyses........................22
14.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................23
14.4.1.
Study Phases ..............................................................................23
14.4.1.1.
Study Phases for Concomitant Medication .................23
14.4.2.
Treatment Emergent Flag for Adverse Events .............................24
14.4.3.
Adverse Events Assignment to Treatment Period........................24
14.4.4.
Concomitant Medication Assignment to Treatment Period...........24
14.5.
Appendix 5: Data Display Standards & Handling Conventions....................25
14.5.1.
Reporting Process .......................................................................25
14.5.2.
Reporting Standards....................................................................25
14.5.3.
Reporting Standards for Pharmacokinetic....................................26
14.6.
Appendix 6: Derived and Transformed Data ...............................................27
14.6.1.
General........................................................................................27
14.6.2.
Study Population..........................................................................27
14.6.3.
Efficacy........................................................................................27
14.6.4.
Safety ..........................................................................................28
14.6.5.
Pharmacokinetic ..........................................................................29
14.6.6.
Population Pharmacokinetic (PopPK) ..........................................29
14.6.7.
Pharmacodynamic.......................................................................29
14.7.
Appendix 7: Reporting Standards for Missing Data.....................................30
14.7.1.
Premature Withdrawals................................................................30
14.7.2.
Handling of Missing Data.............................................................30
14.7.2.1.
Handling of Missing and Partial Dates ........................31
14.8.
Appendix 8: Values of Potential Clinical Importance ...................................32
14.8.1.
Laboratory Values........................................................................32
14.8.2.
ECG.............................................................................................33
14.8.3.
Vital Signs....................................................................................33
14.8.4.
Urinalysis.....................................................................................33
14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................34
14.9.1.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................34
14.9.2.
Population Pharmacokinetic (PopPK) Methodology.....................34
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................35


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14.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................35
14.10.2. Pharmacokinetic / Pharmacodynamic Methodology.....................35
14.11. Appendix 11: Abbreviations & Trade Marks ................................................36
14.11.1. Abbreviations...............................................................................36
14.11.2. Trademarks .................................................................................37
14.12. Appendix 12: List of Data Displays..............................................................38
14.12.1. Data Display Numbering..............................................................38
14.12.2. Mock Example Shell Referencing ................................................38
14.12.3. Deliverables.................................................................................38
14.12.4. Study Population Tables..............................................................39
14.12.5. Efficacy Tables ............................................................................40
14.12.6. Efficacy Figures ...........................................................................40
14.12.7. Safety Tables...............................................................................41
14.12.8. Safety Figures .............................................................................43
14.12.9. Pharmacokinetic Tables...............................................................44
14.12.10.Pharmacokinetic Figures .............................................................45
14.12.11.Pharmacokinetic Population (PopPK) Tables...............................46
14.12.12.Pharmacokinetic Population (PopPK) Figures .............................46
14.12.13.Pharmacodynamic Tables ...........................................................46
14.12.14.Pharmacodynamic Figures ..........................................................46
14.12.15.Pharmacokinetic / Pharmacodynamic Tables ..............................46
14.12.16.Pharmacokinetic / Pharmacodynamic Figures .............................46
14.12.17.ICH Listings .................................................................................47
14.12.18.Non-ICH Listings..........................................................................50
14.13. Appendix 13: Example Mock Shells for Data Displays ................................51


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 208131 (QCL118221):
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 amendment 1 [(Dated: 29/MAY/2018)].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the pharmacokinetic (PK)
profiles of GSK3640254 following 
administration of the mesylate salt 
capsule relative to that of the bis-
hydrochloride salt capsule (reference) 
in healthy participants

GSK3640254 area under the curve from time zero to 
infinity (AUC0-∞), AUC(0-tlast), maximum observed 
concentration (Cmax),Time to Cmax (Tmax), Concentration at 
24 hours post-dose (C24h), relative bioavailability (Frel) 
based on AUC and Cmax
Secondary Objectives
Secondary Endpoints

To provide additional information of 
the safety and tolerability of single 
doses of GSK3640254 in healthy 
participants

AEs, clinical laboratory values, vital signs,
electrocardiogram (ECG) and/or other safety biomarkers


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2.3.
Study Design
Figure 1
Overview of Study Design
Overview of Study Design and Key Features
Design 
Features

This is a single centre open-label 2 period cross over study to evaluate the relative 
bioavailability of a test GSK3640254 mesylate salt capsule against the reference 
GSK3640254 hydrochloride (HCl) capsule.

Each dose of study treatment will be separated by washout period of at least 7 days.
Dosing

Participants will receive a single 200 mg dose (achieved as 2 x 100 mg capsules)
of assigned study treatment during each inpatient period

All participants will be dosed in a fed state following a moderate fat meal 
(approximately 600 calories with approximately 30% of the calories from fat)
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

A randomization schedule was produced using RANDALL NG and distributed to the 
site pharmacist

The randomization number will determine the allocation of treatment sequences (AB 
or BA)
Interim 
Analysis

No formal interim analyses are planned for this study.
2.4.
Statistical Analyses
No formal statistical hypotheses will be tested. All analyses will be descriptive and 
exploratory. An estimation approach providing point estimates and corresponding 
confidence intervals will be used, where appropriate.
Relative Bioavailability
This study is designed to estimate the relative bioavailability of a test GSK3640254 
mesylate salt capsule formulation versus the reference HCl capsule formulation.  No 
formal hypothesis will be tested. Separate mixed effects models will be used to analyse 
the two PK parameters of interest (AUC(0-∞) and Cmax). The dependent variable in each 
model will be the log-transformed PK parameter of interest and the independent variables 


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will include fixed effects for treatment (mesylate salt capsule or HCl capsule) and period, 
as well as a random effect for participant. For each primary pharmacokinetic endpoint, 
point estimates and corresponding 90% confidence intervals will be constructed for the 
ratio of the geometric mean of the test mesylate salt capsule to the geometric mean of the 
reference HCl capsule, (test)/(reference). More detail is provided in Section 9.1.5. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analyses are planned for this study. 
3.2.
Final Analyses
The final planned 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 and Quotient 
procedures.
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
Safety
All randomized participants who received at 
least one dose of study treatment.
Participants will be analysed according to the 
treatment they actually received.
Safety and Study 
population


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Population
Definition / Criteria
Analyses Evaluated
Pharmacokinetic 
(PK)
Participants in the Safety population for whom 
at least one PK sample was obtained, analysed 
and have evaluable drug concentrations 
reported
PK
Refer to Appendix 12: List of Data Displays which details the population used for each display.
The “Enrolled” and “Screened” analysis populations were not defined in the study 
protocol but are defined here to facilitate disclosure requirements and reporting of 
reasons for screen failure. 
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.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan version 1.0 Final dated 24 
May 2018.
o Data will be reviewed prior to 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/or 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
Treatment Group Descriptions
[RandAll NG]
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
An oral dose of 200mg as 2 x 
GSK3640254 HCl Capsule,100 mg 
(reference) following a moderate fat 
meal.
GSK HCl 
1
B
An oral dose of 200 mg as 2 x 
GSK3640254 Mesylate Salt 
Capsule, 100 mg (test) following a 
moderate fat meal.
GSK Mesylate 
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK3640254 200mg mesylate salt vs GSK3640254 200mg HCl (B vs. A)
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 will be used as baseline. Baseline definitions in the table below are applicable to 
each period. 
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
12-lead ECG
X
X
X
Day 1 (Pre-Dose)
Vital Signs
X
X
X
Day 1 (Pre-Dose)
Laboratory 
Assessments
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
Not applicable.


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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Not applicable.
5.4.2.
Examination of Subgroups
Not applicable.
5.5.
Multiple Comparisons and Multiplicity
Not applicable.
5.6.
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
14.3
Appendix 3: Assessment Windows
14.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
14.5
Appendix 5: Data Display Standards & Handling Conventions
14.6
Appendix 6: Derived and Transformed Data
14.7
Appendix 7: Reporting Standards for Missing Data
14.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety Population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays.
7.
EFFICACY ANALYSES
Not Applicable.
8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
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 12: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
Not applicable. 
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.


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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. Plasma GSK3640254 concentration-time data will be listed by 
participant, treatment group and sampling time and summarized by treatment group and 
sampling time for each period of the study. Individual participant profiles for 
GSK3640254 concentration-time data will be presented on both a linear and semi-log 
scale. Linear and semi-log figures for mean and median GSK3640254 plasma 
concentrations versus time will also be generated.
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3
Reporting Standards for Pharmacokinetic)
9.1.1.2.
Derived Pharmacokinetic Parameters
Derivation of pharmacokinetic parameters will be performed by Quotient under the direct 
auspices of CPMS, QSci, GlaxoSmithKline. Pharmacokinetic parameters will be 
calculated by standard non-compartmental analysis according to current working 
practices and using the currently supported version of WinNonlin. 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
AUC(0-∞)
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite 
time.
AUC(0-tlast)
Area under the concentration-time curve from time zero to the time of last sample taken
Cmax
Maximum observed plasma concentration
Tmax
Time to Cmax
C24h
Concentration at 24 hrs post dose 
Clast
Observed plasma concentration at Tlast
Tlast
Time from dosing at which GSK3640254 was last quantifiable in a concentration vs. time 
profile
Tlag
The elapsed time from dosing at which GSK3640254 was first quantifiable in a 
concentration vs time profile. 


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Parameter
Parameter Description
AUC%Extrap
The percentage of AUC extrapolated beyond the last measured time point
t½
Apparent terminal phase half-life, calculated as; t½ = ln2 / lambda_z 
Vd/F
The apparent volume of distribution following extravascular dosing
Cl/F
Oral clearance, the apparent volume of plasma cleared of GSK3640254 per unit time 
following extravascular dosing.
Lambdaz
Terminal phase rate constant 
NOTES:

Additional parameters may be included as required.
All the derived parameters described above will be listed.  For each of these parameters, 
except tmax and tlag, the following summary statistics will be calculated for each 
treatment group:  n, arithmetic mean, standard deviation (SD), median, minimum, 
maximum, geometric mean with associated 95% CI, standard deviation of logarithmically 
transformed data, and the between-participant CV (%CVb) (where %CVb = 100*√ 
(exp(SD2)-1) based on the geometric mean for the log-transformed PK parameters. For 
tmax and tlag, median, maximum, minimum, arithmetic mean and standard deviation will 
be calculated.
9.1.2.
Summary Measure
The parameters used for the treatment comparison of relative bioavailability of the single 
dose of the mesylate salt capsule relative to the single dose of the HCl capsule will be 
area under concentration time curve (AUC(0-∞) or AUC(0-tlast) if AUC(0-∞) cannot be 
derived) and Cmax.
9.1.3.
Population of Interest
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Not applicable.
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: 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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9.1.5.1.
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).
Endpoint / Variables

AUC(0-∞) (or AUC(0-tlast) if AUC(0-∞) cannot be derived) and Cmax
Model Specification

AUC(0-∞) and Cmax will be separately analysed using a mixed effects models. In each model 
the dependent variable will be the log-transformed PK parameter of interest (AUC(0-∞) or 
Cmax). The independent variables will include fixed effects for treatment (mesylate salt
capsule or HCl capsule) and period, and a random effect for participant.
Model Checking & Diagnostics

An unstructured covariance structure for the R matrix will be used by specifying “type=un” 
on the RANDOM line

In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS.

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.

Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Model Results Presentation

The estimated difference and CI obtained on the log scale will be exponentiated to provide 
an estimate of the fed to fasted ratio and its associated 90% CI. Estimates of within-subject 
variability (%CVw) will also be provided (%CVw=SQRT(exp(MSE) – 1)×100).  %CVw 
represents a pooled measure of within-subject variability across all treatments.

Comparative plots of individual PK parameters will be generated by treatment on linear 
and semi-logarithmic scales.

Plots of adjusted geometric mean ratio of test to reference treatment together with 90% 
confidence intervals will be produced.

Listing of individual PK parameter ratios will be generated.

Supportive SAS output from statistical analysis will be generated.
Subgroup Analyses

Not Applicable.
Sensitivity and Supportive Analyses

Not Applicable.


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9.2.
Secondary Pharmacokinetic Analyses
Not applicable.
9.3.
Exploratory Pharmacokinetic Analyses
Not Applicable.
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
Not Applicable
11.
PHARMACODYNAMIC ANALYSES
Not applicable. 
12.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
Not applicable.


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13.
REFERENCES
GUI_51487: Non-compartmental Analysis of Pharmacokinetic Data, CPMS Global. 
Effective Date: 01-NOV-2017
GlaxoSmithKline Document Number 2017N346490_01: 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. Effective Date: 29-MAY-2018


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14.
APPENDICES
14.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
These details are documented in the Protocol Deviation Management Plan (PDMP).
14.1.1.
Exclusions from Per Protocol Population
Not applicable.


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14.2.
Appendix 2: Schedule of Activities
14.2.1.
Protocol Defined Schedule of Events
Table 1
Schedule of Activities
Procedure
Screening 
(up to 28 
days 
before 
Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days 
post last dose) 
or Early 
Discontinuation 
Notes
–
1
1
2
3
4
Outpatient visit
X
X
X
Inpatient stay
X1
X
X
X2
1.
Admission 
in the 
morning
2.
Furlough 
from unit 
after 
assessment
s
Informed 
consent
X
Inclusion and 
exclusion 
criteria
X
X3
3.
Recheck 
clinical 
status at 
admission 
of Period 1
Demography
X
Full physical 
examination 
including 
height and 
weight4
X
4.
See
protocol
Section 
9.4.1 for 
systems to 
be 
examined
Columbia 
Suicide 
Severity Rating 
Scale 
(CSSRS)
X
X
Brief physical 
examination
X5
X5
X
5.
Pre-dose 
and 48 h 
post-dose
See
protocol
Section 
9.4.1 for 
systems to 
be 
examined


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Procedure
Screening 
(up to 28 
days 
before 
Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days 
post last dose) 
or Early 
Discontinuation 
Notes
–
1
1
2
3
4
Medical history 
(includes 
substance 
usage)6
X
6.
Substances: 
Drugs, 
alcohol, 
tobacco and 
caffeine
Urine 
pregnancy 
test7
X
X
X
7.
All female 
participants
Follicle 
stimulating 
hormone 
(FSH)8
X
8.
As needed 
in women to 
confirm 
postmenopa
usal status
HIV, Hepatitis 
B and C 
screening
X
Urine drug 
screen
X
X
Alcohol breath 
test
X
X
Carbon 
monoxide 
breath test
X
X
Laboratory 
assessments 
(haematology, 
clinical 
chemistry and 
urinalysis) 
X
X9
X9
X
9.
48 h post-
dose
Allowable 
windows in 
protocol 
Section 
9.4.4
12-lead ECG
X
X
X10
X10
X10
X
10. Time points 
in Table 2
Allowable 
windows in 
protocol 
Section 
9.4.3
Vital signs
X
X
X11
X11
X11
X
11. Time points 
in Table 2
Allowable 
windows in 
protocol 
Section 
9.4.2


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Procedure
Screening 
(up to 28 
days 
before 
Day 1)
Treatment Periods 1 and 2
Day
Follow-up
(7 to 10 days 
post last dose) 
or Early 
Discontinuation 
Notes
–
1
1
2
3
4
Randomization
X12
12. Pre-dose 
Period 1 
only
Study 
treatment
X
AE review
X
===========================
X
SAE review
X
X
===========================
X
Concomitant 
medication 
review
X
===========================
X
PK blood 
sample 
collection13
===========================
13. Time points 
in Table 2
Table 2
Pharmacokinetic Blood Sampling Collection, ECG ad Vital Sign 
Times
Treatment Periods 1 and 2
Time (h)
Pre-
dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
36
48
72
Dosing 
X
PK 
Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-
lead ECG 
(repeat 
allowed)
X
X
X
X
X
X
Single set 
of Vital 
signs
X
X
X
X
X
X


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14.3.
Appendix 3: Assessment Windows
14.3.1.
Definitions of Assessment Windows for Analyses
All acceptable assessment windows are defined in Section 9.4.2 (vitals), Section 9.4.3 
(ECG), Section 9.4.4 (clinical safety laboratory assessments), and Section 9.5 (PK) of the 
protocol. No assessment windows will be redefined in the RAP.


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14.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
14.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
administration of study treatment. Study phases are defined separately for each period.
Period 1
Study Phase
Definition
Pre-Treatment 
Date < Period 1 Study Treatment Start Date/Time
On-Treatment
Period 1 Study Treatment Start Date/Time ≤Date < Period 1 Study Treatment
Start Date/Time + 5 days
Post-Treatment
Period 1 Study Treatment Start Date/Time + 5 days < Date
Period 2
Study Phase
Definition
Pre-Treatment 
Date < Period 1 Study Treatment Start Date/Time
On-Treatment
Period 2 Study Treatment Start Date/Time ≤ Date < Period 2 Study Treatment 
Start Date/Time + 5 days
Post-Treatment
Period 2 Study Treatment Start Date/Time + 5 days < Date
14.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is 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.


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14.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.).

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period:

Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date 
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.
14.4.3.
Adverse Events Assignment to Treatment Period
Adverse events (AEs) will be assigned to a treatment period and corresponding treatment 
received in that treatment period after the imputations defined in RAP Section 14.7.2.1
have been performed.

Treatment Period 1: all AEs with start date/time at the time of or after IMP 
administration in Treatment Period 1 and before IMP administration in Treatment 
Period 2 

Treatment Period 2: all AEs with start date/time at the time of or after IMP 
administration in Treatment Period 2 
Thus, AEs occurring during the 1st washout will be assigned to the treatment received in 
Treatment Period 1 and AEs occurring during follow-up will be assigned to the treatment 
received in Treatment Period 2.
14.4.4.
Concomitant Medication Assignment to Treatment Period
Concomitant medications (CMs) will be assigned to a treatment period and 
corresponding treatment received in that treatment period after the imputations defined in 
RAP Section 14.7.2.1 have been performed.

Treatment Period 1: all CMs with start date/time at the time of or after IMP 
administration in Treatment Period 1 and before IMP administration in Treatment 
Period 2 

Treatment Period 2: all CMs with start date/time at the time of or after IMP 
administration in Treatment Period 2 
Thus, CMs occurring during the washout period will be assigned to the treatment 
received in Treatment Period 1, and CMs occurring during follow-up will be assigned to 
the treatment received in Treatment Period 2.


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14.5.
Appendix 5: Data Display Standards & Handling 
Conventions
14.5.1.
Reporting Process
Software

The currently supported versions of SAS and WinNonLin software will be used.
Reporting Area
HARP Server
: \\us1salx00259.corpnet2.com
HARP Compound
: \arwork\gsk3640254\mid208121\final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0.
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.
14.5.2.
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):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
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:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 


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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
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.
Note

All displays (TFL) will use the term “Subjects” in order to reflect GSK Display Standards and CDISC 
SDTM/ADaM standards). The term "Subjects" is used to refer to the “Participants” in the protocol.
14.5.3.
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 
[Standards for the Transfer and Reporting of PK Data using HARP (“PK One” 
document)]. 
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. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: FRel
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.


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14.6.
Appendix 6: Derived and Transformed Data
14.6.1.
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.

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    
14.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.

Planned Treatment Duration is defined as one day.
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
14.6.3.
Efficacy
Not applicable.


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14.6.4.
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 Fredericia’s (QTcF) formula 
will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcF and/or QTcB 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 smallest unit of one more significant digit than the number of 
significant digits in the observed values will be added or subtracted (whichever is applicable) in 
order to impute the corresponding number. For example:
o
Example 1: 2 significant digits (as in “<2.2”) will be imputed as 2.19
o
Example 2: 1 significant digit (as in “>5”) will be imputed as 5.1
o
Example 3: 0 significant digits (as in “<0”) will be imputed as -1”.

There will be no imputation in the data listings; all values will be displayed as recorded in 
the database.


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14.6.5.
Pharmacokinetic
Calculation of Pharmacokinetic Parameter Values Not Described in Section 9 (refer to GUI_51487 for 
pharmacokinetic analysis information)
lambda_z  (terminal phase rate constant)

Slope of the line determined by linear regression of logarithmically transformed concentration v. time 
data
%AUCex  (percentage of AUC(0-) obtained by extrapolation)

Calculated as 100 x [AUC(0-) – AUC(0-tlast)] / AUC(0-)
14.6.6.
Population Pharmacokinetic (PopPK)
Not applicable.
14.6.7.
Pharmacodynamic 
Not applicable.


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14.7.
Appendix 7: Reporting Standards for Missing Data
14.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as if he/she 
completed all periods of the study including the last scheduled follow-up visit

Withdrawn subjects 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.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
14.7.2.
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 subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.


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14.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject 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. 
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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14.8.
Appendix 8: Values of Potential Clinical Importance
14.8.1.
Laboratory Values
Division of AIDS (DAIDS, Version 2.0, November 2014) AE grades 2, 3, and 4 of lab 
abnormalities will be listed by subject, period/treatment, visit, and actual date and time.
Haematology
Laboratory Parameter
Units
Category
Potential Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Haemoglobin
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
While Blood Cell Count (WBC)
x109/ L
3
12
Clinical Chemistry
Laboratory Parameter
Units
Category
Potential Clinical Concern Range
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
umol/L
∆from BL
↑ 44.2
Glucose (fasting)
mmol/L
3
9
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
Potential Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
Alkaline phosphatase
U/L
High
2x ULN
Total Bilirubin 
µmol/L
High
1.5xULN
Total Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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14.8.2.
ECG
ECG Parameter
Units
Potential Clinical Concern Range
Lower
Upper
Absolute
PR Interval
msec
<120
>200
QRS Interval
msec
< 60
>120
QTcF Interval
msec
< 320
>450
RR Interval
msec
< 600
> 1200
Change from Baseline
Increase from Baseline QTc
msec
>60
14.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Potential Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
<85
>140
Diastolic Blood Pressure
mmHg
<45
>90
Heart Rate
bpm
<40
>100
Respiratory Rate
Breaths/min
12
20
14.8.4.
Urinalysis
Per IDSL standards, a subject is considered to have urinalysis results of PCI, if there is an 
increase in Protein or an increase in Occult Blood results during the study, or if 
microscopy is performed.


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14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
14.9.1.
Population Pharmacokinetic (PopPK) Dataset Specification
Not applicable.
14.9.2.
Population Pharmacokinetic (PopPK) Methodology
Not applicable.


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14.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
14.10.1.
Pharmacokinetic / Pharmacodynamic Dataset Specification
Not applicable.
14.10.2.
Pharmacokinetic / Pharmacodynamic Methodology
Not applicable.


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14.11.
Appendix 11: Abbreviations & Trade Marks
14.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
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)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 


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Abbreviation
Description
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
14.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
Phoenix
SAS
WinNonlin


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14.12.
Appendix 12: List of Data Displays
14.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.12
Not applicable
Efficacy
Not applicable
Not applicable
Safety
3.1 to 3.18
3.1 to 3.3
Pharmacokinetic
4.1 to 4.7
4.1 to 4.5
Population Pharmacokinetic (PopPK)
Not applicable
Not applicable
Pharmacodynamic and / or Biomarker
Not applicable
Not applicable
Pharmacokinetic / Pharmacodynamic
Not applicable
Not applicable
Section
Listings
ICH Listings
1 to 35
Other Listings
36
14.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: 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
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
14.12.3.
Deliverables
Delivery [Priority] [1]
Description
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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14.12.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Participant Disposition for the Participant 
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC [1]
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC [1]
1.3.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch
ICH E3
SAC [1]
1.4.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC [1]
1.5.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations. For
crossover studies, only a total 
column should be used; the number 
of subjects will not be broken down 
by treatment group. 
SAC [1]
Protocol Deviation
1.6.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3. Only total column is needed
since this is a crossover study.
SAC [1]
Population Analysed
1.7.
Screened
SP1
Summary of Study Populations 
IDSL
SAC [1]


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.8.
Safety
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [1]
1.9.
Enrolled
DM11
Summary of Age Ranges
EudraCT, Only include total column 
SAC [1]
1.10.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT, Only 
include total column
SAC [1]
Prior and Concomitant Medications
1.11.
Safety
MH4
Summary of Medical Conditions
ICH E3 
SAC [1]
1.12.
Safety
CM1
Summary of Concomitant Medications
ICH E3
SAC [1]
14.12.5.
Efficacy Tables
Not applicable.
14.12.6.
Efficacy Figures
Not applicable.


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14.12.7.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
ICH E3, Include column for total across 
all intensities
SAC [1]
3.2.
Safety
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events by 
Overall Frequency
ICH E3
SAC [1]
3.3.
Safety
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity
ICH E3
SAC [1]
3.4.
Safety
AE15
Summary of Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participant and 
Occurrences)
FDAAA, EudraCT
SAC [1]
Laboratory: Chemistry 
3.5.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline 
ICH E3
SAC [1]
Laboratory: Hematology
3.6.
Safety
LB1
Summary of Hematology Changes from Baseline
ICH E3
SAC [1]
3.7.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
ICH E3
SAC [1]
Laboratory: Urinalysis
3.8.
Safety
UR1
Summary of All Urinalysis Results by Visit
SAC [1]
Laboratory: Hepatobiliary (Liver)
3.9.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC [1]


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
3.10.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC [1]
3.11.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL 
SAC [1]
3.12.
Safety
Table 10.17 
from Study 
HAI115711
Summary of Category of QTc Data by Treatment and Visit
SAC [1]
3.13.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC [1]
3.14.
Safety
Table 10.18
from Study 
HAI115711
Summary of Category of QTc Change from Baseline by 
Treatment and Visit
SAC [1]
3.15.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL, Include Baseline values
SAC [1]
Vital Signs
3.16.
Safety
VS1
Summary of Vital Signs
ICH E3
SAC [1]
3.17.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC [1]
Other
3.18.
Safety
CSSRS4
Listing of C-SSRS Suicidal Ideation or Behaviour Data
IDSL
SAC [1]


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14.12.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
As EG9
Line Plot of Selected Clinical Lab Tests Mean (95% CI) Change 
from Baseline by Treatment and Time
Only include scheduled visits and 
for selected lab test (ALT, AST, Bili) 
Plots will be presented with 
treatment groups overlaid
SAC [1]
ECG
3.2.
Safety
EG9
Line Plot of Mean (95% CI) Change from Baseline of ECG Data 
by Treatment and Time
Plots will be presented with 
treatment groups overlaid
Include plots on separate pages for 
QT, QTcF, QTcB, PR, and QRS
SAC [1]
Vital Signs
3.3.
Safety
As EG9
Line Plot of Mean (95% CI) Change from Baseline for Vital Signs 
by Treatment and Time 
Plots will be presented with 
treatment groups overlaid
Include plots on separate pages for 
SBP, DBP, HR
SAC [1]


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14.12.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Bioavailability
4.1.
PK
PK01
Summary of Plasma GSK3640254 Pharmacokinetic 
Concentration-Time Data by Treatment
SAC [1]
4.2.
PK
PK04
Summary of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by Treatment
SAC [1]
4.3.
PK
PK05
Summary Statistics of Log-Transformed Derived Plasma 
GSK3640254 Pharmacokinetic Parameters by treatment
SAC [1]
4.4.
PK 
Non-Standard1
Summary of Result of Plasma GSK3640254 Pharmacokinetic 
Parameter Treatment Comparisons for Relative Bioavailability
PK Parameters: AUC(0-inf), and 
Cmax 
Ratio: Test/Reference 
(Mesylate/HCl)
SAC [1]
4.5.
PK
PK14
Listing of Derived Plasma GSK3640254 Pharmacokinetic 
Parameters by treatment
Sort by participant and treatment
SAC [1]
4.6.
PK
PK08
Listing of Plasma GSK3640254 Pharmacokinetic Concentration-
Time Data by treatment
Sort by participant, period, day, and 
time
SAC [1]
4.7.
PK 
PK15
Listing of Individual Derived Plasma GSK3640254 
Pharmacokinetic Parameters Treatment Ratios
PK Parameters: AUC(0-inf), and 
Cmax 
Ratio: Test/Reference 
(Mesylate/HCl)
SAC [1]


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14.12.10. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Bioavailability
4.1.
PK
PK16b
Individual Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-log)
Linear and Semi-Log Scale 
Paged by participant, overlay all 
treatments for each participant. 
Include LOQ line in plot.
SAC [1]
4.2.
PK 
PK17
Mean Plasma GSK3640254 Concentration-Time Plots (Linear 
and Semi-log)
Linear and Semi-Log Scale 
By treatment. Use nominal times in 
X axis.
SAC [1]
4.3.
PK
PK18
Median Plasma GSK3640254 Concentration-Time Plots (Linear 
and Semi-log)
Linear and Semi-Log Scale 
By treatment. Use nominal times in 
X axis.
SAC [1]
4.4.
PK
PK28
Geometric Mean Treatment Ratio and 90% Confidence Interval 
of GSK3640254 PK Parameters for Relative Bioavailability 
Ratio: Test/Reference 
(Mesylate/HCl)
SAC [1]
4.5.
PK 
PK25
Comparative Plot of Individual Plasma GSK3640254 PK 
Parameters for Relative Bioavailability by treatment (Linear and 
Semi-log)
SAC [1]


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14.12.11. Pharmacokinetic Population (PopPK) Tables
Not applicable. 
14.12.12. Pharmacokinetic Population (PopPK) Figures
Not Applicable
14.12.13. Pharmacodynamic Tables
Not applicable.
14.12.14. Pharmacodynamic Figures
Not applicable.
14.12.15. Pharmacokinetic / Pharmacodynamic Tables
Not applicable.
14.12.16. Pharmacokinetic / Pharmacodynamic Figures
Not applicable.


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14.12.17. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC [1]
2.
Safety
ES3
Listing of Reasons for Study Withdrawal
ICH E3
SAC [1]
3.
Safety
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [1]
4.
Safety
TA2
Listing of Planned and Actual Treatments
IDSL
SAC [1]
Protocol Deviations
5.
Safety
DV2A
Listing of Important Protocol Deviations 
ICH E3
SAC [1]
6.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC [1]
Populations Analysed
7.
Safety
SP3A
Listing of Participants Excluded from Any Population
ICH E3
SAC [1]
Demographic and Baseline Characteristics
8.
Safety
DM4
Listing of Demographic Characteristics
ICH E3
SAC [1]
9.
Safety
DM10
Listing of Race
ICH E3
SAC [1]
Prior and Concomitant Medications
10.
Safety
CP_CM4
Listing of Concomitant Medications
IDSL
SAC [1]


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
11.
Safety
EX4
Listing of Exposure Data
ICH E3
SAC [1]
12.
Safety
Non-
Standard2
Listing of Meal Data
Identical to study 207187 Listing 54
SAC [1]
Adverse Events
13.
Safety
AE9CP
Listing of All Adverse Events
ICH E3
SAC [1]
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [1]
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text
IDSL
SAC [1]
Serious and Other Significant Adverse Events
16.
Safety
AE9CPa
Listing of Serious Adverse Events
ICH E3
SAC [1]
17.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [1]
18.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment
ICH E3
SAC [1]
Hepatobiliary (Liver)
19.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping Events
IDSL
SAC [1]
20.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping Events
IDSL
SAC [1]
21.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL
SAC [1]
All Laboratory
22.
Safety
LB13
Listing of Reference Ranges for Clinical Laboratory Tests
SAC [1]
23.
Safety
LB6
Listing of Clinical Chemistry Data
SAC [1]


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Safety
LB6
Listing of Hematology Data
SAC [1]
25.
Safety
UR2B
Listing of Urinalysis Data 
ICH E3 Sorted by visit 
SAC [1]
26.
Safety
LB6
Listing of All Clinical Chemistry Laboratory Data for Participants with Any 
Value of Potential Clinical Importance OR Outside Normal Range
ICH E3. Display ALL labs for a 
subject who experienced a value of 
potential clinical importance or a 
value outside of normal range
SAC [1]
27.
Safety
LB6
Listing of Clinical Chemistry Laboratory Values of Potential Clinical 
Importance
SAC [1]
28.
Safety
LB6
Listing of All Hematology Data for Participants with Any Value of Potential 
Clinical Importance OR Outside Normal Range
ICH E3. Display ALL labs for a 
subject who experienced a value of 
potential clinical importance or a 
value outside of normal range
SAC [1]
29.
Safety
LB6
Listing of Hematology Laboratory Values of Potential Clinical Importance
SAC [1]
30.
Safety
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC [1]
ECG
31.
Safety
EG4
Listing of All ECG Findings
IDSL. Sort by treatment/period and 
visit
SAC [1]
32.
Safety
EG6
Listing of Abnormal ECG Findings
IDSL
SAC [1]


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
33.
Safety
EG4
Listing of All ECG Values for Participants with Any Value of Potential Clinical 
Importance
IDSL. Display ALL ECGs for a 
subject who experienced a value of 
potential clinical importance
Display ALL ECGs for a subject 
who experienced a value of 
potential clinical importance.
SAC [1]
Vital Signs
34.
Safety
VS5
Listing of Vital Signs 
IDSL
SAC [1]
35.
Safety
VS5
Listing of All Vital Signs Data for Participants with Any Value of Potential 
Clinical Importance
IDSL. Display ALL vital signs for a 
subject who experienced a value of 
potential clinical importance
SAC [1]
14.12.18. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Statistical Analysis
36.
PK
SAS 
output of 
Table 4.4
SAS Output of Summary Results of GSK3640254 PK 
Parameter Treatment Comparisons for the Relative 
Bioavailability
SAC [1]


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14.13.
Appendix 13: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request