Clinical trial NCT03984812
Conditions: HIV Infections
Keywords: DAIDS, FTIH, HIV-1, MAD, SAD
Sponsor: ViiV Healthcare
Start date: 2019-06-17; Completion date: 2020-03-23
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, FTIH study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetic (PK)/pharmacodynamic (PD) attributes of GSK3732394 in healthy subjects. The data gathered in this study will further enable clinical development of GSK3732394 in HIV-infected subjects. Approximately 72 healthy subjects will be randomized in the FTIH study. Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each subject in the SAD cohort will receive a single dose of blinded GSK3732394 or blinded placebo (PBO) in 6:2 ratio. Part 1 will consist of five ascending single-dose cohorts with an additional expansion cohort included as needed. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), randomized to four weekly doses of blinded GSK3732394 or blinded PBO in 6:2 ratio to be administered on Days 1, 8, 15, and 22.

Detailed description:

Arms: arm 1: GSK3732394 10 milligram (mg) or PBO will be administered by subcutaneous (SC) injection to the subjects. arm 2: GSK3732394 40 mg or PBO will be administered by SC injection to the subjects. This is projected dose, dose will be based on PK/PD results from preceding dosing cohorts. arm 3: GSK3732394 130 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 3 will be based on PK/PD results from preceding dosing cohorts. arm 4: GSK3732394 350 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 4 will be based on PK/PD results from preceding dosing cohorts. arm 5: GSK3732394 600 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 5 will be based on PK/PD results from preceding dosing cohorts. arm 6: GSK3732394 800 mg or PBO will be administered by SC injection to the subjects. This is a projected dose and will be given if necessary. The dose administered in Part 1, Cohort 6 (if necessary) will be based on PK/PD results from preceding dosing cohorts. arm 7: GSK3732394 130 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The dose administered in Part 2, Cohort 1 will be based on PK/PD results from preceding dosing cohorts. arm 8: GSK3732394 400 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The administered dose in Part 2, Cohort 2 will be based on PK/PD results from preceding dosing cohorts. arm 9: GSK3732394 600 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The administered dose in Part 2, Cohort 3 will be based on PK/PD results from preceding dosing cohorts and will not exceed the maximum exposure observed in SAD (Part 1).
Interventions: intervention 1: GSK3732394 intervention 2: Placebo
Intervention descriptions: intervention 1: It is composed of an anti-CD4 adnectin, an anti-N17 adnectin, and a peptide inhibitor. This will be provided as a solution for injection in 1 (milliliter) mL glass vials with the unit dose strength of 100 mg/mL intervention 2: Placebo will comprise of 0.9% weight per volume (w/v) sodium chloride.

Protocol documents:
Prot_000.pdf: 
2017N341355_03
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207863
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TITLE PAGE
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of GSK3732394 in Healthy Participants
Protocol Number: 207863
Short Title: GSK3732394 First-Time-in-Human Study 
Compound 
Number:
GSK3732394 
Sponsor Name and Legal Registered Address: 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, local law requires that the Clinical Trial sponsor is a local company 
legal entity.  In these instances, the appropriate company to be identified as Sponsor must 
be agreed with the global ViiV Healthcare clinical team and signed off by the Vice 
President, Global Research and Medical Strategy
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study.
Medical Monitor Name and Contact Information Refer to the Study Reference 
Manual
Regulatory Agency Identifying Number(s): IND Number 131394
Approval Date: 12-SEP-2019
Copyright 2019 the ViiV Healthcare group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 03, DNG 2017N341355_03
12-SEP-2019
Amendment 02, DNG 2017N341355_02
02-JUL-2019
Amendment 01, DNG 2017N341355_01
06-JUN-2019
Original Protocol, DNG 2017N341355_00
11-APR-2019
Amendment 03, 12-SEP-2019
Overall Rationale for the Amendment:  This amendment is based on 3 criteria.
1) Initial dose escalation data following completion of Cohort 1 indicated that Cohort 6 
in the study design will be required.  Flexible language to this affect has been 
removed.
2) Initial dose escalation data following completion of Cohort 1 indicate that anti-drug 
antibodies (ADA) have the potential to appear earlier than indicated pre-clinically.  
Day 7 and Day 10 collection of samples for ADAs have been added in Part 1 and for 
Day 8 in Part 2.
3) The previous consensus between the Sponsor and the Study Site on CD4+ T-cell 
count and CD4 percent values screening values under Amendment 02, requires 
further clarification.
Section # and Name
Description of Change
Brief Rationale
Synopsis Schematic, 
Section 5.1 – Overall 
Design, Paragraph 1 
and Part 1, Paragraph 2
Revised to reflect that Cohort 6 is now a part of the study 
design and is not optional.  Participant numbers are 
updated to reflect Cohort 6 inclusion (Part 1 n = 48 from n 
= 40).
See item 1 above. 
Section 2 – Schedule of 
Activities, Table 2 and 
Table 4
Day 7 and Day 10 collection of samples for ADAs have 
been added in Part 1 and for Day 8 in Part 2.
See item 2 above.
Section 6.2 – Exclusion 
Criteria, Criterion 24
and Section 3.3.1-Risk 
Assessment Table -2nd 
bullet for CD4+ cell 
reduction / Impairment 
in Immune Function
Absolute CD4+ T-cell count <500 cells or CD4 percent 
(CD4%) outside of the normal range for the reference 
laboratory (32% to 64%).
See item 3 above.
Section 8.1.1.1 –
Serious Allergic 
Reaction, 2nd bullet
A delayed hypersensitivity reaction AE with systemic 
symptoms and/or end-organ effects (i.e., serum 
sickness, vasculitis, fever, arthralgia/myalgia, nephritis, 
etc.) of moderate to severe intensity (Grade 2-4 by 
DAIDS criteria)
Bolded language added to 
provide clarity
Not applicable
Other administrative changes for items such as 
typographical errors or grammatical corrections.
Clarity
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................20
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................22
3.3.1.
Risk Assessment .........................................................................23
3.3.2.
Benefit Assessment.....................................................................25
3.3.3.
Acute Monitoring in FTIH Studies ................................................25
3.3.4.
Overall Benefit : Risk Conclusion.................................................25
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................27
5.1.
Overall Design ............................................................................................27
5.2.
Number of Participants ...............................................................................29
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
5.5.1.
Human Starting Dose Forecast....................................................32
5.5.2.
Dose Elevation Strategy ..............................................................33
5.5.3.
Transition to Multiple Ascending Dose Period..............................35
5.5.4.
Dose Escalation Algorithms .........................................................36
5.5.5.
Human Safety and Dose Escalation Committee...........................37
6.
STUDY POPULATION...........................................................................................37
6.1.
Inclusion Criteria.........................................................................................38
6.2.
Exclusion Criteria........................................................................................39
6.3.
Lifestyle Restrictions...................................................................................41
6.3.1.
Meals and Dietary Restrictions ....................................................41
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................41
6.3.3.
Activity .........................................................................................41
6.4.
Screen Failures...........................................................................................41
7.
TREATMENTS.......................................................................................................43
7.1.
Treatments Administered............................................................................43
7.2.
Dose Modification .......................................................................................43
7.3.
Method of Treatment Assignment ...............................................................43
7.4.
Blinding.......................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability..............................................44
7.6.
Treatment Compliance................................................................................45
7.7.
Concomitant Therapy..................................................................................45
7.8.
Treatment after the End of the Study ..........................................................45
8.
DISCONTINUATION CRITERIA.............................................................................46
 
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8.1.
Discontinuation of Study Treatment ............................................................46
8.1.1.
Study Stopping Criteria................................................................46
8.1.1.1.
Serious Allergic Reaction............................................47
8.1.1.2.
Hematological parameters:.........................................48
8.1.1.3.
Pharmacokinetic Dose Adjustment/Stopping 
Criteria for Part 1 (SAD) and Part 2 (MAD) .................48
8.1.1.4.
Liver Enzymes: ............................................................48
8.1.1.5.
Vital Signs/ECGs:.........................................................48
8.1.2.
Individual Participant Stopping Criteria ........................................49
8.1.2.1.
Liver Chemistry Stopping Criteria ...............................49
8.1.2.2.
QTc Stopping Criteria.................................................50
8.1.2.3.
Other Individual Participant Safety-related 
Stopping criteria .........................................................50
8.1.3.
Temporary Discontinuation ..........................................................50
8.1.4.
Rechallenge.................................................................................50
8.2.
Withdrawal from the Study..........................................................................51
8.3.
Lost to Follow Up........................................................................................51
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................51
9.1.
Efficacy Assessments.................................................................................52
9.2.
Safety Assessments ...................................................................................52
9.2.1.
Physical Examinations.................................................................52
9.2.2.
Vital Signs....................................................................................52
9.2.3.
Electrocardiograms......................................................................53
9.2.4.
Clinical Safety Laboratory Assessments ......................................53
9.2.5.
T cell Assessments......................................................................54
9.3.
Adverse Events...........................................................................................54
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................54
9.3.2.
Method of Detecting AEs and SAEs.............................................55
9.3.3.
Follow-up of AEs and SAEs.........................................................55
9.3.4.
Regulatory Reporting Requirements for SAEs .............................55
9.3.5.
Pregnancy ...................................................................................56
9.4.
Treatment of Overdose...............................................................................56
9.5.
Pharmacokinetics .......................................................................................56
9.6.
Pharmacodynamics ....................................................................................57
9.7.
Non-Pharmacokinetic Sample Collection ....................................................57
9.8.
Biomarkers .................................................................................................57
9.8.1.
Immunogenicity Assessments - Anti-GSK3732394 
antibodies ....................................................................................57
9.8.2.
Immunogenicity Assessments - Immune activation......................57
9.9.
Health Economics.......................................................................................58
10. STATISTICAL CONSIDERATIONS........................................................................58
10.1.
Sample Size Determination ........................................................................58
10.2.
Populations for Analyses ............................................................................58
10.3.
Statistical Analyses.....................................................................................58
10.3.1.
Safety Analyses...........................................................................58
10.3.2.
Pharmacokinetic Analyses...........................................................59
10.3.3.
Interim Analyses ..........................................................................59
10.3.4
Final Analyses .............................................................................61
 
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11. REFERENCES.......................................................................................................62
12. APPENDICES........................................................................................................63
12.1.
Appendix 1: Study Governance Considerations..........................................63
12.1.1.
Regulatory and Ethical Considerations ........................................63
12.1.2.
Financial Disclosure.....................................................................63
12.1.3.
Informed Consent Process ..........................................................63
12.1.4.
Data Protection............................................................................64
12.1.5.
Committees Structure ..................................................................64
12.1.6.
Publication Policy.........................................................................64
12.1.7.
Dissemination of Clinical Study Data ...........................................65
12.1.8.
Data Quality Assurance ...............................................................65
12.1.9.
Source Documents ......................................................................66
12.1.10. Study and Site Closure ................................................................66
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................67
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................69
12.3.1.
Definition of AE............................................................................69
12.3.2.
Definition of SAE..........................................................................70
12.3.3.
Recording AE and SAE................................................................71
12.3.4.
Reporting of SAE to Study Sponsor.............................................72
12.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................74
12.4.1.
Definitions....................................................................................74
12.4.2.
Contraception Guidance ..............................................................75
12.4.2.1.
Male participants ........................................................75
12.4.2.2.
Female participants ....................................................75
12.4.3.
Collection of Pregnancy Information ............................................76
12.4.3.1.
Male participants with partners who become 
pregnant.....................................................................76
12.4.3.2.
Female Participants who become pregnant................76
12.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................78
12.6.
Appendix 6: Division Of AIDS (DAIDS) Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 2.1 July 
2017 ...........................................................................................................80
12.7.
Appendix 7: Abbreviations and Trademarks................................................81
12.8.
Appendix 8: Protocol Amendment History...................................................83
 
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1.
SYNOPSIS
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of GSK3732394 in Healthy Participants
Short Title: GSK3732394 First Time in Human Study 
Rationale:
With the introduction of effective combination therapies, Acquired immunodeficiency 
syndrome (AIDS)-related morbidity and mortality has declined significantly and, in many 
parts of the world, human immunodeficiency virus (HIV)-infection has been transformed 
into a treatable chronic condition. Despite the availability of a number of potent and safe 
antiretroviral agents (ARVs) across different therapeutic classes and the availability of 
one pill per day regimens, the burden of lifetime daily dosing remains a significant 
challenge. Successful antiretroviral therapy is dependent on sustaining high levels of 
adherence. Long-acting antiretroviral therapies have the potential to simplify anti-HIV 
dosing demands, which could provide meaningful improvements in adherence to 
prescribed therapies. Increased adherence to combination antiretroviral regimens has 
been associated with improved immunologic and virologic response, reduction in the 
emergence of HIV-resistance, and lower AIDS-related morbidity and mortality. 
GSK3732394 could provide meaningful improvement in the lives of patients living with 
HIV. This novel recombinant protein is composed of three independent and distinct 
biological inhibitors of HIV-1, which may act synergistically with respect to potency and 
resistance and as a long-acting agent that can be administered subcutaneously. The 
projected profile of the compound suggests minimal cross-resistance with currently 
available ARV therapies, and with once-per-week dosing, GSK3732394 may improve 
adherence. As a large protein, many of the complications inherent with orally 
administered small molecules, including drug-drug interactions and food restrictions, 
may be mitigated. Finally, GSK3732394 may have the added convenience of being able 
to be self-administered at home; a necessary feature for a parenteral therapy targeting 
stable-switch patients.
The development plan for GSK3732394 is to investigate the drug as a mono-entity (with 
three mechanisms of action within a single compound), as well as part of a long-acting 
combination regimen.
The current study is a double-blind (sponsor-unblinded), randomized, placebo-controlled, 
two-part, first-time-in-human (FTIH) single- and multiple-ascending dose study to assess 
the safety, tolerability, and pharmacokinetic/pharmacodynamic attributes of 
GSK3732394. The inclusion of healthy participants enhances the safety of the trial by 
allowing the Sponsor to understand the potential immunologic effects of the compound, 
such as impact on the number or function of cluster of differentiation (CD)4+ T-cells and 
the impact of anti-drug antibodies on the pharmacokinetics of GSK3732394, before the 
compound is introduced to immune-compromised patients infected with HIV. The data 
gathered in this study will enable further clinical development of GSK3732394 in 
HIV-infected study participants.
 
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Objectives and Endpoints:
Objective
Endpoint
Primary
To assess the safety and tolerability of single and 
multiple doses of GSK3732394 in healthy participants.
GSK3732394 safety parameters: adverse events; post-
baseline values and changes over time of clinical 
laboratory evaluations (haematology, clinical chemistry, 
urinalysis), vital signs, and ECG parameters from 
predose values
Secondary
To describe the pharmacokinetic (PK) profile of single 
and multiple doses of GSK3732394 in healthy 
participants.
Derived PK parameters for GSK3732394, as data 
allow: 

Part 1 (single dose): AUC(0-t), AUC(0-∞), Cmax, Tmax, 
tlag, Clast, tlast, t1/2,CL/F

Part 2 (Repeated once weekly [QW] dosing):
o First week: AUC(0-t), AUC(0-∞), Cmax, tmax, tlag
o Last week: AUC(0-) Cmax, tmax, C, t1/2, CL/F. 
To examine dose proportionality following single and 
multiple doses of GSK3732394, as data allow.
PK linearity assessment using derived PK parameters, 
as data allow:

Part 1 (single dose): AUC(0-∞), Cmax

Part 2 (Repeat QW dosing): AUC(0-), Cmax, C
To assess accumulation of GSK3732394 after multiple 
doses, as data allow.
Accumulation indices for PK parameters assessed 
across first and last doses of multiple dosing, as data 
allow: RAUC(0-), RCmax, RC.
To characterise CD4 receptor occupancy (RO) profile 
of single and multiple doses of GSK3732394.
Percent of CD4 RO.
To investigate the relationship between GSK3732394 
exposures and CD4 RO.
Cmax, Ctrough, %RO
To characterise potential immunologic impact on, and 
immune responses to, healthy participants who receive 
a single or multiple dose(s) of GSK3732394.

Change from baseline in CD3/CD4/CD8 and 
activated T-cell counts and percentages.

Change from baseline in CD4 median
fluorescence intensity (MFI).

Titers and incidence of anti-GSK3732394 
antibodies.
AUC(0-t) = Area under the plasma concentration time curve from zero (pre-dose) to t; AUC(0-) = Area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time; Cmax= Maximum observed 
concentration; tmax= Time of occurrence of Cmax; tlag = lag time; Clast = last observable concentration, tlast = time of 
last observable concentration; t1/2 = Apparent terminal phase half-life; CL/F= Apparent clearance; AUC(0-) = Area 
under the concentration-time curve at steady state within the dosing interval, C(or Ctrough)= trough serum 
concentration; Accumulation ratios calculated as the ratio of Week 4 (last dose) to Week 1 (first dose) PK 
parameters: RAUC(0-) = AUC(0-) on Week 4  to AUC(0-) on Week 1, RCmax = Cmax on Week 4 to Cmax on Week 1, 
RC= Con Week 4 to Con Week 1.
 
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Overall Design and Schematic:
This is a double-blind (sponsor-unblinded), randomized, placebo-controlled, single and 
multiple-ascending-dose study to evaluate the safety, tolerability and 
PK/pharmacodynamics (PD) of GSK3732394 in healthy participants.  All doses will be 
administered subcutaneously.  This study will be executed in 2 Parts.
In Part 1, the proposed dosing schedule is designed to investigate single ascending doses 
(SAD) of GSK3732394.  In Part 2, the proposed dosing schedule is designed to 
investigate multiple ascending doses (MAD) of GSK3732394 administered weekly for 
four doses.
Dose escalation decisions, including the determination of the subsequent dose in Part 1, 
will be determined based on safety, pharmacokinetic and pharmacodynamic endpoints 
(receptor occupancy) and will be governed by a Safety and Dose Escalation Committee 
(SDEC).
Schematic:
PART 1 
(6 GSK3732394 : 2 PBO)
SAD Cohort 1
(n = 8)
SAD Cohort 2
(n = 8)
SAD Cohort 3
(n = 8)
SAD Cohort 4
(n = 8)
SAD Cohort 5
(n = 8)
SAD Cohort 6
(n = 8)
Single SC Dose
(C RO)
10mg
(<10%)
40mg
(≤25%)
130mg
(≤70%)
350mg
(≤90%)
600mg
(≤95%)
Up to 800mg or to 
repeat a prior dose
PART 2
(6 GSK3732394 : 2 PBO)
MAD Cohort 1
(n = 8)
MAD Cohort 2
(n = 8)
MAD Cohort 3
(n = 8)
4 Subcutaneous Doses (Ctrough RO)
Administered Once Weekly (QW)
130mg
(<70%)
400mg
(≤90%)
600mg
(≤95%)
Note: Doses shown in schematic are nominal and intended to demonstrate general concepts relating to factors 
of escalation as a base case. Dose escalation in Part 1 will be based on target receptor occupancy/exposure and 
governed by safety and PK stopping criteria. Transition to Part 2 will be after the completion of dosing and 
evaluation of SAD Cohort 4 participants and after the predicted exposure of the starting MAD dose is within 
that observed with SAD dosing – maximum predicted AUC, Cmax not exceeding the average maximum 
observed in evaluated SAD cohorts (QW = once every week.).
Number of Participants:
In Part 1, a sufficient number of healthy adults will be screened to provide 8 participants 
for randomization within each of the SAD dosing cohorts. Overall, up to 48 participants 
will be included depending on the number of cohorts required.
In Part 2, a sufficient number of healthy adults will be screened to provide 8 participants 
for randomization within each of the MAD dosing cohort. Overall, up to 24 participants 
will be included depending on the number of cohorts required.
If participants prematurely discontinue the study, additional replacement participants may 
be enrolled at the discretion of the Sponsor.  Assignment of replacement numbers will be 
detailed in the Study Reference Manual (SRM).
 
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Treatment Groups and Duration:
Study participants will have a screening visit within 30 days prior to the first dose of 
GSK3732394 /Placebo (PBO).
In Part 1, participants will receive a single dose of GSK3732394 or PBO (6:2) on Day 1. 
Safety, PK and PD assessments will be performed at timepoints specified in the schedule 
of activity (SOA). Participants will remain in the clinic until the completion of the Day 
14 procedures and will return to the clinic on Days 17, 21, and 24 for follow-up 
assessments, and an end-of-study evaluation on Day 28.
In Part 2, participants will receive doses of GSK3732394 or PBO (6:2) given at 
anticipated weekly intervals. Participants will remain in the clinic until the completion of 
the Day 35 procedures and will return to the clinic on Days 39, 42 and 46 for follow-up 
assessments, and an end-of-study evaluation on Day 49.
Duration of participation through follow-up may be longer if actual PK parameters differ 
significantly from predicted values (e.g. if half-life is significantly longer than the 
predicted); but will not exceed five half-lives.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the SOA, are essential and required for study 
conduct. This section lists the procedures and parameters of each planned study 
assessment. The exact timing of each assessment is listed in the SOA. 
If assessments are scheduled for the same nominal time, then the assessments
should occur in the following order:
1. Vital signs 
2. 12 lead electrocardiogram (ECG)
3. PK/PD sampling
Note: The timing of the assessments should allow blood draws to occur at the
exact nominal time.

The Institutional Review Board/ Independent Ethics Committee (IRB/IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme 
or amendment of the Informed Consent Form.

No more than 500 mL of blood will be collected over each 56-day period during the 
duration of the study, including any extra assessments that may be required.

For serum biomarkers, baseline is defined as Day -1 post-randomization.
 
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Table 1
SCREENING AND FOLLOW-UP/EARLY DISCONTINUATION ASSESSMENTS (Part 1 and Part 2)
Procedure
Screening
(up to 30 days 
prior to Day 1) 1
Follow-up/Early 
Discon Visit 
(~28 days post 
last dose)
Notes
Follow-up Visit to occur approximately 28 days after last study drug administration or 5 half-lives 
(as determined from Part 1 PK data), whichever is longer.
Outpatient Visit
X
X
Informed Consent
X
Inclusion and Exclusion Criteria 
X
Demography
X
Medical History 
X
Full Physical Examination (Including 
Height and Weight at the screening visit)
X
Additional examinations may be performed, or brief examinations made full examinations, by the 
Investigator, as deemed necessary (e.g. where safety or laboratory findings indicate).
Target/Brief Physical Examination
X
12-lead ECG 
X
X

Triplicate ECGs will be used to determine participant eligibility at screening.

Additional tests may be performed by the Investigator, as deemed necessary (e.g. where 
safety or laboratory findings indicate).  Tests will be conducted within site specified standards.
Vital signs
X
X
Urine Drug Screen
X
Alcohol Screen 
X
Cotinine Screen 
X
Pregnancy Test
X
X
HIV, Hep B and Hep C Screen
X
Tuberculosis Test
X
Laboratory assessments
X
X
Pharmacokinetic sample
X
Pharmacodynamic sample
X
Anti- GSK3732394 antibodies
X
Adverse Event Review
X
X
The collection of SAEs will be from the screening visit to the end of the study
Concomitant Medication Review
X
X
1.
Screening must be performed within 30 days prior to receiving the dose of GSK3732394/PBO on Day 1
 
 
 
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Table 2
Part 1 - All Cohorts Inpatient Days -1 to Day 14
Procedure
Day
Day 
-1
Day 1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pre-
dose
0 h
0.5 h
1 h
2 h
4 h
8 h
12h
24h
48h
72h
96h
120h
144h
168h
192h
216h
240h
264h
288h
312h
Admission to Unit
X
Discharge from Unit
X
Urine Drug 
Alcohol/Screen/Cotinine
X
Brief Physical Exam
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Pregnancy Test
X
Meals
Per site usual practice
Laboratory assessments1
X
X
X
X
X
X
X
Randomization
X
Drug administration
X
Pharmacokinetic sample2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic 
sample2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Antidrug Antibody sample
X
X
X
X
Biomarker sample3
X
Urine sample4
X
X
SAE/AE Review5
<=================================================================================================================>
Con Med Review
<=================================================================================================================>
 
 
 
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1.
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis.
2.
The number of PK and PD sampling time points may be reduced/extended in subsequent dosing groups once human PK data are available from initial SAD 
dosing cohorts. An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification. 
3.
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms
4.
Urine will be collected at Day -1 (10mL) and for 24 hours after dose administration for GSK3732394-related material identification in the highest dose cohort 
only.  Details for urine collection and interval is included in the SRM.
5.
To include assessment of injection site(s) as appropriate (see also Section 3.3.1 and Section 8.1, and the SRM).
 
 
 
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Table 3
Part 1 - Outpatient Visit Days 17, 21, 24, 28
Procedure
Day
17
21
24
281, 2
Brief Physical Exam
X
X
X
X
Vital signs
X
X
X
X
12-lead ECG
X
X
Pregnancy Test
X
Laboratory assessments3
X
X
X
X
Pharmacokinetic sample4,5
X
X
X
X
Pharmacodynamic sample4,5
X
X
X
X
Antidrug Antibody sample
X
X
Biomarker sample6
Adverse Event Review7
<=====================================================================================>
Con Med Review
<=====================================================================================>
1.
In the event of terminal half-life longer than predicted, PK/PD and laboratory assessments will occur every four days until an estimated 5 half-lives have elapsed
2.
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at Day 28 Visit, these procedures and those listed in Table 1 Screening and Follow-
up/Early Discontinuation” for Follow-up/Early Discontinuation Visit (~28 days post last dose) may be considered the same.
3.
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis.
4.
An aliquot of this PK serum sample will be used for GSK3732394-related material (serum metabolites) identification.
5.
PK samples collection on Days 17, 21 and 24 are conditional on the PK assessment at up to Day 7 during the conduct of the study and may be adjusted as data become 
available.
6.
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms
7.
To include assessment of injection site(s) as appropriate (see also Section 3.3.1 and Section 8.1, and the SRM).
 
 
 
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Table 4
Part 2 - All Cohorts Inpatient Days -1 to Day 17
Procedure
Day
Day -1
Day 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pre-dose
0 h
0.5 h
1 h
2 h
4 h
8 h
12h
24h
48h
72h
96h
120h
144h
Pre-dose
0 h
24h
48h
72h
96h
120h
144h
Pre-dose
0 h
24h
48h
Admission to Unit
X
Urine Drug/ 
Cotinine/Alcohol Screen
X
Brief Physical Exam
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
Pregnancy Test
X
Meals
Per site usual practice
Laboratory assessments1
X
X
X
X
X
X
X
X
X
Randomization
X
Drug administration
X
X
X
Pharmacokinetic sample2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Antidrug Antibody sample
X
X
X
Biomarker sample3
X
Urine sample4
X
Adverse Event Review5
<=================================================================================================================>
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<=================================================================================================================>
 
 
 
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1.
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis.
2.
An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification. Refer to the windows allowance agreement attached to 
the SRM for timing of trough samples to be drawn on non-dosing days. 
3.
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms
4.
Urine will be collected at Day -1 (10mL) and for 24 hours after dose administration for GSK3732394-related material identification after the 4th MAD dose. Details for urine 
collection and interval is included in the SRM.
5.
To include assessment of injection site(s) as appropriate (see also Section 3.3.1 and Section 8.1, and the SRM).
 
 
 
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Table 5
Part 2 - All Cohorts Inpatient Days 18 to Day 35
Procedure
Day
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
72h
96h
120h
144h
Pre-dose
0h
0.5h
1h
2h
4h
8h
12h
24h
48h
72h
96h
120h
144h
168h
192h
216h
240h
264h
288h
312h
Brief Physical Exam
X5
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
Pregnancy Test
X
Meals
Per site usual practice
Laboratory assessments1
X
X
X
X
X
X
X
Drug administration
X
Pharmacokinetic sample2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Antidrug Antibody sample
X
X
X
Biomarker sample3
Urine sample4
X
Discharge from unit
X
Adverse Event Review5
<=================================================================================================================>
Con Med Review
<=================================================================================================================>
1.
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis.
2.
An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification. Refer to the windows allowance agreement attached to the 
SRM for timing of trough samples to be drawn on non-dosing days.
3.
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms.
4.
Urine will be collected for 24 hours after dose administration for GSK3732394-related material identification after the fourth (4th) MAD dose only.
5.
To include assessment of injection site(s) as appropriate (see also Section 3.3.1 and Section 8.1 and the SRM).
 
 
 
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Table 6
Part 2 - Outpatient Visits Days 38, 42, 46, 49
Procedure
Day
38
42
46
491
Brief Physical Exam
X
X
X
X
Vital signs
X
X
X
X
12-lead ECG
X
X
Pregnancy Test
X
Laboratory assessments2
X
X
X
X
Pharmacokinetic sample3
X
X
X
X
Pharmacodynamic sample
X
X
X
X
Antidrug Antibody sample
X
X
Biomarker sample4
Adverse Event Review5
<=====================================================================================>
Con Med Review
<=====================================================================================>
1.
In the event of terminal half-life longer than predicted from SAD data, PK/PD and laboratory assessments will occur every four days until an estimated 5 half-lives have elapsed.
2.
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis.
3.
An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification. Refer to the windows allowance agreement attached to the 
SRM for timing of trough samples to be drawn on non-dosing days.
4.
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms
5.
To include assessment of injection site(s) as appropriate (see also Section 3.3.1 and Section 8.1 and the SRM).
 
 
 
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The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic/biomarker or other assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) and to ensure appropriate monitoring. 
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the Sponsor and site study files but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF
3.
INTRODUCTION
3.1.
Study Rationale
This is a double-blind (sponsor-unblinded), randomized, placebo-controlled, first-time-in-
human (FTIH) study in a combined single-ascending and multiple-ascending dose 
protocol to assess the safety, tolerability, and pharmacokinetic/pharmacodynamic 
attributes of GSK3732394 in healthy participants.  The data gathered in this study will 
enable further clinical development of GSK3732394 in HIV-infected patients.
3.2.
Background
With the introduction of effective combination therapies, Acquired immunodeficiency 
syndrome (AIDS)-related morbidity and mortality has declined significantly and, in many 
parts of the world, human immunodeficiency virus (HIV)-infection has been transformed 
into a treatable chronic condition. Despite the availability of a number of potent and safe 
antiretroviral agents (ARVs) across different therapeutic classes and the availability of 
one pill per day regimens, the burden of lifetime daily dosing remains a significant 
challenge. Successful antiretroviral therapy is dependent on sustaining high levels of 
adherence. Long-acting antiretroviral therapies have the potential to simplify anti-HIV 
dosing demands, which could provide meaningful improvements in adherence to 
prescribed therapies.  Increased adherence to combination antiretroviral regimens has 
been associated with improved immunologic and virologic response, reduction in the 
emergence of HIV-resistance, and lower AIDS-related morbidity and mortality.
GSK3732394 is a novel biologic with three distinct, non-overlapping mechanisms to 
prevent HIV-1 viral entry. It is composed of an anti-CD4 adnectin, an anti-N17 adnectin, 
and a peptide inhibitor. Adnectins are derived from the 10th type III domain of the human 
fibronectin protein. They are small (~12kDa), compact proteins without disulfide bridges 
and are monomeric in nature. Adnectins are part of the immunoglobulin superfamily, and 
although there is little sequence similarity, the structure of an adnectin resembles an 
antibody variable domain. Thus, adnectins possess binding loops akin to the 
complementarity determining region (CDR) of an antibody, which can be altered to bind 
to a target of interest.
Specifically, the αCD4 adnectin binds to domains 2 and 3 of the cellular CD4 receptor,
preventing necessary conformational change within the virus that allows for effective 
 
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viral entry into the host CD4+ T-cell, thereby inhibiting an early step in the viral 
replication lifecycle. While the anti-CD4 component of GSK3732394 works in a similar 
manner to ibalizumab, a recently approved antiretroviral monoclonal antibody that targets 
Domain 2 of the CD4 receptor, the CD4 receptor binding sites for the two molecules are 
not the same. The αN17 adnectin targets the α-helical N17 region of gp41 and the peptide 
inhibitor targets gp41 upstream of the N17 adnectin. The peptide inhibitor was designed 
to bind to the same α-helical region as enfuvirtide. The αN17 adnectin and the peptide 
inhibitor have similar mechanisms of action in that they both block the formation of the 
6-helical bundle required for virus fusion. At the N-terminal part of GSK3732394 is a 
human serum albumin molecule (HSA), which decreases the antiviral EC50 by about 10-
fold, but significantly enhances the PK of the compound.
Pre-clinical models have demonstrated GSK3732394 is active against most HIV-1 
subtypes. The in vivo efficacy of GSK3732394, as a mono-entity, was comparable to a 
highly active anti-retroviral therapy (HAART) regimen through one-month of dosing in a 
humanized mouse model of HIV-1 infection [GlaxoSmithKline Document Number
2017N344293_00]. The potency and efficacy of the molecule is driven by the action of 
the αCD4 adnectin binding to its target. Not only does this function as a specific inhibitor 
of gp160 bound to the same CD4 molecule, it synergizes the potency of the anti-gp41 
inhibitors (both the adnectin and peptide) by (1) greatly increasing its local concentration 
at the site of action and (2) allowing it to inhibit gp160 that are bound to other CD4 
molecules. This ability to work in trans is the reason why high potency can be obtained at 
low receptor occupancy (RO) on CD4. For instance, in vitro studies showed that an RO 
of ~2.7% of bound CD4 molecules results in an EC90 for GSK3732394.
The projected profile of the compound suggests minimal meaningful cross-resistance 
with currently available ARV therapies. This includes other entry inhibitors, as no cross 
resistance was observed against maraviroc. Also, although the isolated peptide in 
GSK3732394 does exhibit some cross-resistance with enfuvirtide, in the context of the 
full length GSK3732394, minimal cross-resistance is observed against enfuvirtide-
resistant viruses. A similar observation is made with the αCD4 adnectin piece from 
GSK3732394 and ibalizumab, which could share resistance pathways. However, in the 
context of GSK3732394, no cross-resistance is observed.  Pre-clinical pharmacokinetics 
support the consideration of GSK3732394 as a long-acting agent that can be self-
administered subcutaneously. As a large protein, many of the complications inherent with 
orally administered small molecules, including drug-drug interactions and food 
restrictions, may be mitigated. Taken together, these data support continuing compound 
development.
Following its successful evaluation in healthy subjects, GSK3732394 would proceed into 
testing in HIV-infected patients. The transition from healthy participants to HIV-infected 
participants means that, if CD4 binding is maintained, there will be the additional binding 
of the anti-N17 and gp-41 components of the compound to the available HIV virions, 
which is only possible in infected persons.  Given that CD4 counts are generally lower in 
infected patients, the CD4 RO established in healthy participants should either be 
maintained or higher in HIV-infected patients. Thus, with the maintained or improved 
CD4 binding and the additional N17 and gp-41 binding, it is expected that doses resulting 
in targeted ROs in healthy participants should be efficacious in HIV-infected patients.
 
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Detailed information relating to non-clinical pharmacology, safety pharmacology, 
pharmacokinetics and metabolism, toxicology and other pre-clinical data with 
GSK3732394 can be found in the GSK3732394 Investigator’s Brochure (IB) 
(GlaxoSmithKline Document Number 2018N358742_00).
3.3.
Benefit/Risk Assessment
This section outlines the risk assessment and mitigation strategy for this protocol. More 
detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of GSK3732394 may be found in the Investigator’s Brochure
(GlaxoSmithKline Document Number 2018N358742_00).
The main safety concerns with GSK3732394 administration to humans are based on 
theoretical risks relating to the subcutaneous injection of a protein based biologic agent 
and include immunogenicity, allergic reactions, and injection site reactions. In addition, 
reduction in CD4+ expression / count has been noted in preclinical studies with repeated 
dosing of GSK3732394 and with other investigational biologics which target CD4+ 
T-cells (e.g. keliximab and clenoliximab).
Consistent with Sponsor guidance for early phase studies, GSK3732394 will be 
administered in a hospital-based in-patient facility, with sufficient overnight facilities and 
emergency care capabilities.
To minimize the risk of the initial human administration of GSK3732394, a sentinel 
dosing strategy will be utilized in the SAD cohorts: one (1) participant will receive 
GSK3732394 and one (1) participant will receive PBO. After the Sponsor Medical 
Monitor and Primary Investigator have reviewed the safety data through 48 hours post-
dose, the remaining participants from that cohort will be dosed.  This 48-hour dosing 
stagger may be reduced following Cohort 1 if there are no safety or tolerability concerns.
 
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3.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3732394 (also refer to Clinical Investigator’s Brochure (IB, GlaxoSmithKline Document Number 2018N358742_00)
CD4+ cell reduction / 
Impairment in Immune 
Function
In the one-month GLP toxicity study (IB Section 4, GlaxoSmithKline Document Number 
2018N358742_00), conducted in hCD4 transgenic mice, a decrease in the absolute and 
percentage CD4+ T-cells was seen at GSK3732394 doses of 50 and 500 mg/kg (human 
equivalent dose ~284 mg and ~2,835 mg, respectively). This reduction was fully resolved by the 
end of the post-treatment period (Day 57) in mice dosed at 50 mg/kg and partially resolved in 
mice dosed at 500 mg/kg. Similar effects on CD4+ T cell count were observed in the one-month 
GLP TDAR study (CIB Section 4, GlaxoSmithKline Document Number 2018N358742_00); also 
conducted in hCD4 mice.
In an ELISpot assay, conducted in PBMCs from human donors exposed to concentrations of 
GSK3732394 up to 100 µg/mL (projected Cmax at the equivalent human dose of ~1,600 mg), 
there were no dose-dependent changes in MHC Class II-restricted IFN-γ response to a pool of 
peptide antigens from common viruses (IB Section 4, GlaxoSmithKline Document Number 
2018N358742_00). However, in the TDAR study, there was a decrease in anti-KLH IgG 
antibody response was observed at 500 mg/kg; antibody response returned to baseline during 
the 8-week post-treatment period. There was no observed adverse effect on antibody response 
in hCD4 mice dosed at 50 mg/kg. 
Overall, preclinical results suggest reduction in CD4+ T-cell count is likely to precede 
measurable impairment in T-cell-dependent immune function. Based on current predictions, it is 
estimated that CD4+ T-cell reduction could be evident at a forecast Cmax of 93.9 µg/mL (human 
equivalent exposure to 50 mg/kg in mice) following repeated dosing/prolonged exposure.
Eligibility is limited to healthy adult participants with 
no medical history of immune compromise. 
Participants will be excluded if they have screening 
absolute CD4+ T-cell counts <500 cells or CD4 
percent (CD4%) outside of the normal range for the 
reference laboratory (32% to 64%).  See Section 6.2. 
CD3/CD4/CD8 and activated T-cell counts and 
percentages will be monitored throughout the study. 
Dosing will be stopped if two participants experience 
confirmed Grade 2 reductions in absolute CD4+ T-
cell count (Division of AIDS [DAIDS] Criteria v 2.1; 
Appendix 6, Section 12.6) or have confirmed >25% 
reduction in baseline %CD4, following an injection of 
GSK3732394. 
Dosing will also be stopped if one participant 
experiences a confirmed Grade 3 reduction of CD4+ 
T-cell count (Appendix 6, Section 12.6), or have a 
confirmed drop in CD4% >40%, see Section 8.1.
Immunogenicity
As with any protein- or peptide-based therapy, GSK3732394 has the potential to induce antidrug 
antibodies. The chemical structure and characteristics of GSK3732394 suggest the compound 
has medium to high risk of inducing anti-drug antibodies (immunogenicity) in humans. 
Anti-GSK3732394 antibodies have been observed in nonclinical studies in cynomolgus 
monkeys and human CD4 (hCD4) mice. Although ADA responses were also noted in the GLP 
toxicology study in hCD4 mice treated with 50 or 500 mg/kg every other day for one month (IB 
Section 4, GlaxoSmithKline Document Number 2018N358742_00) in general, systemic 
exposure and PD (RO) were maintained throughout the dosing period. 
Animal studies are generally not predictive of immunogenicity and sequelae related to 
immunogenicity in humans.  
The emergence of anti-GSK3732394 antibodies will be 
actively monitored and characterized during the 
207863 study, including the impact of ADAs on drug 
clearance / pharmacokinetics of the compound.  See 
Section 9.8.1.
Cytokine Release 
In an in vitro cytokine release assay (CRA, IB Section 4, GlaxoSmithKline Document Number 
Participants will be closely monitored in an in-patient 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Syndrome
2018N358742_00), a dose-responsive IL-8 cytokine release was observed in human PBMCs 
incubated with GSK3732394 (starting at concentrations as low as 1.0 µg/mL). No GSK3732394-
related changes were observed with IL-2, IL-6, IL-10, IFN-γ or TNFα. Results of CRA assays 
are often not well-correlated with the human experience.
The physical properties and biological target of GSK3732394 suggest the potential for 
GSK3732394 to induce hyper-immune activation and clinically significant cytokine release is 
believed to be quite low.
unit throughout the dosing of GSK3732394 and for 
14 days of post-dosing follow-up. On-site study 
personnel qualified to manage acute cases of 
serious allergic reactions, see Section 8.1.1.1.  
Discontinuation criteria are provided in Section 8.1.
Percent activated CD4 cells will be monitored 
routinely. 
Biomarkers of immune reaction/activation will be 
collected and analyzed in participants exhibiting 
signs and symptoms consistent with hypersensitivity. 
See Section 9.8.1.
Local injection site 
reactions
Among hCD4+ transgenic mice treated as part of the one-month GLP toxicity study, there was a 
slight increase in the incidence and/or severity of minimal to mild inflammation observed in the 
injection site dermis and/or subcutis of animals dosed with GSK3732394 versus vehicle. These 
changes were reversible.
Injection sites will be actively monitored for adverse 
reactions following administration of GSK3732394, as 
part of routine physical assessment. Adverse reactions 
will be recorded within the safety database as adverse 
events as appropriate (see also Section 8.1.1).
Drug interactions
No formal drug-interaction studies have been conducted with GSK3732394. However, because 
of GSK3732394’s biological format the potential for drug/drug interactions is low.
Appropriate exclusion criteria relating to the use of 
concurrent medications throughout the study are 
provided in Section 6.2.
 
 
 
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3.3.2.
Benefit Assessment
This is a study in healthy participants and as such there is no expected benefit to 
administration of GSK3732394. Participation in this study may contribute to the 
development of new therapies for HIV. There may be benefit to individual participants 
from the medical evaluations and assessments that could identify conditions that the 
participant was previously unaware of.
3.3.3.
Acute Monitoring in FTIH Studies
Consistent with Sponsor Guidance for early phase studies, this study will be conducted in 
a hospital based clinical research unit with prior experience with first-time-in-human 
trials and with immediate access to hospital facilities for the treatment of medical 
emergencies.  In addition, a standard battery of safety related assessments will be actively 
monitored. Refer to the SOA for safety assessments. 
3.3.4.
Overall Benefit : Risk Conclusion
To date, GSK3732394 has not been administered to human participants. Given the non-
clinical profile to date, the overall risk to participants at the proposed single and multiple 
doses of GSK3732394 is predicted to be low.  Routine safety and tolerability will be 
evaluated from reported adverse events (AEs), scheduled physical examinations, vital 
sign measurements, 12-lead ECGs, and clinical laboratory test results as well as 
continued observation by clinical staff.  
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies.  The in-house periods as 
detailed in the Time and Events table will allow for continuous medical monitoring for all 
subjects following the first dose in each treatment group.  Subjects will only be 
discharged from the unit 14 days post-dosing, if the Investigator deems it safe to do so.
Considering the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with GSK3732394 are justified by the 
anticipated benefits that may be afforded by the future development of a new therapy in 
an area of continued need.  
 
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4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
To assess the safety and tolerability of single and 
multiple doses of GSK3732394 in healthy participants.
GSK3732394 safety parameters: adverse events; post-
baseline values and changes over time of clinical 
laboratory evaluations (hematology, clinical chemistry, 
urinalysis), vital signs, and ECG parameters from 
pre-dose values
Secondary
To describe the pharmacokinetic (PK) profile of single 
and multiple doses of GSK3732394 in healthy 
participants.
Derived PK parameters for GSK3732394, as data allow: 

Part 1 (single dose): AUC(0-t), AUC(0-∞), Cmax, Tmax, 
tlag, Clast, tlast, t1/2,CL/F

Part 2 (Repeated QW dosing):
o First week: AUC(0-t), AUC(0-∞), Cmax, tmax, tlag
o Last week: AUC(0-) Cmax, tmax, C, t1/2, CL/F. 
To examine dose proportionality following single and 
multiple doses of GSK3732394, as data allow.
PK linearity assessment using derived PK parameters, 
as data allow:

Part 1 (single dose): AUC(0-∞), Cmax

Part 2 (Repeat QW dosing): AUC(0-), Cmax, C
To assess accumulation of GSK3732394 after multiple 
doses, as data allow.
Accumulation indices for PK parameters assessed 
across first and last doses of multiple dosing, as data 
allow: RAUC(0-), RCmax, RC.
To characterise CD4 receptor occupancy (RO) profile 
of single and multiple doses of GSK3732394.
Percent of CD4 RO.
To investigate the relationship between GSK3732394 
exposures and CD4 RO.
Cmax, Ctrough, %RO
To characterise potential immunologic impact on, and 
immune responses to, healthy participants who receive 
a single or multiple dose(s) of GSK3732394.

Change from baseline in CD3/CD4/CD8 and 
activated T-cell counts and percentages.

Change from baseline in CD4 median
fluorescence intensity (MFI).

Titers and incidence of anti-GSK3732394 
antibodies.
Exploratory
To model the relationship between GSK3732394 
exposures and CD4 RO.
Estimating parameters descriptive of the relationship 
including Concentration resulting in 50% RO (EC50), as 
data allow.
To explore the correlation between GSK3732394 
exposure and observed safety outcomes.
Occurrence of AEs /laboratory abnormalities and 
corresponding plasma concentrations / doses of 
GSK3732394.
To explore serum and urine metabolite(s) 
investigations of GSK3732394.
Identification of any compound-related degradants
AUC(0-t) = Area under the plasma concentration time curve from zero to t; AUC(0-) = Area under the concentration-
time curve from time zero (pre-dose) extrapolated to infinite time; Cmax= Maximum observed concentration; tmax= 
Time of occurrence of Cmax; tlag = lag time; Clast = last observable concentration, tlast = time of last observable 
concentration; t1/2 = Apparent terminal phase half-life; CL/F= Apparent clearance; AUC(0-) = Area under the 
concentration-time curve at steady state within the dosing interval, C= trough serum concentration; Accumulation 
ratios calculated as the ratio of Week 4 (last dose) to week 1 (first dose) PK parameters: RAUC(0-) = AUC(0-) on 
Week 4  to AUC(0-) on Week 1, RCmax = Cmax on Week 4 to Cmax on Week 1, RC= Con Week 4 to Con Week 1.
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase 1, 2 Part, double-blind (sponsor-unblinded), randomized, placebo-
controlled, single and multiple-ascending-dose study to evaluate the safety, tolerability 
and pharmacokinetics/pharmacodynamics of GSK3732394 in healthy participants. Up to 
approximately 72 healthy participants will be randomized in Part 1 (SAD, n=48) and Part 
2 (MAD, n=24). The total number of cohorts in the SAD will be six and the total number 
of cohorts in the MAD will be a maximum of three. All dosing and post-dosing follow-up 
(through 14 days post-dosing) will be conducted in a hospital based inpatient clinical trial 
unit. A final follow-up visit will take place at least 14 days after discharge from the 
inpatient unit (approximately 28 days post-last dose). Time & Events (T&E) Schedule of 
Activities tables are included in the Schedule of Activities section of this protocol 
(Section 2).
A summary of the overall study design, including proposed doses, sample size, and order, 
is presented in Table 7 and Table 8.  
 
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Table 7
Part 1 (Base case)
Cohort
Target CD4 Receptor 
Occupancy (RO)
Forecast Dose1
(mg)
Forecast Pharmacology
Min
Max
Ibalizumab based leveraging
1
<10%
<60%
10
No activity
2
≤25%
≤80%
40
Some minimal activity
3
≤70%
≤95%
130
Sparingly active
4
≤90%
≤98%
350
Active (if target mediated drug disposition 
[TMDD], likely observed)
5
≤95%
≤100%
600
Active (if TMDD, likely observed)
1  Doses listed are proposed/base case.  After Cohort 1, actual doses will be decided based on PK, RO, and safety 
data from prior cohorts.
Note:  An additional cohort (6) of up to 800mg or to repeat a prior dose may be included (See Section 5.5.2).
Table 8
Part 2 (Base case)
MAD
(6 active: 2 PBO)
Cohort 1
(n= 8)
Cohort 2
(n= 8)
Cohort 3
(n= 8)
Four weekly SC doses1
130mg
400mg
600mg
1  Doses listed are proposed/base case.  Actual doses will be decided based on PK, RO, and safety data from prior 
cohorts in Part 1 and Part 2.
As described in detail below, the proposed dosing schedule is designed to investigate 
single doses of GSK3732394 in Part 1 and then, at a suitable cross-over point, begin 
repeated once-weekly dosing of GSK3732394 in Part 2.
Part 1 (SAD):
In Part 1, the proposed dosing schedule is designed to investigate SAD of GSK3732394 
in healthy participants. All doses will be administered subcutaneously.
The SAD portion of the study will be conducted in six separate cohorts of eight healthy 
adult participants each. Each of the participants in the SAD cohorts will receive a single 
dose of blinded GSK3732394 or blinded PBO (GSK3732394 : PBO = 6:2, per their 
randomization assignment). Details of the starting dose and dose escalation can be found
in Section 5.5.1 and Section 5.5.2, respectively. Dose escalation decisions, including the 
determination of subsequent doses in Part 1, will be determined by the Safety and Dose 
Escalation Committee (SDEC). See Section 5.5.5.
To conservatively assess safety, at the start of each of the SAD cohorts, 2 out of these 
participants will serve as sentinel participants with one receiving blinded GSK3732394 
and the other receiving blinded PBO. The investigator may stagger dose administration 
time as needed for the sentinel participants. These sentinel participants will be followed 
clinically for 48 hours after dose administration to monitor for emergence of adverse 
events. If there are no safety concerns, in the judgment of the PI, on review of the 
48-hour safety data (e.g. vital signs, ECGs, and adverse events) for the sentinel 
 
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participants, the remaining 6 participants will subsequently be administered either 
GSK3732394 or PBO, according to randomization schedules. The investigator may 
stagger dose administration time as needed.  The 48-hour dosing stagger may be reduced 
following Cohort 1 if there are no safety or tolerability concerns (see Section 5.5.2, 
Section 5.5.3, and Section 5.5.4).
Part 2 (MAD):
In Part 2, the proposed dosing schedule is designed to investigate multiple ascending 
doses (MAD) of GSK3732394 in healthy participants administered weekly for a total of 
four doses. All doses will be administered subcutaneously.
Part 2 consists of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), 
each with 8 participants (GSK3732394 : PBO = 6:2) who will receive four weekly doses
of GSK3732394 or PBO on Days 1, 8, 15, and 22. Details of starting dose and dose 
escalations in Part 2 (MAD) can be found in Section 5.5.3.
The starting MAD dose will be a dose identified in the SAD that achieves mean RO at 
Ctrough of at least 20%. The maximum dose in the MAD will not exceed that cleared in the 
SAD portion of the trial and will not be >9x the starting MAD dose.  The predicted 
exposure (Cmax) for the final MAD dosing per a given cohort (fourth dose) will not 
exceed the maximum exposure observed in SAD.  The intermediate dose, used in MAD 
Cohort 2, will be approximately halfway between the starting and maximum doses 
administered in MAD Cohorts 1 and 3, respectively.
The start of the MAD investigation will be after completion of dosing and evaluation of 
SAD Cohort 4 participants and after the predicted exposures of MAD Cohort 1 are within 
that covered by exposures examined within the SAD portion of the trial – maximum 
predicted Cmax (of any of the four doses administered to a MAD Cohort) not exceeding 
the average maximum observed in evaluated SAD cohorts. See Section 5.5.3.
Participants in both Part 1 and Part 2 will have a screening visit within 30 days prior to 
first dose and a follow-up visit 28 days after the last dose in both Part 1 (SAD) and Part 2 
(MAD) of the study. Duration of study participation will be approximately 4 weeks for 
SAD participants and 7 weeks for MAD participants, unless the actual PK parameters 
differ significantly from predicted base case values.
5.2.
Number of Participants
In Part 1, sufficient healthy adults will be screened into the study to provide 
approximately 8 participants per cohort. Overall, up to 48 participants will be included 
depending on the number of cohorts required.
In Part 2, sufficient healthy adults will be screened into the study to provide 
approximately 8 participants per cohort. Overall, up to 24 participants will be included 
depending on the number of cohorts required.
Participants will not be replaced if the reason for discontinuation from the study is due to 
a safety concern.  If participants prematurely discontinue the study for non-safety 
 
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reasons, additional replacement participants may be enrolled at the discretion of the 
Sponsor.  These replacement participants will be assigned to the same treatment sequence 
and same dose as the corresponding participant who prematurely discontinued from the 
study.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit and the last scheduled procedure shown in the 
Schedule of Activities. 
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
This first-time-in-human (FTIH) study will assess the safety, tolerability, and PK/PD 
attributes of GSK3732394 in healthy participants.  The data gathered in this study will 
enable further clinical development of GSK3732394 including a Phase 2a proof-
of-concept study in HIV-infected participants.
A healthy participant population is appropriate for this FTIH study. This will allow for 
robust data to be collected in a population free of confounding co-morbidities, 
concomitant medications, and other intrinsic and extrinsic factors that increase variability 
of these data. In addition, the preclinical safety profile of GSK3732394 supports 
evaluation in healthy participants.
In Part 1 (SAD), a flexible dose escalation design is planned. The starting dose selection 
is based upon preclinical safety, PK and PD data as described in Section 5.5.1. Dose 
escalation will be based on PK, PD and safety data from all prior cohorts. The dose 
escalation jumps between cohorts are projected to progressively decline from the 
previous dose of GSK3732394 and will not exceed 4-fold (see Section 3.3.1 and Section 
5.5).
Transition to Part 2, the multiple ascending dose portion of the study, is dependent on 
clearance of exposures correlating with an anticipated therapeutic effect in humans (mean 
Ctrough RO of at least 20% in Part 1). Subsequent dosing in Part 2 will only be 
administered if there is no identified dose-limiting toxicity identified at the corresponding 
dose in the SAD portion of the study (see Section 5.5.2, Section 5.5.3, and Section 5.5.4). 
The inpatient observation period of at least 14 days (or at least 3 half-lives if longer) after 
the last dose provides an opportunity to ensure that adverse events have resolved or are 
resolving prior to discharge of participants from the inpatient unit. Additionally, the 
inpatient period provides a controlled environment that reduces the likelihood of 
participants engaging in routine daily activities that may result in adverse events or 
otherwise confound the safety evaluation of study treatment.
 
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This study includes a PBO arm within each dosing cohort to allow for a valid evaluation 
of adverse events attributable to GSK3732394 versus those independent of 
investigational therapy.
5.5.
Dose Justification
Human PK was forecast using allometric scaling of cynomolgus monkey IV and SC PK 
data. PK characteristics were identified using murine PK studies in transgenic 
humanized-CD4 mice investigating GSK3732394 PK at doses up to 500 mg/kg. These 
data support the human PK parameters allometrically predicted from the cynomolgus
monkey and described linear PK and the absence of target mediated drug disposition 
(TMDD) whilst binding CD4.
A starting dose of 10 mg is proposed which compares conservatively across a variety of 
approaches used to evaluate safe starting doses. The chosen starting dose assumes the 
most potent response determined preclinically forecasting a Ctrough CD4 receptor 
occupancy of <10%. The consequences of binding at this rate of occupancy suggests no 
CD4+ T cell reduction and no pharmacological activity. The subsequent dosing cohorts 
will target prespecified receptor occupancies allowing for flexibility in responding to 
emerging PK and pharmacological data.
Predicted Pharmacokinetics
GSK3732394 is predicted to have linear pharmacokinetics with an elimination half-life of 
approximately 50 hours. The evaluation of the preclinical data and the prediction process 
are detailed in the Clinical Pharmacology Review (GlaxoSmithKline Document Number
2018N365256_01). Briefly, the pharmacokinetics were allometrically scaled from 
observed cynomolgus PK which closely matched those of mice. There was no preclinical 
evidence of target mediated drug disposition. However, an FDA approved αCD4 
monoclonal antibody (ibalizumab) has demonstrated TMDD within its preclinical and 
clinical data and these data have been used to anticipate, if TMDD should occur, at what 
doses this is likely to happen (when CD4 receptor occupancy is >90% for a period of 
time).
The predicted human PK have been used to forecast starting and subsequent doses (Table 
9). These data will be assessed as PK data is acquired within the SAD. Attention will be 
paid to any emerging evidence of supra-proportional increases in exposure (although 
TMDD is not expected) and/or any extension in PK.
Table 9
Predicted parameters for a two-compartment PK model describing 
GSK3732394’s human disposition
Parameter
Predicted Value
%CVa
Clearance (mL/hr/kg)
1.45
30
V1 (mL/kg)
58.6
20
Q2 (mL/hr/kg)
1.60
ND
V2 (mL/kg)
35.7
ND
KA (hr-1)
0.0778
20
F2
0.582
ND
ALAG2 (hr)
0.151
ND
a Assumed variability for human PK simulations
ND – not determined
 
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5.5.1.
Human Starting Dose Forecast
The 10 mg starting dose is forecast to cause trough CD4 receptor occupancy (RO) of 4% 
and maximal CD4 RO of 53%. The forecast is based on predicted human PK (based on 
cyno PK) and RO observed with GSK3732394 concentrations in transgenic hCD4 mice. 
The starting dose of 10 mg is lower than the assessed thresholds [Table 10]:
1. It is lower (28.4-fold and 2.84-fold following application of a 10x safety factor) than 
the human allometric equivalent of the HED NOAEL (established at 50 mg/kg in 
hCD4 Tg mice) 
2. It is lower (130.4-fold) than the NOAEL exposure matching based on Cmax.
3. It is lower (83-fold) than the MABEL as calculated in vitro in hPBMCs.
4. It is lower (2-fold) than the MABEL as calculated in vivo in the Transcure HIV-
infected mice.
5. It is lower (4.4-fold) than ibalizumab's molecular weight-adjusted minimally effective 
single dose of 1 mg/kg (equivalent to 44mg GSK3732394). The 10 mg starting dose 
for GSK3732394 also yields CD4 RO that is lower than that established with 
ibalizumab's minimally effective dose – where GSK3732394 predicted mean RO at 
Cmax for 10 mg is 53% vs. ibalizumab at 1mg/kg Ctrough is 50-70% RO.
6. It only exceeds (3.3-fold) the predicted dose for a human adult established within an 
in vitro anti-viral assay where the results have little relevance given that the assay 
assessed binding and anti-viral effects across the complete GSK3732394 compound, 
including the anti-N17 and peptide components. This effect can only be considered 
in the presence of HIV virus, not in non-HIV-infected persons.
Table 10
Summary of starting dose assessments ordered by technique
Approach
Predicted Dose 
Human Adult (mg)
PD-coverage (dose-fold) 
to 10 mg starting dose
HED with safety factor of 10x (50 mg/kg hCD4 mouse 
toxicology)
28.4
2.84-fold
NOAEL exposure matching (50 mg/kg hCD4 mouse 
toxicology)
1,304
130.4-fold
MABEL
CD4 receptor occupancy In vitro
20% RO in hPBMCs
830
83-fold
Anti-viral effect In vitro
Human trough equivalent to EC50 in NLRepRlic Virus in MT-2 
cells
3.3
0.33-fold
In vivo
Human trough equivalent to mouse trough associated with 
minimal effect in Transcure anti-viral experiment achieving 
10% RO
20
2-fold
Other marketed products
Equivalent (adjusting for molecular weights) to minimally 
effective dose of 1 mg/kg Ibalizumab
44
4.4-fold
Note: safety-fold coverage for predicted human exposure at 10 mg dose to NOAEL exposure in hCD4 mouse: Cmax 
(148-fold) and AUC (57-fold)
 
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Safety Margins
Table 11 below lists the predicted safety cover for GSK3732394 at various planned doses 
in the SAD FTIH study and indicate that even with highest dose planned (800 mg), there 
is a ~2-fold margin for Cmax:
Table 11
Projected mean GSK3732394 AUC, Cmax, calculated C-average and 
Ctrough following single doses of GSK3732394, with Fold Cover to 
hCD4 NOAEL exposures
Dose
(mg)
Predicted Human Plasma Exposures
Safety Margins
AUC 
(µg.h/mL)
Cmax
(µg/mL)
C-average 
(µg/mL)
Ctrough
(µg/mL)
AUC
Cmax
C-average
Ctrough
10
57
0.6
0.3
0.09
57.2
147.7
200.1
349.7
40
228
2.5
1.4
0.38
14.3
36.9
50.0
87.4
130
741
8.3
4.4
1.23
4.4
11.4
15.4
26.9
350
1996
22.2
11.9
3.32
1.6
4.2
5.7
10.0
600
3422
38.1
20.4
5.70
1.0
2.5
3.3
5.8
8001
4562
50.8
27.2
7.59
0.7
1.8
2.5
4.4
Key: 
NOAEL exposures in hCD4 transgenic mouse are:
AUC = 3,260 µg.h/mL; Cmax = 93.9 µg/mL; calculated C-average = 67.9 µg/mL; Ctrough at 48 h = 33.2 µg/mL
Safety margin = At mouse 50mg/kg NOAEL exposure parameter value/predicted human plasma exposure parameter
1 An additional cohort of up to 800mg, or to repeat a previous dose, may be included as required
5.5.2.
Dose Elevation Strategy
The dose elevation strategy applied the predicted PK and trough concentration – receptor 
occupancy relationship to predetermine target receptor occupancies for the ascending 
dose cohorts. The target receptor occupancies were chosen leading to minimize the jump 
magnitude between latter cohorts and optimised against a forecast dose-response 
relationship based on preclinical pharmacology. The PK – RO model was that defined 
from the hCD4 mouse data and extrapolated to human. The receptor occupancy 
consequences are described in Table 12 relative to ibalizumab anti-viral and CD4 data.
 
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Table 12
The receptor occupancy consequences relative to ibalizumab anti-
viral and CD4 data
Cohort
Target CD4 Receptor 
Occupancy (RO)
Forecast Dose
(mg)
Forecast Pharmacology
Min
Max
Ibalizumab based leveraging
1
<10%
<60%
10
No activity
2
≤25%
≤80%
40
Some minimal activity
3
≤70%
≤95%
130
Sparingly active
4
≤90%
≤98%
350
Active (if TMDD, likely observed)
5
≤95%
≤100%
600
Active (if TMDD, likely observed)
This escalation plan assumes an effective dose 90 (ED90) of ~400 mg allowing further 
escalation to 600 mg. The jump ratios between cohorts are: 4.0x, 3.5x, 2.9x and 1.7x. 
This allows characterization of the concentration-RO relationship for modelling and 
interpolation.
Based on ibalizumab-based leveraging of pharmacology, the first dose is forecast to be 
completely inactive. The second cohort is forecast to only achieve a scarce time-period 
where GSK3732394 levels would be forecast to be minimally pharmacologically active. 
The third cohort was chosen so that GSK3732394 levels would be above the minimal 
activity threshold with minimal duration at fully active levels. The fourth and fifth 
cohorts were chosen so that GSK3732394 would be at active levels with only the 
duration extending in the move from cohorts 4 to 5.
After each cohort, the data will be reviewed – the data consists of the PK, RO, 
relationship between PK and RO, and safety data. At each cohort dose review, a dose 
will be proposed that meets the RO requirements for the next dosing cohort. Dosing will 
be adjusted if it exceeds a 4-fold jump, if the PK is non-linear (as assessed by PK 
modelling), or if there are any observations that indicate the dose would carry a risk of 
safety concerns.
If there are no safety concerns, then the endorsement of the next cohort’s dose can occur
considering the PK and RO assessment:
1.
If the PK is either: as predicted (cohort 1) and/or displays dose linearity (Cohort 2+)
2.
If the RO is as predicted and follows the forecast PK-RO relationship
If either of these criteria are not met, then the following assessments should be made and 
endorsed by the sponsor and their review panel:
Pharmacokinetics
•
If the PK displays non-linear characteristics i.e. TMDD or ADA, the PK data will be 
modelled to accurately predict the time course of the subsequent dose meeting the RO 
target. 
•
If the exposure caused by the subsequent dose increases by more than 4-fold, then a 
dose will be chosen to constrain exposure to a maximum predicted increase of 4-fold.
 
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Receptor Occupancy
If the PK-RO relationship is not as forecast, then this will be re-evaluated using the 
available human data to anticipate:
•
The ED90
o
If ED90>600mg, then adjust doses and cohorts, as needed and include an 
additional cohort with a maximum dose of 800mg as required.
o
If ED90<600mg, then adjust doses and cohorts, as needed with a dose jump 4
times and including an intervening cohort, as required.
5.5.3.
Transition to Multiple Ascending Dose Period
The starting dose in Part 2 (MAD) will be a dose identified in Part 1 (SAD) that achieves 
a mean RO at Ctrough of at least 20%. The predicted exposure (Cmax) for MAD doses will 
not exceed the maximum exposures observed in SAD and will not be >9x the starting 
MAD dose.  The intermediate MAD dose will be approximately halfway between the 
starting and maximum MAD dose.  If a mean RO at Ctrough of at least 20%, is not 
achieved in Part 1 Cohorts 1 through 4; then Part 1 Cohort 5 and an additional Cohort (if 
needed) will complete prior to transitioning to Part 2 (MAD).
The start of the MAD investigation will be after completion of dosing and evaluation of 
SAD Cohort 4 participants and after the predicted exposure of the starting MAD dose is 
within that observed with SAD dosing – maximum predicted Cmax not exceeding the 
average maximum observed in Part 1 cohorts.
Part 1 dose reviews will be performed if either the PK or PK-RO relationship deviates
from that which is forecast. Schematics showing the decision flow-charts for Part 1
(SAD) escalation(s) (Figure 1) and the transition to Part 2 (MAD), with escalation 
strategy for Part 2 (Figure 2), are available in Section 5.5.4.
 
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5.5.4.
Dose Escalation Algorithms
Figure 1
Decision Flow for Dose Escalation(s) in Part 1
No
Yes
No
Project RO and propose next 
dose at 4-fold increase
Yes
Part 1 Dosing – with sentinel dosing
Review Dose Limiting Toxicities (DLTs)
See Section 8.1.11
Yes
No
If Target Mediated 
Drug Disposition 
(TMDD) is Observed 
(or there is a supra-
proportional increase 
in exposure), then:
Perform TMDD 
modelling
Project RO and 
propose next dose 
at 4-fold increase
Adjust/extend PK 
and/or RO 
sampling times
Transition to Part 2 
will be conditional 
on completion of 
Part 1
No
Analyze PK, RO, and PK-RO Relationship
Yes
If < 600mg, then
adjust doses and 
cohorts, as needed
If >600mg, then
adjust doses and cohorts, as 
needed, and include Cohort 6
A maximum dose of 800 mg may be considered, if required 
to achieve >90% ROtrough
Is PK Linear?
Is observed PK as predicted (see Table 112)?
Predicted PK-RO 
met?
Estimate and update 
ED90
Are DLT Stopping Criteria Met?
1  See Section 8.1.1
2  See Table 11
 
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Figure 2
Decision Flow from Part 1 (SAD) to Part 2 MAD
No
No
Yes
Escalate to 
next Part 1 
Dose
No
Yes
See section 8.1.11
Use a dose from Part 1 with 20% RO at Ctrough as starting dose for Part 2 (Cohort 1)
Perform PK modelling (determine proportion of 
subjects) and determine influence on PK, then 
evaluate TMDD effect.
(If TMDD is observed in Part 1, then transition to 
Part 2, conditional on completion of Part 1)
Escalate to next dose cohort (in 
Part 2) – steady state exposures 
≤ latest Part 1 dose and 
≤ NOAEL Cmax 93.9 µg/mL)
1. Predict a dose that will have steady state 
exposures ≤ last Part 1 Cohort and ≤ NOAEL Cmax
93.9µg/mL
2. Account for immunogenicity and update 
immunogenicity influence on PK with Part 2, 
Cohort 2.
3. Evaluate for a dose / dosing regimen that will have 
steady state exposures ≤ last Part 1 Cohort and
≤ NOAEL Cmax 93.9µg/mL for Part 2, Cohort 3.
20% RO at Ctrough in Part 1 
and Cohort 4 Complete?
DLT Stopping Criteria Met?
Is PK influenced by 
immunogenicity?
Yes
Transition to Part 2 (MAD) dependent on Ctrough in Part 1 (SAD) of at least 20% RO
1  See Section 8.1.1
5.5.5.
Human Safety and Dose Escalation Committee
This study will utilize a Safety and Dose Escalation Committee (SDEC) made up of at 
least the following: Sponsor and Site staff (including safety physicians and clinicians, PI, 
Sub-Investigator, Medical Monitor, clinical pharmacokineticist/ pharmacologist, data 
manager, pharmacovigilance, and statistician) and/or their delegates. The committee will 
evaluate data including but not limited to: AEs, vital signs, laboratory findings, ECG 
parameters, and PK/PD data. The SDEC will meet when data are available from a 
minimum of four active treated participants through the Day 7 assessments in Part 1 and 
through the Day 29 assessments in Part 2.  The blinding of personnel is discussed in 
Section 7.4. The construct and function of the SDEC will be documented in a Charter.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISICS
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
3. Participants who are able to understand and comply with protocol requirements and 
timetables, instructions, and protocol-stated restrictions
WEIGHT
4. Body mass index within the range 19-30 kg/m2 inclusive, in addition to a weight 
range of 50kg - 100kg.
SEX
5. Male and female healthy volunteers.
Male participants:
A male participant must agree to use contraception as detailed in Appendix 4 (Section 
12.4) of this protocol during the treatment period and for at least 100 days after the 
last dose of study treatment and refrain from donating sperm during this period.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 4
(Section 12.4), not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in (see Appendix 4
(Section 12.4), OR

A WOCBP who agrees to follow the contraceptive guidance in (see Appendix 4
(Section 12.4) during the treatment period and for at least 28 days prior to first 
dose, and 40 days after, the last dose of study treatment.
 
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INFORMED CONSENT
6. Capable of giving signed informed consent as described in Appendix 1 (Section 
12.1.3) which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.
7. A signed and dated written informed consent must be completed prior to the 
participant’s entry into the study.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
History or presence of cardiovascular, dermatological, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting 
a risk when taking the study intervention; or interfering with the interpretation of 
data.
2.
Abnormal blood pressure (as determined by the investigator).
3.
Symptomatic herpes zoster within 3 months prior to screening.
4.
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, TB testing that includes: 

a positive tuberculin skin test (TST; defined as a skin induration >5 mm at 48 to 
72 hours), and regardless of Bacillus Calmette-Guerin (BCG) or other 
vaccination history) 
OR

a positive (not indeterminate) QuantiFERON-TB Gold test.
NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made 
by the investigator according to local licensing and standard of care. The 
QuantiFERON-TB Gold test can only be used in countries where it is licensed, and 
the use of this test is dependent on previous treatment(s). This test may not be suitable 
if previous treatment(s) produced significant immunosuppression.
5.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell 
or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years.
6.
Breast cancer within the past 10 years.
7.
History of severe injection site reaction (i.e., required emergency care or 
hospitalization) following any prior injection, including reaction to vaccines.
8.
History of clinically significant allergy or prior hypersensitivity, including those with 
a documented yeast allergy.
9.
History of, or current concern for, a chronic immune deficiency disorder including, 
but not limited to: diabetes, sickle cell anemia, and malnutrition.
10. Hemoglobin levels below the normal range (as determined for gender).
 
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11. Platelet count <130,000/mm3.
12. Creatinine clearance (CrCL) <90 mL/min.
13. Alanine transaminase (ALT) >1.1x upper limit of normal (ULN).
14. Bilirubin >1.1xULN (isolated bilirubin >1.1xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
15. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
16. QTcF >450 msec.
PRIOR/CONCOMITANT THERAPY
17.
Intended use of over-the-counter or prescription medication within 7 days prior to 
dosing.  Specific medications listed in Section 7.7 may be allowed.
18. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines 
during the study.
19. Treatment with biologic agents (such as monoclonal antibodies including marketed 
drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
20. Exposure to immune-modulating medications (including corticosteroids) within 30-
days of Screening.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
21. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 56 days.
22. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
23. Current enrolment or past participation within the last 30 days before signing of 
consent in this or any other clinical study involving an investigational study 
intervention or any other type of medical research.
DIAGNOSTIC ASSESSMENTS 
24. Absolute CD4+ T-cell count <500 cells or CD4 percent (CD4%) outside of the 
normal range for the reference laboratory (32% to 64%).
25. Presence of Hepatitis B surface antigen (HBsAg) at screening.
26. Positive Hepatitis C antibody test result at screening.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
27. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing.
28. Positive pre-study drug/alcohol screen.
 
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29. Positive human immunodeficiency virus (HIV) antibody test
OTHER EXCLUSIONS
30. History of regular alcohol consumption within 6 months of the study defined as: an 
average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half 
pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
31. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 
months prior to screening.
32. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants should arrive fasted for the screening visit only and will be allowed to eat 
during the screening visit after blood draw for clinical chemistry has been completed.
6.3.2.
Caffeine, Alcohol, and Tobacco
Participants will abstain from ingesting caffeine- or xanthine-containing products (eg, 
coffee, tea, cola drinks, and chocolate) for 24 hours before the start of dosing until after 
collection of the final pharmacokinetic and pharmacodynamic sample.
Use of alcohol or tobacco products will not be allowed from screening until after the final 
follow-up visit.
Participants must have a negative drug test at screening and admission to the clinical unit
and must abstain from recreational drug use from screening until after the final follow-up 
visit.
6.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. 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 randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
 
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Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 
 
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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.
7.1.
Treatments Administered
Table 13
Treatment Administration
Study Treatment Name:
GSK3732394
Placebo-0.9% w/v sodium chloride
Dosage formulation:
Solution for injection
Solution for injection
Unit dose 
strength(s)/Dosage 
level(s):
100 mg/mL
Volume to match active dose
Route of Administration 
Subcutaneous injection
Subcutaneous injection
Dosing instructions:
Details can be found in Study Reference 
Manual
Details can be found in Study 
Reference Manual
Packaging and Labelling
Study Treatment will be provided in 1mL glass 
vials. Each will be labelled as required per 
country requirement. 
Sourced by unit
7.2.
Dose Modification
The decision to proceed to the next dose level in both Part 1 (SAD) and Part 2 (MAD) 
will be made by the Safety and Dose Escalation Committee, based on safety, tolerability, 
and PK/PD data obtained from the prior dose level(s).
7.3.
Method of Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedules generated by the Sponsor or their delegate, prior to the start of the study, using 
validated internal software.
Each subject scheduled to receive study drug will receive a treatment allocation number 
when randomized. Study treatment will be administered at the study visits summarized in
the Schedule of Assessments.
7.4.
Blinding
This will be a double-blind study with participants and the site staff blinded, except for an 
unblinded pharmacist at the site who will prepare the blinded drug product. The blinded 
drug product will be administered by site staff not involved with assessments (to prevent 
unblinding due to the viscosity of active drug product vs. placebo). 
The Sponsor will be unblinded. For dose escalation, the Sponsor study team physicians, 
statistician, and clinical pharmacokinetic staff and/or their delegate will have access to 
unblinded data. The Sponsor will present data at SDEC meetings in a blinded fashion 
when interacting with site staff. Other Sponsor staff will remain blinded unless 
unblinding becomes necessary. The blind may be broken if, in the opinion of the
investigator, it is in the participant’s best interest for the investigator to know the study 
 
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treatment assignment. The Sponsor study team must be notified before the blind is
broken unless identification of the study treatment is required for a medical emergency
in which the knowledge of the specific blinded study treatment will affect the immediate
management of the participant’s condition. In this case, the Sponsor study team must be
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF, as applicable.
Participants will be randomized in a 3:1 ratio to receive study treatment (GSK3732394 :
PBO) within a cohort. Investigators will remain blinded to each participant’s assigned 
study treatment throughout the course of the study.
Unblinded monitors, and in the event of a Quality Assurance audit, the auditor(s), will 
be allowed access to un-blinded study treatment records at the site(s) to verify that
randomization/dispensing has been done accurately.
A participant will be withdrawn if the participant’s treatment code is unblinded by
the investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.
Sponsor’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators
in accordance with local regulations and/or Sponsor policy.
7.5.
Preparation/Handling/Storage/Accountability

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.

An unblinded pharmacist or designee will prepare blinded study treatment and 
provide to authorize study staff for administration.

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.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
 
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unintentional occupational exposure notify the Study Sponsor Medical Monitor 
and/or Sponsor study contact.
7.6.
Treatment Compliance
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
GSK3732394 /PBO will be administered by subcutaneous injection to participants at the 
site.  Administration will be documented in the source documents and reported in the 
CRF, including location of injection site(s).
7.7.
Concomitant Therapy
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days or 5 half-lives (whichever is 
longer) before the start of study treatment until completion of the follow-up visit, unless, 
an emergency situation in the opinion of the investigator or otherwise previously 
discussed with the Medical Monitor.  
Permitted Medications are:
•
Acetaminophen, at doses of 2 grams/day, is permitted for use any time during the 
study.
•
In the event of irritation from ECG leads, up to 2.5% topical hydrocortisone may be
used at the discretion of the investigator.
•
Female subjects of childbearing potential are permitted to use the contraceptive 
methods outlined in Appendix 4, Section 12.4 and in Inclusion Criterion 5.
Any medication (including over-the-counter or prescription medicines, vitamins, and/or
herbal supplements) or vaccine that a participant is receiving at the time of enrolment or 
receives during the study must be recorded and reviewed with the Study Sponsor Medical 
Monitor. The following details should be included in the record:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
7.8.
Treatment after the End of the Study
Since this is a study that includes healthy participants, no additional treatment from 
Sponsor, including GSK3732394, will be provided after the completion of the study.
 
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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

At the discretion of the Investigator in consultation with the Study Sponsor Medical 
Monitor for safety (including lab abnormalities or intercurrent illness), psychiatric, 
compliance, or administrative reasons.

A Serious Adverse Event (SAE), regardless of its severity, that is considered be 
clinically significant and reasonably attributable to dosing with GSK3732394, in the 
opinion of the Investigator.  

A Grade 2-4 Acute Allergic reaction (DAIDS criteria), reasonably attributable to 
dosing with GSK3732394, in the opinion of the Investigator.

A Grade 2-4 Hematologic AE (DAIDS criteria), reasonably attributable to dosing 
with GSK3732394, in the opinion of the Investigator.

A Grade 3-4 Injection Site reaction (DAIDS criteria), reasonably attributable to 
dosing with GSK3732394, in the opinion of the Investigator.

Grade 3-4 AE or Grade 3-4 clinically significant laboratory abnormality that is 
considered to be reasonably attributable to dosing with GSK3732394 in the opinion 
of the Investigator.

Termination of the study by the Sponsor. 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 incarceration or involuntary treatment 
of either a psychiatric or physical (e.g., infectious disease) illness

Unblinding of unauthorized Site Staff, including the PI, for any reason

Repeat non-adherence by the participant with the requirements of the protocol or 
treatment (as determined by Investigator in consultation with the Study Sponsor 
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 chooses to withdraw from the study, he/she should complete an end-of-
study/early termination evaluation per SOA.
8.1.1.
Study Stopping Criteria
Safety parameters and the available pharmacokinetic parameters from the previous 
cohorts will be fully assessed by the SDEC before the next cohort is dosed. Any trends 
towards drug-related changes will be fully evaluated. The decision to dose escalate will 
be based on the nature, severity and frequency of any safety and/or tolerability 
 
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observations. The decision to dose escalate may be delayed from the planned two-week 
interval to allow the collection of additional safety data if clinically indicated. 
Dose escalation will be paused (until all of the cumulative safety data is reviewed by 
the Study Team and the VSLC) if the following number of participants, within an 
ongoing cohort of 6 active participants, develops these clinically significant AEs or 
changes in safety parameters (see also Section 8.1.1.1 through Section 8.1.1.5): 

One participant experiences an AE of Grade 4 intensity assessed as related to 
GSK3732394, as reported by the PI.

One participant experiences a Serious Adverse Event (SAE) or death assessed as 
related to GSK3732394, as reported by the PI.

One participant experiences a Grade 3 injection site reaction (per DAIDS criteria) 
related to dosing with GSK3732394. 

Two participants experience an AE of Grade 3 intensity assessed as related to 
GSK3732394, as reported by the PI.

Two participants with confirmed QTcF ≥500 msec.

≥25% of participants (within a dosing cohort or across the entire study) receiving 
GSK3732394 have a ≥ Grade 2 intensity AE, lab abnormality (with the exception of 
asymptomatic changes in lipid panel), or injection site reaction (per DAIDS criteria)

Or if the pattern of adverse events observed in a cohort are consistent across 
participants, poorly tolerable, and clinically significant.
In addition, the safety parameters listed below [i.e. dose limiting toxicities (DLTs)] will 
be monitored carefully and will be reviewed with the SDEC prior to all dose escalations. 
The intensity applied to all Adverse Events (AEs) will be determined using DAIDS 
criteria.  The toxicity applied to all laboratory abnormalities will be determined using 
DAIDS criteria (See Appendix 6, Section 12.6). If clinically significant findings are 
observed in a considerable number of participants as outlined below, then dose escalation 
will be paused until all of the cumulative safety data is reviewed by the SDEC and shared 
with the ViiV (Sponsor) Safety and Labelling Committee (VSLC). The VSLC is 
comprised of senior representatives from various departments, including clinical 
development, toxicology, pharmacovigilance, epidemiology, and medical affairs.
8.1.1.1.
Serious Allergic Reaction
If the following allergic reactions are observed in 1 or more participants within the 
ongoing cohort of 6 active participants, the dose escalation will be paused until all of 
the cumulative safety data is reviewed by the Study Team and the Sponsor VSLC:

An acute hypersensitivity reaction adverse event (AE) (i.e, angioedema, 
bronchospasm, hives, hypotension, rash with concurrent 
fever/transaminitis/eosinophilia, etc.) of moderate to severe intensity (Grade 2-4 by 
DAIDS criteria) or, 

A delayed hypersensitivity reaction AE with systemic symptoms and/or end-organ 
effects (i.e., serum sickness, vasculitis, fever, arthralgia/myalgia, nephritis, etc.) of 
moderate to severe intensity (Grade 2-4 by DAIDS criteria).
NOTE:  An event is defined as any observed change (or laboratory abnormality 
confirmed by a repeat blood sample) as outlined in Appendix 6, Section 12.6.
 
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8.1.1.2.
Hematological parameters:
If the following number of participants within the ongoing cohort of 6 active 
participants, develops clinically significant hematological changes (as outlined 
below), the dose escalation will be paused until all of the cumulative safety data is 
reviewed by the Study Team and the Sponsor VSLC:

Two participants treated with GSK3732394 experience a confirmed reduction in 
baseline CD4 percent (CD4%) >25% at any time during the inpatient period or post-
dosing outpatient follow-up; or 

Two participants treated with GSK3732394 experience a confirmed absolute CD4+ 
T-cell count that meets DAIDS Grade 1 toxicity (<400 cells/mm3) during the 
inpatient period or post-dosing outpatient follow-up; or

One participant treated with GSK3732394 experiences a confirmed reduction in 
baseline CD4 percent (CD4%) >40% at any time during the inpatient period or post-
dosing outpatient follow-up: or

One participant treated with GSK3732394 experiences a confirmed absolute CD4+ T-
cell count that meets DAIDS Grade 2 or greater toxicity (<300 cells/mm3).
8.1.1.3.
Pharmacokinetic Dose Adjustment/Stopping Criteria for Part 1 (SAD)
and Part 2 (MAD)
Pharmacokinetic stopping criteria for dose escalation across the study (Part 1 [SAD] and 
Part 2 [MAD]) will be applied if there is emerging evidence for a reduction in % CD4+ 
T-cells (>20% median maximum decline in CD4% among subjects receiving active drug) 
across any preceding dosing cohort.  Under such circumstances, dose escalation will not 
progress beyond any single participant with exposures greater than NOAEL of
93.9 µg/mL for Cmax.  
As part of routine dose escalation, Bayesian probability that any individual at the next 
scheduled dosing level will exceed the Cmax NOAEL exposure will be calculated.  This 
probability, together with the safety, tolerability, PK and PD data of the previous cohorts, 
will be used to guide the selection of the next dose.
8.1.1.4.
Liver Enzymes:
If the following clinical chemistry changes are observed in 1 or more participants 
within the ongoing cohort of 6 active participants, the dose escalation will be paused 
until all of the cumulative safety data is reviewed by the Study Team and VSLC.

ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (>35% direct) – requires rapid evaluation, 
hepatology consult, and prompt notification of the Study Sponsor Medical Monitor

ALT ≥ 3xULN
8.1.1.5.
Vital Signs/ECGs:
If the following vital signs/ECG changes are observed in 1 or more participants 
within the ongoing cohort of 6 active participants, the dose escalation will be paused 
until all of the cumulative safety data is reviewed by the Study Team and the VSLC:

Mean heart rate taken from the 12-lead ECG falls to less than or equal to 35 bpm or 
rises to greater than or equal to 120bpm on ECGs completed in triplicate over a 
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
Mean heart rate taken from the 12-lead ECG changes by more than 60bpm from pre-
dose baseline of that dosing day on ECGs completed in triplicate over a <5min time 
period.

Symptomatic or asymptomatic arrhythmia of any clinical significance as outlined 
below:
o
Sustained (5 or more beats for a duration of 30 seconds or more) or non-sustained 
(5 or more beats for a duration of less than 30 seconds) ventricular arrhythmias.
o
Sustained (5 or more beats for a duration of 30 seconds or more) supraventricular 
arrhythmias including atrial fibrillation and flutter
o
Complete bundle branch block
o
Pauses > 3 seconds

Mean systolic blood pressure changes by more than 30mmHg and/or diastolic blood 
pressure changes by more than 20mmHg from pre-dose baseline upon blood pressure 
recordings completed in triplicate, at least 1min apart.
8.1.2.
Individual Participant Stopping Criteria
8.1.2.1.
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 intervention for abnormal liver tests is required when:

A participant meets one of the conditions outlined in Figure 3.

When in the presence of abnormal liver chemistries not meeting protocol-
specified stopping rules, the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Figure 3
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*
 
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Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 5, Section 12.5.
8.1.2.2.
QTc Stopping Criteria
The Fridericia QT correction formula (QTcF) must be used for each individual 
participant to determine eligibility for and discontinuation from the study.  This formula 
may not be changed or substituted once the participant has been enrolled.
The QTcF stopping criteria is based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-minute) recording period.  
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTcF > 500 msec,

Change from baseline: 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.
8.1.2.3.
Other Individual Participant Safety-related Stopping criteria 
A participant will be withdrawn if they develop a: Serious adverse event (SAE); Grade 2-
4 allergic reaction; a Grade 2-4 abnormality in any hematology-related laboratory 
parameter; or a Grade 3-4 injection site reaction that is judged by the investigator to be 
plausibly related to the administration of active study medication, or any other AE that is 
deemed clinically significant by the investigator and is judged by the investigator to be 
related to the dosing of study product.
A participant may be withdrawn from the study if they present with any dose limiting 
toxicity as defined in Section 8.1.1. If dose limiting toxicity (DLT) is observed in an 
individual, and dose-interruption criteria are not otherwise met (per Section 8.1.1), the 
Investigator or designee may use their medical judgment and stop any further dosing and 
must immediately inform the Sponsor medical monitor or designee. Together, the PI and 
Medical Monitor will decide further management of the individual participant. The 
SDEC may be convened at any time in request of a comprehensive review of the data to 
help in decision-making around the management of an individual participant or
subsequent dosing.
8.1.3.
Temporary Discontinuation
Temporary discontinuation in this study is not allowed.
8.1.4.
Rechallenge
Study treatment restart or rechallenge in this study is not allowed.
 
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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 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.
Refer to the Section 2 for data to be collected at the time of study discontinuation 
and/follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the Section 2. 
•
Protocol waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
•
Adherence to the study design requirements, including those specified in the Section 
2, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 
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•
Procedures conducted as part of the participant’s routine clinical management (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 
500 mL in a 56-day period.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples
9.1.
Efficacy Assessments
Not applicable.
9.2.
Safety Assessments
Planned time points for all safety assessments are provided in the Section 2.
9.2.1.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight 
will also be measured and recorded.
A targeted/brief physical examination will include, at a minimum, assessments of the skin 
(including injection site), respiratory, cardiovascular system, and abdomen (liver and
spleen).
Injection sites will be examined as part of both complete and targeted physical exams.
9.2.2.
Vital Signs
Single oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
All blood pressure and pulse measurements will be assessed in semi-supine position with 
a completely automated device. Manual techniques will be used only if an automated 
device is not available.
Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (e.g., television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of single 
oral temperature, pulse rate, respiratory rate, and blood pressure measurements. If 
abnormalities in pulse or blood pressure are noted, repeat recordings should be measured 
in triplicate, at least 1 minute apart. The average of the 3 readings will be recorded on the
CRF.
 
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9.2.3.
Electrocardiograms
The frequency of ECGs in the SAD and MAD arises from emerging literature suggesting 
frequent QT evaluation early in development may mitigate the need for a formal TQT 
study (Darpo, 2010)
12-lead ECG recordings will be obtained after the participant has been in a semi-supine 
position for at least 5 minutes using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Participant eligibility will be 
based upon triplicate ECG recordings.  Single recordings will be made at all other time 
points.
If any abnormalities in ECG interval are noted (including prolongation of the QT 
interval), ECGs should be repeated in triplicate with recordings over a 5min time period. 
Refer to Section 8.1.2.2 QTc Stopping Criteria for QTc withdrawal criteria and additional 
QTc readings that may be necessary.
At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes apart. 
The full set of triplicates should be completed in less than 4 minutes.
At least one of these ECGs will be available and reviewed by the PI on site to evaluate 
for QT prolongation. Additional ECGs beyond those described in the SoA table can be 
obtained by the PI should they suspect a prolongation in the QT interval.
9.2.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and Section 2
for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 2 days after the last dose of study treatment 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 Section 2.
 
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9.2.5.
T cell Assessments
A battery of tests to determine the effects of GSK3732394 on T cells will be collected as 
noted in the SoA, including:

CD4/CD8/CD3 absolute number and percent (as part of hematology panel, see 
Section 12.2)

CD4 median fluorescence intensity (MFI) (as part of pharmacodynamic assessment)

Activated CD4 T-cells (CD4+/CD25+) (as part of pharmacodynamic assessment)
9.3.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3, Section 12.3. 
As described Appendix 3, Section 12.3 and Appendix 6, Section 12.6, 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 adults, the DAIDS criteria will be 
used in later clinical trials (Phase 2a and beyond).  Additionally, the DAIDS criteria have 
a more conservative grading scale relative to others.  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 and/or study (see 
Section 8). 
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information
•
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2). However, any SAEs assessed as related 
to study participation (e.g., study intervention, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a ViiV/GSK product will be 
recorded from the time a participant consents to participate in the study.
•
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 case report form (CRF) not the AE section.
•
All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3, 
Section 12.3.
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
it being available.
 
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•
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.
9.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3, 
Section 12.3.
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. 
9.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in
Appendix 3, Section 12.3.
9.3.4.
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met. 
•
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
•
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
•
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., 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.
 
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9.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 40 
days after last dose of study medication.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4, 
Section 12.4.3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.4.
Treatment of Overdose
For this study, any dose of GSK3732394 greater than the specified dose for that cohort 
will be considered an overdose.
In the event of an overdose, the Investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities 
GSK3732394 can no longer be detected systemically (approximately 11 days).
3.
Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant. No dose 
modifications are permitted without prior discussion and consent from the SDEC.
9.5.
Pharmacokinetics
Serum samples of approximately 1 mL (from 2 ml of blood) will be collected for 
measurement of serum concentrations of GSK3732394 and GSK3732394-related 
material identification as specified in the SoA. A maximum of 5 samples may be 
collected at additional time points during the study if warranted and agreed upon between 
the investigator and the sponsor. Instructions for the collection and handling of biological 
samples will be provided by the sponsor. The actual date and time (24-hour clock time) 
of each sample will be recorded.  Processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
Samples will be used to evaluate the PK of GSK3732394. Samples collected for analyses 
of GSK3732394 serum concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study.
Once the serum has been analyzed for GSK3732394, any remaining serum may be 
analyzed for other GSK3732394-related materials and the results reported under a 
separate protocol.
 
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Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.6.
Pharmacodynamics
Venous blood samples of approximately 2 mL will be collected for measurement of 
CD4+ T cell receptor occupancy, CD4+ T cell MFI, and activated T cells (CD25+) at 
time points specified in the SoA. The actual date and time (24-hour clock time) of each 
sample will be recorded.  Processing, storage and shipping procedures are provided in the
Study Reference Manual (SRM).
9.7.
Non-Pharmacokinetic Sample Collection
Urine samples will be collected from each subject prior to dosing (the pre-dose sample 
can be collected up to 48 hours before dosing) and during the timepoints noted in the 
SoA.  Urine collection will be only during the highest dose cohort in both Part 1 (SAD) 
and Part 2 (MAD) for 24 hours after the last dose. Processing, storage and shipping 
procedures are provided in the SRM. 
Urine will be analysed for possible GSK3732394-related metabolites. If identified, 
results will be reported under a separate protocol.
9.8.
Biomarkers
Collection of serum samples for biomarker research is also part of this study. The 
following samples for biomarker research are required and will be collected from 
participants in this study are specified in the SoA (see Section 2).
Other samples may be used for research to develop methods, assays, related to the 
mechanism of action of the study treatment.
9.8.1.
Immunogenicity Assessments - Anti-GSK3732394 antibodies
Serum samples for testing for antibodies against GSK3732394 will be collected at the 
time points indicated in the SOA. The actual date and time of each blood sample 
collection will be recorded.  Processing, storage and shipping procedures are provided in 
the SRM. 
The presence of anti-GSK3732394 antibodies will be determined in serum samples using 
a validated bioanalytical method, which includes a screening assay, confirmation assay 
and titer analysis. Positive samples may be further characterized with additional assays to 
determine the specificity of the anti-GSK3732394 antibodies to the different domains of 
GSK3732394.
9.8.2.
Immunogenicity Assessments - Immune activation
Serum samples for biomarkers of immune activation (cytokines including but not limited 
to IFN, IL6, IL8, TNF, and IL2) will be collected at baseline and after dosing only if 
clinically indicated (i.e., participant displays signs or symptoms of immune activation).
Processing, storage and shipping procedures are provided in the SRM.
 
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9.9.
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 statistical hypotheses are to be tested. Sample size is based on feasibility. No 
formal calculation of power or sample size (i.e., sample size sensitivity or robustness) 
will be performed. A sample size of approximately 8 participants (6 active:2 placebo) in 
each SAD and MAD cohort should be sufficient to provide useful estimates of inter-
participant variability for GSK3732394, PK and PD parameters and initial safety 
assessments. Although the sample size is not based on statistical criteria, general 
probabilities can be determined on the likelihood of observing AEs. With 6 participants 
receiving each dose of active study treatment, if the true adverse outcome rate is 5%, the 
chance of seeing at least 1 adverse outcome at a given dose is 26%. Similarly, if the true 
adverse outcome rate is 20%, the chance of seeing at least 1 adverse outcome at a given 
dose is 74%.
Sample size re-estimation is not planned.
Data will be reviewed by the Safety and Dose Escalation Committee (SDEC) prior to 
each dose escalation; no other interim analysis is planned.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who passed screening and entered the study. Included are: Randomized 
Participants.
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.
Safety
All participants who received at least 1 dose of study treatment. Participants will be analyzed 
according to the treatment they received.
Pharmacokinetic 
(PK)
All participants in the Safety population who had at least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as non-missing values).
10.3.
Statistical Analyses
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population and details will be 
provided in the Reporting and Analysis Plan (RAP). 
 
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Endpoint
Statistical Analysis Methods
Adverse events 
(AEs)
The proportion of participants reporting AEs will be tabulated by treatment and by cohort. AEs will 
also be tabulated by severity and relationship. AEs will be tabulated using MedDRA preferred 
terms. The number and percentage of participants experiencing each specific AEs (All AEs, 
Grade 2 or higher, and SAEs) will be tabulated by severity and by relationship to study product. 
For the calculations in these tables, each participant’s AEs will be counted once under the 
maximum severity or the strongest relationship to study product. AEs leading to withdrawal will 
also be summarized by treatment.
Clinical 
laboratory
Laboratory results will be included in the reporting of this study for hematology, clinical chemistry, 
and urinalysis. Based upon laboratory normal ranges, the laboratory test results will be 
categorized according to the normal range as low (below the lower limit), normal (within the 
normal range) and high (above the upper limit). Summary statistics for change from baseline will 
also be tabulated.
Vital signs 
assessments
The following Vital Signs measurements will be tabulated: supine systolic and diastolic blood 
pressure, pulse rate, respiratory rate and temperature. Summary statistics for change from 
baseline will also be tabulated.
10.3.2.
Pharmacokinetic Analyses
All pharmacokinetic analyses will be performed on the Pharmacokinetic Population.  For 
the PK endpoints in this study, no formal hypotheses will be tested.
Endpoint
Statistical Analysis Methods
Secondary
Plasma GSK3732394, concentration-time data will be analysed by non-compartmental methods 
using WinNonlin Professional 5.2 or higher, Phoenix (Pharsight Corporation) or comparable 
software. Calculations will be based on the actual sampling times recorded during the study.
From the plasma concentration-time data, the following pharmacokinetic parameters will be 
determined, as data permit: 
Part 1 (single dose)
Area under the plasma drug concentration versus time curve (AUC(0-t) and AUC(0 ∞)), maximum 
observed plasma drug concentration (Cmax), time to maximum observed plasma drug 
concentration (tmax), tlag, Clast, tlas, ttrough plasma drug concentration (Ctrough) and terminal half-life 
(t1/2,) CL/F
Part 2 (Repeated weekly dosing):
First week: AUC(0-t), AUC(0-tau), AUC(0 ∞), Cmax, tmax, tlag
Last week: AUC(0-), Cmax, tmax, Ctrough, t1/2, CL/F
Part 1 (single dose)
Dose proportionality will be assessed by visual inspection of dose normalised AUC(0-∞) [or if not 
available AUC(0-t)] and Cmax values versus dose. Analysis of these loge-transformed parameters 
may be carried out, using the power model.
Part 2:
The extent of accumulation after repeat dosing, the observed accumulation ratio, may be 
determined. Accumulation indices for PK parameters assessed across first and last doses of 
multiple dosing, as data allow: RAUC(0-tau), RCmax, RCtrough. For repeat dosing, AUC(0-tau), Cmax, 
Ctrough will be analyzed versus dose for the dose-proportionality. 
Further details will be included in the RAP
10.3.3.
Interim Analyses
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available PK/PD data will be reviewed internally prior to each dose escalation. Dose 
escalation can only occur after the Safety and Dose Escalation Committee (SDEC) has 
found that the safety, PK/PD profiles are supportive to proceed with the evaluation of the 
next higher dose level.
 
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PK/RO modelling will be performed to determine the parameters Emax, EC50 and Hill-
coefficient, as data permits.
Beginning with the second dose in Part 1 and each subsequent dose throughout the study, 
the Bayesian probability of any individual participant exceeding the Cmax NOAEL 
exposure of 93.9 µg/mL at that dose will be calculated, using the accumulated PK data of 
participants receiving GSK3732394 among the previous cohorts. Observations on 
placebo will be excluded. This probability, together with safety and tolerability data of 
the preceding cohorts, will be used to help selection of the next dose. The Bayesian 
probability of exceeding the Cmax threshold can be calculated for additional potential 
doses to aid in dose selection if necessary. 
The Bayesian probability will be based on Whitehead’s model shown below
[Whitehead, 2001].
yi =θ1 +θ2 di +εi
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th
participant. θ1 and θ2 are population intercept and slope, respectively. i is the random 
error of the i-th participant.
For the prediction of the second dose in Part 1 and Part 2, θ2 will be assumed to equal 1 
(representing a dose proportionality assumption). This will allow for the estimation of the 
remaining parameters of the model using data from only one dose level.
Bayesian model Operating Characteristics (OC)
Here we explore the operating characteristics of the planned highest expected dose of the 
MAD portion of the study of 600mg. We are interested in the probability that no 
participant will exceed Cmax NOAEL of 93.9 µg/mL. Additionally, we are interested in 
the predicted maximum exposure among the 6 participants receiving the 600mg dose. We 
simulated data for 1000 trials using Whitehead’s model, based on different Cmax
variability (CV%) assumptions ranging from 30% to 60% (assuming dose 
proportionality: θ2=1) and θ1=log(0.06355). The value of θ1 values is based on the predicted 
human exposure using preclinical data. Each simulation contains data for 2 cohorts of 6 
participants each on active doses of 130mg and 400mg.
For each simulated trial the MCMC procedure was used assuming Whitehead’s model for 
log(Cmax) response (without assuming dose proportionality) with noninformative priors 
on the model parameters. Ten thousand (10,000) iterations were used and, for each 
iteration simulated log(Cmax) value, each of six participants on the planned top dose of 
600mg using the posterior distribution of log(Cmax) obtained from the MCMC procedure. 
The proportion of iterations with any of the six new observations exceeding log(93.9) is the 
Bayesian probability (using data from the preceding doses) of any participant on the 
600mg dose exceeding the NOAEL exposure of 93.9 µg/mL.
Additionally, we calculated the maximum Cmax exposure among the 6 participants (by 
transforming the log(Cmax)value) and averaged the max value across all iterations. This is 
the predicted maximum exposure among the 6 participants on the 600mg dose.
 
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Table 14 shows the predicted value of the maximum exposure among the 6 participants 
on the 600mg dose, averaged across all 1000 simulations, depending on CV%. Also 
shown in Table 6 is the percentage of 1000 simulated trials with Bayesian probability of 
any individual exceeding the Cmax NOAEL below the thresholds of 40%, 50%, and 60%.
Table 14
Predicted Maximum Cmax Value of 6 Participants on 600mg Dose and 
Percentage of Trials with Bayesian Probability Less Than the 
Threshold (40%, 50%, or 60%)
CV%
Cmax (µg/mL)
Probability Threshold
40%
50%
60%
30
61.2
99.0%
99.9%
99.9%
40
72.8
88.9%
94.9%
98.6%
50
87.5
72.8%
84.3%
91.6%
60
106.0
59.1%
71.5%
82.7%
Based on Table 14, when the Cmax variability is low-moderate, the predicted maximum 
Cmax exposure among the 6 participants on the 600mg dose is below the NOAEL of  
93.9 µg/mL and the majority of simulated trials had Bayesian probability of any 
individual exceeding the Cmax NOAEL below the thresholds of 40%, 50%, and 60%.
10.3.4
Final Analyses
Final analyses will be performed after the completion of the study and final datasets 
authorization. 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by participant, treatment and day; summaries will be 
presented by treatment, day, and time for each part. 
Unless stated otherwise, descriptive summaries will include n, mean, standard deviation 
(SD), coefficient of variation (%CV), median, minimum, and maximum, geometric mean 
with associated 95% confidence interval (CI), and the between-participant CV (%CVb) 
for continuous variables, whereas n and percent will be used as summary statistics for 
categorical variables.
 
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11.
REFERENCES
Bussiere JL. “Animal models as indicators of immunogenicity of therapeutic proteins in 
humans.” Dev Biol, 01-Jan-2003, 112:135-9.
Darpo B. The thorough QT/QTc study 4 years after the implementation of the ICH E14 
guidance. British Journal of Pharmacology. 2010;159(1):49-57. doi:10.1111/j.1476-
5381.2009.00487.
GlaxoSmithKline Document Number 2017N344293_00. Evaluation of the antiviral 
efficacy of GSK3732394 (BMS-986197) in a humanized mouse model of HIV-1 
infection. Effective Date December 2017.
GlaxoSmithKline Document Number 2018N358742_00. GSK3732394 Investigator’s 
Brochure, Version 1.0. 10-April-2019
GlaxoSmithKline Document Number 2018N365256_01. Clinical Pharmacology Review; 
Chakradhar Lagishetty (GSK) and Mark Baker (ViiV Healthcare), 14-MAR-2019.
Whitehead J, Patterson S, Webber D, Francis S, Zhou Y, Easy-to-implement Bayesian 
methods for dose-escalation studies in healthy participants, Biostatistics. 2001;2(1):47-
61.
 
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12.
APPENDICES
12.1.
Appendix 1: Study Governance Considerations
12.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
12.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
12.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
 
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consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 

Participants who are rescreened are required to sign a new ICF.
12.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
12.1.5.
Committees Structure
This study will be reviewed and approved by an Internal Review Committee prior to 
initiation.
12.1.6.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
 
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12.1.7.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator will 
be provided reasonable access to statistical tables, figures, and relevant reports and 
will have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.

ViiV/GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.

ViiV/GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis..

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will be 
in accordance with GSK Policy.

ViiV/GSK intends to make anonymized patient-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
12.1.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan and/or Task Order between 
ViiV/GSK and the Study Site.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).
 
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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. 
12.1.9.
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.

The clinical site in this study, utilizes a validated proprietary bedside data capture 
system to retain the source data.
12.1.10.
Study and Site Closure
ViiV/GSK or its designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 15 will be performed by the local laboratory.

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.

Pregnancy Testing:

Refer to Section 6.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
 
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Table 15
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Count
Hemoglobin
Hematocrit
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Lymphocyte 
Phenotype
Absolute number and 
Percent of:
CD3+
CD4+
CD8+
Clinical Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose
Calcium
Alkaline phosphatase
Amylase
Lipase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only)

Serum alcohol and urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)]

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed)2

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)]

Creatinine clearance (CrCL) for GFR estimation

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 5 (Section 12.5).  All events of ALT 3 × upper limit of 
normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
 
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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
12.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study 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 (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
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.
 
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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
 
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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.
12.3.3.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
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, 
 
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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 ViiV/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 ViiV/GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of receipt 
of the information.
12.3.4.
Reporting of SAE to Study Sponsor
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
 
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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/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SRM.
 
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12.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
12.4.1.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
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, confirmation with more than one FSH measurement 
>40 IU/L or mIU/mL is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
 
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12.4.2.
Contraception Guidance
12.4.2.1.
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 16 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 for at 
least 30 days from last dosing.
In addition, male participants must refrain from donating sperm for duration of study and 
for at least 100 days, or 5 half-lives plus 90-days for sperm turnover, whichever is longer, 
from last dosing.
12.4.2.2.
Female participants
Non-pregnant female participants of childbearing potential are eligible to participate if 
they agree to use a highly effective method of contraception consistently and correctly as 
described in Table 16. 
Table 16
Highly Effective Contraceptive Methods
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:  To be used during the treatment period and for at 
least 28 days prior to first dose, and 40 days after, the last dose of study treatment.
Highly Effective Methodsb That Have Low User Dependency Failure rate <1% / year when used consistently and 
correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)c
Bilateral tubal occlusion
Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent Failure rate <1% / year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable
Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
 
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a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction)
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test conducted at Screening 

Additional pregnancy testing will be performed in WOCBP on a monthly basis, 
including at the end-of-study evaluation

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed 
12.4.3.
Collection of Pregnancy Information
12.4.3.1.
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive GSK3732394.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
12.4.3.2.
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 
 
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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 fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 4 (Section 12.4.3).  While the investigator is not 
obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
intervention and be withdrawn from the study.
 
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12.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Table 17
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 intervention

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 subject until liver chemistries resolve, 
stabilise, or return to within pre-dose (see 
MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR >1.5

Repeat liver chemistries (include ALT, aspartate 
transaminase [AST], alkaline phosphatase, bilirubin 
and INR) and perform liver event follow up 
assessments within 24 hrs

Monitor subjects twice weekly until liver chemistries 
resolve, stabilise or return to within pre-dose

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 INR) and perform liver 
event follow up assessments within 24-72 hrs

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within pre-dose

Viral hepatitis serology3

Obtain international normalized ratio (INR) and 
recheck with each liver chemistry assessment until 
the transaminases values show downward trend

Obtain blood sample for pharmacokinetic (PK) 
analysis, obtained as soon as possible in relation to 
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 
acetaminophen, herbal remedies, other over the 
counter medications.

Record alcohol use on the liver event alcohol intake 
case report form
If ALT≥3xULN AND bilirubin 2xULN or INR >1.5:

Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG) or gamma 
globulins.

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator interventions.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
 
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approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 
 
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12.6.
Appendix 6: Division Of AIDS (DAIDS) Table For Grading 
The Severity Of Adult And Pediatric Adverse Events Version 
2.1 July 2017
See https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-
grading-the-severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf?sfvrsn=2
 
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12.7.
Appendix 7: Abbreviations and Trademarks
ADA
Antidrug antibody
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ARV
Anti-retroviral
AUC(0-t)
Area under the plasma concentration time curve from zero to t
AUC(0-)
Area under the curve (Area under the concentration-time curve at steady state within the 
dosing interval) 
AUC(0-24)
Area under the concentration time curve from zero to 24
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 zero to time of last sample taken 
BMI
Body mass index
BMS
Bristol-Myers Squibb
bpm
Beats per minute
CD
Cluster of differentiation
CDR
Complementarity determining region
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
CL/F
Apparent clearance 
Clast
Last observable concentration
Cmax
Maximum observed concentration 
C
Trough concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials 
CRF
Case report form
CSR
Clinical study report
CV
Cardiovascular
CV%
Coefficient of variation
DAIDS
Division of AIDS
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram 
FDA
Food and Drug Administration 
FSH
Follicle Stimulating Hormone
FTIH
First-time-in-human
GCSP
Global Clinical Safety and Pharmacovigilance 
GCP
Good Clinical Practices
GI
Gastrointestinal
HAART
Highly Active Anti-retroviral Therapy
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C
hCD 
Human Cluster of Differentiation
HIV-1
Human immunodeficiency virus-1
HIPAA
Health Insurance Portability and Accountability Act
HRT
Hormonal Replacement Therapy
ICF
Informed consent form 
IEC
Independent Ethics Committee 
IL
Interleukin
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IRB
Institutional Review Board 
MAD
Multiple ascending dose
MFI
Median Fluorescence Intensity
MOA
Mechanisms of action
NOAEL
No observed adverse effect level
 
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NQ
Non-quantifiable
OC
Operating Characteristics
PBO
Placebo
PD
Pharmacodynamic 
PI
Principal Investigator 
PK
Pharmacokinetic 
RAUC(0-)
AUC(0-) on week 4  to AUC(0-) on week 1
RCmax
Cmax on week 4 to Cmax on week 1
RC
Con week 4 to Con week 1
RAP
Reporting and Analysis Plan 
RO
Receptor occupancy
SAD
Single ascending dose
SAE
Serious Adverse Event 
SD
Standard deviation 
SDEC
Safety and Dose Escalation Committee
SOA
Schedule of Activities
SRM
Study Reference Manual 
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Apparent terminal phase half-life
tlag
Lag time
Tlast
Time of last observable concentration
tmax
Time of occurrence of Cmax 
TMDD
Target mediated drug disposition
ULN
Upper limit of normal 
VSLC
ViiV Safety and Labelling Committee
WOCBP
Women of Childbearing Potential 
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV
Healthcare
NONE
MedDRA
Phoenix
QuantiFERON
WinNonlin
 
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12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment (Amendment 03) Summary of Changes Table for the current 
amendment is located directly before the Table of Contents (TOC).
Protocol Amendment 02 Changes – Effective 02-JUL-2019
Overall Rationale for the Amendment:  This amendment results from a consensus 
between the Sponsor and the Study Site, that a confirmation of CD4+ T-cell count and 
CD4 percent values in healthy individuals with values within the normal range at 
screening, to be unnecessary.  The removal of this confirmatory test is not determined to 
have effect on the evaluation of participant safety by the Sponsor or Study Site.
Section # and Name
Description of Change
Brief Rationale
Section 3.3.1 – Risk 
Assessment
Removed the word “confirmed” from 2nd bullet of the 
Mitigation Strategy for “CD4+ cell reduction / Impairment in 
Immune Function”
Unnecessary testing for 
participants.
Section 6.2 –
Exclusion Criteria, 
Criterion 24
Removed “(to be confirmed at baseline, e.g., Day -1)” from 
this criterion.
Unnecessary testing for 
participants.
 
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Protocol Amendment 01 Changes – Effective 06-JUN-2019
Overall Rationale for the Amendment:  This amendment results from FDA “Study May 
Proceed” letter for IND Opening (Number 131394, Reference ID 4441322) dated 31-
MAY-2019.  FDA requested 9 clinical changes to the protocol, listed below.
Section # and Name
Description of Change
Brief Rationale
Section 5.1 – Overall 
Design, Part 1, 
Paragraph 3
Revised to include sentinel participants for every SAD 
cohort rather than only the first three SAD cohorts.
FDA requested change, 
Clinical item #5
Section 5.2 – Number 
of Participants, 
Paragraph 3
Revised to clarify that participants will not be replaced if 
they discontinue study due to reasons of safety.
FDA requested change, 
Clinical item #4
Section 6.2, Exclusion 
Criterion #4
Revised for clarity. Prior text could be understood to mean 
that a volunteer with a positive PPD but negative CXR 
(latent TB) would be eligible. Revised to clarify exclusion 
for either a positive PPD or a positive QuantiFERON gold.
FDA requested change, 
Clinical item #6
Section 6.2, Exclusion 
Criterion #8
Revised to also exclude volunteers who have documented 
yeast allergies.
FDA requested change, 
Clinical item #1
Section 6.2, Exclusion 
Criteria #10 and #11 
(new criteria)
Revised laboratory abnormality exclusion criteria.
FDA requested change, 
Clinical items #2c and #2d.
Section 6.2, Exclusion 
Criterion #12 (new 
criterion)
Requested renal exclusion criterion to limit enrolment to 
volunteers with normal renal function.
FDA requested change, 
Clinical item #3
Section 6.2, Exclusion 
Criterion #13
Revised laboratory abnormality exclusion criteria.
FDA requested change, 
Clinical item #2a.
Section 6.2, Exclusion 
Criterion #13
Revised laboratory abnormality exclusion criteria.
FDA requested change, 
Clinical item #2b.
Section 8.1, 
Discontinuation of 
Study Treatment, new 
bullet
Revised to include:  “Grade 3-4 AE or Grade 3-4 clinically 
significant laboratory abnormality that is considered to be 
reasonably attributable to dosing with GSK3732394 in the 
opinion of the investigator.”
FDA requested change, 
Clinical item #7
Section 8.1.1, Study 
Stopping Criteria
Consolidated “Other Study Stopping Criteria” previously 
listed in Section 8.1.1.6 into Section 8.1.1.
FDA requested change, 
Clinical item #8
Appendix 2, Table 15
Added Amylase and Lipase under Clinical Chemistry and 
added creatinine clearance under Other Screening Tests
FDA requested change, 
Clinical items #3 and #9.
Not applicable
Other administrative changes for items such as 
typographical errors or grammatical corrections.
Clarity
 
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
207863 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of GSK3732394 in 
Healthy Participants 
Compound Number  : GSK3732394 
Effective Date  
: 04-MAY-2020 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Synoptic Clinical Study Report for Protocol 207863. 
• 
This RAP is intended to describe the safety, tolerability, pharmacokinetic, and 
pharmacodynamic analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of the 
Part 1 (Single Ascending Dose) Statistical Analysis Complete (SAC) deliverable. 
Due to early termination of the study only the first 3 cohorts were completed. This 
document will only include the reporting plan for subjects enrolled in the study. 
• 
Only the primary and secondary endpoints are to be analysed due to the early 
termination.  
 
Author(s): 
Lead 
Date 
 
30-APR-2020 
Principal Statistician (Infectious Diseases, Biostatistics) 
Co-Author 
 
30-APR-2020 
Manager (Clinical Pharmacology Modelling Simulation) 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
207863 
 
2 
 
RAP Team Review Confirmations (Method: E-mail) 
Approver 
Date 
 
30-APR-2020 
Principal Programmer (Infectious Disease, Biostatistics) 
 
30-APR-2020 
Clinical Science Director (ViiV Healthcare, Clinical 
Development) 
Clinical Statistics and Clinical Programming Line Approvals (Method: Pharma 
TMF eSignature) 
Approver 
 
Statistics Leader (ID, Clinical Statistics) 
 
Programming Director (ID, Clinical 
Programming) 
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Analyses ..................................................................................... 10 
3. 
PLANNED ANALYSES .......................................................................................... 11 
3.1. 
Interim Analyses ......................................................................................... 11 
3.2. 
Final Analyses ............................................................................................ 11 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 12 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 13 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 13 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 14 
6. 
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Overview of Planned Study Population Analyses ........................................ 15 
7. 
SAFETY ANALYSES ............................................................................................. 16 
7.1. 
Adverse Events Analyses ........................................................................... 16 
7.2. 
Clinical Laboratory Analyses ....................................................................... 16 
7.3. 
Other Safety Analyses ................................................................................ 17 
7.3.1. 
Vital Signs .................................................................................... 17 
7.3.2. 
Electrocardiograms ...................................................................... 18 
7.3.3. 
Liver Events ................................................................................. 18 
8. 
PHARMACOKINETIC ANALYSES ......................................................................... 19 
8.1. 
Pharmacokinetic Parameter Definitions and Summaries ............................. 19 
8.1.1. 
Endpoint / Variables ..................................................................... 19 
8.1.1.1. 
Drug Concentration Measures .................................... 19 
8.1.1.2. 
Derived Pharmacokinetic Parameters......................... 19 
8.1.2. 
Summary Measure ...................................................................... 20 
8.1.3. 
Population of Interest ................................................................... 20 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 20 
8.1.5. 
Statistical Analyses / Methods ..................................................... 20 
8.2. 
Statistical Analysis of derived PK Parameters ............................................. 20 
8.2.1. 
Endpoint / Variables ..................................................................... 21 
8.2.2. 
Summary Measure ...................................................................... 21 
8.2.3. 
Population of Interest ................................................................... 21 
8.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 21 
8.2.5. 
Statistical Analyses / Methods ..................................................... 21 
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8.2.5.1. 
Statistical Methodology Specification .......................... 21 
9. 
PHARMACODYNAMIC ANALYSES....................................................................... 23 
9.1. 
Pharmacodynamic Parameters and Summaries ......................................... 23 
9.1.1. 
Endpoint / Variables ..................................................................... 23 
9.1.2. 
Summary Measure ...................................................................... 23 
9.1.3. 
Population of Interest ................................................................... 24 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 24 
9.1.5. 
Statistical Analyses / Methods ..................................................... 24 
10. REFERENCES ....................................................................................................... 25 
11. APPENDICES ........................................................................................................ 26 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 26 
11.2. 
Appendix 2: Schedule of Activities .............................................................. 27 
11.3. 
Appendix 3: Assessment Windows ............................................................. 33 
11.3.1. 
Definitions of Assessment Windows for Analyses ........................ 33 
11.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 34 
11.4.1. 
Study Phases .............................................................................. 34 
11.4.1.1. Study Phases for Concomitant Medication ................. 34 
11.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 34 
11.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 35 
11.5.1. 
Reporting Process ....................................................................... 35 
11.5.2. 
Reporting Standards .................................................................... 35 
11.5.3. 
Reporting Standards for Pharmacokinetic Data ........................... 36 
11.6. 
Appendix 6: Derived and Transformed Data ............................................... 37 
11.6.1. 
General ........................................................................................ 37 
11.6.2. 
Study Population .......................................................................... 37 
11.6.3. 
Safety .......................................................................................... 37 
11.6.4. 
Pharmacokinetic .......................................................................... 38 
11.6.5. 
Pharmacodynamic ....................................................................... 38 
11.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 40 
11.7.1. 
Premature Withdrawals ................................................................ 40 
11.7.2. 
Handling of Missing Data ............................................................. 40 
11.7.2.1. Handling of Missing and Partial Dates ........................ 40 
11.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 42 
11.8.1. 
Laboratory Values ........................................................................ 42 
11.8.2. 
ECG ............................................................................................. 42 
11.8.3. 
Vital Signs .................................................................................... 42 
11.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 43 
11.9.1. 
Abbreviations ............................................................................... 43 
11.9.2. 
Trademarks ................................................................................. 44 
11.10. Appendix 10: List of Data Displays.............................................................. 45 
11.10.1. Data Display Numbering .............................................................. 45 
11.10.2. Deliverables ................................................................................. 45 
11.10.3. Study Population Tables .............................................................. 46 
11.10.4. Safety Tables ............................................................................... 47 
11.10.5. Pharmacokinetic Tables ............................................................... 49 
11.10.6. Pharmacokinetic Figures ............................................................. 50 
11.10.7. Pharmacodynamic Tables ........................................................... 50 
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11.10.8. ICH Listings ................................................................................. 51 
11.10.9. Non-ICH Listings .......................................................................... 53 
 
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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 207863: 
Revision Chronology: 
Original Protocol, 
DNG 
2017N341355_00 
11-APR-2019 
Original 
Amendment 01, DNG 
2017N341355_01 
06-JUN-2019 
This amendment results from FDA “Study 
May Proceed” letter for IND Opening (Number 131394, 
Reference ID 4441322) dated 
31-MAY-2019. FDA requested 9 clinical changes to the 
protocol. 
Amendment 02, DNG 
2017N341355_02 
02-JUL-2019 
This amendment results from a consensus 
between the Sponsor and the Study Site, that a confirmation 
of CD4+ T-cell count and 
CD4 percent values in healthy individuals with values within 
the normal range at 
screening, to be unnecessary. The removal of this 
confirmatory test is not determined to 
have effect on the evaluation of participant safety by the 
Sponsor or Study Site. 
Amendment 03, DNG 
2017N341355_03 
12-SEP-2019 
This amendment is based on 3 criteria. 
1) Initial dose escalation data following completion of Cohort 1 
indicated that Cohort 6 
in the study design will be required. Flexible language to this 
affect has been 
removed. 
2) Initial dose escalation data following completion of Cohort 1 
indicate that anti-drug 
antibodies (ADA) have the potential to appear earlier than 
indicated pre-clinically. 
Day 7 and Day 10 collection of samples for ADAs have been 
added in Part 1 and for 
Day 8 in Part 2. 
3) The previous consensus between the Sponsor and the 
Study Site on CD4+ T-cell 
count and CD4 percent values screening values under 
Amendment 02, requires 
further clarification. 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology. 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
No changes or deviations 
specified in protocol amendment 
3. 
• 
No Statistical Analysis or 
outputs to be generated for 
Part 2 (Multiple Ascending 
Dose) or exploratory 
objectives/endpoints 
• 
Study terminated prior to 
multiple dosing 
• 
Full CSR 
• 
Synoptic CSR 
• 
Early study termination 
during Part 1 for non-safety 
reasons. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To assess the safety and 
tolerability of single and multiple 
doses of GSK3732394 in healthy 
participants. 
• 
GSK3732394 safety parameters: adverse events; 
post-baseline values and changes over time of 
clinical laboratory evaluations (haematology, clinical 
chemistry, urinalysis), vital signs, and ECG 
parameters from predose values 
Secondary Objectives 
Secondary Endpoints 
• 
To describe the pharmacokinetic 
(PK) profile of single and multiple 
doses of GSK3732394 in healthy 
participants. 
• Derived PK parameters for GSK3732394, as data 
allow: Part 1 (single dose): AUC(0-t), AUC(0-∞),  Cmax, 
Tmax, tlag, Clast, tlast, t1/2,CL/F 
Part 2 (Repeated Once Weekly [QW] dosing): 
First week: AUC(0-t), AUC(0-∞), Cmax, tmax, tlag 
• 
Last week: AUC(0- ), Cmax, tmax, Ctrough, t1/2, CL/F.  
• 
To examine dose proportionality 
following single and multiple doses 
of GSK3732394, as data allow. 
• PK linearity assessment using derived PK 
parameters, as data allow: 
Part 1 (single dose): AUC(0-∞), Cmax 
• 
Part 2 (Repeat QW dosing): AUC(0-), Cmax, C.  
• 
To assess accumulation of 
GSK3732394 after multiple doses, 
as data allow. 
• 
Accumulation indices for PK parameters assessed 
across first and last doses of multiple dosing, as data 
allow: RAUC(0-), RCmax, RC. 
• 
To characterise CD4 receptor 
occupancy (RO) profile of single 
and multiple doses of 
GSK3732394. 
• 
Percent of CD4 RO. 
• 
To investigate the relationship 
• 
Cmax, Ctrough, %RO 
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Objectives 
Endpoints 
between GSK3732394 exposures 
and CD4 RO. 
• To characterise potential 
immunologic impact on, and 
immune responses to, healthy 
participants who receive 
a single or multiple dose(s) of 
GSK3732394. 
• Change from baseline in CD3/CD4/CD8 and 
activated T-cell counts and percentages. 
• Change from baseline in CD4 mean fluorescence 
intensity (MFI). 
• Titers and incidence of anti-GSK3732394 
antibodies. 
Exploratory Objectives 
Exploratory Endpoints 
• 
To model the relationship between 
GSK3732394 exposures and CD4 
RO. 
• 
Estimating parameters descriptive of the relationship 
including Concentration resulting in 50% RO (EC50), 
as data allow. 
• 
To explore the correlation between 
GSK3732394 exposure and 
observed safety outcomes. 
• 
Occurrence of AEs /laboratory abnormalities and 
corresponding plasma concentrations / doses of 
GSK3732394. 
• 
To explore serum and urine 
metabolite(s) investigations of 
GSK3732394. 
• 
Identification of any compound-related degradants 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 2 Part, double-blind (sponsor-unblinded), randomized, placebo-controlled, 
single and multiple-ascending-dose study. 
• 
In Part 1, a sufficient number of healthy adults will be screened to provide 
approximately 8 participants for randomization within each of the SAD dosing 
cohorts. Overall, up to approximately 48 participants will be included 
depending on the number of cohorts required. 
• 
In Part 2, a sufficient number of healthy adults will be screened to provide 
approximately 8 participants for randomization within each of the 3 MAD 
dosing cohort. Overall, up to approximately 24 participants will be included 
depending on the number of cohorts required. 
Dosing 
• In Part 1, the proposed dosing schedule is designed to investigate SAD of 
GSK3732394 in healthy participants. All doses will be administered 
subcutaneously. The SAD portion of the study will be conducted in at least five, 
but no more than six, separate cohorts of approximately eight healthy adult 
participants each. Each of the participants in the SAD cohorts will receive a 
single dose of blinded GSK3732394 or blinded PBO (GSK3732394 : PBO = 
6:2, per their randomization assignment). Details of the starting dose and dose 
escalation can be found in Section 5.5.1 and Section 5.5.2, respectively, of the 
protocol. Dose escalation decisions, including the determination of subsequent 
doses in Part 1, will be determined by the Safety and Dose Escalation 
Committee (SDEC). See Section 5.5.5 of the protocol. 
• In Part 2, the proposed dosing schedule is designed to investigate multiple 
ascending doses (MAD) of GSK3732394 in healthy participants administered 
weekly for a total of four doses. All doses will be administered subcutaneously. 
• Part 2 consists of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 
2, and 3), each with approximately 8 participants (GSK3732394 : PBO = 6:2) 
who will receive four weekly doses of GSK3732394 or PBO on Days 1, 8, 15, 
and 22. Details of starting dose and dose escalations in Part 2 (MAD) can be 
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Overview of Study Design and Key Features 
found in Section 5.5.3 of the protocol. 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• In Part 1, participants will receive a single dose of GSK3732394 or PBO 
(6:2) on Day 1. Safety, PK and PD assessments will be performed at 
timepoints specified in the schedule of activity (SOA). Participants will 
remain in the clinic until the completion of the Day 14 procedures and will 
return to the clinic on Days 17, 21, and 24 for follow-up assessments, and 
an end-of-study evaluation on Day 28. 
• 
In Part 2, participants will receive doses of GSK3732394 or PBO (6:2) 
given at anticipated weekly intervals. Participants will remain in the clinic 
until the completion of the Day 35 procedures and will return to the clinic 
on Days 39, 42 and 46 for follow-up assessments, and an end-of-study 
evaluation on Day 49. Duration of participation through follow-up may be 
longer if actual PK parameters differ significantly from predicted values 
(e.g. if half-life is significantly longer than the predicted); but will not exceed 
five half-lives. 
Interim 
Analysis 
• No formal interim analyses (IA) are planned for this study. However, safety, 
tolerability, PK, and PD data will be reviewed before each dose escalation in 
Part 1 (single dose), Part 2 (repeat dose) and prior to MAD transition which will 
occur after at least the first 4 SAD cohorts.   
 
2.4. 
Statistical Analyses 
The main purpose of this study is to assess the safety, tolerability, and 
pharmacokinetic/pharmacodynamic attributes of subcutaneous doses of GSK3732394 in 
healthy participants. No formal hypotheses will be tested. Results will be descriptive in 
nature. Statistical modelling on select pharmacokinetic parameters will be performed to 
estimate dose proportionality. Point estimates with 90% confidence intervals will be 
reported, as appropriate. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available PK/PD data will be reviewed internally prior to each dose escalation and prior 
to transitioning to MAD dosing. Dose escalation can only occur after the Safety and Dose 
Escalation Committee (SDEC) has found that the safety, PK/PD profiles are supportive to 
proceed with the evaluation of the next higher dose level. The details of internal review 
process to support dose-escalation are included in the SDEC charter document. 
After each cohort, the data will be reviewed – the data consists of the PK, RO, 
relationship between PK and RO, and safety data.  At each cohort dose review, a dose 
will be proposed that meets the RO requirements for the next dosing cohort. Non-
compartmental analysis (NCA) PK analysis will be performed to obtain PK parameters.  
Beginning with the second dose in Part 1 and each subsequent dose throughout the study, 
the Bayesian probability of any individual participant exceeding the Cmax No Observed 
Adverse Effect Level (NOAEL) exposure of 93.9 µg/mL (Protocol Section 5.5.1) at that 
dose will be calculated, using the accumulated PK data of participants receiving 
GSK3732394 among the previous cohorts.  Observations on placebo will be excluded. 
This probability, together with safety and tolerability data of the preceding cohorts, will 
be used to help selection of the next dose.  The Bayesian probability of exceeding the 
Cmax threshold can be calculated for additional potential doses to aid in dose selection if 
necessary.  
The Bayesian probability will be based on Whitehead’s model shown below 
[Whitehead, 2001] using non-informative priors for the model parameters. 
yi =θ1 +θ2 di +εi 
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th 
participant. θ1 and θ2 are population intercept and slope, respectively. i is the random 
error of the i-th participant. 
 
For the prediction of the second dose in Part 1 and Part 2, θ2 will be assumed to equal 1 
(representing a dose proportionality assumption). This will allow for the estimation of the 
remaining parameters of the model using data from only one dose level. 
 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants at the time of termination of the study 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. 
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3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG 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 were 
randomized. 
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 participants who received at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received. 
Note: Participants who were not randomized but 
received at least one dose of study treatment should be 
listed. 
• 
Study Population 
• 
Safety 
Pharmacokinetic 
(PK) 
All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values). 
• 
PK 
• 
PD 
Refer to Section 11.10: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF 
(ClinBase). 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptors 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
Part 1 
A 
GSK3732394 Single dose level 1 
GSK3732394 Single Dose 
10 mg 
1 
B 
GSK3732394 Single dose level 2  
GSK3732394 Single Dose 
20 mg 
2 
C 
GSK3732394 Single dose level 3 
GSK3732394 Single Dose 
80 mg 
3 
P 
Placebo 
Single Dose Placebo 
4 
NOTES: 
• Order represents treatments being presented in TLF, as appropriate. 
 
5.2. 
Baseline Definitions 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. The Table below illustrates this 
rule for the planned Study Assessments. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline. 
Parameter 
Study Assessments Considered as Baseline 
Baseline to use in 
Data Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Part 1 
 
 
 
 
Vital Signs, ECG 
X 
 
X 
Day 1 (Pre-Dose) 
PK sample, PD 
Sample 
 
 
X 
Day 1 (Pre-Dose) 
Lab 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. 
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5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
11.3 
Appendix 3: Assessment Windows 
11.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
11.5 
Appendix 5: Data Display Standards & Handling Conventions 
11.6 
Appendix 6: Derived and Transformed Data 
11.7 
Appendix 7: Reporting Standards for Missing Data 
11.8 
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, concomitant medications, and 
exposure will be based on GSK Core Data Standards.  Details of the planned displays are 
presented in Section 11.10: List of Data Displays. 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the safety population, unless otherwise specified. 
All details of the planned displays are provided in Section 11.10: List of Data Displays. 
Unless otherwise specified, endpoints/variables will be summarized using descriptive 
statistics and listed. 
7.1. 
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 Section 11.10: List of Data Displays. 
AEs will be coded to the preferred term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA) V22.1. AEs will be graded by the investigator according 
to the Division of AIDS (DAIDS) Criteria Version 2.1. 
Injection site reactions will be reported as adverse events and included in the adverse 
events displays. Multiple symptoms of injection site reactions will be reported as separate 
adverse events for each reported symptom.  
A summary of non-serious AEs that occurred in strictly 5% of the participants or above 
will be provided (even with the limited sample size of the study, no rounding for the 
percentage will be used in terms of 5% threshold).  
A summary of number and percentage of participants with any adverse event by 
maximum grade will be produced. AEs will be sorted by PT in descending order of total 
incidence. The summary will use the following algorithms for counting the participant: 
• Preferred term row: Participants experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade.  
• Any event row: Each participant with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
The following listings will be provided: 
• 
All adverse events 
• 
Subject Numbers for Individual AEs  
 
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests (with lymphocyte subset [CD4/CD8/CD3]), Urinalysis, and liver function 
tests will be based on GSK Core Data Standards. The details of the planned displays are 
in Section 11.10: List of Data Displays. Haematology, clinical chemistry and urinalysis 
parameters collected are listed below: 
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Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Lymphocyte 
Phenotype 
Absolute number and 
Percent of: 
CD3+ 
CD4+ 
CD8+ 
Clinical Chemistry 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
Glucose 
Calcium 
Alkaline phosphatase 
Amylase 
Lipase 
 
 
 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• 
Serum alcohol and urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)] 
• 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed)2 
• 
Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)] 
• 
Creatinine clearance (CrCL) for GFR estimation 
• 
The results of each test must be entered into the CRF. 
 
Laboratory toxicity grading will follow DAIDS grading criteria. Parexel data 
management will apply the grading in the SDTM dataset.  
7.3. 
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 Section 11.10: List of Data Displays. 
 
7.3.1. 
Vital Signs 
Vital sign values and change from baseline will be summarized. In addition, the number 
of subjects with worst case vital sign results relative to potential clinical importance 
(PCI) criteria post-baseline relative to baseline will be summarized by test and category.   
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7.3.2. 
Electrocardiograms 
A summary of the number and percentage of subjects of all ECG findings will be 
displayed by treatment.  Additionally, summary statistics of ECG values and change from 
baseline in ECG values will be presented. 
 
7.3.3. 
Liver Events 
The number of events does not support a summary. Liver monitoring/stopping event 
reporting will therefore only be listed for participants with liver events. In addition, 
listings will be produced for medical conditions and substance use for participants with 
liver events. 
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8. 
PHARMACOKINETIC ANALYSES 
All PK analyses planned for the study are either part of the secondary or exploratory 
objectives. Due to study termination, only secondary PK analyses will be reported. The 
PK analyses will be based on the PK population, unless otherwise specified.  
8.1. 
Pharmacokinetic Parameter Definitions and Summaries 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin version 8.0. All calculations of non-compartmental parameters for the final 
analysis will be based on planned sampling times. Planned sampling times will be used 
due to early termination of the study and the frequency of PK sampling times in Part 1. 
Pharmacokinetic parameters listed will be determined from the plasma concentration-
time data, as data permits. 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
tlag 
Lag time before observation of drug concentrations (after single dose only) 
Clast 
last observable concentration 
tlast 
time of last quantifiable concentration 
t1/2 
Apparent terminal phase half-life calculated as 
 
(NOTE: λz is the terminal phase rate constant). 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the loge trapezoidal rule for each decremental trapezoid. 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity will be calculated (after 
single dose only) as:  
 
AUC(0-∞) = AUC(0-t)+C(t)/λz 
 
(NOTE: λz is the terminal phase rate constant). 
%AUCex 
[The percentage of AUC(0-∞) obtained by extrapolation (%AUCex) will be calculated as: 
[AUC(0-∞) – AUC(0-t)] / AUC(0-∞) x 100 
CL/F 
Apparent Clearance 
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NOTES: 
• 
Additional parameters may be included as required. 
8.1.2. 
Summary Measure 
• All the derived PK parameters will be summarized through descriptive statistics.  
• Part 1 (single dose): AUC(0-t), AUC(0-∞), %AUCex, tmax, tlag, t1/2, Cmax, Clast, tlast, CL/F 
8.1.3. 
Population of Interest  
These descriptive summaries will be based on the PK population. 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Only completely administered doses of treatment will be considered for analysis. 
Participants may be replaced until the desired cohort size is attained. No imputation will 
be done for missing data after a participant withdrawal.  
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Section 11.10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
8.2. 
Statistical Analysis of derived PK Parameters 
The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles).  
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department. 
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8.2.1. 
Endpoint / Variables 
AUC(0-∞) and Cmax in the single dose study part. 
8.2.2. 
Summary Measure 
The summary measure will be the point estimates and 90% CIs of mean slopes of 
loge(dose) in the single dose study part. 
8.2.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the PK population, unless 
otherwise specified. 
8.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Only completely administered doses of treatment will be considered for analysis. 
Analyses will be based on available PK parameters. No imputation will be done for 
missing PK parameters for any participant. 
 
8.2.5. 
Statistical Analyses / Methods 
8.2.5.1. 
Statistical Methodology Specification 
• The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles).  
• Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department. 
 
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Pharmacokinetic Statistical Analyses - Dose Proportionality in single dose (Power Model)  
Endpoint / Variables 
• For SAD part: AUC(0-∞), Cmax 
Model Specification 
• Power model  
 
where y denotes the PK parameter being analyzed and dose denotes the total dose 
administered to a subject. 
• loge transformed data will be analyzed by fitting the following linear  model: 
 
• Data from all available doses in each part of the study will be considered.  
Model Checking & Diagnostics 
• 
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.  
• 
If there are any departures from the distributional assumptions, alternative transformations, 
such as data squared or square root of data, will be explored.  
Model Results Presentation 
Estimates of slope   will be reported along with corresponding 90% confidence 
intervals. If the CI contains 1 then we shall assume Dose Proportionality to hold. 
 
 
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9. 
PHARMACODYNAMIC ANALYSES 
9.1. 
Pharmacodynamic Parameters and Summaries 
The primary Pharmacodynamic measure is CD4 receptor occupancy (%RO) after single 
dose administration. Secondary measures include the component parameters of the %RO 
calculation and measures of activated T-cells. 
 
9.1.1. 
Endpoint / Variables 
CD4 receptor occupancy (%RO), component parameters used to calculate %RO, and 
active T-cells. The parameters are measured via flow cytometry and are reported as 
median fluorescence intensity.  
9.1.2. 
Summary Measure 
The following PD parameters will be summarized descriptively by treatment at each 
timepoint and also as change from baseline. 
Parameter 
Note 
CD3+CD8+CD25+ (%CD8+) 
Measures activated T-
cell 
CD3+CD8+ CD4(ADX6940)_AF647 MFI 
Used in %RO calculation 
CD3+CD4(OKT4)+CD25+ (%CD4(OKT4)) 
Measures Activated T-
cell 
CD3+CD8- CD4(OKT4)_PE MFI 
Used in %RO calculation 
CD3+CD8- CD4(ADX6940)_AF647 MFI 
Used in %RO calculation 
CD3+CD8- CD4(ADX6940)_AF647 Adjusted MFI 
Used in %RO calculation 
% Free 
Calculated % Free 
%RO 
Calculated % RO 
NOTE: 
Additional parameters may be included as required. 
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9.1.3. 
Population of Interest 
The primary pharmacodynamics analyses will be based on the PK population, unless 
otherwise specified. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Since %RO is being reported descriptively, missing values will not be imputed and 
summaries will be based on observed data. 
9.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Section 11.10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
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10. 
REFERENCES 
• Whitehead J. et al., Easy-to-implement Bayesian methods for dose-escalation studies 
in healthy participants, Biostatistics, 2, 47cs, 2, 47v 2001 
 
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11. 
APPENDICES 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
N/A as per-protocol population is not defined as an analysis population.  
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11.2. 
Appendix 2: Schedule of Activities 
The following is the protocol-defined Schedule of Activities pertaining the Part 1 of the 
study.  
Table 2 
SCREENING AND FOLLOW-UP/EARLY DISCONTINUATION 
ASSESSMENTS (Part 1 and Part 2) 
Procedure 
Screening 
(up to 30 
days prior 
to Day 1) 1 
Follow-
up/Early 
Discon 
Visit (~28 
days post 
last dose)  
Notes 
Follow-up Visit to occur approximately 28 days after last study 
drug administration or 5 half-lives (as determined from Part 1 
PK data), whichever is longer. 
Outpatient Visit 
X 
X 
 
Informed Consent 
X 
 
 
Inclusion and Exclusion 
Criteria  
X  
 
 
Demography 
X  
 
 
Medical History  
X 
 
 
Full Physical Examination 
(Including Height and 
Weight at the screening 
visit) 
X 
 
Additional examinations may be performed, or brief 
examinations made full examinations, by the Investigator, as 
deemed necessary (e.g. where safety or laboratory findings 
indicate). 
Target/Brief Physical 
Examination 
 
X 
12-lead ECG  
X 
X 
• Triplicate ECGs will be used to determine participant 
eligibility at screening. 
• Additional tests may be performed by the Investigator, as 
deemed necessary (e.g. where safety or laboratory 
findings indicate).  Tests will be conducted within site 
specified standards. 
Vital signs 
X 
X 
Urine Drug Screen 
X 
 
Alcohol Screen  
X 
 
Cotinine Screen  
X 
 
Pregnancy Test 
X 
X 
HIV, Hep B and Hep C 
Screen 
X 
 
 
Tuberculosis Test 
X 
 
 
Laboratory assessments 
X 
X 
 
Pharmacokinetic sample 
 
X 
 
Pharmacodynamic 
sample 
 
X 
 
Anti- GSK3732394 
antibodies 
 
X 
 
Adverse Event Review 
X 
X 
The collection of SAEs will be from the screening visit to the 
end of the study 
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Procedure 
Screening 
(up to 30 days 
prior to Day 1) 1 
Follow-up/Early 
Discon Visit 
(~28 days post 
last dose)  
Notes 
Follow-up Visit to occur approximately 28 days after last study drug administration or 5 half-lives 
(as determined from Part 1 PK data), whichever is longer. 
Concomitant Medication Review 
X 
X 
 
1. Screening must be performed within 30 days prior to receiving the dose of GSK3732394/PBO on Day 1 
 
 
Table 3 
Part 1 - All Cohorts Inpatient Days -1 to Day 14 
Procedure 
Day 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Pre-
dose 
0 h 
0.5 h 
1 h 
2 h 
4 h 
8 h 
12h 
24h 
48h 
72h 
96h 
120h 
144h 
168h 
192h 
216h 
240h 
264h 
288h 
312h 
Admission to Unit 
X 
 
  
Discharge from Unit 
 
X 
Urine Drug 
Alcohol/Screen/Cotinine 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Brief Physical Exam 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meals 
Per site usual practice 
Laboratory assessments1 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic sample2 
 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacodynamic 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Procedure 
Day 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Pre-
dose 
0 h 
0.5 h 
1 h 
2 h 
4 h 
8 h 
12h 
24h 
48h 
72h 
96h 
120h 
144h 
168h 
192h 
216h 
240h 
264h 
288h 
312h 
sample2 
Antidrug Antibody sample 
X 
  
 
  
  
  
  
  
  
  
  
  
  
X  
  
  
X  
  
  
  
X 
Biomarker sample3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample4 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SAE/AE Review5 
<=================================================================================================================> 
Con Med Review 
<=================================================================================================================> 
1. Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis. 
2. The number of PK and PD sampling time points may be reduced/extended in subsequent dosing groups once human PK data are available from initial SAD 
dosing cohorts.  An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification.  
3. Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms 
4. Urine will be collected at Day -1 (10mL) and for 24 hours after dose administration for GSK3732394-related material identification in the highest dose cohort 
only.  Details for urine collection and interval is included in the SRM. 
5. To include assessment of injection site(s) as appropriate (see also Protocol Section 3.3.1 and Protocol Section 8.1, and the SRM).  
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Table 4 
Part 1 - Outpatient Visit Days 17, 21, 24, 28 
Procedure 
Day 
17 
21 
24 
281, 2 
Brief Physical Exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
X 
Pregnancy Test 
 
 
 
X 
Laboratory assessments3 
X 
X 
X 
X 
Pharmacokinetic sample4,5 
X 
X 
X 
X 
Pharmacodynamic sample4,5 
X 
X 
X 
X 
Antidrug Antibody sample 
 
X 
 
X 
Biomarker sample6 
 
 
 
 
Adverse Event Review7 
<=====================================================================================> 
Con Med Review 
<=====================================================================================> 
6. 
In the event of terminal half-life longer than predicted, PK/PD and laboratory assessments will occur every four days until an estimated 5 half-lives have elapsed 
7. 
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at Day 28 Visit, these procedures and those listed in Table 2 Screening and Follow-
up/Early Discontinuation” for Follow-up/Early Discontinuation Visit (~28 days post last dose) may be considered the same. 
8. 
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis. 
9. 
An aliquot of this PK serum sample will be used for GSK3732394-related material (serum metabolites) identification. 
10. PK samples collection on Days 17, 21 and 24 are conditional on the PK assessment at up to Day 7 during the conduct of the study and may be adjusted as data become 
available. 
11. Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms 
12. To include assessment of injection site(s) as appropriate (see also Protocol Section 3.3.1 and Protocol Section 8.1, and the SRM). 
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Table 5 
Part 2 - All Cohorts Inpatient Days -1 to Day 17 
Procedure 
Day 
Day -1 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Pre-dose 
0 h 
0.5 h 
1 h 
2 h 
4 h 
8 h 
12h 
24h 
48h 
72h 
96h 
120h 
144h 
Pre-dose 
0 h 
24h 
48h 
72h 
96h 
120h 
144h 
Pre-dose 
0 h 
24h 
48h 
Admission to Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug/ 
Cotinine/Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical Exam 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meals 
Per site usual practice 
Laboratory assessments1 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic sample2 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pharmacodynamic sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Antidrug Antibody sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Biomarker sample3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Review5 
<=================================================================================================================> 
Con Med Review 
<=================================================================================================================> 
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1. 
Laboratory assessments include hematology (with lymphocyte subset [CD4/CD8/CD3], clinical chemistry and urinalysis. 
2. 
An aliquot of the PK serum sample will be used for GSK3732394-related material (serum metabolites) identification.  Refer to the windows allowance agreement attached to 
the SRM for timing of trough samples to be drawn on non-dosing days.  
3. 
Serum for biomarkers of immune activation will be collected at baseline and post-treatment in the event of clinical symptoms 
4. 
Urine will be collected at Day -1 (10mL) and for 24 hours after dose administration for GSK3732394-related material identification after the 4th MAD dose. Details for urine 
collection and interval is included in the SRM. 
5. 
To include assessment of injection site(s) as appropriate (see also Protocol Section 3.3.1 and Protocol Section 8.1, and the SRM). 
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11.3. 
Appendix 3: Assessment Windows 
• Nominal time will be used for all analysis except PK analysis where planned and 
actual time will be used. 
11.3.1. 
Definitions of Assessment Windows for Analyses 
The visit assigned to the assessment as entered in the eCRF (nominal visit) will be used 
for reporting. 
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11.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
11.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment. 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
In-Patient 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date +14 Days 
Out-Patient 
Follow up 
Date > Study Treatment Stop Date + 14 Days 
 
11.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
11.4.2. 
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 14 days (in-patient setting) 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 14 
days. 
• 
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date 
+ 14 days. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
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11.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
11.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
US1SALX00259 
HARP Compound 
Compound: GSK3732394, study: 207863, reporting effort: final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1). 
Generation of RTF Files 
• 
RTF files will be generated for SAC. 
11.5.2. 
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. 
• 
Display all numeric variables with the same number of decimal places as the collected precision. 
• 
Display minimum and maximum values with the same number of decimal places as the collected 
precision. 
• 
Display the mean and percentiles (e.g. median, Q1, and Q3) with one additional decimal place. 
• 
Display the standard deviation and standard error with two additional decimal places. 
• 
Within a column, align all data values or summary statistics along the decimal point. 
• 
The reported precision for PK concentration data will be 1 decimal place but may be altered by 
parameter depending on the significant digits. 
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. 
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• 
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.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and 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. 
11.5.3. 
Reporting Standards for Pharmacokinetic Data 
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 
[SOP_514512]. 
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 
None. All PK parameters will be derived by the CPMS Pharmacokineticist. 
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. 
 
Loge-transformed data: 
N, n, geometric mean, 90% CI of geometric mean, standard deviation (SD) of loge 
transformed data and between subject 
geometric coefficient of variation (CVb (%)) will be reported. 
CVb (%) = √ (exp(SD2) – 1) * 100 
[NOTE: SD = SD of loge transformed data] 
 
Parameters Not Being Loge Transformed: Tmax and T1/2. 
 
 
 
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11.6. 
Appendix 6: Derived and Transformed Data 
11.6.1. 
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. 
• 
If there are two values within a time window (as per Section 11.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken. 
• 
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     
 
11.6.2. 
Study Population 
Treatment Compliance 
• 
Treatment compliance will be evaluated by comparing randomized and actual doses of each participant 
in the listing. 
Extent of Exposure 
• 
For the single dose portion of the study each participant receives a single dose. Therefore, no 
cumulative dose will be calculated per participant.  
11.6.3. 
Safety 
 
ECG Parameters 
RR Interval 
• IF RR interval (msec) is not provided directly, then RR can be derived as : 
[1] If QTcF is machine read, then:  
 
• 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive. 
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ECG Parameters 
Corrected QT Intervals 
• When not entered directly in the eCRF (ClinBase), corrected QT intervals by Fredericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements. 
• IF RR interval (msec) is provided then missing QTcF will be derived as :  
               
 
 
11.6.4. 
Pharmacokinetic 
PK parameters 
• 
The PK Population will include all subjects who undergo PK sampling and have 
evaluable PK assay results. 
• 
See Section 8.1 for derived Pharmacokinetic parameters 
11.6.5. 
Pharmacodynamic 
% Receptor Occupancy  
 
CD4 Free Receptor (%Free) and CD4 Receptor Occupancy (%RO) will be calculated as follows: 
 
 
 
 
 
Note: The adjusted MFI (Δ) will be used to calculate Free Receptor and Receptor Occupancy 
values in the AF647 channel. Delta MFI values will be calculated as follows: (CD3+CD8- 
CD4(ADX6940)_AF647 MFI)  - (CD3+CD8+ CD4(ADX6940)_AF647 MFI). %Free and %RO will be 
in the SDTM data. 
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% Receptor Occupancy  
 
Limit of Detection (LOD) of the Receptor Occupancy Assay 
The limit of detection (LOD) of the receptor occupancy assay will be calculated using the cumulative 
placebo data of the study. The limit of detection (LOD) will be calculated as follows. For each placebo 
subject the average of (3+8- 647 Delta / 3+8- OKT4_PE) will be calculated across all timepoints where both 
measures are available. This average value will be used to calculate %RO at each timepoint i as: 
 
%ROi=(1-(3+8- 647 Deltai/ 3+8- OKT4_PEi)/Mean(3+8- 647 Deltai/ 3+8- OKT4_PEi))*100. 
 
The subject standard deviation (SDsubject) of these %ROi values will be calculated for each placebo subject 
and LODsubject will be calculated as: 
LODsubject=Mean(%ROi)1 + 3*SDsubject 
The cumulative LOD will be calculated by averaging the LODsubject across all placebo subjects. Imputed 
%RO is defined as 0 for all timepoints where the Assay-Reported %RO is below LOD except for the 
timepoint immediately prior to an Assay-Reported %RO above LOD and the timepoint immediately after an 
Assay-Reported %RO above LOD. The imputed %RO for these timepoints will be ½ of the LOD. Assay-
reported %RO will be used for summaries and both assay-reported and imputed %RO will be listed. 
 
 
                                                 
1 Note: Mean(%ROi)=0 by definition using the above average adjustment 
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11.7. 
Appendix 7: Reporting Standards for Missing Data 
11.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Subject study completion (i.e. as specified in the protocol) was defined having 
completed all phases of the study including the last visit and the last scheduled 
procedure shown in the Schedule of Activities.  
• 
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. 
11.7.2. 
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. 
11.7.2.1. 
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 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
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Element 
Reporting Detail 
Medications/
Medical 
History 
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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11.8. 
Appendix 8: Values of Potential Clinical Importance 
11.8.1. 
Laboratory Values 
Element 
Reporting Detail 
Laboratory 
Values and 
Adverse 
Events 
• The Division of AIDS (DAIDS) grading for severity of laboratory toxicities and 
clinical adverse events, version 2.1, July 2017 will be used to assign grades 
to laboratory values. 
• When deriving the Grading for severity of laboratory toxicity only numeric 
criteria are considered. The following note will be included in the listing 
including laboratory severity output: “Grades were derived based on numeric 
criteria as defined in DAIDS Version 2.1 and did not take into consideration of 
clinical signs or symptoms which is needed for the final grade associated with 
the adverse event.” 
• Reference ranges for all laboratory parameters collected throughout the 
study are provided by the laboratory. A laboratory value that is outside the 
reference range is considered either high abnormal (value above the upper 
limit of the reference range) or low abnormal (value below the lower limit of 
the reference range). Note: a high abnormal or low abnormal laboratory value 
is not necessarily of clinical concern. The laboratory reference ranges will be 
provided on the listings of laboratory data. Clinical laboratory test results 
outside of the reference range will be flagged in the listings. 
 
11.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
450  
Absolute PR Interval 
msec 
110 
220 
Absolute QRS Interval 
msec 
75 
110 
QTc Interval (Bazett) 
msec 
 
450 
QTc Interval (Fridericia) 
msec  
 
450 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
60 
11.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
85 
160 
Diastolic Blood Pressure 
mmHg 
45 
100 
Heart Rate 
bpm 
40 
110 
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11.9. 
Appendix 9: Abbreviations & Trade Marks 
11.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
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 
LOD 
Limit of Detection 
MMRM 
Mixed Model Repeated Measures 
MFI 
Median Fluorescence Intensity 
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 
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Abbreviation 
Description 
RAMOS 
Randomization & Medication Ordering System  
RO 
Receptor Occupancy 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
Tmax 
Time Taken to Maximum Observed Plasma Drug Concentration 
Tlag 
Lag time before observation of drug concentrations 
t1/2  
Terminal phase half-life 
tau 
Dosing interval 
Cmax 
Maximum observed concentration 
Ctau 
Trough concentration 
Clast 
last observable concentration 
tlast 
time of last quantifiable concentration 
AUC 
Area under the concentration-time curve 
CL/F 
Apparent Clearance 
NOAEL 
No Observed Adverse Effect Level 
DAIDS 
Division of AIDS 
11.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 
 
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11.10. 
Appendix 10: List of Data Displays 
11.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.3 
NA 
Safety 
3.1 to 3.17 
NA 
Pharmacokinetic 
4.1 to 4.3 
4.1 to 4.3 
Pharmacodynamic 
6.1 to 6.2 
NA 
Section 
Listings 
ICH Listings 
1 to 25 
Other Listings 
26 to 29 
 
11.10.2. 
Deliverables 
Delivery 
Description 
SAC 
Final Statistical Analysis Complete 
 
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11.10.3. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
Safety 
ES1 
 
Summary of Subject Disposition for the Subject Conclusion 
Record 
ICH E3, FDAAA, EudraCT 
SAC  
1.2. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Epoch 
ICH E3 
 
SAC  
1.3. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
 
SAC  
Protocol Deviation 
1.4. 
Safety 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Population Analysed 
1.5. 
Screened 
SP1 
Summary of Study Populations  
IDSL 
 
SAC 
Demographic and Baseline Characteristics 
1.6. 
Safety 
DM1  
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC  
1.7. 
Safety 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC  
 
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11.10.4. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.1.  
Safety 
AE5B 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term 
ICH E3 
 
SAC  
3.2.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
FDAAA, EudraCT 
 ‘ 
SAC  
Laboratory: Chemistry  
3.3.  
Safety 
LB1 
Summary of Clinical Chemistry Data  
 
SAC 
3.4.  
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline 
 
SAC 
3.5.  
Safety 
LB16 
Summary of Worst Case Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3 
 
SAC 
Laboratory: Hematology 
3.6.  
Safety 
LB1 
Summary of Hematology Data 
 
SAC  
3.7.  
Safety 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3 
 
SAC  
3.8.  
Safety 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
 
SAC  
Laboratory: Urinalysis 
3.9.  
 Safety 
UR1 
Summary of Urine Data 
 
SAC  
3.10. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
ICH E3 
 
SAC  
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ECG 
3.11. 
 Safety 
EG2 
Summary of ECG Values 
 
SAC  
3.12. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC  
3.13. 
Safety 
EG11 
Summary of Increase in QTc Values Post-Baseline Relative to 
Baseline by visit and Category 
Add Visit Column before category. 
Replace “Maximum” in shell program 
with summary per visit. 
Use the following categories: 
• 
<=10ms 
• 
>10ms-20ms 
• 
>20-30ms 
• 
>30-60ms 
• 
>60ms 
SAC 
3.14. 
Safety 
EG1 
Summary of ECG Findings  
IDSL 
SAC 
Vital Signs 
3.15. 
Safety 
VS1 
Summary of Vital Signs 
 
SAC  
3.16. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC  
3.17. 
Safety 
VS7 
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline 
IDSL 
SAC 
 
 
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11.10.5. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK 
PK01 
Summary of GSK3732394 Plasma PK Concentration-
Time Data by Treatment 
 
SAC  
PK Parameters 
4.2.  
PK 
PK06 
Summary of Derived GSK3732394 Plasma Pharmacokinetic 
Parameters (non-transformed and log-transformed) by 
Treatment 
 
SAC 
PK Statistical Analysis Table 
4.3.  
PK 
mid207187 
Table 4.4 
Summary Results of Single Dose Proportionality 
Assessment Using Power Model  
(reference study 
mid207187 Table 4.4) 
SAC  
 
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11.10.6. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
4.1.  
PK 
PK16a 
Individual GSK3732394 Plasma Concentration-Time Plots 
(Linear and Semi-Log) by Treatment  
Overlay all individual profiles 
per treatment in a plot. 
Separate plots by treatment. 
SAC  
4.2.  
 
PK 
 
PK17 
Median GSK3732394 Plasma Concentration-Time Plots 
(Linear and Semi-Log) 
 
SAC  
4.3.  
 
PK 
 
PK18 
Mean GSK3732394 Plasma Concentration-Time Plots 
(Linear and Semi-Log) 
 
SAC  
 
11.10.7. 
Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PD 
6.1.  
PK 
LB1 
Summary of Pharmacodynamic Parameters by 
Treatment 
 
SAC 
6.2.  
PK 
LB1 
Summary of Pharmacodynamic Parameters Changes 
from Baseline by Treatment 
 
SAC 
 
 
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11.10.8. 
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  
2.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
SAC 
3.  
Safety 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC  
4.  
Safety 
BL1 
Listing of Subjects for Whom the Treatment Blind was 
Broken 
ICH E3 
 
SAC  
5.  
Safety 
TA1 
Listing of Randomized and Actual Treatment 
IDSL 
SAC  
Protocol Deviations 
6.  
Safety 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
 
SAC  
7.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC  
Demographic and Baseline Characteristics 
8.  
Safety 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC  
9.  
Safety 
DM9 
Listing of Race 
ICH E3 
SAC  
Concomitant Medications 
10.  
Safety 
CM3 
Listing of Concomitant Medications 
IDSL 
 
SAC 
Exposure 
11.  
Safety 
EX3 
Listing of Exposure Data 
ICH E3 
SAC 
Adverse Events 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.  
Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
SAC  
13.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse 
Events 
ICH E3 
SAC  
Serious and Other Significant Adverse Events 
14.  
Safety 
AE8CPA 
 
Listing of Serious Adverse Events (Fatal & Non-Fatal) 
 
ICH E3 
 
SAC  
15.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from 
Study 
ICH E3 
SAC  
Hepatobiliary (Liver) 
16.  
Safety  
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC 
17.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline 
IDSL 
SAC 
18.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver 
Stopping Events 
IDSL 
SAC  
19.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver 
Stopping Events 
IDSL 
list available substance use 
data for subjects with liver 
events 
SAC  
All Laboratory 
20.  
Safety 
 
LB5A 
Listing of All Laboratory Data 
ICH E3 
 
SAC 
ECG 
21.  
Safety 
EG3 
Listing of All ECG Values 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
22.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Any Value 
of Potential Clinical Importance 
 
SAC 
23.  
Safety 
EG5 
Listing of All ECG Findings 
 
SAC 
Vital Signs 
24.  
Safety 
VS4 
Listing of All Vital Signs 
 
SAC 
25.  
Safety 
VS4 
Listing of All Vital Signs for Subjects with Values of 
Potential Clinical Importance 
 
SAC 
 
11.10.9. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
26.  
PK 
PK07 
Listing of GSK3732394 Plasma PK Concentration-Time 
Data  
 
SAC  
27.  
PK 
PK13 
Listing of Derived GSK3732394 Plasma PK Parameters 
 
SAC  
PD 
28.  
PK 
PK07 
Listing of Assay-Reported and Imputed %Receptor 
Occupancy 
Replace Concentration in 
Example Shell with %RO and 
add Column for Imputed %RO 
SAC 
Immunogenicity 
29.  
PK 
IMM2 
Listing of Immunogenicity Results 
 
SAC 
 
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