Clinical trial NCT06214052
Conditions: HIV Infections
Keywords: Human immunodeficiency virus Proof of concept Antiviral Agents Virus Diseases
Sponsor: ViiV Healthcare
Start date: 2024-02-07; Completion date: 2024-06-12
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, ability of VH4524184 when given alone to reduce the amount of HIV (viral load) in people with HIV-1 infection who have never received antiretroviral therapy (treatment-naïve). Data from this study will be used to decide how VH4524184 can be best included in a full-treatment regimen for HIV-1 in the future.

Detailed description:

Arms: arm 1: Participants received VH4524184, administered as Dose 1 (low dose) on Day 1, Day 4, and Day 7. On Day 10, participants began open-label standard-of-care (SOC) antiretroviral therapy (ART), which was selected by the investigator and locally sourced. Participants were monitored weekly until Day 38. arm 2: Participants received VH4524184, administered as Dose 2 (medium dose) on Day 1, Day 4, and Day 7. On Day 10, participants began open-label SOC ART, which was selected by the investigator and locally sourced. Participants were monitored weekly until Day 38. arm 3: Participants received VH4524184, administered as Dose 3 (high dose) on Day 1, Day 4, and Day 7. On Day 10, participants began open-label SOC ART, which was selected by the investigator and locally sourced. Participants were monitored weekly until Day 38. arm 4: Participants received matching Placebo to the study intervention on Day 1, Day 4, and Day 7. On Day 10, participants began open-label SOC ART, which was selected by the investigator and locally sourced. Participants were monitored weekly until Day 38.
Interventions: intervention 1: VH4524184 intervention 2: Matching Placebo intervention 3: Antiretroviral therapy
Intervention descriptions: intervention 1: VH4524184 was administered as tablets orally at Day 1. intervention 2: VH4524184 Matching Placebo was administered as tablets orally at Day 1. intervention 3: Antiretroviral therapy was administered as available and as per investigator's recommendation.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Primary Study Intervention(s) 
VH4524184 
Other Study Intervention(s) 
N/A 
Study Identifier 
218806  
EU CT Number  
2023-507173-18-00 
Approval Date 
29 Sep 2023  
Title 
A Randomized, Double-Blind (Sponsor Unblinded), 
Placebo-Controlled, Study to Investigate the Antiviral 
Effect, Safety, Tolerability and Pharmacokinetics of 
VH4524184 in HIV-1 Infected Treatment Naïve Adults  
Compound Number/Name  
GSK4524184 (also known as VH4524184) 
Brief Title 
VH4524184 Proof-of-Concept in Treatment-Naïve Adults 
Living with HIV-1 
Sponsor 
ViiV Healthcare group of companies 
Sponsor Name and Legal Registered Address 
(excluding US):  
ViiV Healthcare UK Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS, UK 
US IND Sponsor Name and Legal Registered Address: 
ViiV Healthcare Company 
410 Blackwell Street 
Durham, NC 27701, US 
Sponsor signatory 
Scott McCallister, MD  
Vice President and Head, Physician Center of Excellence 
Medical monitor name and contact can be found in local study contact information 
document 
©2023 ViiV Healthcare and the GSK group of companies. 


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Protocol Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other study 
conduct procedures and/or study conduct documents provided by ViiV Healthcare. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the ViiV Healthcare study intervention and other study-related duties and functions as 
described in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality Assurance 
procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-site or 
elsewhere without the approval of ViiV Healthcare and the express physical and/or 
digital informed consent of the participant.  
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). To co-operate with representative(s) of ViiV 
Healthcare in the monitoring and data management processes of the study with 
respect to data entry and resolution of queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the study intervention(s), and more generally about their financial 
ties with the sponsor. ViiV Healthcare will use and disclose the information solely for 
the purpose of complying with regulatory requirements. 
Hence, I: 


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• 
Agree to supply ViiV Healthcare with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that ViiV Healthcare may disclose any information about such ownership 
interests and financial ties to regulatory authorities. 
• 
Agree to provide ViiV Healthcare with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 


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Study identifier 
218806 
 
EU CT number 
2023-507173-18-00 
Approval date 
29 Sep 2023 
 
 
Title 
A Randomized, Double-Blind (Sponsor Unblinded), 
Placebo-Controlled, Study to Investigate the 
Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of VH4524184 in HIV-1 Infected 
Treatment Naïve Adults 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 19 
1.1. 
Synopsis ..................................................................................................... 19 
1.2. 
Schema ...................................................................................................... 23 
1.3. 
Schedule of activities (SoA) ........................................................................ 24 
1.3.1. 
Screening and Monotherapy Period ............................................. 25 
1.3.2. 
Open Label Follow-up Period....................................................... 31 
2. 
INTRODUCTION .................................................................................................... 33 
2.1. 
Study rationale ............................................................................................ 33 
2.2. 
Background ................................................................................................ 33 
2.2.1. 
Unmet Medical Need ................................................................... 33 
2.3. 
Benefit/risk assessment .............................................................................. 35 
2.3.1. 
Risk assessment .......................................................................... 36 
2.3.2. 
Benefit assessment ..................................................................... 41 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 41 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 42 
3.1. 
Primary estimand ........................................................................................ 43 
3.1.1. 
Antiviral activity ............................................................................ 43 
3.2. 
Key secondary estimand(s) ........................................................................ 43 
3.2.1. 
Safety and tolerability................................................................... 43 
3.2.2. 
Pharmacokinetic profile ................................................................ 45 
4. 
STUDY DESIGN .................................................................................................... 45 
4.1. 
Overall design ............................................................................................. 45 
4.2. 
Scientific rationale for study design ............................................................. 47 
4.2.1. 
Participant input into design ......................................................... 48 
4.3. 
Justification for dose ................................................................................... 48 
4.4. 
End-of-study definition ................................................................................ 49 
5. 
STUDY POPULATION ........................................................................................... 49 
5.1. 
Inclusion criteria .......................................................................................... 49 
5.2. 
Exclusion criteria ......................................................................................... 51 
5.2.1. 
Medical Conditions ...................................................................... 51 
5.2.2. 
Prior/Concomitant Therapy .......................................................... 53 
5.2.3. 
Prior/Concurrent Clinical Study Experience ................................. 53 
5.2.4. 
Diagnostic Assessments .............................................................. 54 
5.2.5. 
Other Exclusion Criteria ............................................................... 55 
5.3. 
Lifestyle considerations ............................................................................... 55 
5.3.1. 
 and dietary restrictions ...................................................... 55 
5.3.2. 
Alcohol and tobacco .................................................................... 55 
5.3.3. 
Activity ......................................................................................... 56 
5.3.4. 
Other restrictions ......................................................................... 56 
5.4. 
Screen failures ............................................................................................ 56 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study intervention .................... 56 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 57 
6.1 
Study intervention(s) administered .............................................................. 57 
CCI


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6.2 
Preparation, handling, storage, and accountability ...................................... 59 
6.3 
Assignment to study intervention ................................................................ 59 
6.4 
Blinding, masking ........................................................................................ 59 
6.4.1 
Randomization and treatment assignment ................................... 60 
6.4.2 
Central Laboratory ....................................................................... 60 
6.4.3 
Emergency unblinding ................................................................. 60 
6.5 
Study intervention compliance .................................................................... 61 
6.6 
Dose modification ....................................................................................... 61 
6.7 
Continued access to study intervention after the end of the study ............... 61 
6.8 
Treatment of overdose ................................................................................ 62 
6.9 
Prior and concomitant therapy .................................................................... 62 
6.9.1 
Permitted Medications ................................................................. 63 
6.9.2 
Prohibited Medications ................................................................. 63 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 64 
7.1 
Discontinuation of study intervention ........................................................... 64 
7.1.1 
Capturing reason for discontinuation in the eCRF ........................ 65 
7.1.2 
Liver chemistry stopping criteria ................................................... 66 
7.1.3 
QTc Stopping criteria ................................................................... 66 
7.1.4 
Pregnancy ................................................................................... 67 
7.1.5 
Suicidal ideation and behavior ..................................................... 67 
7.1.6 
Hypersensitivity reactions Stopping Criteria ................................. 67 
7.1.7 
Temporary discontinuation ........................................................... 67 
7.1.8 
Rechallenge ................................................................................. 67 
7.2 
Participant discontinuation/withdrawal from the study ................................. 68 
7.3 
Lost to follow-up.......................................................................................... 69 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 70 
8.1 
Administrative and baseline procedures ..................................................... 71 
8.1.1 
Collection of demographic data .................................................... 71 
8.1.2 
Medical/vaccination history .......................................................... 71 
8.2 
Efficacy assessments ................................................................................. 71 
8.2.1 
Quantitative HIV-1 RNA ............................................................... 71 
8.2.2 
Lymphocyte Subsets by Flow Cytometry ..................................... 71 
8.3 
Safety assessments .................................................................................... 72 
8.3.1 
Physical examination/history directed physical examination......... 72 
8.3.2 
Vital signs .................................................................................... 72 
8.3.3 
Electrocardiograms ...................................................................... 72 
8.3.4 
Clinical safety laboratory tests ..................................................... 73 
8.3.5 
Pregnancy testing for participants of childbearing potential .......... 73 
8.3.6 
Suicidal ideation and behavior risk monitoring ............................. 74 
8.3.7 
Study pausing rules ..................................................................... 75 
8.4 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 75 
8.4.1 
Time period and frequency for collecting AEs and SAEs ............. 76 
8.4.2 
Method of detecting AEs and SAEs ............................................. 76 
8.4.3 
Follow-up of AEs and SAEs ......................................................... 76 
8.4.4 
Regulatory reporting requirements for SAEs ................................ 76 
8.4.5 
Pregnancy reporting .................................................................... 77 
8.4.6 
Cardiovascular events and death events ..................................... 78 


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8.4.7 
Disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs ..................................................... 78 
8.4.8 
Contact information for reporting SAEs and study holding 
rules ............................................................................................. 79 
8.4.9 
Participant card ............................................................................ 79 
8.5 
Pharmacokinetics ....................................................................................... 79 
8.6 
Pharmacodynamics .................................................................................... 81 
8.7 
Genetics ..................................................................................................... 81 
8.8 
Biomarkers ................................................................................................. 81 
8.9 
Immunogenicity assessments ..................................................................... 81 
8.10 
Health economics or medical resource utilization and health 
economics .................................................................................................. 81 
9 
STATISTICAL CONSIDERATIONS ........................................................................ 82 
9.1 
Statistical hypotheses ................................................................................. 82 
9.2 
Analysis sets ............................................................................................... 82 
9.3 
Statistical analyses ..................................................................................... 83 
9.3.1 
General considerations/definitions ............................................... 83 
9.3.2 
Primary endpoint/estimand analysis ............................................. 83 
9.3.3 
Secondary endpoints/estimands analyses ................................... 84 
9.3.4 
Exploratory endpoints/estimands analysis ................................... 85 
9.4 
Interim analysis ........................................................................................... 86 
9.5 
Sample size determination .......................................................................... 86 
9.5.1 
Sample size considerations ......................................................... 86 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 88 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 88 
10.1.1 
Regulatory and ethical considerations ......................................... 88 
10.1.2 
Financial disclosure ..................................................................... 88 
10.1.3 
Informed consent process ............................................................ 89 
10.1.4 
Recruitment strategy .................................................................... 89 
10.1.5 
Data protection ............................................................................ 89 
10.1.6 
Committee structure .................................................................... 90 
10.1.7 
Dissemination of Clinical Study Data ........................................... 91 
10.1.8 
Data quality assurance ................................................................ 91 
10.1.9 
Source documents ....................................................................... 92 
10.1.10 Study and site start and closure ................................................... 92 
10.1.11 Publication policy ......................................................................... 93 
10.2 
Appendix 2: Clinical laboratory tests ........................................................... 94 
10.3 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 97 
10.3.1 
Definition of AE ............................................................................ 97 
10.3.2 
Definition of SAE .......................................................................... 98 
10.3.3 
Unsolicited AE ............................................................................. 99 
10.3.4 
Definition of CV events .............................................................. 100 
10.3.5 
Definition of TEAE ..................................................................... 100 
10.3.6 
Recording assessment and follow-up of AEs, SAEs and 
pregnancies ............................................................................... 100 
10.3.7 
Timeframes for Reporting SAEs, PSRAEs, Pregnancy, and 
Liver Events ............................................................................... 104 
10.4 
Appendix 4: Contraceptive and barrier guidance ....................................... 106 


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10.4.1 
Definitions .................................................................................. 106 
10.4.2 
Contraception guidance ............................................................. 107 
10.5 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments ............................................................................................. 108 
10.6 
Appendix 6: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Corrected version 2.1, July 2017 .............. 111 
10.6.1 
Estimating Severity Grade for Parameters Not Identified in 
the Grading Table ...................................................................... 111 
10.6.2 
QTc prolongation using the Fridericia formula ............................ 111 
10.7 
Appendix 7 : CDC Classification for HIV-1 Infection .................................. 112 
11 REFERENCES ..................................................................................................... 114 
 


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LIST OF TABLES 
PAGE 
Table 1 
Screening and Monotherapy Period Schedule of Activities ..................... 25 
Table 2 
Open Label Follow-up Period Schedule of Activities .............................. 31 
Table 3 
Objectives and Endpoints ....................................................................... 42 
Table 4 
Study Intervention(s) Administered......................................................... 57 
Table 5 
Study Arm(s) .......................................................................................... 58 
Table 6 
Contact information for reporting SAEs and study holding rules ............. 79 
Table 7 
Intensive Pharmacokinetic Sampling 
 .......... 80 
Table 8 
Expected precision of the estimated maximum VLD for various 
sample sizes and assumptions of data variability ................................... 87 
Table 9 
Protocol-required safety laboratory tests ................................................ 94 
Table 10 
Timeframes for Reporting SAEs, PSRAEs, Pregnancy, and Liver 
Events .................................................................................................. 104 
LIST OF FIGURES 
Figure 1 
Study design overview ........................................................................... 23 
................. 48 
CCI
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
%CVb 
Percentage between-participant coefficient of variation 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AIH 
Autoimmune Hepatitis 
ALT 
Alanine aminotransferase 
Anti-HBc 
Antibody to Hepatitis B core antigen / Hepatitis B core antibody 
Anti-HBs 
Antibody to Hepatitis B surface antigen 
ART 
Anti-retroviral therapy 
ARV 
Antiretroviral  
AST 
Aspartate aminotransferase 
AUC(0-∞) 
Area under the curve zero to infinity 
BLQ 
Below the limit of quantification 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CA 
Competent authority 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease - Improved Prediction Equations 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
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Abbreviation 
Definition 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 or Coronavirus 
CPK 
Creatine phosphokinase 
CPK 
Creatine phosphokinase 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CRF/eCRF 
Case report form/electronic case report form 
CSR 
Clinical study report 
CSSRS 
Columbia Suicide Severity Rating Scale 
CV 
Cardiovascular 
DAIDS 
Division of AIDS 
DDI 
Drug-drug interaction 
DILI 
Drug induced liver injury 
DNA 
Deoxyribonucleic acid 
DRE 
Disease-related event 
EC90 
Concentration of drug required for 90% inhibition of the viral 
replication 
ECG 
Electrocardiogram 
ED 
Early discontinuation 
EMA 
European Medicines Agency 
EOS 
End-of-study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration, United States of America 
FSFV 
First participant first visit 
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Abbreviation 
Definition 
FSH 
Follicle stimulating hormone 
FTiH 
First-time in human 
GCP 
Good clinical practices 
GGT 
Gamma glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
GSK 
GlaxoSmithKline 
H 
Hour 
HbcAb 
Hepatitis B core antibody / Antibody to Hepatitis B core antigen 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HBV DNA 
Hepatitis B virus deoxyribonucleic acid 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HCVAb 
Hepatitic C virus antibody 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HIV-1 RNA 
human immunodeficiency virus type 1 ribonucleic acid 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICSR 
Individual case safety reports 
IDSL 
Integrated data standards library 


C O N FI D E N TI A L  
 
T M F -1 7 0 0 8 5 8 0  
 
2 1 8 8 0 6  
1 3  
A b bre vi ati o n  
Defi niti o n  
I E C 
I n d e pe n de nt et hics c o m mittee 
I g G 
I m m u n o gl o b uli n G 
I M P 
I n v esti gati o nal me dici nal pr o d uct 
I N D 
I n v esti gati o nal Ne w Dr u g 
I N R 
I nter nati o nal n or malize d rati o 
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal re vie w b o ar d 
I U D 
I ntr a uteri ne de vice 
I W R S 
I nteracti ve we b res p o nse s yste m 
L D H  
lactate de h y dr o ge nas e 
L D L  
l o w-de nsit y li p o pr otei n 
L S L V  
Last p artici pa nt last visit  
M A D  
M ulti ple Asce n di n g D os e  
Ma x  
Ma xi m u m  
M C H  
Mea n c or p usc ular h e m o gl o bi n  
M C V  
Mea n c or p usc ular v ol u m e  
M DI  
Meta b olis m de pe n de nt i n hi bit or  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI  
M y ocar dial i nfarcti o n 
Mi n  
Mi n ute or mi ni m u m  
M S D S  
Material Safet y Data S heet  
NI M P  
N o n -i n vesti gati o nal me dici nal pr o d uct 
N O A E L  
N o o bser ve d a d verse effect le vel  
C CI


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Abbreviation 
Definition 
NQ 
Non-quantifiable 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PI 
Personal information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
POC 
Proof of concept 
POCBP 
Participant of childbearing potential 
PONCBP 
Participant of nonchildbearing potential 
POP PK 
Population pharmacokinetics 
PP 
Per protocol 
PrEP 
Pre-exposure prophylaxis 
PSRAE 
Possible Suicidality-Related AE 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PWH 
Persons with HIV 
QTc 
Corrected QT interval 
QTcF 
QT Interval corrected for heart rate according to Fridericia’s 
formula 
QTL 
Quality tolerance limit 
RBCs 
Red blood cells 
RNA 
Ribonucleic acid 
RPR 
Rapid plasma regain 
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Abbreviation 
Definition 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SIB 
Suicidal ideation and behavior 
SoA 
Schedule of activities 
SoC 
Standard of care 
SoC ART 
Standard of care antiretroviral therapy 
SRT 
Safety Review Team 
SUSARs 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum observed plasma concentration 
TN 
Treatment-naïve 
TOC 
Table of contents 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
VH 
ViiV Healthcare 
VLD 
Viral load decline 
VSLC 
ViiV Healthcare’s Safety and Labelling Committee 
WBC 
White blood cell 


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Abbreviation 
Definition 
WT 
Wild type 
 
Term 
Definition 
Blinding: 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an acceptable 
level of quality will appropriate personnel be unblinded or 
when required in case of a SAE. 
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e., by a dated 
signature or by generation through a validated process) to 
have the same information, including data that describe 
the context, content, and structure, as the original. 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Evaluable 
Evaluable participants are defined as those who have PK 
concentration data to allow estimation of the maximum 
change from baseline (Day 1) in plasma HIV-1 
ribonucleic acid (RNA) through Day 10 
Intervention number 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational medicinal 
product 
An IMP is a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical 
study, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, or 
when used for an unauthorized indication, or when used to 
gain further information about the authorized form. 
Medicinal products with a marketing authorization are 
IMPs when they are to be used as the test substance, 
reference substance, or comparator in a clinical study, 
provided the requirement(s) in the definition is/are met. 
Investigator 
A person responsible for the conduct of the clinical study 
at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 


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Term 
Definition 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions 
Participant number 
A unique identification number is assigned to each 
participant who consents to participate in the study. 
Participant 
Term used throughout the protocol to denote an individual 
who has been contacted to participate or who participates 
in the clinical study as a recipient of the study intervention 
(vaccine(s)/product(s)/control). 
Synonym: subject 
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Remote visit 
This term refers to the visit conducted in the place other 
than the study site. 
Source data 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are 
contained in source documents (original records or 
certified copies). 
Study intervention 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Note: “Study intervention” and “study treatment” are used 
interchangeably unless otherwise specified. 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 
collect final data for the primary outcome 
measures, secondary outcome measures, and AEs (that is, 
the last participant's last visit or LSLV). 


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Term 
Definition 
Study monitor 
An individual assigned by the sponsor and responsible for 
assuring proper conduct of clinical studies at 1 or more 
investigational sites. 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled, 
Study to Investigate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of 
VH4524184 in HIV-1 Infected Treatment Naïve Adults 
Brief Title: VH4524184 Proof-of-Concept in Treatment-Naïve Adults Living with HIV-1 
Rationale:  
VH4524184 is a 
 
 The in vitro 
antiviral potency of VH4524184 is comparable 
 
 with a likely high genetic barrier to resistance. 
This proof of concept (POC) study is designed to gain information on the antiviral effect, 
safety, tolerability and pharmacokinetic (PK) properties of VH4524184 orally 
administered to adults infected with HIV-1 who have yet to initiate treatment.  
Clinical development of VH4524184 is ongoing. Study 218803 is an ongoing first time in 
human (FTiH) study evaluating the safety, tolerability and PK properties of 
 
 VH4524184 in healthy participants and 218804 is a planned FTiH study 
evaluating the safety, tolerability and PK properties of 
 
VH4524184 in healthy participants. Study 218803 has shown VH4524184 to be generally 
well-tolerated in healthy participants to date (63 participants received VH4524184 as of 
27 July 2023) and has thus far demonstrated a favorable PK profile suitable for 
progression to treatment-naïve (TN) adults with HIV-1 in this Phase 2a POC 10-day, 
monotherapy study, 
.  
The data gathered from this study, together with data from the ongoing Phase 1 studies 
, will inform subsequent clinical trials and 
Phase 2b clinical development.  
 
 
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Objectives, Endpoints, and Estimands:  
Objective(s) 
Endpoint(s) 
Primary 
• 
To evaluate the antiviral activity of orally 
administered VH4524184 in TN participants with 
HIV-1 during 10 days of monotherapy 
• 
Maximum change from baseline (Day 1) in 
plasma HIV-1 ribonucleic acid (RNA) through 
Day 10. 
Secondary 
• 
To assess the safety and tolerability of orally 
administered VH4524184  
• 
Incidence of adverse events (AEs), severity of 
AEs and proportion of participants who 
discontinue treatment due to AEs 
• 
Change from baseline and maximum toxicity 
grade increase from baseline for liver panel 
laboratory parameter (Alanine Transaminase 
(ALT), Aspartate aminotransferase (AST), 
total bilirubin, direct bilirubin, alkaline 
phosphatase, albumin and total protein) 
• 
To characterize the pharmacokinetic profile of 
orally administered VH4524184  
As data permits, PK measures that include: 
• 
Maximum observed plasma drug 
concentration (Cmax), 
• 
Time to maximum observed plasma drug 
concentration (tmax), 
• 
Concentration on Day 10 
• 
To evaluate any relationship between 
VH4524184 exposure and change in plasma HIV-
1 RNA 
• 
Correlation of VH4524184 PK parameters 
with maximum plasma HIV-1 RNA change 
from baseline through Day 10 
• 
To assess the occurrence of emergent genotypic 
or phenotypic resistance after 10 days of 
monotherapy with VH4524184 
• 
Genotypic and phenotypic data from baseline 
(Day 1) and Day 10 will be compared for 
amino acid substitutions and VH4524184 fold 
change IC50. 
• 
To assess the immunologic effects of VH4524184 
when administered over 10 days in participants 
living with HIV 
• 
Change from baseline in CD4+ T-cell count to 
Day 10 
Tertiary 
• 
To further assess the safety and tolerability of 
orally administered VH4524184 
• 
Post baseline values and changes over time 
of vital signs, electrocardiogram (ECG) 
parameters and suicidality scores. 
• 
Absolute values, change from baseline and 
maximum toxicity grade increase from 
baseline for hematology, coagulation and 
remaining chemistry panels 
 
Overall Design: 
This is a Phase 2a POC, multi-center, randomized, double-blind (sponsor unblinded), 
placebo-controlled, adaptive clinical study to evaluate the antiviral effect, safety, 
tolerability and PK/PD of orally administered VH4524184 over 10 days in up to 
approximately 28 antiretroviral therapy (ART) naive adults with HIV-1 and detectable 
viremia. 


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This study will be conducted in 2 parts. In Part 1, 21 treatment naïve (TN) participants 
will be randomized to 1 of 3 cohorts. Within each cohort, 6 participants will receive 
VH4524184 and 1 will receive matching placebo 
 
  
Part 2 of the study is optional. The conduct of Part 2 is dependent on the informal interim 
evaluation of the exposure-antiviral response data from Part 1 using available preliminary 
clinical data from Part 1. Interim analysis of Part 1 will determine if evaluation of a fourth 
dose of VH4524184 would be informative to properly characterize the exposure-antiviral 
relationship. If evaluation of a fourth dose is needed, Part 2 will be conducted and will 
include 1 additional cohort in which up to 6 participants would receive VH4524184 and 1 
would receive matching placebo. Part 2 may evaluate 1 additional dose, with the dose and 
frequency informed by PK/PD modelling of Part 1 data.  
In both Part 1 and Part 2, each dose of VH4524184 will be evaluated as double-blind 
(Sponsor unblinded) monotherapy for 10 days (primary endpoint). On Day 10, participants 
will start open-label standard-of-care (SOC) antiretroviral therapy (ART) that is selected 
by the investigator and locally sourced. Participants will be followed weekly through 
Day 38. 
 
 
  
All participants will be screened for eligibility preferably within approximately 7 to 14 
days before being randomized into a 10-day study intervention period. The screening 
period may be extended to 28 days to allow, at a minimum, receipt of all screening results 
and/or to accommodate scheduling. 
Following screening, the study requires a total of 9 in-clinic visits (5 in-clinic visits will 
occur in the Monotherapy Period; 4 in-clinic visits will occur in the Open Label Follow-
Up Period) and 3 virtual visits (3 virtual visits will occur in the Monotherapy Period; 
participant may choose to attend the visit in-clinic and this is acceptable). 
 
 
  
If participants prematurely discontinue the study for non-safety reasons, additional 
participants may be recruited with randomization and assignment to the same cohort (to 
ensure a minimum of 5 evaluable participants in each of cohorts 1, 2 and 3, and optional 
cohort 4) at the discretion of the Sponsor in consultation with the Investigator. Participants 
will not be replaced if the reason for discontinuation is the original participant meeting 
stopping criteria. 
Total duration of study participation is approximately 45 to 66 days based on the 
following:  
• 
Screening Period: 7 to 14 days, with a maximum of 28 days permitted in some 
cases for screening/qualification period. 
• 
Monotherapy Period: 10 days for treatment with the study intervention and 
assessment at all planned visits.  
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• 
Open Label Follow-up Period: 28 days for follow up visits while on SOC ART 
including the final follow up visit.  
See Section 1.3 (Schedule of Activities) for additional details of activities during 
screening, the monotherapy period and the standard of care (SOC) period.  
Number of Participants:  
Approximately 28 antiretroviral therapy (ART) naïve participants may be enrolled in this 
study.  Part 1 of the study will enroll approximately 21 participants. If Part 2 of the study 
is conducted, approximately 7 additional participants will be enrolled. 
Data Monitoring/Other Committee:  
A safety review team (SRT) is in place for each ViiV Healthcare product. It comprises of 
a global cross-functional team responsible for the ongoing assessment of benefit-risk for a 
product. The SRT contribute to the continual blinded assessment of incoming new 
efficacy, safety and PK information. An external data and safety monitoring committee is 
not utilized in this study due to the relatively small size and early phase of the trial. This is 
further supported by the lack of significant safety findings from the available pre-clinical 
toxicity studies and preliminary clinical study of VH4524184. 
ViiV Healthcare Safety and Labelling Committee (VSLC) is a governance group that will 
review data and the team’s recommendation when any pausing/stopping rules are met. The 
VSLC will govern whether enrollment may be resumed/modified, a given treatment arm 
will be stopped, or the study stopped. The VSLC is comprised of senior representatives 
from various departments, including clinical development, safety, toxicology, 
pharmacovigilance, epidemiology, and medical affairs. 


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1.2. 
Schema  
Figure 1 
Study design overview 
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1.3. 
Schedule of activities (SoA) 
The schedule of study visits and expected study procedures and activities are detailed in 
Table 1 (Screening Period, Monotherapy Period) and Table 2 (Open Label Follow-up 
Period and Early Discontinuation Visit). 
While unlikely, the timing of assessments in Part 2 may be adjusted based on the interim 
analyses of the PK and/or antiviral results to ensure appropriate monitoring (e.g., to 
obtain data closer to the time of peak plasma concentrations or to maximal viral load 
decline). Any non-safety driven changes in the timing of the planned study assessments 
will be documented and communicated to investigators but will not constitute a protocol 
amendment. 
Any emerging safety issues that constitute a substantial amendment and require alteration 
of the safety monitoring scheme or amendment of the ICF will be approved by 
appropriate regulatory agencies and IECs/IRBs before implementation. 
 


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1.3.1. 
Screening and Monotherapy Period 
Table 1 
Screening and Monotherapy Period Schedule of Activities 
Clinical Procedures 
Screening 
VH4524184 Monotherapy Treatment Period (Double Blind) 
Day 1→Day 10 
 
 
 
Visit  
1 
Visit  
2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit  
7 
Visit  
8 
 
 
~7 to 14 days 
before Day 1 
Day  
1  
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
6 
Day  
7 
Day  
8 
Day  
9 
Day 
10 
Notes 
 
Screening: In an effort to minimize delays to starting the open-label standard-of-care combination antiretroviral regimen, the screening period will be conducted in as short a time as 
possible and ideally within 14 days. However, if necessary, screening period may be extended up to 28 days to allow receipt of all screening results and/or to accommodate scheduling. 
Visits 
Outpatient visit 
D10 
The Monotherapy Treatment Period requires a minimum 
of 8 visits over a 10-day period. 
• Days 1, 2, 3, 4, 7 and 10 are fixed visits. No window. 
• Visit 5 may be conducted on Day 5 or 6. 
• Visit 7 may be conducted on Day 8 or 9. 
• Assessments at Visit 3 (Day 3), Visit 5 (Day 5 or Day 
6), and Visit 7 (Day 8 or Day 9), may be conducted 
by telephone to minimize participant burden, 
although the participant may choose to attend the 
visit in the clinic, and this is acceptable.  
• Day 10: Complete all Day 10 assessments prior to 
the start of standard of care ART. 
The visit schedule for each participant will be pre-
planned and weekend, work schedules, and clinic hours 
will be appropriately considered.   
Order of assessments: Assessments, should occur in 
the following order:  
1) ECG (if applicable); 2) Vital sign assessment; (3) 
eCSSRS; 4) Blood draw (on PK days, HIV RNA to be 
collected at same time as pre-dose PK sample [with no 
Telephone call  
(Clinic visit allowed) 
. 
. 
. 
D3 
 
D5 or D6 
. 
D8 or D9 
. 
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Clinical Procedures 
Screening 
VH4524184 Monotherapy Treatment Period (Double Blind) 
Day 1→Day 10 
 
 
 
Visit  
1 
Visit  
2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit  
7 
Visit  
8 
 
 
~7 to 14 days 
before Day 1 
Day  
1  
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
6 
Day  
7 
Day  
8 
Day  
9 
Day 
10 
Notes 
preference as to which is drawn first])  
 
 All Day 10 
assessments must be completed prior to administration 
of the first dose of standard of care ART. 
Clinical and Other Assessments 
Informed consent 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
Confirmation of no 
prior use of Anti-
retroviral Therapy 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
Inclusion / Exclusion 
Criteria 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
See Section 5.1 and Section 5.2 
Demography 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
Medical History 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
Smoking history and alcohol intake to be included within 
the review of medical history. 
See Section 8.1.2 
CDC HIV 
Classification 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
See Section 10.7: Appendix 7. 
12-lead ECG 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
ECG obtained locally (site). QT interval corrected for 
heart rate according to Fridericia’s formula (QTcF). 
• 
Screening:  Collect single ECG reading to 
determine eligibility. A single repeat is allowed, if 
needed. 
See Section 7.1.3, Section 8.3.3. 
Vital Signs 
S 
D1 
D2 
. 
D4 
. 
. 
D7 
. 
. 
D10 
Body temperature, pulse rate, respiratory rate, and 
blood pressure will be recorded (before blood collection 
for laboratory tests). See Section 8.3.2. 
eCSSRS suicidality 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
D10 
See Section 8.3.6. 
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Clinical Procedures 
Screening 
VH4524184 Monotherapy Treatment Period (Double Blind) 
Day 1→Day 10 
 
 
 
Visit  
1 
Visit  
2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit  
7 
Visit  
8 
 
 
~7 to 14 days 
before Day 1 
Day  
1  
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
6 
Day  
7 
Day  
8 
Day  
9 
Day 
10 
Notes 
Physical exam 
S (c) 
D1 (b) 
D2 (b) 
. 
. 
. 
. 
. 
. 
. 
D10 (b) 
Complete (c) physical exam to be performed at 
Screening and Day 38 or at Early Discontinuation (ED) 
and will include assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems. 
Brief (b) physical exam to be performed at Day 1, Day 2, 
and Day 10, and may be targeted to include, at a 
minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
At the discretion of the investigator, a brief physical 
examination may be made a complete physical 
examination. 
Any abnormalities to be recorded as AEs. See Section 
8.3.1 
Height, Weight, BMI 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
D10 
Height, and weight to be measured at screening to 
calculate BMI. Height from screening can be used to 
calculate BMI on Day 10, Day 38/ED.  
AE/SAE assessment 
S 
D1 
D2 
D3 
D4 
D5 or D6 
D7 
D8 or D9 
D10 
• AE/SAE assessment, HIV-associated conditions, and 
concomitant medication reviews must be conducted 
with a participant during each day indicated. On the 
day when the participant does not come to the clinic, 
these assessments can be done via telephone.   
• Non-serious AEs are assessed from the time of first 
dose. 
• Serious AEs (SAEs) are assessed from the time of 
signing informed consent until the final visit in the 
Follow-up Phase. 
HIV-associated 
conditions 
S 
D1 
D2 
D3 
D4 
D5 or D6 
D7 
D8 or D9 
D10 
Concomitant 
medication review 
S 
D1 
D2 
D3 
D4 
D5 or D6 
D7 
D8 or D9 
D10 
 
 


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Laboratory Assessments 
Hepatitis B and C 
serologies 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
See Appendix 10.2 for details of clinical laboratory tests. 
Syphilis RPR  
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
Drug, alcohol and 
cotinine screening 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
Follicle stimulating 
hormone and 
estradiol 
S 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
To be completed as needed in participants (female sex 
assigned at birth) of nonchildbearing potential (PONCBP)  
to confirm post-menopausal status. 
Pregnancy Test 
S (s) 
D1 (u) 
D2 (u) 
. 
D4 (u) 
. 
. 
. 
. 
. 
D10 (u) 
To confirm that participants (female sex assigned at 
birth) of childbearing potential are not pregnant. (s)= 
serum; (u) urine. If urine test cannot be confirmed as 
negative, a serum test is required. 
Plasma for HIV-1 
genotype/phenotype 
S 
D1 
D2 
. 
D4 
. 
. 
D7 
. 
. 
D10 
 
Lymphocyte T-cell 
subsets (CD4, CD8) 
S 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
D10 
 
Hematology / 
Chemistry / 
Coagulation/ Urine 
S 
D1 
D2 
. 
D4 
. 
. 
D7 
. 
. 
D10 
See Appendix 10.2 for details of clinical laboratory tests. 
Includes fasting glucose and fasting lipid panel. 
Plasma for storage 
S 
D1 
D2 
. 
D4 
. 
. 
D7 
. 
. 
D10 
Plasma samples for storage will be collected at each 
outpatient visit, starting at Screening including 
unscheduled visits. These samples will be used when 
needed, such as when samples are lost or where 
quantity is insufficient for testing. In the event samples 
are not used by study completion, they may be utilized 
for additional research on antiretroviral resistance and/or 
HIV-1 disease biology/host immune response.  
HIV-1 RNA 
S 
D1 
D2 
. 
D4 
. 
. 
D7 
. 
. 
D10 
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Plasma PK sampling 
 
Study Treatment 
Interactive Web 
Response System for 
Central 
Randomization 
. 
D1 
. 
. 
. 
. 
. 
. 
. 
. 
. 
 
VH4524184/placebo 
administration  
Dispensation of 
standard of care ART 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
D10 
Standard of care antiretroviral therapy (SoC ART) will be 
chosen by the investigator. The first dose of SoC ART 
will be at Day 10, after the completion of all Day 10 
assessments. Choice of SoC ART will be informed by 
local treatment guidelines, accepted clinical practice and 
accessibility.  
If allowed per local regulatory guidelines and desired by 
participant and Investigator, SoC treatment will be 
continued for up to an additional 3 months following 
completion of follow-up assessments (post Day 38) 
Adherence 
counselling 
. 
. 
. 
. 
. 
. 
. 
. 
. 
. 
D10 
Adherence counseling may be provided by clinic and/or 
pharmacy staff consistent with local standards of care 
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and site SOPs. Counseling should be provided in a 
participant-centered manner, tailored as needed to the 
information, skills building, and support needs of each 
participant. Discussions to be documented within site 
source files. 
AE= Adverse Events; (b)= Brief physical exam; BMI= Body Mass Index; (c)= Complete physical exam; CDC= Centers for Disease Control and Prevention;  D1= Day 1; D2=Day 2; D3=Day 3; D4=Day 4; 
D5=Day5; D6=Day 6; D7= Day 7; D8=Day 8; D9= Day 9; ECG= electrocardiograph; HIV-1= human immunodeficiency virus type 1; (i)= Intensive PK visit;  PK= Pharmacokinetic RNA= ribonucleic acid; SAE= 
Serious Adverse Events; S= Screening; Standard of Care antiretroviral therapy = SoC ART; VH4524184=Investigational Product 


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1.3.2. 
Open Label Follow-up Period 
Table 2 
Open Label Follow-up Period Schedule of Activities 
Clinical Procedures 
Open Label Follow-Up Period 
Early 
Discontinuation 
 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
 
Notes 
Day 17 
(+/- 2 day) 
Day 24 
(+/- 2 day) 
Day 31 
(+/- 2 day) 
Day 38  
(+/- 2 days) 
Visits 
Outpatient visit 
D17 
D24 
D31 
D38 
ED 
Early Discontinuation: Additional follow-up visits/contacts beyond Day 38 are permitted if 
a participant experiences a safety event that requires follow-up monitoring. 
Clinical and Other Assessments 
12-lead ECG 
. 
. 
. 
D38 
ED 
12-lead ECG schedule: Day 38 or at Early Discontinuation- single reading. 
Vital Signs 
D17 
D24 
D31 
D38 
ED 
 
eCSSRS suicidality 
. 
. 
. 
D38 
ED 
 
Physical exam  
D17 (b) 
D24 (b) 
D31 (b) 
D38 (c) 
ED (c) 
Complete (c) physical exam to be performed at Screening and Day 38 or at Early 
Discontinuation and will include assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.  
Brief (b) physical exam to be performed at Day 17, Day 24 and Day 31, and may be 
targeted to include, at a minimum, assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).  At the discretion of the investigator, a brief 
physical examination may be made a complete physical examination. 
See Section 8.3.1.  
Any abnormalities to be recorded as AEs. 
Height, Weight, BMI 
. 
. 
. 
D38 
ED 
Height and weight to be measured at screening to calculate BMI. Height from screening 
can be used to calculate BMI on Day 10, Day 38/ED. 
AE/SAE assessment 
D17 
D24 
D31 
D38 
ED 
• AE/SAE assessment, HIV-associated conditions, and concomitant medication review 
must be conducted with a participant during each day indicated.  
• Non-serious AEs are assessed from the time of first dose. 
• Serious AEs (SAEs) are assessed from the time of signing informed consent until the 
final visit in the Follow-up Phase. 
HIV-associated conditions 
D17 
D24 
D31 
D38 
ED 
Concomitant medication 
review 
D17 
D24 
D31 
D38 
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Clinical Procedures 
Open Label Follow-Up Period 
Early 
Discontinuation 
 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
 
Notes 
Day 17 
(+/- 2 day) 
Day 24 
(+/- 2 day) 
Day 31 
(+/- 2 day) 
Day 38  
(+/- 2 days) 
Laboratory Assessments 
Pregnancy Test 
D17(u) 
D24(u) 
D31(u) 
D38(u) 
ED(u) 
(s)= serum; (u) urine. If urine test cannot be confirmed as negative, a serum test is 
required. 
Plasma for HIV-1 
genotype/phenotype 
. 
. 
. 
. 
ED 
 
Lymphocyte T-cell subsets 
(CD4, CD8) 
. 
. 
. 
D38 
ED 
 
Hematology / Chemistry / 
Coagulation/ Urine 
D17 
D24 
D31 
D38 
ED 
See Appendix 2, Section 8.3.4 for details of clinical laboratory tests.  
Includes fasting glucose and fasting lipid panel. 
Plasma for storage 
D17 
D24 
D31 
D38 
ED 
Plasma samples for storage will be collected at each outpatient visit starting at Screening 
including unscheduled visits. These samples will be used when needed, such as when 
samples are lost or where quantity is insufficient for testing. In the event samples are not 
used by study completion, they will be utilized for additional research on antiretroviral 
resistance and/or HIV-1 disease biology/host immune response. See Section 8.8 for 
more details. 
HIV-1 RNA 
. 
. 
. 
D38 
ED 
 
Plasma PK sampling 
To be collected at the same time as HIV-1 RNA samples (with no preference as to which 
is drawn first). 
Standard of Care ART 
Dispense standard of care 
ART 
D17 
D24 
D31 
D38 
ED 
Standard of care antiretroviral therapy (SoC ART) will be chosen by the investigator. 
Choice will be informed by local treatment guidelines, accepted clinical practice and 
accessibility. If allowed per local regulatory guidelines and desired by participant and 
Investigator, standard-of-care treatment will be continued for up to an additional 3 
months following completion of follow-up assessments (post Day 38) 
Adherence counselling 
D17 
D24 
D31 
D38 
ED 
Adherence counseling may be provided by clinic and/or pharmacy staff consistent with 
local standards of care and site SOPs. Counseling should be provided in a participant-
centered manner, tailored as needed to the information, skills building, and support 
needs of each participant. Discussions to be documented within site source files. 
AE= Adverse Events; (b)= Brief physical exam; ART= antiretroviral therapy; BMI= Body Mass Index; (c)= Complete physical exam; D10= Day 10; D17=Day 17; D24=Day 24; D31=Day 31; D38=Day 38; 
ECG= electrocardiograph; ED=Early Discontinuation; HIV-1= human immunodeficiency virus type 1; PK= Pharmacokinetic RNA= ribonucleic acid; SAE= Serious Adverse Events: Standard of care 
antiretroviral therapy (SoC ART)
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2. 
INTRODUCTION 
2.1. 
Study rationale 
VH4524184 is a 
 INSTI 
 
. The in vitro antiviral potency of VH4524184 is 
 
with a likely high genetic barrier to resistance. 
This POC study is designed to gain information on the antiviral effect, safety, tolerability 
and PK properties of VH4524184 orally administered to adults infected with HIV-1 who 
have yet to initiate treatment.  
Clinical development of VH4524184 is ongoing. Study 218803 is an ongoing FTiH study 
evaluating the safety, tolerability and PK properties of 
 VH4524184 in 
healthy participants and 218804 is a planned FTiH study evaluating the safety, 
tolerability and PK properties of 
 VH4524184 in healthy 
participants. Study 218803 has shown VH4524184 to be generally well-tolerated in 
healthy participants to date (63 participants received VH4524184 as of 27 July 2023) and 
has thus far demonstrated a favorable PK profile suitable for progression to TN adults 
with HIV-1 in this Phase 2a POC 10-day, monotherapy study, 
 
  
The data gathered from this study, together with data from the ongoing Phase 1 studies 
, will inform subsequent clinical trials and 
Phase 2b clinical development.  
2.2. 
Background 
2.2.1. 
Unmet Medical Need 
Globally, approximately 39 million people are currently living with HIV/AIDS. This 
worldwide epidemic continues to grow at a rate of 1.3 million new infections and causes 
0.6 million deaths per year[UNAIDS, 2023]. HIV-1 treatment requires life-long therapy 
with a minimum of two antiretroviral (ARV) medicines with different mechanisms of 
action.  
Management of HIV chronically is associated with long-term toxicity of anti-retroviral 
therapy (ART) as well as the possibility of development and transmission of resistant 
virus. Long-term toxicities may impact the CNS, CV system, alterations in metabolism 
and impaired renal function. Regimens which avoid particular classes of agents may help 
avoid or manage comorbidities among persons with HIV (PWH) and the use of treatment 
regimens with fewer medicines have the potential to reduce long-term toxicities by 
reducing ARV exposure. Treatment failure remains a continuing concern in clinical care 
due to the presence and emergence of resistant strains and tolerability issues. In addition, 
managing an aging population of PWH with an increasing prevalence of comorbidities 
and polypharmacy requires ARVs with the potential for fewer drug-drug interactions.  
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ARVs are notably effective, having converted an inevitably fatal infection into a chronic 
condition, but there is an opportunity for developing more conveniently dosed and better 
tolerated ARV regimens. There remains on-going need for new ARV agents with 
improved safety and tolerability. 
 
 
 
 
 
 
 
  
 
 
  
Summaries of the non-clinical studies of VH4524184 and safety and PK clinical data 
 of VH4524184 in study 218803 are included in the IB [GSK 
Document No RPS-CLIN-069016].  
The safety and pharmacokinetic profile of 
 VH4524184 are being 
characterized in healthy volunteers in the ongoing study 218803.    
2.2.1.1. 
Study 218803 – 
 FTiH VH4524184 
Study 218803 is a double-blind (sponsor-unblinded), randomized, placebo-controlled, 
FTIH study in a combined single- and multiple-dose protocol to investigate the safety, 
tolerability and PK of VH4524184 in healthy participants [GSK Document Number 
TMF-16041100]. This study is designed to evaluate:  
• the safety, tolerability, and PK properties of VH4524184 when administered as 
single and multiple ascending dosing 
  
• the safety, tolerability, and PK of the VH4524184 
  
• 
  
• any effect of VH4524184 on the activity of CYP3A using midazolam as a probe. 
Dose-proportional increases in geometric mean plasma concentrations of VH4524184 
were observed 
     
, without further increases in exposure following 
 
. VH4524184 geometric mean observed time to maximum 
concentration and half-life were 
 
 
 
 
 
 
 
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. 
Overall, there have been no clinically significant safety findings, SAEs, deaths, trends in 
vital signs, laboratory parameters, ECG parameters nor discontinuations due to AEs.  
Forty-five participants were exposed to single doses of VH4524184 or placebo in the 
SAD part of the study. Twelve participants experienced a total of 17 AEs, the majority of 
which were mild in severity, per the Investigator, except for an AE of back pain 
(moderate). Three participants experienced AEs considered by the Investigator to be 
related to study drug, these included 2 reports of constipation (1 in 
 and 
1 in 
, both mild in severity per the Investigator) and AEs of eye pain 
and headache in a participant in the 
.   
Twenty-seven participants were exposed to VH4524184 or placebo 
 in 
the MAD part of the study. Thirteen participants experienced 21 AEs, all of which were 
mild, per the Investigator, except for 3 moderate AEs (all unrelated: headache,  
abdominal pain and rib fracture). One participant experienced 2 AEs of fatigue, which 
were considered by the investigator to be related to study drug.  
 
. The treatment periods were separated 
by 
 washout period. Four participants experienced 6 AEs, all of 
which were mild. One participant experienced an AE of diarrhea on study Day 1, which 
was considered by the Investigator to be related to study drug.  
2.3. 
Benefit/risk assessment 
Pre-clinical safety assessment studies together with safety and PK clinical data 
 
 of VH4524184 in study 218803, which are summarized in the VH4524184 
IB [GSK Document Number [RPS-CLIN-069016], have not highlighted any issues with 
the potential to impact safety in humans. The clinical parameters which will be monitored 
throughout the study, as described in the SoA (Section 1.3), are based primarily on ADRs 
which have been observed 
, both during clinical development and from 
post-marketing experience. For 
 
 
  
To ensure the overall safety of participants (including, but not limited to, the potential 
risks as outlined in the table below), this clinical trial will include relatively healthy 
treatment-naïve adults living with HIV-1 who will be actively monitored by receiving 
frequent clinical, ECG, and laboratory evaluations during their participation in the trial.  
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of VH4524184 may be found in the IB. 
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2.3.1. 
Risk assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention VH4524184 
Hepatotoxicity   
Clinical trials have shown that elevations of 
liver enzymes and/or hepatitis can potentially 
occur with 
; these 
events are uncommon. No hepatotoxic events 
attributed to VH4524184 were observed in 
 
FTIH Study 218803.  
Standard Medical Monitoring practices and 
Clinical Safety Data Review processes including 
review of relevant emerging data. 
Use of protocol defined measures to minimize the 
risk of hepatotoxicity in subjects i.e., specific 
exclusion criteria based on screening hepatic 
transaminases (ALT/AST values), detailed liver 
stopping criteria and toxicity management 
guidance for suspected DILI or other clinically 
significant liver chemistry elevations, see 
Appendix 10.5 for required actions and follow-up 
assessments in the event of liver stopping criteria 
having been met). 
Informed consent forms will include notification of 
the potential for hepatotoxicity. 
Depression (including suicidal ideation and 
behaviors, particularly in patients with a pre-
existing history of depression or psychiatric 
illness) 
Depression and suicidal ideation and behaviors 
have been observed 
. These events 
occur particularly in patients with a pre-existing 
history of depression or psychiatric illness. 
 
Participants with any history of major depressive 
disorder with or without suicidal features, or 
anxiety disorders, that required medical 
intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or 
chronic (>6 months) outpatient treatment will be 
excluded from the study. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 provide the evidence for this 
risk. 
No psychiatric events were observed in 
 
FTIH Study 218803. 
Participants in the study will undergo intensive 
physical exam and laboratory testing. In addition, 
participants will undergo continuous evaluation for 
all treatment-emergent adverse events, including 
those related to depression, anxiety, and suicidal 
ideation/behavior during their participation in the 
trial; there are clinical stopping criteria based 
upon incidence and intensity of treatment-
emergent AEs.  
All participants will be administered the CSSRS 
questionnaire at screening, Day 10, Day 38, or at 
Early Discontinuation. In the event of a positive 
CSSRS (abnormal) response confirmed by the 
investigator, or other report of suicidal ideation 
and behavior by the participant at any time during 
the study, the PI/sub-investigator (SI) will arrange 
for urgent specialist psychiatric evaluation and 
management.  
Informed consent forms will include notification of 
the potential for depression and suicidal 
ideation/behavior. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Hypersensitivity reactions (HSR) 
Hypersensitivity is an uncommon but 
recognized risk for anti-retroviral regimens 
containing 
, 
regardless of dose. Hypersensitivity-type 
reactions have been 
. 
These reactions were characterized by rash 
and constitutional findings, and sometimes 
organ dysfunction, including liver injury. 
 
The cases which have been reported in 
association 
 have 
predominantly presented within angioedema 
and urticaria. While a casual association with 
more severe or systemic hypersensitivity 
reactions has not been identified with 
 to date, there remains a 
theoretical risk of such reactions with or without 
hepatic symptoms. 
No events indicative of hypersensitivity were 
observed in Study 218803.  
Standard Medical Monitoring practices and 
Clinical Safety Data Review processes including 
review of relevant emerging data from ongoing 
studies.  
Participants with history of drug hypersensitivity, 
delayed-type hypersensitivity or severe 
hypersensitivity reactions, as well as history of 
hypersensitivity to the study drugs are excluded 
(Section 5.2).  
Specific/detailed toxicity management guidance 
for HSR is included in the protocol (Section 7.1.6).  
Informed consent forms will include notification of 
the potential for HSR.  
Co-medications during the monotherapy phase 
should be limited to those that are medically 
necessary. Co-medications should be discussed 
with the ViiV medical monitor. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
HIV Resistance to VH4524184 
There is an intrinsic risk of resistance 
(genotypic changes or decreased phenotypic 
susceptibility) to any developmental ARV – 
particularly when given in monotherapy  
Prior 
 Proof of Concept studies: Data 
from the monotherapy studies for 
 
 showed a decline in HIV-1 RNA over the 
10 day treatment duration. No 
 
resistance associated mutations were observed 
and no resistance to existing and commercially 
available classes of antiretroviral medications 
(e.g., reverse transcriptase or protease 
inhibitors) was observed. Of note, there is no 
known cross-resistance between 
 and 
other classes of ARVs. 
This Phase 2a study is limited to 10 days of 
monotherapy. 
Doses of VH4524184 in all active therapy Cohorts 
were selected to ensure that from Day 1 
throughout the dosing period, 
 
 
 
 
Study conduct will ensure strict adherence to 
criteria addressing concurrent medications. 
Effects on embryo-fetal development  
Available data from non-clinical studies has not 
demonstrated any adverse findings. 
POCBP must use acceptable forms of non-
hormonal contraception through to Day 38. 
POCBP will have pregnancy testing conducted 
prior to study intervention and during the study. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Doses used in the Monotherapy Period have 
been studied in 
 FTIH study 218803. 
Supportive pre-clinical data 
Participants who become pregnant after 
administration of the first study intervention dose 
must not receive subsequent doses of the study 
intervention but may continue other study 
procedures at the discretion of the investigator. 
 
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2.3.2. 
Benefit assessment 
This study in HIV-1 infected, TN and otherwise healthy participants is a short-term 
monotherapy design. There is no expected longer-term anti-HIV benefit to administration 
of VH4524184 during this study; however, participants will transition to standard of care 
ART on study Day 10. Potential delays in initiating combination ART as a result of 
participating in this study are expected to be short and are not expected to have any 
clinically relevant impact upon study participant outcomes. 
2.3.3. 
Overall benefit-risk conclusion 
Given the preclinical profile of VH4524184, safety data obtained from VH4524184 study 
218803, the established safety profile of other 
 and the 
planned clinical procedures and evaluations in this study, the potential risks to adult 
participants with HIV-1 who are treatment naïve and otherwise relatively healthy 
receiving 10 days of VH4524184 monotherapy followed by SOC are low, evaluable, and 
manageable. 
To date, the benefit-risk profile of VH4524184 has been favorable in the clinical 
development program, with no new key safety concerns identified that would preclude 
the ongoing investigations. 
Considering risk mitigation strategies incorporated into the study protocols or study 
management, the potential/identified risks with use of VH4524184 are justified by the 
anticipated benefits; therefore, the benefit-risk profile of VH4524184 supports continued 
clinical development for the treatment of HIV-1 infection. 
 
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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 3 
Objectives and Endpoints  
 
Objective(s) 
Endpoint(s) 
Primary 
• 
To evaluate the antiviral activity of orally 
administered VH4524184 in TN participants with 
HIV-1 during 10 days of monotherapy 
• 
Maximum change from baseline (Day 1) in 
plasma HIV-1 RNA through Day 10. 
Secondary 
• 
To assess the safety and tolerability of orally 
administered VH4524184  
• 
Incidence of AEs, severity of AEs and proportion 
of participants who discontinue treatment due to 
AEs 
• 
Change from baseline and maximum toxicity 
grade increase from baseline for liver panel 
laboratory parameter (ALT, AST, total bilirubin, 
direct bilirubin, alkaline phosphatase, albumin and 
total protein) 
• 
To characterize the pharmacokinetic profile of 
orally administered VH4524184  
As data permits, PK measures that include: 
• 
Cmax, 
• 
tmax 
• 
Concentration on Day 10 
• 
To evaluate any relationship between 
VH4524184 exposure and change in plasma HIV-
1 RNA 
• 
Correlation of VH4524184 PK parameters with 
maximum plasma HIV-1 RNA change from 
baseline through Day 10 
• 
To assess the occurrence of emergent genotypic 
or phenotypic resistance after 10 days of 
monotherapy with VH4524184 
• 
Genotypic and phenotypic data from baseline 
(Day 1) and Day 10 will be compared for amino 
acid substitutions and VH4524184 fold change 
IC50. 
• 
To assess the immunologic effects of VH4524184 
when administered over 10 days in participants 
living with HIV 
• 
Change from baseline in CD4+ T-cell count to 
Day 10 
Tertiary 
• 
To further assess the safety and tolerability of 
orally administered VH4524184 
• 
Post baseline values and changes over time of 
vital signs, ECG parameters and suicidality 
scores. 
• 
Absolute values, change from baseline and 
maximum toxicity grade increase from baseline 
for hematology, coagulation and remaining 
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3.1. 
Primary estimand 
3.1.1. 
Antiviral activity 
• 
The primary objective is to evaluate the antiviral activity of orally administered 
VH4524184 in TN participants with HIV-1 during 10 days of monotherapy. The 
estimand is described by the following attributes: 
• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoint:  
Maximum change from baseline (Day 1) in plasma HIV-1 RNA through Day 10 
• 
Treatment:  
- 
VH4524184 or placebo 
 
• 
Intercurrent events: 
- 
Discontinuation of study treatment due to any reason will be addressed using 
while on-treatment strategy, i.e. any HIV-1 RNA data available after study 
treatment discontinuation day + 1 and prior to starting SOC will be excluded from 
calculation of max VLD 
- 
Use of SOC or other antiviral medication prior to Day 10 will be addressed using 
while on-treatment strategy, i.e., HIV-1 RNA collected after initiation of SOC, 
if for any reason this takes place prior to Day 10, will be excluded from 
calculation of max VLD 
- 
Use of prohibited medication will be addressed using treatment policy strategy, 
i.e., any HIV-1 RNA data available after use of prohibited medication will be 
used in calculation of max VLD 
- 
• 
Population-level summary:  
Mean of maximum change from baseline in log10 HIV-1 RNA during Days 1-10 
Rationale for estimand: Interest lies in evaluating efficacy of orally administered 
VH4524184 
, or use of prohibited medications and not 
in combination with other antiretroviral medication. 
3.2. 
Key secondary estimand(s) 
3.2.1. 
Safety and tolerability 
• 
The secondary objective is to assess the safety and tolerability of orally administered 
VH4524184. The estimand is described by the following attributes: 
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• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoints:  
- 
Incidence of AEs, severity of AEs and proportion of participants who discontinue 
treatment due to AEs  
- 
Change from baseline and maximum toxicity grade increase from baseline for 
liver panel laboratory parameter 
• 
Treatment:  
VH4524184 or placebo 
 followed by SOC on Days 10-38 
• 
Intercurrent events: 
- 
Discontinuation of study treatment due to any reason will be addressed using 
treatment policy strategy, i.e. all safety data after study treatment 
discontinuation will be used  
- 
Use of SOC medication prior to Day 10 will be addressed using while on-
treatment strategy, i.e., safety data collected after initiation of SOC, if for any 
reason this takes place prior to Day 10, will be excluded from monotherapy safety 
summaries  
- 
Use of prohibited medication will be addressed using treatment policy strategy, 
i.e., all safety data will be used regardless of the use of prohibited medication 
- 
• 
Population-level summary:  
AEs: 
- 
Number and percentage of participants with AEs 
- 
Number and percentage of participants with AEs by severity grade 
- 
Number and percentage of participants with AEs leading to study treatment 
discontinuation 
Liver panel laboratory parameters: 
- 
Summary statistics (mean, SD, median, min, max, etc.) of change from baseline  
- 
Number and percentage of participants with maximum toxicity grade increase 
relative to baseline 
Rationale for estimand: Interest lies in evaluating safety and tolerability of orally 
administered VH4524184 irrespective of study treatment discontinuation, 
 
, or use of prohibited medications and not in combination with other antiretroviral 
medication. 
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3.2.2. 
Pharmacokinetic profile 
Another secondary objective is to characterize the PK profile of orally administered 
VH4524184. The estimand is described by the following attributes: 
• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoints: as data permits  
- 
Maximum observed plasma drug concentration (Cmax) 
- 
Time to maximum observed plasma drug concentration (tmax) 
- 
Concentration on Day 10 
• 
Treatment:  
VH4524184 or placebo 
 followed by SOC on Days 10-38 
• 
Intercurrent events: 
- 
Discontinuation of study treatment due to any reason will be addressed using 
while on-treatment strategy, i.e. PK data after study treatment discontinuation 
will be excluded from use in noncompartmental analyses. 
- 
Use of SOC medication prior to Day 10 will be addressed using while on-
treatment strategy, i.e., PK data collected after initiation of SOC, if for any 
reason this takes place prior to Day 10, will be excluded  
- 
Use of prohibited medication will be addressed using treatment policy strategy, 
i.e., all PK data will be used regardless of the use of prohibited medication 
- 
 of study treatment will be addressed using while on-
treatment strategy, i.e., PK data collected 
 will be 
excluded from use in noncompartmental analyses. 
• 
Population-level summary:  
Summary statistics (e.g. arithmetic mean, SD, median, min, max, geometric mean, 
SD (log), %CVb, etc.) 
Rationale for estimand: Interest lies in characterizing the PK profile of orally 
administered VH4524184 which could be biased by study treatment discontinuation, 
, or use of SOC medication prior to day 10. 
4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a Phase 2a POC, multi-center, randomized, double-blind (sponsor unblinded), 
placebo-controlled, adaptive clinical study to evaluate the antiviral effect, safety, 
tolerability and PK/PD of orally administered VH4524184 over 10 days in up to 
approximately 28 ART naive adults with HIV-1 and detectable viremia. 
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This study will be conducted in 2 parts. In Part 1, 21 TN participants will be randomized 
to 1 of 3 cohorts. Within each cohort, 6 participants will receive VH4524184 and 1 will 
receive matching placebo 
  
Part 2 of the study is optional. The conduct of Part 2 is dependent on the informal interim 
evaluation of the exposure-antiviral response data from Part 1 using available preliminary 
clinical data from Part 1. Interim analysis of Part 1 will determine if evaluation of a 
fourth dose of VH4524184 would be informative to properly characterize the exposure-
antiviral relationship. If evaluation of a fourth dose is needed, Part 2 will be conducted 
and will include 1 additional cohort in which up to 6 participants would receive 
VH4524184 and 1 would receive matching placebo. Part 2 may evaluate 1 additional 
dose, with the dose and frequency informed by PK/PD modelling of Part 1 data.  
In both Part 1 and Part 2, each dose of VH4524184 will be evaluated as double-blind 
(Sponsor unblinded) monotherapy for 10 days (primary endpoint). On Day 10, 
participants will start open-label SOC ART that is selected by the investigator and locally 
sourced. Participants will be followed weekly through Day 38. 
 
 
  
All participants will be screened for eligibility preferably within approximately 7 to 14 
days before being randomized into a 10-day study intervention period. The screening 
period may be extended to 28 days to allow, at a minimum, receipt of all screening results 
and/or to accommodate scheduling. 
Following screening, the study requires a total of 9 in-clinic visits (5 in-clinic visits will 
occur in the Monotherapy Period; 4 in-clinic visits will occur in the Open Label Follow-
up Period) and 3 virtual visits (3 virtual visits will occur in the Monotherapy Period; 
participant may choose to attend the visit in clinic and this is acceptable). 
 
 
  
If participants prematurely discontinue the study for non-safety reasons, additional 
participants may be recruited with randomization and assignment to the same cohort (to 
ensure a minimum of 5 evaluable participants in each of cohorts 1, 2 and 3, and optional 
cohort 4) at the discretion of the Sponsor in consultation with the Investigator. 
Participants will not be replaced if the reason for discontinuation is the original 
participant meeting stopping criteria. 
Total duration of study participation is approximately 45 to 66 days based on the 
following:  
• 
Screening Period: 7 to 14 days, with a maximum of 28 days permitted in some 
cases for screening/qualification period. 
• 
Monotherapy Period: 10 days for treatment with the study intervention and 
assessment at all planned visits.  
• 
Open Label Follow-up Period: 28 days for follow up visits while on SOC ART 
including the final follow up visit.  
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See Section 1.3 (Schedule of Activities) for additional details of activities during 
screening, the monotherapy period and the SOC period.  
4.2. 
Scientific rationale for study design 
This is a Phase 2a, multi-center, randomized, double-blind (sponsor unblinded), placebo-
controlled, adaptive design, proof of concept clinical study to evaluate the antiviral effect, 
safety, tolerability, and PK/PD of 10 days of orally administered VH4524184 
monotherapy, an investigational HIV-1 
, in ART naive 
HIV-1 viremic adults. 
On Day 10, all participants will switch to standard-of-care antiretroviral therapy selected 
by the investigator 
         
 
 
Though there are commercially available/approved 
 available data suggests that 
 resistance does not occur during short periods of 
 monotherapy; therefore, 
dosing with VH4524184 will not interfere with selection of the ART regimen selected by 
the investigator on Day 10 and any subsequent regimen following completion of the 
study. 
The purpose of this study is to evaluate the short-term safety and effect on reducing HIV-
1 RNA levels from baseline for different doses of orally administered VH4524184. This 
study will facilitate an initial understanding of the antiviral activity and safety profile of 
VH4524184 in an HIV positive ARV naïve adult population, while limiting the 
monotherapy exposure to reduce the likelihood of development of viral resistance. The 
data gathered from this study, together with data from the 2 ongoing Phase 1 studies will 
inform subsequent clinical trials and Phase 2b clinical development 
 
 
 
There is an established precedence to use a randomized placebo-controlled short-term 
monotherapy design in a small number of participants when initially evaluating the 
activity of new investigational HIV anti-viral agents. This design allows an early 
understanding of the anti-viral potency and emerging safety profile across different doses 
while limiting the duration of exposure to the fewest number of HIV-infected 
participants. The placebo control maintains the blind, reduces bias in the investigator's 
evaluation and management of safety events, and permits a comparison of safety and 
efficacy outcomes between the investigational product and placebo. 
The 2-part adaptive design will allow for interim evaluation of the exposure-antiviral 
response data to determine if evaluation of a fourth dose of VH4524184 would be 
informative to properly characterize the exposure-antiviral relationship. If a fourth dose is 
not needed, then exposing additional participants to the investigational product can be 
avoided. 
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4.2.1. 
Participant input into design  
Community advisors living with HIV were engaged in development of this short-term 
monotherapy proof-of-concept study design. The group of highly experienced patient 
advocates provided feedback on protocol feasibility and informed guidance for study 
implementation (such as considerations for assessment of site facilities, potential services 
to ease participant burden during longer visits and travel to site, potential inclusion of 
POCBP in the study population, and considerations for the development of the informed 
consent document).   
4.3. 
Justification for dose 
The pharmacokinetics following 
 VH4524184 has been 
characterized in study 218803 [IB, 2023]. The 
 cohort in 218803 
. Exposures in the highest dosing cohort in this study will be 
lower than what has been observed in 218803 and based on the tolerability and safety 
profile in the FTiH 
 study, dosing in the PoC protocol is considered safe. A POP PK 
model was developed from participant VH4524184 PK observations collected in study 
218803. 
 
. Details for POP PK model 
development are described in the 218804 Human Dose Prediction Report [GSK Study 
report TMF-16733560]. The POP PK model is being leveraged herein to simulate 
VH4524184 exposures that achieve desired trough concentrations across 3 dosing 
Cohorts. The in vitro target trough concentration for VH4524184 is 
 
. Doses of 
 were selected 
for this study to establish an in vivo dose-response relationship by targeting typical 
subject trough concentrations that 
 
  
Figure 2 
Simulated Plasma concentrations of VH4524184 Achieved Following 
Dosing of 
  
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The maximum reduction of HIV-1 RNA from baseline (~ 2 – 2.5 log10 reduction) has 
been consistent across 
  [Markowitz, 2006; Min, 2011; Spreen, 2013; 
Gallant, 2017]. 
 of VH4524184 
 is anticipated to achieve 
maximum Day 10 reduction of HIV-1 RNA from baseline for all participants. Depending 
on the virologic response observed in the three planned cohorts, an additional cohort may 
be enrolled to further describe the relationship between VH4524184 exposure and HIV-1 
RNA levels. In this instance, PK/PD modeling will be used to inform the dose and 
frequency of the optional Part 2 cohort.  
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
10 days of double blind monotherapy, 4 weeks of Investigator chosen SOC and the Day 
38 EOS. The EOS  is defined as the date of the last visit of the last participant in the 
study. 
Part 2 of the study is optional. Completion of the study at the end of Part 1 will not be 
considered an early termination. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 Approximately 28 TN participants who are viremic at baseline (confirmed HIV-1 RNA 
≥ 3,000 copies/mL) and have CD4 T-cell counts ≥200 c/µL will be recruited. Part 1 of the 
study will enroll approximately 21 participants. If Part 2 of the study is conducted, 
approximately 7 additional participants will be enrolled. 
All participants will be screened for eligibility preferably within approximately 7 to 14 
days. The screening period may be extended to 28 days to allow, at a minimum, receipt 
of all screening results and/or to accommodate scheduling. If the screening period lasts 
beyond 14 days, notification of the medical monitor is required.  
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following 
criteria apply: 
1. Participant must be 18 to 65 years of age inclusive at the time of signing the informed 
consent. 
2. Participants who are overtly healthy (other than HIV infection) as determined by the 
Investigator or medically qualified designee based on a medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.  
3. Positive HIV antibody test 
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4. Documented HIV infection and Screening plasma HIV-1 RNA ≥ 3,000 copies/mL. A 
single repeat of this test is allowed within a single Screening period to determine 
eligibility. 
5. Screening CD4+ T-cell count ≥200 cells/mm3  
6. Treatment-naïve: No antiretrovirals (ARVs, in combination or monotherapy) received 
after the diagnosis of HIV-1 infection. 
7. HIV Pre-exposure or post-exposure prophylaxis: No prior use of any INSTI 
(including cabotegravir) for HIV pre-exposure or post-exposure prophylaxis.  
8. Body weight ≥50.0 kg (110 lbs.) for men and ≥45.0 kg (99 lbs) for women and BMI 
within the range 18.5-31.0 kg/m2 (inclusive - applies to males and females). 
9. All participants in the study should be counselled on safe sexual practices including 
the use and benefit/risk of effective barrier methods (e.g., male condom) and on the 
risk of HIV transmission to an uninfected partner. 
10. Male or female   
a. Male Participants:  
• 
No restrictions for male participants  
b. Female Participants:  
• 
A female participant (female sex assigned at birth) is eligible to participate 
if she is not pregnant or breastfeeding, and 1 of the following conditions 
applies:  
• Is a PONCBP as defined in Section 10.4.1.1.  There is no requirement for 
PONCBP to use a highly effective method of contraception or complete 
pregnancy testing. 
OR 
• Is a POCBP and is using a non-hormonal contraceptive method that is 
highly effective (failure rate of <1% per year when used consistently and 
correctly) as described in Section 10.4.2, during the study, and through the 
last visit in the Follow-up Period (Day 38).  The Investigator should 
evaluate potential for contraceptive method failure (e.g., noncompliance, 
recently initiated) in relationship to the first dose of study intervention. 
11.  A participant of childbearing potential must have a negative serum hCG test at 
screening, and negative urine hCG test at Day 1, before the first dose of study 
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• If a urine test cannot be confirmed as negative (e.g. ambiguous result), a 
serum pregnancy test is required.  In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
• The Investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease risk for inclusion of a 
female with an early undetected pregnancy. 
12. Capable of giving signed informed consent as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form and stated in this protocol. 
13. Participant must be willing and able to start standard-of-care ART as selected with 
the investigator on Study Day 10. 
5.2. 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical Conditions 
1. Participants with primary HIV infection, evidenced by acute retroviral syndrome 
(e.g., fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) 
documented viremia without antibody production and/or evidence of recent (within 3 
months) documented seroconversion. 
2. Any evidence of an active CDC Stage 3 disease [CDC, 2014], except cutaneous 
Kaposi’s sarcoma not requiring systemic therapy during the study.   
3. Untreated syphilis infection [positive RPR at screen] without documentation of 
treatment.  Participants who have successfully completed treatment at least 7 days 
previously are eligible if recruitment is open. 
4. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, 
or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or 
penile intraepithelial neoplasia; or other localized malignancies require agreement 
between the investigator and the study medical monitor for inclusion of the 
participant prior to randomization. Treatment with radiation therapy or cytotoxic 
chemotherapeutic agents within 30 days of study drug administration or anticipated 
need for such treatment within the study. 
5. Any pre-existing physical or mental condition which, in the opinion of the 
Investigator, may interfere with the participant’s ability to comply with the dosing 
schedule and/or protocol evaluations or which may compromise the safety of the 
participant. 
6. Any history of significant underlying psychiatric disorder, in the opinion of the 
Investigator or Medical Monitor, including but not limited to schizophrenia, bipolar 
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schizotypal (personality) disorder; or a clinical assessment of suicidality based on the 
responses on the eCSSRS. 
7. Any history of major depressive disorder with or without suicidal features, or anxiety 
disorders, that required medical intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient 
treatment. Participants with other conditions such as adjustment disorder or 
dysthymia that have required shorter term medical therapy (<6 months) without 
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the Medical Monitor. 
8. 
9. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
10. Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome or sudden cardiac death. Any significant arrhythmia or 
ECG finding (e.g., prior myocardial infarction, sinoatrial pauses, bundle branch 
block, or conduction abnormality) which, in the opinion of the Investigator OR ViiV 
Medical Monitor, will interfere with the safety for the individual participant. 
11. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination and will be the screening ECG entered into the eCRF):  
  
Males  
Females  
Heart rate1  
<45 or >100 
bpm  
<50 or >100 bpm  
PR interval  
<120 or >200 msec  
QRS duration  
<70 or >110 msec  
QTcF interval 2,3  
>450 msec  
>470 msec 
1 A heart rate from 100 to 110 bpm can be rechecked by ECG within 30 minutes to verify eligibility.  
2 QTcF > 480 msec in participants with bundle branch block.  
3 The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF), it is either 
machine-read or manually over-read. The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject will be determined prior to initiation of the study - QTcF will be used 
for this study. In other words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.  
To assess any potential impact on participant eligibility with regard to safety, the 
investigator must refer to the IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions, 
contraindications, AEs, drug interactions, and other significant data pertaining to the 
study drugs. 
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5.2.2. 
Prior/Concomitant Therapy  
12. Treatment with immunomodulating agents (such as systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (such as 
hydroxyurea or foscarnet) within 30 days of study drug administration. 
13. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) prior to dosing. Specific medications listed in Section 
6.9.1 may be allowed. 
14. History of sensitivity to any of the study medications, or their components or drugs of 
their class, or a history of drug hypersensitivity (including delayed hypersensitivity or 
severe hypersensitivity reactions) or other allergy that, in the opinion of the 
investigator or Medical Monitor, contraindicates their participation. 
15. Participants who require concomitant medications known to be associated with a 
prolonged QTc.   
16. Participants receiving any protocol-prohibited medication(s) and who are unwilling or 
unable to switch to an alternate medication (See Section 6.9.2). 
5.2.3. 
Prior/Concurrent Clinical Study Experience 
17. The participant has ever received an investigational HIV vaccine 
(immunotherapeutic or immunomodulatory). 
18. Exposure to an experimental drug or experimental vaccine within either 30 days, 5 
half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to the first dose of study intervention. 
• Note: Receipt of a SARS-CoV-2 vaccine that has received emergency, 
conditional, or standard market authorization is allowed at least 14 days 
prior to study entry (i.e., Screening) if the Principal Investigator (PI) 
determines that the benefit-risk profile for that individual study 
participant is favorable.  The use of other investigational COVID 
vaccines that have not received emergency, conditional, or standard 
market authorization and are still only used in clinical studies will not 
be allowed at this time. 
19. Participation in the study would result in donation of blood in excess of 500 mL 
within 56 days. 
20. Exposure to more than four new investigational drugs or vaccines within 12 months 
prior to the first dosing day. 
21. Current enrollment or past participation within the last 30 days, 5 half-lives or twice 
the duration of the biological effect of the investigational product (whichever is 
longer) before signing of consent in any other clinical study involving an 
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5.2.4. 
Diagnostic Assessments 
22. presence of HBsAg or HBcAb at screening:  
• 
Note: Evidence of HBV infection based on the results of testing at 
Screening for HBsAg. 
• Patients who are negative for HBsAg should also be tested for anti-HBc, 
anti-HBs and HBV DNA and excluded according to the following 
algorithm: 
• Participants negative for anti-HBs but positive for anti-HBc (negative 
HBsAg status) and positive for HBV DNA are excluded. 
• Participants positive for anti-HBc (negative HBsAg status) and positive 
for anti-HBs (past and/or current evidence) are immune to HBV and are 
not excluded. 
• 
Note: HBV DNA testing will only be performed during screening and 
prior to randomization for participants with positive anti-Hbc and both 
negative HBsAg and anti-HBs (past and/or current evidence). 
23. Positive Hepatitis C antibody test result at Screening AND positive on reflex to 
Hepatitis C RNA. 
• Note: Participants with positive Hepatitis C antibody due to prior 
resolved disease can be enrolled only if a confirmatory negative 
Hepatitis C RNA test is obtained (central lab will automatically reflex to 
HCV RNA on positive HCVAb). 
24. Positive Hepatitis C RNA test result at Screening. 
• Note: Test is optional and participants with negative hepatitis C 
antibody test are not required to also undergo hepatitis C RNA testing. 
25. Any Grade 3-4 laboratory abnormality is exclusionary (with the exception of Grade 
3-4 CPK and lipid abnormalities (e.g., total cholesterol, triglycerides, etc) following 
discussion and agreement by Sponsor Medical Monitor). A single repeat of any lab 
abnormality is allowed within a single Screening period to determine eligibility. 
26. Alanine aminotransferase (ALT) > 1.5 x ULN and / or total bilirubin >1.5xULN 
(isolated bilirubin >1.5xULN is acceptable if total bilirubin is fractionated and direct 
bilirubin <35%). A single repeat of ALT and / or bilirubin is allowed within a single 
Screening period to determine eligibility. 
27. Creatinine clearance (eGFR) of < 60 mL/min/1.73 m2 using CKD-EPI equation 
(2021) 
28. Any acute laboratory abnormality at screen which, in the opinion of the investigator, 
should preclude participation in the study of an investigational compound. 


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5.2.5. 
Other Exclusion Criteria 
29. Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening. A positive 
screen for marijuana / THC is not exclusionary. 
30. Heavy use of tobacco or nicotine containing products (≥ 20 cigarettes per day or 
equivalent, as determined by the investigator). 
31. During the study, alcohol consumption will be limited to the following:  
• An average weekly intake of <14 drinks for males or <7 drink for females.  
One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled 
spirits.  
5.3. 
Lifestyle considerations 
5.3.1. 
 and dietary restrictions  
• 
Participants will be required to fast for at least 8 hours (overnight) prior to the 
morning check-in for the Days 1, 2, 4, 7, 10, 17, 24, 31 and 38/Early Discontinuation 
Visits.  
• 
Blood work for the safety labs and HIV-1 RNA will be drawn at the beginning of 
any clinic visit and, when applicable, before consumption of any meal and 
dosing. See Section 1.3 (Schedule of Activities) and Section 8 (Study Assessments 
and Procedures) for order of assessments. 
• 
Refrain from excessive consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 
3 days prior to the first dose of study medication through the Day 10 visit. Excessive 
consumption is defined as more than 1 glass of red wine or juice or 1 fruit per day, in 
combination.  
5.3.2. 
Alcohol and tobacco 
• 
No alcohol consumption is allowed 8 hours prior to each blood collection for clinical 
laboratory tests and on intensive PK days 
 until after the final 
assessment of the day and release from the clinic.  Overall limitations on alcohol 
consumption are described in Section 5.2.5.  
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• 
Only clinically mild to moderate use (< 20 cigarettes per day or equivalent, as 
determined by the investigator) of tobacco or nicotine containing products will be 
allowed during study participation, with extremely limited use on the intensive PK 
days 
 to ensure it does not interfere with appropriate collection of 
samples, until after the final assessment of the day and release from the clinic.  
5.3.3. 
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 study participation. 
5.3.4. 
Other restrictions 
Not applicable 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently randomized to study intervention. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, information from any previous trials with the same IP, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Screening assessments that yield abnormal results (e.g., a safety 
laboratory parameter) may be repeated once within the screening window at the 
discretion of the investigator. Individuals who failed initial screening but passed 
rescreening may be admitted into the study based upon clinical judgement with 
consultation with the ViiV medical monitor as necessary. 
Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. Previously assigned participant numbers are to be recorded 
in the participants’ CRF/eCRF. All screening procedures should be repeated at the 
rescreening visit. 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study 
intervention 
Not applicable 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions.  
6.1 
Study intervention(s) administered 
Table 4 
Study Intervention(s) Administered 
Intervention Label 
VH4524184 
 
Placebo to match VH4524184 
 
Intervention Name 
VH4524184 
 
Placebo to match VH4524184 
 
Intervention Description 
 
 
Type  
Drug 
Drug 
Dose Formulation 
 
 
Unit Dose Strength(s) 
 
Not applicable 
Dosage Level(s) 
Variable depending on dose 
Variable depending on dose 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP and NIMP/AxMP. 
IMP  
IMP  
Sourcing 
Provided centrally by the sponsor  
Provided centrally by the sponsor  
Current alias 
GSK4524184  
Not applicable 
 
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Table 5 
Study Arm(s) 
1 The dose and frequency to be evaluated in Part 2 will be based on preliminary analyses of exposure and response data from Part 1. As a result, the arm description and the 
placebo to match in Part 2 would then be aligned to the specific dose that is chosen.
Arm Title 
VH4518424 
 
Placebo for 
VH4524184 
 
VH4518424 
 
 
Placebo for 
VH4524184 
 
VH4518424 
 
Placebo for 
VH4524184 
 
VH4518424  
 
Placebo for 
VH4524184
 
 
Part 
Part 1 
Part 1 
Part 1 
Part 1 
Part 1 
Part 1 
Part 2 
Part 2 
Arm Type 
Experimental 
Placebo 
Experimental 
Placebo 
Experimental 
Placebo 
Experimental 
Placebo 
Regimen 
number 
1 
2 
3 
4 
5 
6 
7 
8 
Arm 
Description 
 
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6.2 
Preparation, handling, storage, and accountability 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention. 
• 
All study intervention 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, the head of the medical institution (where applicable), 
or authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the pharmacy manual. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  
• 
A MSDS/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is 
required by local laws, or is available upon request from GSK. 
6.3 
Assignment to study intervention 
All participants will be centrally assigned to randomized study intervention using an 
IWRS. Before the study is initiated, the log-in information and directions for the IWRS 
will be provided to each site.  
Study intervention will be dispensed at the study visits as summarized in the SoA. 
Unused study intervention 
 may not be offered to the study 
participant beyond the expected dosing schedule as outlined in the SoA and may not be 
offered to any other person. 
6.4 
Blinding, masking 
This is a double-blind (sponsor unblinded) placebo-controlled study in which participants 
and investigators are blinded to study intervention at a participant level.  
The specific intervention to be taken by a participant will be assigned using an IWRS. 
The site will contact the IWRS prior to the start of study intervention administration for 
each participant. 
 Potential bias will be reduced by the following:  
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6.4.1 Randomization and treatment assignment 
All participants will be randomized, according to the randomization schedule generated 
prior to the study by the Biostatistics Department at GSK using validated internal 
software. Each participant scheduled to receive study drug will receive a treatment 
allocation number when randomized. 
Participants and investigators will know to which double blinded arms (Cohorts 1, 2, 3 or 
4) participants are assigned to.  
The blinding strategy for this study is further structured to ensure that no one at VH/GSK 
who is involved in the management of individual participants is unblinded to treatment at 
the participant level. As a general principle during study conduct, members of the 
VH/GSK study team and other VH/GSK staff will remain blinded to the assignment for 
individual participants aside from where unblinding is necessary to support the informal 
planned interim analyses or becomes necessary for safety reasons. 
Refer to Section 9.4 for more details about preservation of the blind during the conduct of 
the informal planned interim analyses.  
6.4.2 Central Laboratory 
The central laboratory in charge of HIV-1 RNA testing will be blinded to the study 
intervention assignment. Codes will be used to link the participant and study to each 
sample. There will be no link between the study intervention groups and the identity of 
the participant. 
The investigator, site staff and VH/GSK will be unblinded to HIV-1 RNA results 
performed at screening in order to determine HIV status for eligibility purposes.  
The investigator, site staff, and VH/GSK study team members involved in participant 
management, will be blinded to HIV-1 RNA results during the monotherapy and follow-
up periods. 
Refer to Section 9.4 for more details about preservation of the blind during the conduct of 
the informal planned interim analyses. 
6.4.3 Emergency unblinding 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator may, at the investigator’s discretion, contact 
VH/GSK to discuss the situation prior to unblinding a participant’s intervention 
assignment unless this could delay emergency treatment for the participant. If a 
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within 24 hours of this occurrence. The date and reason for the unblinding must be 
recorded. 
If the investigator is unable to access the IWRS they can contact the GSK helpdesk based 
on the information provided in the pharmacy manual. A physician other than the 
investigator (e.g., an emergency room physician) or participant/participant’s caregiver or 
family member may also request emergency access to the participant’s study intervention 
information as per participant card. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded.  
VH/GSK’s Global Safety staff may unblind the intervention assignment for any 
participant with an SAE. If the SAE requires that an expedited regulatory report be sent 
to 1 or more regulatory agencies, a copy of the report, identifying the participant’s 
intervention assignment, may be sent to investigators in accordance with local regulations 
and/or GSK policy. 
6.5 
Study intervention compliance 
 
. The date and time of each dose 
administered 
 will be recorded in the source documents.  
6.6 
Dose modification 
Modifications to the dose are not applicable in this study.  
6.7 
Continued access to study intervention after the end of the 
study 
Continued access to VH4524184 after the end of the study is not permitted since 
therapeutic benefit has not yet been established.  
Given the lack of longer-term clinical benefit (Section 2.3.2), ViiV Healthcare recognizes 
the balance between the need to conduct an early phase monotherapy clinical study (for 
the larger and long term unmet medical need) and the need for HIV-1 infected treatment 
naïve patients to receive ART as soon as possible after diagnosis. To meet both needs, 
this study design is efficient in screening (shortest period: approximately 7 to 14 days) 
and the monotherapy treatment with VH4524184 (period: 10 days). On study Day 10, 
following the scheduled blood collection as per SoA, participants will commence 
standard-of-care ART selected and prescribed by the investigator and sourced as per local 
requirements.  
After this time, the investigator is responsible for ensuring that participants continue to 
receive ART, whether or not the Sponsor is providing reimbursement for post-study 
treatment. 
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The Sponsor recognizes some HIV-1 infected adults may encounter barriers to accessing 
ART. Where it has been determined by the Investigator to be an acceptable option, 
participants receiving study treatment will have the option (but are not required if no 
access barrier) to receive reimbursement from the Sponsor for locally marketed ARVs 
after the completion of the study (i.e., Day 38 EOS which includes 10 days of double-
blind monotherapy and 28 days of investigator chosen SOC) for up to a maximum of 90 
days. The selection of ARVs will be investigator-chosen based upon local standard of 
care. 
6.8 
Treatment of overdose 
An overdose is any dose of study intervention given to a participant that exceeds the 
planned, randomized dose for an individual within a given dose group.  
In the event of an overdose, the investigator should: 
1. Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study intervention should be interrupted or whether the dose 
should be reduced. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
VH4524184 can no longer be detected systemically 
 as medically 
appropriate. 
3. Obtain a plasma sample for PK analysis if requested by the medical monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose. 
6.9 
Prior and concomitant therapy 
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study. Chemoprophylaxis for HIV-associated 
conditions is encouraged, if appropriate, at the discretion of the participant and their 
physician.  
Because vaccines may cause a temporary increase in the level of HIV-1 plasma RNA, it 
is highly recommended that a vaccine, if necessary, be given at least 14 days prior to 
Screening (if an experimental vaccine, within at least 30 days prior to first dose). Please 
discuss with medical monitor if planning to give vaccines during this time.  
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
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The VH medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.9.1 Permitted Medications 
1. Acetaminophen/paracetamol at doses of ≤2 g/day or NSAIDs are permitted for use 
any time during the study and their use documented in the CRF. 
2. In the event of irritation from ECG leads, up to 2.5% topical hydrocortisone may be 
used at the discretion of the investigator. 
3.  Other concomitant medications may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor if required. 
4. Participants must notify their Investigator of any current or proposed concomitant 
medication, whether prescribed or over-the counter because of the potential for 
interactions between such treatments and the study medications. 
6.9.2 Prohibited Medications 
See Section 5.2.2. 
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7 DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of the study intervention. In rare instances, it may be necessary for a 
participant to permanently discontinue study intervention.  
If study intervention is permanently discontinued, the participant should remain in the 
study, continue to comply with all other aspects of the protocol (such as starting the first 
dose of standard of care ART on Day 10) and be followed according to the SoA (Section 
1.3) to the EOS as defined in the protocol. 
If participants prematurely discontinue study treatment prior to Day 10 (primary 
endpoint), participants may be replaced at the discretion of the Sponsor in consultation 
with the investigator.  
Participants will not be replaced if the reason for discontinuation from the study 
treatment is due to a safety concern which the investigator considers reasonably 
attributable to study treatment e.g., when a participant meets stopping criteria. Refer to 
Section 7.1.2 (Liver chemistry stopping criteria), Section 7.1.3 (QTc stopping criteria) 
and Section 7.1.5 (Suicidal ideation and behavior) and Section 7.1.6 (Hypersensitivity 
reactions). 
A participant may be discontinued from the study intervention at any time if any of the 
protocol individual stopping criteria are met:  
• Emergence of any positive (abnormal) CSSRS response, or participant report of 
suicidal ideation and behavior at any time during the study, confirmed by the 
investigator or a clinician (or qualified designee) during the monotherapy period. 
• Pregnancy 
• ≥ Grade 3 AE (or clinically significant laboratory abnormality) suspected to be 
related to VH4524184. 
• An SAE, regardless of its severity, that is considered to be clinically significant 
and reasonably attributable to dosing with VH4524184, in the opinion of the 
Investigator.   
• A grade ≥2 rash with concurrent fever with or without concurrent elevations in 
liver biochemistry reasonably attributable to dosing with VH4524184, in the 
opinion of the Investigator.   
• Emergent medical condition that is judged by the Investigator as to jeopardize the 
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• Termination of the study by the Sponsor. Safety data will be reviewed by the 
Sponsor instream by single case and collectively. If a safety concern 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. 
• 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) 
• Clinical criteria for stopping study are met (as outlined below in Section 7.1) 
7.1.1 Capturing reason for discontinuation in the eCRF 
The primary reason for premature discontinuation of the study intervention will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
 
Lack of efficacy 
 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Specify 
 
Physician Decision 
Specify 
Pregnancy 
 
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
 
Sponsor terminated study treatment 
 
Study terminated by Sponsor 
 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
 
 
 
 


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7.1.2 Liver chemistry stopping criteria 
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met: 
Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal. 
Refer to Section 10.5 for required Liver Safety Actions and Follow up Assessments 
Discontinuation of study intervention for abnormal liver tests is required by the 
investigator when a participant meets 1 of the conditions outlined in the algorithm or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules 
if the investigator believes that it is in best interest of the participant. 
Refer to Section 8.3.7 for information about study pausing criteria.  
7.1.3 QTc Stopping criteria 
The Fridericia QT correction (QTcF) formula will be used in the study. 
• 
A participant that meets either bulleted criterion based on ECG readings will be 
withdrawn from study treatment. 
• QTcF >500 msec, 
• Change from baseline:  QTcF>60 msec 
• 
The 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. 


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• 
The QTcF stopping criteria is based on averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.   
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in in QTcF >60 msec) after enrollment, the investigator or qualified designee 
will determine if any change in participant management is needed. This review of the 
ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
7.1.4 Pregnancy 
Participants who become pregnant during the study should discontinue study drug. Refer 
to Section 8.4.5 for reporting requirements. 
7.1.5 Suicidal ideation and behavior 
Participants who experience a confirmed positive eCSSRS, or who report suicidal 
ideation and/or behavior at any time during the study, should have study drug withdrawn 
and should be referred for further medical assessment and treatment as appropriate. The 
participant should be encouraged to continue in the study and be followed as per the SoA 
(See Section 1.3)   
See Section 8.3.6, Suicidal ideation and behavior risk monitoring, for additional 
guidance. 
7.1.6 Hypersensitivity reactions Stopping Criteria 
Any participant with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the IP will be withdrawn from the study. Participants should be 
treated as clinically appropriate and followed until resolution of the AE.  
Participants may continue IP for Grade 1 or 2 allergic reactions at the discretion of the 
Investigator. The participant should be advised to contact the Investigator immediately if 
there is any worsening of symptoms or if further systemic signs or symptoms develop. 
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed. 
7.1.7 Temporary discontinuation 
Temporary discontinuation of VH4524184/placebo is not allowed in this study. 
7.1.8 Rechallenge 
Rechallenge with VH4524184/placebo is not allowed in this study. 


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7.1.8.1 
Study Intervention Restart or Rechallenge After Liver Stopping Criteria 
Are Met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study are not allowed. 
7.2 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason).  
A participant may be withdrawn from the study at any time at the discretion of the 
investigator for safety, behavioral, or adherence reasons. Discontinuing from the study 
for safety reasons should be infrequent.  
As described in Section 7.1, participants who meet a safety stopping criteria or who 
discontinue study intervention due to a safety reason, should remain in the study, 
continue to comply with all other aspects of the protocol (such as starting the first dose of 
standard of care ART on Day 10) and be followed according to the SoA (Section 1.3) to 
the EOS as defined in the protocol. 
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 reasons prior to Day 10 
(primary endpoint), additional replacement participants may be enrolled at the discretion 
of the sponsor and investigator. These replacement participants will be assigned to the 
same treatment sequence and same dose as the corresponding participant who 
prematurely discontinued from the study.  
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. The participant will be permanently discontinued from the study intervention 
and the study at that time. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 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, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
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The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF based on the list below:  
Reasons 
Additional items/Sub-reasons 
AE 
 
Lack of efficacy 
 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Specify 
 
Physician Decision 
Specify 
Pregnancy 
 
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
 
Study terminated by Sponsor 
 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
 
 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.6.5). 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant 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, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether 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 


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address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study intervention. Public sources may be searched 
for vital status information. If vital status of the participant is determined as deceased, 
this will be documented and the participant will not be considered lost to follow-up. 
Sponsor personnel will not be involved in any attempts to collect vital status 
information. 
8 STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Subjects who have signed informed consent 
but are not eligible to proceed should be recorded in the eCRF with a status of ‘screen 
failure’. 
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA. 
• In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements.   
• Safety/laboratory/analyte results (e.g., HIV RNA (viral loads) that could unblind the 
study will not be reported to investigative sites or other blinded personnel until the 
study has been unblinded. 
• The maximum amount of blood collected from each participant over the duration of 
the study or any 56 day period while enrolled in the study, including any extra 
assessments that may be required, will not exceed 500 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• Pharmacokinetic results that could unblind the study will not be reported to 
investigative sites or other blinded personnel. 
• Order of assessments: Assessment procedures should occur in the following order:  


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1. ECG (if applicable) 
2. Vital sign assessment 
3. CSSRS 
4. Blood draws; (HIV RNA to be collected at same time as pre-dose PK 
sample [with no preference as to which is drawn first]) 
5.  
 
•  All Day 10 assessments must be completed prior to administration of the 
first dose of standard of care ART. 
8.1 
Administrative and baseline procedures 
8.1.1 Collection of demographic data 
Record demographic data such as year of birth, sex at birth, current sex, current gender 
identity, race, and ethnicity in the participant’s eCRF.  
Collection of these demographic data is necessary to assess and monitor the diversity of 
the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2 Medical/vaccination history 
Obtain the participant’s medical and disease history by interviewing the participant 
and/or review of the participant’s medical records. Record any pre-existing conditions 
(including reasons for taking concomitant medications), signs and/or symptoms present 
prior to the first dose of study intervention in the eCRF. 
8.2 
Efficacy assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1 Quantitative HIV-1 RNA 
Plasma for quantitative HIV-1 RNA will be collected at timepoints listed in Section 1.3. 
An HIV-1 RNA PCR assay (Cobas HIV-1) with a linear range of 20 to 10,000,000 
copies/mL will be used. Details concerning the handling, labeling and shipping of these 
samples to the central laboratory will be supplied in the Laboratory Manual.  
8.2.2 Lymphocyte Subsets by Flow Cytometry 
Blood samples will be obtained from each participant for the analysis of lymphocyte 
subsets by flow cytometry at the timepoints listed in Section 1.3. Details concerning the 
handling, labeling and shipping of these samples will be supplied in the Central 
Laboratory Manual. Refer to the List of Clinical Laboratories and Key Vendors 
document for laboratory names and addresses of the clinical laboratories used in this 
study.  
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8.3 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1 Physical examination/history directed physical examination 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal, and neurological systems. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). At the discretion of the 
investigator, a brief physical examination may be made a complete physical 
examination. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Height and weight measurements will be used to calculate BMI.  
8.3.2 Vital signs 
• 
Body temperature, pulse rate, respiratory rate, and blood pressure will be recorded 
(before blood collection for laboratory tests). 
• 
Body temperature will be assessed as per site’s standard practice and should be 
measured at the same location throughout the study.  
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions. Blood pressure and 
pulse measurements will be assessed in a semi-supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• 
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 in the eCRF.  
8.3.3 Electrocardiograms 
• 
12-lead ECG(s) will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and [QTc] intervals. Each ECG recording will be obtained after the participant 
has been in a semi-supine position for at least 5 minutes. The ECG should be read 
locally. Contact the VH medical monitor with any concerns. 
• 
If clinically indicated, the ECG should be repeated twice more (triplicate obtained) 
with recordings obtained as closely as possible in succession. Data from the average 
of 3 ECGs will be used for any action taken. Triplicate ECGs should be obtained if 
the investigator determines an ECG abnormality is clinically significant or if the 
investigator is unable to determine the significance of abnormalities relating to rate, 
rhythm, or intervals (including prolongation of the QT interval),  
• 
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8.3.4 Clinical safety laboratory tests 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed in accordance 
with lab manual and the SoA (Section 1.3). 
• 
The investigator must review the laboratory results, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents.  
• 
Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal from 
dosing of the study intervention until EoS visit (i.e., Day 38) should be repeated until 
the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
- 
In the absence of a diagnosis, abnormal laboratory findings 
assessments or other abnormal results the investigator considers 
clinically significant will be recorded as an AE or SAE, if they meet 
the definition of an AE or SAE (refer to Section 10.3.1 and Section 
10.3.2).  
- 
If clinically significant values do not return to normal/baseline within 
a period of time judged reasonable by the investigator, the etiology 
should be identified, and the sponsor notified. 
- 
If laboratory values from non-protocol-specified laboratory tests 
performed at the institution’s local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (e.g, SAE or AE), then the results must be recorded. 
8.3.5 Pregnancy testing for participants of childbearing potential 
• 
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• 
Refer to Section 1.3 (Schedule of Activities) for pregnancy testing schedule. 
• 
POCBP must perform a pregnancy test before the administration of any dose of 
study intervention during the Monotherapy Period. Pregnancy testing will continue 
throughout the Follow-up Period.  
• 
Serum samples will be sent for pregnancy testing for the Screening Visit. At the Day 
1 Visit (before start of study treatment), a urine test must be used to confirm 
pregnancy status prior to administration of study treatment. 
• 
Pregnancy testing must be done even if the participant is menstruating at the time of 
the study visit. The study intervention may only be administered if the pregnancy test 
is negative. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. 


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• 
Refer to Section 8.4.5 (Pregnancy reporting) for pregnancy reporting requirements 
and information on study continuation for participants who become pregnant during 
the study. 
8.3.6 Suicidal ideation and behavior risk monitoring 
Although VH4524184 is not being developed for a neurologic or psychiatric condition, 
participants will be excluded based on any pre-existing psychiatric condition (including 
assessment using the CSSRS). Depression (including suicidal ideation and behaviors, 
particularly in patients with a pre-existing history of depression or psychiatric illness) are 
adverse drug reactions 
.  
Participants receiving VH4524184 should be monitored appropriately and observed 
closely for SIB or any other unusual changes in behavior. Participants who experience 
signs of SIB should undergo a risk assessment. All factors contributing to SIB should be 
evaluated and the participant should not receive any additional doses of VH4524184.  
Assessment of suicidal ideation and behavior / intervention emergent suicidal ideation 
and behavior will be monitored using the electronic CSSRS (see SoA, Section 1.3 for 
details) at Screening, on Day 10 and the final follow-up visit, as well as at early 
termination, if applicable. As described in Section 7.1, any positive (abnormal) CSSRS 
response indicating SIB, or SIB reported by the participant at any other time during the 
study, will result in withdrawal of study drug. In either case (screening or post-dose) of 
positive (abnormal) response confirmed by the investigator, the PI/SI will arrange for 
urgent specialist psychiatric evaluation and management.  
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation. Screening visit questions will be in 
relation to lifetime experiences and current experiences (within the past 2 months) and all 
subsequent questioning in relation to the last assessment. A response graded as level 4 or 
5 for suicidal ideation and/or any positive response to questions addressing suicidal 
behavior is considered a positive CSSRS which then should be confirmed by the 
investigator following an interview with the participant.  
Participants who experience a confirmed positive CSSRS, or who report SIB at any other 
time during the study, should have study drug withdrawn and should be referred for 
further medical assessment and treatment as appropriate. The participant should be 
encouraged to continue in the study and be followed as per the SoA.  (See Section 1.3).   
Additionally, the investigator will collect information using the PSRAE eCRF form in 
addition to the AE (non-serious or SAE) eCRF form on any subject that experiences a 
possible suicidality-related AE while participating in this study. This may include, but is 
not limited to, an event that involves suicidal ideation, a preparatory act toward imminent 
suicidal behavior, a suicide attempt, or a completed suicide. The investigator will 
exercise his or her medical and scientific judgment in deciding whether an event is 
possibly suicide related. PSRAE forms should be completed and reported to VH/GSK 
within 1 week of the investigator diagnosing a possible suicidality-related AE. 
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8.3.7 Study pausing rules 
Participant safety will be continuously monitored by the Medical Monitor, designated 
Safety Lead (or delegate), throughout the study. Pertinent findings and conclusions are 
shared with the product’s SRT for review of the overall benefit-risk profile of the 
product. The Sponsor’s governance group, VSLC will review data and the team’s 
recommendation when any pausing/stopping rules are met. The VSLC is comprised of 
senior representatives from various departments, including clinical development, safety, 
toxicology, pharmacovigilance, epidemiology, and medical affairs. The VSLC will 
govern whether enrollment may be resumed/modified, a given treatment arm will be 
stopped, or the study stopped. (See Section 10.1.6 for more details on VSLC) 
The following study pausing criteria would be applied:  
• Death of a participant, regardless of investigator’s assessment of causality  
• Any Grade 4 event or an SAE, regardless of its severity, that is considered to be 
clinically significant and reasonably attributable to dosing with VH4524184 in the 
opinion of the investigator or the Sponsor.  
• Any Grade 3 or higher AE (of the same type) in 2 or more participants, leading to 
the decision to withdraw from the study (by the investigator), assessed by the 
investigator as reasonably attributable to VH4524184.  
• Any Grade 2 or higher rash with evidence of systemic involvement (e.g., fever, 
liver transaminase elevation and/or eosinophilia) that the investigator considers 
reasonably attributable to VH4524184 occurring in two or more participants.  
• Any Grade 4 laboratory abnormality (of the same type) or Grade 3 laboratory 
abnormalities (of the same type, with the exception of an asymptomatic Grade 4 
lipid abnormalities or CPK increase) that the investigator considers reasonably 
attributable to VH4524184, in two or more participants.  
• Any participant meeting liver stopping criteria that the investigator considers 
reasonably attributable to VH4524184.  
• Any participant meeting QTc stopping criteria that the investigator considers 
reasonably attributable to VH4524184.  
• Clinically significant arrhythmia in two or more participants. 
8.4 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting 
For definitions relating to safety information see Section 10.3 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or study 
(see Section 7). This includes events reported by the participant (or, when appropriate, by 
a caregiver, surrogate, or the participant’s legally authorized representative). 


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The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
(AEs and SAEs: Definitions and procedures for recording, evaluating, follow-up, and 
reporting), and/or Section 10.6 (Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events). 
8.4.1 Time period and frequency for collecting AEs and SAEs 
All SAEs will be collected from the signing of the ICF until the final follow-up visit. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as 
AEs. 
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 Section 10.3 and/or Section 
10.7. The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available. 
A post study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Section 10.3.6. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the investigator 
must record it in the medical records. If the investigator considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 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 resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.6.5. 
8.4.4 Regulatory reporting requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and the 


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safety of a study intervention under clinical investigation are met. See Section 8.4.1 
for reporting timeframes. 
• 
For SAEs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.6.3. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
8.4.5 Pregnancy reporting 
Participants who become pregnant after the first study intervention dose must not receive 
subsequent doses of the study intervention but may continue other study procedures at the 
discretion of the investigator. 
• 
Details of all pregnancies in female participants will be collected after the start of 
study treatment in the Monotherapy Period (Day 1) and until the final visit in the 
Follow-up Period (Day 38). Report all pregnancies to the Medical Monitor. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form (initial notification form or pregnancy follow-up form) and submit 
it to the sponsor within 24 hours of learning of the female participant’s pregnancy 
(see Section 10.3.7). 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. See Section 10.3.7 for reporting 
timeframes. 
• 
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
All investigators are strongly encouraged to report all pregnancies exposed to 
standard of care ART to the Antiretroviral Pregnancy Registry (APR) as soon as the 
pregnancy is identified. Pregnancies can be reported to the Registry at 
SM_APR@APRegistry.com via the data forms available at www.APRegistry.com. 


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8.4.6 Cardiovascular events and death events 
For any CV events detailed in Appendix Section 10.3.4 and all deaths, whether or not 
they are considered SAEs, specific CV and Death sections of the eCRF will be required 
to be completed. These sections include questions regarding CV (including sudden 
cardiac death) and non-CV death.  
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific CV section of the eCRF 
within 1 week of receipt of a CV Event data query prompting its completion.   
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
8.4.7 Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
The events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(Section 10.7) will be recorded on the HIV-Associated Conditions eCRF page if they 
occur. However, these individual events or outcomes, as well as any sign, symptom, 
diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these 
events or outcomes are not reported to VH/GSK as AEs and SAEs even though such 
event or outcome may meet the definition of an AE or SAE, unless the following 
conditions apply: 
• The investigator determines that the event or outcome qualifies as an SAE under 
part ‘f’ of the SAE definition (Section 10.3.2), or 
• The event or outcome is in the investigator’s opinion of greater intensity, 
frequency or duration than expected for the individual participant, or 
• The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
• Death occurring for any reason during a study, including death due to a disease-
related event, will always be reported promptly, or 
• Lymphomas and invasive cervical carcinomas are excluded from this exemption; 
they must be reported as SAEs even if they are considered to be HIV-related. 
• If any of the above conditions are met then record the DRE on the SAE page 
rather than the HIV Associated Conditions eCRF. 


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8.4.8 Contact information for reporting SAEs and study holding rules 
Table 6 
Contact information for reporting SAEs and study holding rules 
Safety Topic  
Contact  
Reporting SAEs  
Email uk.gsk-rd-gcsp-ctsm-admin@gsk.com  
Available 24/24 hours and 7/7 days  
Questions regarding SAEs  
Contact the VH medical monitor  
Questions regarding any other safety event 
that may meet a safety stopping criteria  
Contact the VH medical monitor  
8.4.9 Participant card 
The investigator (or designee) must provide the participant/participant’s LAR(s) with a 
“participant card” containing information about the clinical study. The 
participant/participant’s LAR(s) must be instructed to always keep the participant card in 
their possession for the duration of the study. In an emergency, this card serves to inform 
the responsible attending physician/LAR/caregiver/family member that the participant is 
in a clinical study and that relevant information may be obtained by contacting the 
investigator(s) or their back up. 
8.5 
Pharmacokinetics 
• 
Intensive and single PK sampling is pre-specified as per the SoA (Section 1.3). 
• 
Otherwise on single PK draw days 
 a single PK sample will be 
drawn in conjunction with the study visit and as close to an every 24-hour post last 
dose cycle as possible. 
• 
Collected PK samples may not be analyzed if concentrations below the limit of 
quantification were previously achieved or if the participant was assigned to placebo. 
• 
Refer to Table 7 for the permissible windows 
, dosing and PK draws for 
intensive PK days. 
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Table 7 
Intensive Pharmacokinetic Sampling 
 
 
Time of Event 
Window 
Time Relative to Dosing 
Hour:Minute 
Dosing 
Day 
 
Not 
applicable 
Pre-dose PK collection 
Not 
applicable 
Collect pre-dose sample prior to dosing. There 
is allowance to collect the sample earlier and 
up to 90 minutes prior to dosing 
Administer study treatment and start 
the clock for subsequent blood 
draws. 
Not 
applicable 
00:00 
• Instructions for the collection and handling of biological samples will be provided by 
the sponsor and central laboratory. 
- 
Blood samples of approximately 2 mL will be collected and processed to 
plasma for measurement of plasma concentrations of study intervention. 
- 
The actual date and time (24-hour clock time) of each sample will be 
recorded. 
- 
Samples to be stored in an upright position at -70°C or colder until 
shipment to the test laboratory. Refer to the List of Clinical Laboratories 
and Key Vendors document for laboratory names and addresses of the 
clinical laboratories used in this study. 
• A maximum of 2 mL samples may be collected at additional timepoints during the 
study if warranted and agreed upon between the Investigator and the sponsor. The 
timing of sampling may be altered during the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.  
• Plasma samples will be used to evaluate the PK concentrations of VH4524184 and 
may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study. 
• Intervention concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been unblinded. 
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8.6 
Pharmacodynamics 
See Section 8.2 and Section 8.5 for relevant efficacy and PK assessments. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Plasma samples for exploratory resistance testing will be collected according to the 
schedule described in Section 1.3 and as detailed in the Laboratory Manual. 
Resistance results will not be available in time to inform the treatment management 
of participants during the study. Samples from Day 1 (pre-dose) and Day 10 will be 
batch tested for viral genotypic and phenotypic on treatment changes and/or 
resistance to the 
 using the Monogram Biosciences Inc. based assays. Plasma 
from additional timepoints may be assayed if needed. 
Additional blood samples may be drawn for local genotypic/phenotypic analysis, 
according to local guidelines. These tests are optional and will be conducted in 
accordance with local guidelines for the management of HIV-1 infection and, if 
available, may be used to guide the choice of standard of care ART. Locally obtained 
genotypic/phenotypic results will be retained in the participant’s medical record at 
the site and will not be transferred to VH/GSK. 
VH/GSK may store samples for up to 20 years after the end of the study to achieve 
study objectives. Additionally, with participants’ consent, samples may be used for 
further research by VH/GSK or others such as universities or other companies to 
contribute to the understanding of HIV-1 or other diseases, the development of 
related or new treatments, or research methods. 
8.9 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study.  
8.10 Health economics or medical resource utilization and health 
economics 
Health economics OR Medical resource utilization and health economics parameters are 
not evaluated in this study. 
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9 STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. If methods in the 
SAP differ from the methods described in the protocol, the SAP will be followed. 
9.1 
Statistical hypotheses 
The primary objective will be addressed using an estimation approach (descriptive 
statistics) with no hypothesis testing. The primary treatment effect to be estimated is the 
maximum change from baseline in plasma HIV-1 RNA over the monotherapy period.  
9.2 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility. 
• 
Study Population 
Randomized  
• 
All participants who were randomly assigned to study 
intervention in the study. 
• 
The screened, enrolled and randomized populations must 
be nested, i.e. the enrolled population must be a subset of 
the screened population, the randomized population must 
be a subset of the enrolled population. 
• 
Study Population 
Safety 
• 
All participants who received at least 1 partial or full dose of 
study intervention. 
• 
Participants will be analyzed according to the study 
intervention they actually received. 
• 
Safety 
Full Analysis Set 
(FAS) 
• 
All randomized participants who received at least 1 full dose 
of study intervention.  
• 
Data will be reported according to the randomized study 
intervention. 
• 
Efficacy 
Per-protocol (PP) 
• 
All participants in the FAS for whom there were no major 
protocol deviations that impact the primary analyses. 
• 
Data will be reported according to the study intervention 
actually received. 
• 
Specific details of major protocol deviations that would 
exclude participants from the PP analysis set will be 
provided in the SAP. 
• 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety analysis set who had at least 1 
non-missing PK assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• 
Data will be reported according to the actual study 
intervention. 
• 
PK 
9.3 
Statistical analyses 
9.3.1 General considerations/definitions  
Data will be summarized by study intervention and dose level, unless otherwise specified. 
Data will be summarized either by visit or separately for the monotherapy period and 
overall (i.e., monotherapy period plus SOC period), as appropriate for each endpoint, 
unless otherwise specified.  
For all endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. 
Continuous and categorical variables will be summarized using the following descriptive 
statistics, unless otherwise specified: 
• 
Continuous data: n (number of participants used for the summary), arithmetic mean, 
SD, median, interquartile range, minimum and maximum. For PK data, geometric 
mean, SD of log-transformed data and geometric %CVb may also be used. 
• 
Categorical data: number and percentage of participants 
9.3.2 Primary endpoint/estimand analysis  
See Section 3.1 for definition of primary endpoint/estimand. 
9.3.2.1 
Definition of endpoint/estimands 
Plasma HIV-1 RNA values will be used for the primary efficacy analysis. Change from 
baseline will be calculated for each participant at each assessment time point during the 
monotherapy period in the original and log10 scales. Maximum change from baseline 
during the monotherapy period will be calculated for each participant from the set of 
available change from baseline values at each assessment time point in the original and 
log10 scales. The log10 transformation is used to allow for direct comparisons with data 
from other compounds publicly available in the same scale, and hence aid in 
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9.3.2.2 
Main Analytical Approach 
The primary efficacy analysis will be based on the Full Analysis Set.  
Maximum change from baseline in plasma HIV-1 RNA during monotherapy will be 
summarized by study intervention and dose level, in original and log10 scales. 
In addition, change from baseline in plasma HIV-1 RNA at each assessment time point 
during monotherapy will be summarized by study intervention and dose level, in original 
and log10 scales. 
For participants who withdraw from study prior to the end of monotherapy period, 
preventing assessment of primary endpoint, no imputation will be performed for missed 
assessments after their study withdrawal. 
9.3.2.3 
Supplementary/supportive analysis 
A supplementary analysis could be conducted to summarize maximum change from 
Baseline and change from baseline by visit in plasma HIV-1 RNA during the 
monotherapy period based on the Per Protocol analysis set. Details will be provided in 
the SAP. 
9.3.3 Secondary endpoints/estimands analyses 
See Section 3.2 for definition of secondary endpoints/estimands.  
9.3.3.1 
Safety analyses 
All safety analyses will be performed on the Safety analysis set. Safety data will be 
presented in tabular format and summarized descriptively according to GSK’s IDSL.  
The number and proportion of participants with AEs will be tabulated overall and by 
severity grade, by study intervention and dose level. The number and proportion of 
participants with AEs leading to discontinuation of study intervention will also be 
tabulated by dose level. In AE tabulations, each participant’s AE will be counted once 
under the maximum severity. AEs will be tabulated using MedDRA preferred terms. AEs 
will be tabulated for the monotherapy period and overall (i.e., monotherapy period plus 
SOC period) separately.  
For liver panel laboratory parameters, summary statistics of change from baseline values 
by visit will be presented by study intervention and dose level. Number and percentage of 
participants with maximum toxicity grade increase from baseline for liver panel 
parameters will be presented by study intervention and dose level; this will be done 
separately for the monotherapy period and overall (i.e., monotherapy period plus SOC). 
No imputation will be performed for missed assessments while participants are on study 
or after study withdrawal. 


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9.3.3.2 
Pharmacokinetic analyses 
All pharmacokinetic analyses will be performed on the pharmacokinetic analysis set.  
Pharmacokinetic analysis will be the responsibility of the CPMS Department at GSK. 
Plasma concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin 8.1 or higher, Phoenix (Pharsight Corporation) or comparable software to 
derive the PK parameters. This analysis will be based on actual sampling times recorded 
during the study. Individual plasma PK parameters for each participant will be 
determined, including but not limited to Cmax and tmax.  
Data summaries of plasma concentration and pharmacokinetic parameter data will be the 
responsibility of Clinical Statistics. Plasma concentrations will be presented in graphical 
form and will be summarized descriptively by dose level. PK parameters will be 
summarized descriptively by dose level.  
The data from this study will be reported in the study report. The data also may be 
combined with the data from other studies for a population PK analysis, which will be 
reported separately. 
No imputation will be performed for missed plasma concentrations and PK parameters 
while on study or after study withdrawal. 
9.3.3.3 
Pharmacokinetic-Pharmacodynamic analyses 
Pharmacokinetic-pharmacodynamic analyses will be the responsibility of the CPMS 
Department at GSK. The relationship between selected PK parameters (e.g., 
concentrations on Day 10) and selected PD parameters (e.g., maximum change from 
baseline in log10 plasma HIV-1 RNA) will be explored graphically. Where relationships 
are apparent, exposure-response models will be used to characterize the relationship and 
assess the impact of covariates. The details of such exposure-response analysis will be 
outlined in a separate CPMS analysis plan and may be presented separately from the 
main study report. 
9.3.3.4 
Virology analyses 
Genotypic assessments will be analyzed separately by the study virologist.  
9.3.3.5 
Immunology analyses 
The immunology analyses will be performed using the safety analysis set. Change from 
baseline in CD4+ T-cell count will be summarized descriptively.  
9.3.4 Exploratory endpoints/estimands analysis 
Details on the analyses of exploratory endpoints and other analyses will be included in 
the SAP.  


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9.4 
Interim analysis 
An informal planned interim analysis will be conducted after all participants in Part 1 
have completed their monotherapy period.  
The planned interim analysis will evaluate the PK and pharmacodynamic (antiviral 
activity) of VH4524184 and inform the need for Part 2, as well as future clinical 
development of VH4524184. 
Additional interim analyses may be performed during the course of the study to inform 
internal decision-making activities and/or support regulatory requests. No changes to the 
conduct of the study will be implemented as a result of these analyses. 
The final EoS analysis will be conducted after the completion of the study (i.e., when all 
participants complete the SOC period on Day 38 visit) and final datasets authorization. At 
the EoS analysis all primary, secondary and exploratory objectives will be evaluated with 
two exceptions: the analysis of the viral resistance and pharmacogenetics (if done) may 
be evaluated at a later stage and each of these outcomes reported separately. 
9.5 
Sample size determination 
The sample size is based on feasibility and no formal calculation of power or sample size 
has been performed. 
9.5.1 Sample size considerations 
Based on viral load decline data from 2 previous POC studies investigating 
 [Min, 
2011; Spreen, 2013] we assumed the maximum VLD from baseline in log10 scale for 
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individual participants follows a normal distribution. The expected precision of the 
estimated maximum VLD in log10 scale, measured by the 95% CI width, under various 
sample sizes and assumed data variability (reflected by the sample SD) is shown in the 
table below.  
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS international ethical guidelines 
o 
Applicable ICH GCP guidelines 
o 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
o 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
o 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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10.1.3 Informed consent process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will 
be required to physically or digitally sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that physical or digital informed consent 
was obtained before the participant was enrolled in the study and the date the physical 
or digital consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A physical or digital copy of the ICF(s) must be provided to the participant. 
• Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period. 
In case of unexpected pregnancy, the participant must be informed that PI such as date of 
birth and sex of the baby will be collected as part of safety follow-up. Consent for 
collection of information about the baby may be obtained from the participant and/or 
their partner as per local regulations. 
10.1.4 Recruitment strategy 
Participants will be recruited into this study using a variety of methods, including but not 
limited to: investigators existing databases, local advertising, digital recruitment 
campaigns, and online prescreening and referral to site. Recruitment materials will be 
reviewed and approved by the IRB/IEC before use. 
10.1.5 Data protection 
• Participants will be assigned a unique identifier by the investigator. 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. 
• VH/GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 


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• The participant must be informed that their 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, that their data will be used as described in 
the informed consent. 
• The participant must be informed that their 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. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  
10.1.6 Committee structure 
Participant safety will be routinely monitored by the VH medical monitor and the GSK 
safety lead(s). Pertinent findings and conclusions are shared with the product’s SRT for 
periodic review of the overall benefit risk profile of the product and escalated, as 
necessary to VSLC. 
An SRT is in place for each VH product. It comprises of a global cross-functional 
VH/GSK team responsible for the ongoing assessment of benefit-risk for a product. The 
SRT contribute to the continual blinded assessment of incoming new efficacy, safety and 
PK information. An external data and safety monitoring committee is not utilized in this 
study due to the relatively small size and early phase of the trial. This is further supported 
by the lack of significant safety findings from the available pre-clinical toxicity studies 
and preliminary clinical study of VH4524184. 
VSLC is a governance group that will review data and the team’s recommendation when 
any pausing/stopping rules are met. The VSLC will govern whether enrollment may be 
resumed/modified, a given treatment arm will be stopped, or the study stopped. The 
VSLC is comprised of senior representatives from various departments, including clinical 
development, safety, toxicology, pharmacovigilance, epidemiology, and medical affairs. 
ViiV Healthcare has transferred certain sponsor obligations (e.g., clinical operations, 
study intervention management, data management, statistics and programming, clinical 
pharmacology and modelling and simulation, regulatory, pharmacovigilance, etc.) to 
GSK who are supporting VH in the conduct of this study. 
Refer to the List of Clinical Laboratories and Key Vendors document for the names and 
addresses for the clinical laboratories, contractors and subcontractors used by VH in this 
study. 


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10.1.7 Dissemination of Clinical Study Data 
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or VH Clinical Study Register in compliance with 
applicable regulations/VH policy. VH/GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier disclosure, 
VH/GSK will follow those timelines.  
• Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. VH/GSK will also provide the 
investigator with the full summary of the study results, including a summary of trial 
results understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities.   
• VH/GSK will provide the investigator with the randomization codes and participant-
level line listings for their site only after completion of the full statistical analysis. 
• VH/GSK intends to make anonymized participant-level data from this study 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 study participants are used to maximum effect in the creation of 
knowledge and understanding. 
10.1.8 Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs 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. 
• Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• QTLs will be predefined in the QTL plan to identify systematic issues that can impact 
participant right, safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
involvement of central reading mechanism) methods, responsibilities, and 


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requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 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 CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different 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.  
• When copies of source documents are shared externally for review by a central reader 
mechanism (e.g., endpoint adjudication committee; expert reader), documents are 
stored by the external body for 25 years. 
10.1.9 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 eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in source data 
acknowledgment or monitoring guidelines. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF 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. 
10.1.10 
Study and site start and closure 
Start of study and first act of recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date) at a country-level. 


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Study/Site Termination 
VH/GSK or designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of VH/GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• 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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
 
 


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10.2 Appendix 2: Clinical laboratory tests 
• The clinical safety laboratory tests detailed in Table 9 will be performed by the 
central laboratory. 
• Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response evaluation, 
the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 9 
Protocol-required safety laboratory tests  
Laboratory Tests 
Parameters 
Hematology 
▪ 
Platelet count 
▪ 
Red blood cell (RBC) count 
▪ 
RBC indices 
▪ 
Mean corpuscular volume (MCV) 
▪ 
Mean corpuscular hemoglobin (MCH) 
▪ 
%Reticulocytes 
▪ 
WBC count with 
differential: 
▪ 
Neutrophils 
▪ 
Lymphocytes 
▪ 
Monocytes 
▪ 
Eosinophils 
▪ 
Basophils 
▪ 
Hemoglobin 
▪ 
Hematocrit 


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Laboratory Tests 
Parameters 
Clinical chemistry1 
▪ Blood urea nitrogen 
(BUN)/Urea 
▪ Potassium 
▪ Creatinine2 
▪ Sodium 
▪ Bicarbonate 
▪ Magnesium 
▪ Phosphate 
▪ Calcium 
▪ Glucose (fasting) 
▪ Creatine 
phosphokinase 
(CPK)5 
▪ 
Aspartate aminotransferase (AST)/serum glutamic-
oxaloacetic transaminase (SGOT) 
▪ 
Alanine aminotransferase (ALT)/serum glutamic-pyruvic 
transaminase (SGPT) 
▪ 
Alkaline phosphatase3 
▪ 
Total bilirubin 
▪ 
Direct bilirubin4 
▪ 
Total protein 
▪ 
Amylase 
▪ Lipase (fasting) 
▪ 
Fasting lipid panel (cholesterol, triglycerides, high-density 
lipoprotein [HDL], low-density lipoprotein [LDL])   
Coagulation 
▪ Prothrombin time (PT)  
▪ Partial thromboplastin time (PTT)  
International normalized ratio (INR)  
Routine urinalysis 
▪ Specific gravity 
▪ pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
▪ Microscopic examination (if blood or protein is abnormal) 
▪ 
Epithelial cells  
▪ 
Red Blood cells  
▪ 
WBC  
▪ 
Casts 
▪ 
Crystals  
▪ 
Culture (if positive: specify pathogen) 


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Laboratory Tests 
Parameters 
Other screening tests ▪ Follicle stimulating hormone and estradiol (as needed in PONCBP only [See Section 
10.4.1] Contraceptive and barrier guidance - Definitions) 
▪ Highly sensitive (serum or urine) human chorionic gonadotropin (hCG) pregnancy test 
participants female at birth.[See Section 1.3, Schedule of Activities] 
▪ Serum or urine alcohol, cotinine, and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
▪ Serology [(HIV antibody 4th generation test, HBsAg, and HCV antibody Hepatitis B 
surface antibody (anti-HBs) and if indicated hepatitis B DNA (by PCR), and hepatitis C 
virus antibody)], with reflex to HCV RNA (by PCR) if positive. 
▪ Syphilis positive rapid plasma reagin (RPR) 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 Liver 
Chemistry Stopping Criteria and Section 10.5: Liver Safety: Suggested Actions and Follow-up Assessments. All 
events of ALT ≥3 × upper limit of normal (ULN) and total 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 to VH/GSK in 24 hours (excluding studies of hepatic impairment or 
cirrhosis). 
2. 
To assess the kidney function, use the CKD-EPI equation (2021).  
3. 
If alkaline phosphatase is elevated, consider fractionating. 
4. 
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN 
5. 
Recommend repeat testing if CPK is elevated to ensure the result is transient or due to exercise. A history 
regarding use of drugs known to cause increase of CPK (such as statins), physical activity or exercise preceding 
the CPK evaluation should be obtained. 
 
 


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10.3 Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1 Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• Events that occur as a result of protocol-mandated procedures (i.e. invasive 
procedures, modification of participant’s previous therapeutic regimen). 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, admission for routine examination.). 
• 
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. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
DRE, typically associated with the disease under study. These events will be 
recorded in the participant’s eCRF and will be monitored by SRT  on a routine 
basis. However, if 1 or both of the following conditions apply, then the event 
should be reported promptly to VH/GSK as an SAE (see Section 8.4.8): 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or 
• 
The investigator considers that there is a reasonable possibility that the event was 
related to the administration of the study intervention 
10.3.2 Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 
one or more of the criteria listed: 
a. 
Results in death 
b. Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (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 
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other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g. Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
h. Other situations: 
• 
Possible Hy’s Law case: ALT ≥ 3x ULN AND total bilirubin ≥2x ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
o 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3 Unsolicited AE  
• 
Definition of unsolicited AE 
• 
An unsolicited AE is an AE that was not solicited using a participant diary and that 
is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participants will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in 
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• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by 
review of available medical records at the next visit. 
10.3.4 Definition of CV events  
CV definition: 
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
10.3.5 Definition of TEAE 
TEAE Definition: 
• 
A TEAE is an event that emerges during treatment, having been absent pre-
treatment or worsens relative to the pre-treatment state. 
10.3.6 Recording assessment and follow-up of AEs, SAEs and pregnancies 
10.3.6.1 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to VH/GSK in lieu of completion of the GSK required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by VH/GSK. In this case, all participant identifiers, with the exception of 


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the participant number, will be redacted on the copies of the medical records before 
submission to VH/GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
10.3.6.2 
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 according to the DAIDS 
toxicity scales (refer to Section 10.6).  
• 
Where a DAIDS toxicity scale is not available for a particular event or parameter, 
then the investigator will instead make an assessment of intensity using 1 of the 
severity categories described in the functional DAIDS table shown in Section 10.6. 
• 
Note: An event is defined as ‘serious’ when it meets at least 1 of the pre-defined 
outcomes as described in the definition of an SAE. 
• 
Note: Grade 4 DAIDS toxicity grades for laboratory parameters that are 
asymptomatic would not necessarily be considered SAEs, a clinical correlation 
would be necessary. 
10.3.6.3 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the 
initial report to VH/GSK. However, it is very important that the investigator always 
make an assessment of causality for every event before the initial transmission of the 
SAE data to VH/GSK. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
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• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.6.4 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.6.5 
Follow-up of AEs, SAEs or pregnancies 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by VH/GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide VH/GSK with a copy of any postmortem 
findings including histopathology.  
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information. 
• 
After the initial AE/SAE/pregnancy or any other event of interest, 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. 
Follow-up during the study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until the end of the 
study or until the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, VH/GSK will be provided with any available postmortem findings, including 
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Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to VH/GSK using the paper pregnancy follow-up 
report and the AE Report if applicable. Generally, the follow-up period does not need to 
be longer than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to VH/GSK as described in the Section 10.3.6.7. 
10.3.6.6 
Updating of SAE and pregnancy information after removal of write 
access to the participant’s eCRF 
When additional SAE or pregnancy information is received after write access to the 
participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the Study contact for reporting SAEs (refer to Section 
8.4.8. 
10.3.6.7 
Reporting of SAEs and pregnancies 
SAE Reporting to VH/GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to VH/GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline 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 offline, then the site can report this information on a paper SAE form (see next 
section) or to the VH medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned competent authority (CA) via the national 
spontaneous reporting system.  These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.8 


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SAE Reporting to VH/GSK via Paper Data Collection Tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the VH medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.8. 
10.3.7 Timeframes for Reporting SAEs, PSRAEs, Pregnancy, and Liver 
Events 
Table 10 
Timeframes for Reporting SAEs, PSRAEs, Pregnancy, and Liver 
Events  
 
Initial Reports 
Follow-up Information  
on a Previous Report 
Type of Event 
Timeframe 
Documents 
Timeframe 
Documents to be 
Updated 
All SAEs 
24 hours 
SAE eCRF a 
24 hours 
SAE eCRF a 
Possible 
Suicidality 
Related Adverse 
Event (SAE) 
SAE eCRFa   
24 hours 
SAE eCRF a 
SAE eCRFa   
24 hours 
SAE eCRF a 
PSRAE eCRF 
and Form 
1 week 
PSRAE eCRF and Form 
PSRAE eCRF 
and Form  
1 week 
PSRAE eCRF and Form 
Possible 
Suicidality 
Related Adverse 
Event (AE) 
1 week 
AE eCRF 
1 week 
AE eCRF 
PSRAE eCRF and Form 
PSRAE eCRF and Form 
Pregnancy  
24 hours 
Pregnancy Initial 
Notification Form 
24 hours 
Pregnancy Follow-up 
Form 
ALT 3×ULN 
and bilirubin 
2×ULN (>35% 
direct)d or 
international 
normalized ratio 
(INR) >1.5 
24 hours b 
SAE eCRF a 
24 hours 
SAE eCRF a 
Liver Event eCRF c 
Liver Event eCRF c 
Liver Imaging and/or 
Liver Biopsy eCRFs, if 
applicable c 
 Liver Imaging and/or 
Liver Biopsy eCRFs, if 
applicable c 


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a. 
See Section 10.3.6.7 Reporting of SAE to ViiV Healthcare/GSK.  For each SAE, the investigator(s) must 
document in the medical notes that they have reviewed the SAE and have provided an assessment of causality. If 
the electronic system (eCRF) is unavailable, then the site will use the paper SAE data collection tool to report the 
event within 24 hours. Paper reports will be dated and signed by the investigator (or designee).   
b. 
The Medical Monitor must be contacted at onset of liver chemistry elevations to discuss participant safety. 
c. 
 Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, 
as applicable) should be completed as soon as possible. 
d. 
All events of ALT≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or international normalized ratio (INR) >1.5 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required, and the threshold value stated will not apply to participants receiving anticoagulants. 
e. 
Complete and submit SAE eCRF if applicable. 
 
 


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10.4 Appendix 4: Contraceptive and barrier guidance  
10.4.1 Definitions 
10.4.1.1 
Participants of childbearing Potential (POCBP) 
Participants in the following categories are considered POCBP (fertile): 
• 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
• 
From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
Note: Menarche is the first onset of menses in a young participant assigned female at 
birth. Menarche is normally preceded by several changes associated with puberty 
including breast development and pubic hair growth. 
10.4.1.2 
Participant of Nonchildbearing Potential (PONCBP) 
Participants in the following categories are considered PONCBP: 
1. Premenarchal: Tanner stage 1 (prepubertal) 
2. Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. If reproductive 
status is questionable, additional evaluation should be considered. 
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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than 1 FSH measurement (>40 IU/L or mIU/mL) is required. 
• Females on HRT and whose menopausal status is in doubt must discontinue HRT 
for at least 3 months to allow confirmation of postmenopausal status before study 
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10.4.2 Contraception guidance 
Participants of childbearing potential must agree to use contraception/barrier as detailed 
below: 
NON-HORMONAL CONTRACEPTIVESa ALLOWED DURING THE STUDY FOR POCBP 
INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly. 
• 
IUD 
• 
Bilateral tubal occlusion 
Highly Effective Methodsb That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 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. 
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 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 
 


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10.5 Appendix 5: Liver safety: suggested actions and follow-up 
assessments  
Liver chemistry stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology  
Liver Chemistry Stopping Criteria and Required Follow Up Assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND total bilirubin ≥2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, report as an SAE1,2,3. 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention 
• Report the event to VH medical monitor 
within 24 hours 
• Complete the liver event form and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments 
as described in the Follow Up Assessment 
column 
• Do not restart or rechallenge participant 
with study intervention  
• Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING) 
MONITORING: 
If ALT≥3xULN AND total bilirubin  2xULN 
or INR >1.5 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow up 
assessments within 24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND total bilirubin < 2xULN 
• Viral hepatitis serology3 
• 
Syphilis screening 
• 
Drugs of abuse screen, including alcohol 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, documenting the date and 
time of the most recent VH4524184 dose4  
• Obtain serum CPK, LDH, GGT, GLDHand 
serum albumin 
• Fractionate bilirubin, if total bilirubin 
1.5xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal 
pain, jaundice, fever or rash on the liver 
event form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, recreational drugs, and other 
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Liver Chemistry Stopping Criteria  
and INR ≤1.5: 
• Perform liver chemistries (include ALT, 
AST, alkaline phosphatase, total bilirubin 
and INR) and perform liver event follow up 
assessments within 24-72 hours 
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Record alcohol use on the liver event 
alcohol intake form 
If ALT≥3xULN AND total bilirubin 2xULN 
or INR >1.5 obtain the following in addition to 
the assessments listed above: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins 
• Serum acetaminophen adduct assay 
should be done (where available) to 
assess potential acetaminophen 
contribution to liver injury unless 
acetaminophen use is very unlikely in the 
preceding week (e.g., where the 
participant has been resident in the 
clinical unit throughout). The site must 
contact the VH medical monitor when this 
test is required. 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging form and/or Liver 
Biopsy eCRF forms. 
o In participants when serology 
raises the possibility of AIH 
o In participants when suspected 
DILI progresses or fails to resolve 
on withdrawal of study 
intervention 
o In participants with acute or 
chronic atypical presentation. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, which is indicative of 
direct bilirubin elevations suggesting liver injury.  
2. 
All events of ALT ³3xULN and total bilirubin ³2xULN (>35% direct bilirubin) or ALT ³3xULN and INR >1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants 
3. 
Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing) and hepatitis E IgM antibody  
4. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best approximation. 


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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 lab manual 
5. 
Liver biopsy may be considered and discussed with local specialists if available, for instance: 
• 
In participants when serology raises the possibility of AIH 
• 
In participants when suspected DILI progresses or fails to resolve on withdrawal of study intervention 
• 
In participants with acute or chronic atypical presentation. 
 
 


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10.6 Appendix 6: Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected version 2.1, July 
2017 
VERSION 2.1, July 2017 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized 
for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE 
term. 
• For more information, please refer to the DAIDS grading table Version 2.1, July 
2017 at (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). 
10.6.1 Estimating Severity Grade for Parameters Not Identified in the 
Grading Table 
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as Grade 5 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
    GRADE 3 
    SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Clinical adverse 
event  NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
with 
intervention 
or 
hospitalization 
indicated 
Potentially life-threatening 
symptoms causing 
inability to perform basic 
self-care functions with 
intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
10.6.2 QTc prolongation using the Fridericia formula 
The DAIDS AE Grading Table provides grading for QTc prolongation using the Bazett 
formula. When the Fridericia formula is used, QTc prolongation should be graded as 
shown: 
Severity Grade 1 
460 msec or greater but less than 480msec 
Severity Grade 2 
480 msec or greater but less than 500 msec 
Severity Grade 3 
500 msec or greater OR 60 msec or greater than baseline AND 480 msec or 
greater 
Severity Grade 4 
Life-threatening consequences (e.g., Torsades de Pointes, other serious 
ventricular dysrhythmias) 
 
 


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10.7 Appendix 7 : CDC Classification for HIV-1 Infection  
Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-lymphocyte 
percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-lymphocyte percentage 
should only be considered if the count is missing. 
HIV infection, stage 0 
Indicates early HIV infection, inferred from a negative or indeterminate HIV test result 
within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages. 
HIV infection, stage 1 
Laboratory confirmation of HIV infection with no AIDS-defining condition, and 
• CD4+ T-lymphocyte count of ≥500 cells/L, or 
• CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%. 
HIV infection, stage 2 
Laboratory confirmation of HIV infection with no AIDS-defining condition, and 
• CD4+ T-lymphocyte count of 200 to 499 cells/L, or 
• CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%. 
HIV infection, stage 3 (AIDS) 
Laboratory confirmation of HIV infection, and 
• CD4+ T-lymphocyte count of <200 cells/L, or 
• CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or 
• Documentation of an AIDS-defining condition (see below). 
Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte count 
of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes of >14%.  
HIV infection, stage unknown 
Laboratory confirmation of HIV infection, and 
• No information on CD4+ T-lymphocyte count or percentage, and 
• No information on presence of AIDS-defining conditions. 
Stage-3-defining opportunistic illnesses in HIV infection 
• Candidiasis of bronchi, trachea, or lungs  


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• Candidiasis of esophagus  
• Cervical cancer, invasive 
• Coccidioidomycosis, disseminated or extrapulmonary  
• Cryptococcosis, extrapulmonary  
• Cryptosporidiosis, chronic intestinal (>1 month's duration) 
• Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
• Cytomegalovirus retinitis (with loss of vision) 
• Encephalopathy, HIV-related  
• Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age >1 month) 
• Histoplasmosis, disseminated or extrapulmonary  
• Isosporiasis, chronic intestinal (>1 month's duration)  
• Kaposi's sarcoma  
• Lymphoma, Burkitt's (or equivalent term)  
• Lymphoma, immunoblastic (or equivalent term)  
• Lymphoma, primary, of brain  
• Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary  
• Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary  
• Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary 
• Pneumocystis jirovecii pneumonia  
• Pneumonia, recurrent 
• Progressive multifocal leukoencephalopathy  
• Salmonella septicemia, recurrent  
• Toxoplasmosis of brain, onset at age >1 month  
• Wasting syndrome attributed to HIV. 
Source: [CDC, 2014] 


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11 
REFERENCES 
CDC Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10 
Gallant JE, Thompson M, DeJesus E, et al. Antiviral Activity, Safety, and 
Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults. J 
Acquir Immune Defic Syndr. 2017 May 1;75(1):61-66. doi: 
10.1097/QAI.0000000000001306. PMID: 28196003; PMCID: PMC5389589. 
GSK Document Number RPS-CLIN-033920: VH4524184 Investigator’s Brochure 
Version 00 19/AUGUST/2022  
GSK Document Number RPS-CLIN-069016: VH4524184 Investigator’s Brochure 
Version 01 25/SEPTEMBER/2023 
GSK Document Number TMF-16041100: 218803: A Phase 1 Double-Blind (sponsor-
unblinded), Placebo-Controlled Randomized, Single and Multiple Ascending Dose First-
Time-in-Human Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 
VH4524184 and the Potential for Changes in Cytochrome P450 3A (CYP3A) Activity. 
2023. 
Posner K, Oquendo MA, Gould M, et al. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035-1043. 
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UNAIDS [Internet] Global AIDS Epidemiological Estimates Update 2021 [cited on 18 
August 2021]. Available from  https:// Global HIV & AIDS statistics — Fact sheet | 
UNAIDS accessed 11  August  2023 
 
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Signature Page for  218806 TMF-17008580 v1.0
Signature Page for TMF-17008580 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 29-Sep-2023 14:54:28 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  218806
Official Title of Study: A Randomized, Double-Blind (Sponsor Unblinded), 
Placebo-Controlled, Study to Investigate the Antiviral Effect, Safety, Tolerability 
and Pharmacokinetics of VH4524184 in HIV-1 Infected Treatment Naïve Adults
NCT number: NCT06214052
Date of Document: 11-Jan-2024


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Statistical Analysis Plan (SAP) (4.0) October 2023 
Template Doc ID: TMF-11918393 
Parent Doc ID: VQD-SOP-071708 
TITLE PAGE 
Protocol Title: 
A Randomized, Double-Blind (Sponsor Unblinded), Placebo-
Controlled, Study to Investigate the Antiviral Effect, Safety, 
Tolerability and Pharmacokinetics of VH4524184 in HIV-1 
Infected Treatment Naïve Adults 
 
 
Study Number: 
218806 
Compound Number: GSK4524184 (also known as VH4524184) 
Abbreviated Title: 
VH4524184 Proof-of-Concept in Treatment-Naïve Adults 
Living with HIV-1 
Acronym: 
INSIGHT 
Sponsor Name: ViiV Healthcare UK Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
©2023 ViiV group of companies or its licensor. 
Information Type: 
Statistical Analysis Plan (SAP) 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 4 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 5 
1.2. 
Study Design ................................................................................................ 9 
2. 
STATISTICAL HYPOTHESES ............................................................................... 10 
2.1. 
Multiplicity Adjustment ................................................................................ 10 
3. 
ANALYSIS SETS ................................................................................................... 10 
3.1. 
Exclusions from the Per Protocol Analysis Set ............................................ 11 
4. 
STATISTICAL ANALYSES ..................................................................................... 12 
4.1. 
General Considerations .............................................................................. 12 
4.1.1. 
General Methodology .................................................................. 12 
4.1.2. 
Baseline Definition ....................................................................... 13 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 13 
4.2.1. 
Definition of endpoint(s)/estimands .............................................. 13 
4.2.2. 
Main analytical approach ............................................................. 14 
4.2.3. 
Sensitivity analyses ..................................................................... 15 
4.2.4. 
Supplementary analyses .............................................................. 15 
4.3. 
Secondary Endpoints Analyses .................................................................. 16 
4.3.1. 
Definition of endpoints/estimands ................................................ 16 
4.3.2. 
Main analytical approach ............................................................. 16 
4.4. 
Tertiary Endpoints Analyses ....................................................................... 19 
4.4.1. 
Vital Signs .................................................................................... 19 
4.4.2. 
ECG ............................................................................................. 20 
4.4.3. 
Suicidality Scores ........................................................................ 20 
4.4.4. 
Hematology, coagulation, urinalysis and remaining 
chemistry lab parameters ............................................................. 20 
4.5. 
Other Safety Analyses ................................................................................ 21 
4.5.1. 
Extent of Exposure ...................................................................... 21 
4.6. 
Other Analyses ........................................................................................... 22 
4.6.1. 
Subgroup analyses ...................................................................... 22 
4.6.2. 
Other pharmacokinetic analyses .................................................. 22 
4.7. 
Interim Analyses ......................................................................................... 24 
4.8. 
Final Analyses ............................................................................................ 24 
4.9. 
Changes to Protocol Defined Analyses ....................................................... 25 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 25 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 25 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 25 
6.1.1. 
Participant Disposition ................................................................. 25 
6.1.2. 
Demographic and Baseline Characteristics .................................. 26 


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6.1.3. 
Protocol Deviations ...................................................................... 26 
6.1.4. 
Prior and Concomitant Medications ............................................. 27 
6.1.5. 
Medical Conditions ...................................................................... 27 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 27 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 27 
6.2.2. 
Study Period ................................................................................ 28 
6.2.3. 
Study Day and Reference Dates .................................................. 29 
6.2.4. 
Assessment Window ................................................................... 30 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 31 
6.2.6. 
Handling of Partial Dates ............................................................. 31 
6.2.7. 
Trademarks ................................................................................. 33 
7. 
REFERENCES ....................................................................................................... 34 
 


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VERSION HISTORY  
SAP Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
SAP 
11 Jan 2024 
Version 1 
(29/SEP/20
23) 
Not 
Applicable 
Original version 
 


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the CSR for 
Study 218806. Details of the planned interim analysis, as well as the final analyses, are 
provided. 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the antiviral activity of orally 
administered VH4524184 in TN 
participants with HIV-1 during 10 days of 
monotherapy 
• 
Maximum change from baseline (Day 1) 
in plasma HIV-1 ribonucleic acid (RNA) 
through Day 10. 
Secondary 
• 
To assess the safety and tolerability of 
orally administered VH4524184 
• 
Incidence of adverse events (AEs), 
severity of AEs and proportion of 
participants who discontinue treatment 
due to AEs. Change from baseline and 
maximum toxicity grade increase from 
baseline for liver panel laboratory 
parameter (Alanine Transaminase (ALT), 
Aspartate aminotransferase (AST), total 
bilirubin, direct bilirubin, alkaline 
phosphatase, albumin and total protein) 
• 
To characterize the pharmacokinetic 
profile of orally administered VH4524184 
As data permits, PK measures that include: 
• 
Maximum observed plasma drug 
concentration (Cmax),  
• 
Time to maximum observed plasma drug 
concentration (tmax),  
• 
Concentration on Day 10 
• 
To evaluate any relationship between 
VH4524184 exposure and change in 
plasma HIV1 RNA 
• 
Correlation of VH4524184 PK 
parameters with maximum plasma HIV-1 
RNA change from baseline through Day 
10 
• 
To assess the occurrence of emergent 
genotypic or phenotypic resistance after 
10 days of monotherapy with VH4524184 
• 
Genotypic and phenotypic data from 
baseline (Day 1) and Day 10 will be 
compared for amino acid substitutions 
and VH4524184 fold change IC50. 
• 
To assess the immunologic effects of 
VH4524184 when administered over 10 
days in participants living with HIV 
• 
Change from baseline in CD4+ T-cell 
count to Day 10 
Tertiary 


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Objectives 
Endpoints 
• 
To further assess the safety and 
tolerability of orally administered 
VH4524184 
• 
Post baseline values and changes over 
time of vital signs, electrocardiogram 
(ECG) parameters and suicidality scores. 
• 
Absolute values, change from baseline 
and maximum toxicity grade increase 
from baseline for hematology, 
coagulation and remaining chemistry 
panels 
 
Primary estimand 
The primary objective is to evaluate the antiviral activity of orally administered 
VH4524184 in TN participants with HIV-1 during 10 days of monotherapy.  
The estimand is described by the following attributes: 
• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoint:  
Maximum change from baseline (Day 1) in plasma HIV-1 RNA through Day 10 
• 
Treatment:  
VH4524184 or placebo 
 
• 
Intercurrent events: 
• 
Discontinuation of study treatment due to any reason will be addressed using 
while on-treatment strategy, i.e. any HIV-1 RNA data available after study 
treatment discontinuation day + 1 and prior to starting standard of care (SOC) 
will be excluded from calculation of max VLD  
• 
Use of SOC or other antiviral medication prior to Day 10 will be addressed 
using while on-treatment strategy, i.e., HIV-1 RNA collected after initiation of 
SOC, if for any reason this takes place prior to Day 10, will be excluded from 
calculation of max VLD  
• 
Use of prohibited medication will be addressed using treatment policy 
strategy, i.e., any HIV-1 RNA data available after use of prohibited medication 
will be used in calculation of max VLD  
• 
• 
Population-level summary:  
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Mean of maximum change from baseline in log10 HIV-1 RNA during Days 1-10 
 
Rationale for estimand: Interest lies in evaluating efficacy of orally administered 
VH4524184 
 or use of prohibited medications and not 
in combination with other antiretroviral medication. 
 
Secondary estimands 
The secondary objective is to assess the safety and tolerability of orally administered 
VH4524184. 
The estimand is described by the following attributes: 
• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoint:  
• 
Incidence of AEs, severity of AEs and proportion of participants who 
discontinue treatment due to AEs 
• 
Change from baseline and maximum toxicity grade increase from baseline for 
liver panel laboratory parameter 
• 
Treatment:  
VH4524184 or placebo 
 followed by SOC on Days 10-38 
• 
Intercurrent events: 
• 
Discontinuation of study treatment due to any reason will be addressed using 
treatment policy strategy, i.e. all safety data after study treatment 
discontinuation will be used 
• 
Use of SOC or other antiviral medication prior to Day 10 will be addressed 
using while on-treatment strategy, i.e., safety data collected after initiation of 
SOC, if for any reason this takes place prior to Day 10, will be excluded from 
monotherapy safety summaries 
• 
Use of prohibited medication will be addressed using treatment policy 
strategy, i.e., all safety data will be used regardless of the use of prohibited 
medication 
• 
• 
Population-level summary:  
AEs:  
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• 
Number and percentage of participants with AEs  
• 
Number and percentage of participants with AEs by severity grade  
• 
Number and percentage of participants with AEs leading to study treatment 
discontinuation 
Liver panel laboratory parameters: 
• 
Summary statistics (mean, SD, median, min, max, etc.) of change from baseline 
• 
Number and percentage of participants with maximum toxicity grade increase 
relative to baseline 
Rationale for estimand: Interest lies in evaluating safety and tolerability of orally 
administered VH4524184 irrespective of study treatment discontinuation, 
 
, or use of prohibited medications and not in combination with other antiretroviral 
medication. 
 
Another secondary objective is to characterize the PK profile of orally administered 
VH4524184. 
The estimand is described by the following attributes: 
• 
Population:  
Overtly healthy (other than HIV-1 infection) treatment naïve individuals 
• 
Endpoints:  
As data permits, 
• 
Maximum observed plasma drug concentration (Cmax)  
• 
Time to maximum observed plasma drug concentration (tmax)  
• 
Concentration on Day 10 
• 
Treatment:  
VH4524184 or placebo 
 followed by SOC on Days 10-38 
• 
Intercurrent events: 
• 
Discontinuation of study treatment due to any reason will be addressed using 
while on-treatment strategy, i.e. PK data after study treatment discontinuation 
will be excluded from use in noncompartmental analyses. 
• 
Use of SOC or other antiviral medication prior to collection of HIV-1 RNA and 
PK specimens on Day 10 will be addressed using while on-treatment strategy, 
i.e., PK data collected after initiation of SOC, if for any reason this takes place 
prior to Day 10, will be excluded 
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• 
Use of prohibited medication will be addressed using treatment policy 
strategy, i.e., all PK data will be used regardless of the use of prohibited 
medication 
• 
 of study treatment will be addressed using while on-
treatment strategy, i.e. PK data collected 
 will be 
excluded from use in noncompartmental analyses. 
• 
Population-level summary:  
Summary statistics (e.g. arithmetic mean, SD, median, min, max, geometric mean, 
SD (log), %CVb, etc.)  
Rationale for estimand: Interest lies in characterizing the PK profile of orally 
administered VH4524184 which could be biased by study treatment discontinuation, 
, or use of SOC medication prior to day 10. 
 
1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
Phase 2a POC, multi-center, randomized, double-blind (sponsor 
unblinded), placebo-controlled, adaptive clinical study  
• 
Orally administered VH4524184 monotherapy over 10 days in 
antiretroviral therapy (ART) naive adults with HIV-1 and 
detectable viremia 
• 
Total duration of study participation is approximately 45 to 66 
days based on the following: 
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Overview of Study Design and Key Features 
• 
Screening Period: 7 to 14 days, with a maximum of 28 
days permitted in some cases for screening/qualification 
period 
• 
Monotherapy Period: 10 days for treatment with the 
study intervention and assessment at all planned visits 
• 
Open Label Follow-up Period: 28 days for follow up 
visits while on SOC ART including the final follow up 
visit 
Study 
intervention 
VH4524184 or placebo 
 followed by SOC on Days 
10-38 
Study 
intervention 
Assignment 
Participants will be randomly assigned to one of 3 dose levels (
 
). Within each dose level, participants will be randomly 
assigned to receive VH4524184 or placebo in a 6:1 ratio.  
Interim 
Analysis 
An informal interim analysis will be conducted after all Part 1 
participants complete their monotherapy phase. 
2. 
STATISTICAL HYPOTHESES  
The primary objective will be addressed using an estimation approach (descriptive 
statistics) with no hypothesis testing. The primary treatment effect to be estimated is the 
maximum change from baseline in plasma HIV-1 RNA over the monotherapy period. 
2.1. 
Multiplicity Adjustment 
No adjustment for multiplicity will be made. 
3. 
ANALYSIS SETS  
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study 
Population 
Randomized 
• 
All participants who were randomly assigned to 
study intervention in the study. 
 
• 
Study 
Population 
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Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Safety 
• 
All randomized participants who received at least 
1 partial or full dose of study intervention. 
• 
Participants will be analyzed according to the 
study intervention they actually received 
• 
Study 
Population 
• 
Safety 
Full Analysis Set 
(FAS) 
• 
All randomized participants who received at least 
1 full dose of study intervention.  
• 
Data will be reported according to the randomized 
study intervention. 
• 
Study 
Population 
• 
Efficacy 
Per-Protocol (PP) 
• 
All participants in the FAS for whom there were no 
major protocol deviations that impact the primary 
analyses. 
• 
Data will be reported according to the study 
intervention actually received. 
• 
Specific details of major protocol deviations that 
would exclude participants from the PP analysis 
set are provided in Section 3.1. 
• 
Efficacy 
• 
The PP set 
will not be 
used for 
analysis if it 
is the same 
as FAS 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety analysis set who had 
at least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as 
non-missing values). 
• 
Data will be reported according to the actual study 
intervention. 
• 
PK 
3.1. 
Exclusions from the Per Protocol Analysis Set  
A participant meeting any of the following criteria prior to the end of monotherapy period 
will be excluded from the primary analysis based on the PP analysis set:  
Number 
Exclusion Description 
01 
Missed at least one dose or received a partial dose 
02 
Took at least one incorrect dose 
03 
Missed the Day 1 or Day 10 HIV-1 RNA assessment 
04 
Missed more than 1 post-baseline HIV-1 RNA assessment between 
Day 1 and Day 10 
05 
Started the SoC medication prior to Day 10 
06 
07 
Violated any of the inclusion criteria or met any of the exclusion 
criteria 
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Number 
Exclusion Description 
08 
Met other Important Protocol Deviations occurring during the 
monotherapy period meriting exclusion from the PP analysis set as 
they have the potential to significantly impact primary analysis. 
Protocol deviations will be adjudicated throughout the study conduct 
and will be classified as important (yes/no), along with determination 
on whether they should trigger exclusion from the PP analysis set 
and finalised prior to DBL. 
*Medical monitor and PK lead will review the list of prior and concomitant medications used by 
participants in the study and determine which ones meet the criteria of strong/moderate inducers/inhibitors 
described here prior to DBL. 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
Note: participant-level data will be available interactively via Reporting & Analysis Plan 
Improving Design and Delivery of Outputs Data Viewer (RAPIDO DV) at SAC. Only 
selected listings specified in the Output and Programming Specifications (OPS) will be 
created in a static fashion. See OPS for the list of selected listings. 
The term “Analysis Set” in the SAP will be referred to as “Population” in the displays. The 
term “Participant” in the SAP will be referred to as “Subject” in the displays of the OPS 
document.  
4.1.1. 
General Methodology 
If participants prematurely discontinue the study for non-safety reasons, additional 
participants may be recruited with randomization and assignment to the same cohort (to 
ensure a minimum of 5 evaluable participants in each of cohorts 1, 2 and 3, and optional 
cohort 4) at the discretion of the Sponsor in consultation with the Investigator. 
Participants will not be replaced if the reason for discontinuation is the original 
participant meeting stopping criteria. ‘Discontinuation’ of study intervention refers to any 
participant who has not received all planned doses of the study intervention. In rare 
instances, it may be necessary for a participant to permanently discontinue study 
intervention. 
Data will be summarized by study intervention (VH4524184 or placebo) and dose level, 
unless otherwise specified. In other words, placebos from each dose level will be grouped 
collectively, while active participants from each dose level will be grouped separately. As 
such, if optional Part 2 is not used, the following groups will be summarized: VH184 
, VH184 
, VH184 
, and PBO. If optional Part 2 is used, the following 
groups will be summarized: VH184 
, VH184 
, VH184 
, VH184 Dose 
Level 4 (to be determined by interim analysis) and PBO.  
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Data will be summarized either by visit or separately for the monotherapy period and 
overall (i.e., monotherapy period + follow-up), as appropriate for each endpoint, unless 
otherwise specified.  
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center are unlikely to be informative and will not, therefore, be provided. 
Continuous and categorical variables will be summarized using the following descriptive 
statistics, unless otherwise specified:  
• Continuous data: n (number of participants used for the summary), arithmetic 
mean, standard deviation (SD), median, interquartile range, minimum and 
maximum. For PK data, geometric mean, SD of log-transformed data and 
geometric %CVb may also be used.  
• Categorical data: number and percentage of participants 
Confidence intervals will use 95% confidence levels unless otherwise specified. 
PK values collected outside analysis visit windows will be excluded from data summaries 
(applies to both tables and figures) but will be included in listings. Figures with 
participant level information will include all values (i.e. irrespective of being 
within/outside of analysis visit windows). 
Only lab data from central laboratory will be included in lab data summaries. Lab data 
from local laboratories, if any, will be included in listings (and flagged appropriately).  
No imputation for missing values will be performed.  
4.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. If Day 1 pre-
dose ECG has been assessed more than once (e.g. in triplicate), the average of the 
available ECG measurements will be used as baseline value. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Baseline will not be rederived for the Follow-Up period.  
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of endpoint(s)/estimands 
See section 1.1 for definition of primary endpoint/estimand.  


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Change from baseline at the time point where the HIV-1 RNA is minimum (nadir) during 
the monotherapy period will be calculated for each participant in the original and log10 
scales. The change from baseline at nadir is the primary endpoint used to construct the 
primary estimand (see section 1.1). According to primary estimand definition (section 
1.1), if SoC medication starts prior to Day 10 (for any reason), change from baseline 
values after SoC initiation will be excluded from calculation of change from baseline at 
nadir.  
Note, the change from baseline at nadir during monotherapy is typically the maximum 
change from baseline in HIV-1 RNA, or in other words the maximum Viral Load Decline 
(VLD). However, for participants who have all their post-baseline HIV-1 RNA values 
during monotherapy higher than the baseline value (e.g. as is the potential with some 
participants randomized to placebo) the change from baseline at nadir is the minimum 
change from baseline. Also, if a (placebo) participant has a high increase from baseline in 
HIV-1 RNA and then a smaller decrease from baseline (or vice versa), the maximum 
change from baseline is at the point where HIV-1 RNA is its peak (zenith); the change 
from baseline at nadir will be used in this case in the primary analysis. From now on, in 
this document by “maximum change from baseline in HIV-1 RNA” during monotherapy 
we will mean the “change in HIV-1 RNA at nadir”. 
The log10 transformation is used to allow for direct comparisons with data from other 
compounds publicly available in the same scale, and hence aid in interpretation. 
4.2.2. 
Main analytical approach 
The primary efficacy analysis will be based on the Full Analysis Set.  
Maximum change from baseline in plasma HIV-1 RNA during monotherapy will be 
summarized in original and log10 scales using descriptive statistics as described in section 
4.1.1.  
In addition, change from baseline in plasma HIV-1 RNA at each assessment time point 
during monotherapy will be summarized in original and log10 scales.  
Any missing HIV-1 RNA data (e.g., due to missed visits in the clinic, loss to follow-up or 
for any other reason) will not be imputed and will remain missing. Whatever HIV-1 RNA 
data are available for a participant during monotherapy and prior to starting SoC will be 
used to calculate maximum VLD. 
If a participant withdraws from study prior to the end of monotherapy period, preventing 
assessment of primary endpoint, no imputation will be performed for missed assessments 
after their study withdrawal. 
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4.2.3. 
Sensitivity analyses 
The primary analysis described in section 4.2.2 will be repeated on the PP analysis set, 
and on the Safety analysis set if any participant receives treatment other than the one to 
which they were randomized.  
None of the IEs specified in section 1.1 for the primary estimand are applicable for the 
PP analysis set, as none of them can occur in participants within the PP analysis set 
(because of criteria in section 3.1). All available HIV-1 RNA data from the monotherapy 
period on the PP analysis set will be used for the sensitivity analysis.  
4.2.4. 
Supplementary analyses 
4.2.4.1. 
Summaries of HIV-1 RNA change from baseline by visit 
Change from baseline in plasma HIV-1 RNA will be calculated for each participant at 
each assessment time point during the monotherapy and follow-up periods in the original 
and log10 scales. Change from baseline at each assessment time point during 
monotherapy and follow-up will be summarized in original and log10 scale using 
descriptive statistics as described in section 4.1.1.  
Mean (95% CI) and median of change from baseline in plasma HIV-1 RNA in the log10 
scale will be plotted by visit for the monotherapy period. 
These analyses will be performed on the FAS, PP analysis set, and Safety analysis set if 
any participant receives treatment other than the one to which they were randomized. 
4.2.4.2. 
Modelling of HIV-1 RNA change from baseline 
A mixed-effects linear model will be fitted using plasma HIV-1 RNA change from 
baseline (on log10 scale) during the monotherapy period from all dosing levels as the 
outcome measure, with day, dosing group, day and dosing group interaction and baseline 
HIV-1 RNA (on log scale) as fixed effects and participant as a random effect. Day will be 
treated as a continuous variable. The Kenward & Roger (KR2) degrees of freedom 
approach will be used [Kenward & Roger, 2009]. Data from placebos across dosing 
levels will be analyzed as a single placebo group. Thus, for Part 1, 4 dosing groups will 
be considered: VH4524184 
, VH4524184 
, VH4524184 
 and Placebo. 
The model will be used to estimate the rate of decline in HIV-1 RNA and its 90% CI for 
each dosing group.  
Model assumptions 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 warranted, alternative models or 
data transformations may be explored.  
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This analysis will be performed on the FAS, PP analysis set, and Safety analysis set if 
any participant receives treatment other than the one to which was randomized. 
4.3. 
Secondary Endpoints Analyses 
4.3.1. 
Definition of endpoints/estimands 
See section 1.1 for definition of secondary endpoints/estimands.  
4.3.2. 
Main analytical approach 
All secondary Safety and PK analyses will be performed on the Safety and PK analysis 
set, respectively. 
4.3.2.1. 
Adverse events analyses 
AEs will be tabulated using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred terms and graded by the investigator according to the Division of AIDS 
(DAIDS) Criteria Version 2.1. 
The number and percentage of participants reporting AEs during the monotherapy period 
will be summarised using the following categories and subcategories: 
• AEs  
o Overall  
o By System Organ Class and Maximum Grade  
• AEs leading to permanent discontinuation of study treatment  
• AEs leading to withdrawal from study  
• Drug-related AEs  
o Overall  
o By Maximum Grade  
• Drug-related Non-serious AEs  
• Common (≥5%) non-Serious AEs  
• SAEs by System Organ Class and Maximum Grade  
• Drug-related SAEs  
 
The Common (≥5%) non-Serious AEs display will also include the number of events of 
an AE. 
Selected displays from the above list will be repeated for AEs with onset during the 
follow-up period and during either the monotherapy or the follow-up period. AEs with 
onset in the monotherapy period which continue in the follow-up period will only be 
included in AE summaries for the monotherapy period. See OPS for the exact AE tables 
to be repeated for follow-up and monotherapy + follow-up. 


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A listing of all AEs will be provided. All planned AE displays are provided in the OPS 
document. 
4.3.2.2. 
Liver panel laboratory analyses 
Change from baseline values for liver panel laboratory parameters will be summarised by 
assessment visit. Visits up to Day 10 (inclusive) will exclude any liver panel values 
assessed under SoC, if SoC starts earlier for any reason, in line with the Estimand 
definition (section 1.1). 
Laboratory toxicities will be graded according to the DAIDS Criteria Version 2.1. For 
liver panel lab tests that are gradable by DAIDS (e.g. ALT, AST), summary of worst-case 
grade increase from baseline grade will be provided. This summary will display the 
number and percentage of participants with a maximum post-baseline grade increase 
from their baseline grade. Also, maximum increase subtotals (i.e. max increase in grade 
to any grade between 1 and 4, max increase to grade 2-4 or max increase to grade 3-4) 
will be included. The grade increases are determined by comparing the baseline grade to 
the worst-case post-baseline grade (e.g., Increase to Grade 1, Increase to Grade 2 etc.) 
and maximum grade increase subtotals (e.g., Increase to Grades 1 to 4, Increase to Grades 
2 to 4, Increase to Grades 3 to 4). The grading subtotals are determined by adding the 
counts for each worst-case grade change within the subtotal category, e.g., ‘Increase to 
Grades 1 to 4’ is a subtotal of all worst-case increases to Grade 1, to Grade 2, to Grade 3, 
and to Grade 4. Participants with missing baseline value are to be assumed to have a 
Grade 0 at baseline. The determination of the worst case during the post-baseline period 
takes into account both planned and unscheduled assessments. This summary will be 
produced while participants are under the monotherapy period, as well as overall (i.e. 
monotherapy + follow-up).  
For lab tests that are not gradable by DAIDS, summaries of worst-case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to 
normal or no changes from baseline, and increases to high will be summarized for the 
worst-case post-baseline. If a subject has a decrease to low and an increase to high during 
the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories.  
Liver panel data for participants with at least one abnormal lab value will be included in 
the listing of chemistry laboratory parameters.  
More details of all planned displays are provided in the OPS document. 
4.3.2.3. 
Pharmacokinetic analyses 
Pharmacokinetic analysis will be the responsibility of the CPMS Department at GSK. 
Plasma concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin 8.1 or higher, Phoenix (Pharsight Corporation) or comparable software to 
derive the PK parameters. All calculations of non-compartmental parameters for the End 
of Study (EoS) analysis will be based on actual sampling times recorded during the study.  


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For the calculation of the area under the concentration-time curve (AUC), the linear 
trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for those 
arising from decreasing concentrations (i.e., Linear Up/Log Down calculation method in 
Phoenix WinNonlin Professional). A minimum number of three data points (not 
including Cmax) should be used in calculating λz.  
The following pharmacokinetic parameters will be determined from the plasma 
concentration-time data, as data permits, and they will be included in the final SDTM 
datasets: 
PK Parameter 
Definition 
Cmax 
Maximum observed plasma concentration (
 
) 
tmax 
Time to first occurrence of Cmax (
) 
C10 
Concentration on Day 10 
AUC(0-∞) 
Area under the plasma concentration time curve from 
time zero to infinity (
) calculated as 
AUC(0-∞)= AUC(0-t)+C𝑙𝑎𝑠𝑡𝜆𝑧
⁄
 
AUC(0-tlast) 
Area under the plasma concentration vs time curve 
from time = 0 hours to the last observed quantifiable 
concentration 
) 
AUC(0-10) 
Area under the plasma concentration vs time curve 
from time = 0 hours to Day 10 
Note: Additional Parameters may be included as required 
At interim analysis, preliminary PK data will be analysed by CPMS to select appropriate 
doses for Part 2 of the study (if used).  
Pharmacokinetic concentrations collected within the PK analysis visit windows will be 
summarised at every scheduled time point using descriptive statistics. PK concentrations 
sampled outside the PK sampling windows will be included in listings and in participant 
level figures but will not be included in data summaries. For each compound, derived PK 
parameters (excluding AUC0-10) will be summarised using descriptive statistics (AUC0-10 
will be used only for analyses to explore relationship between PK exposure and 
immunologic endpoints; see section 4.3.2.6). 
PK concentrations derived after discontinuation of study treatment will be excluded from 
PK data summaries, in accordance with the ‘while on-treatment’ strategy for IE, as 
described in section 1.1.  
If a participant takes an incorrect dose or misses a dose, PK concentrations and PK 
parameters inferred until the next dose or until the end of monotherapy period (if 
incorrect dose is the last one) may be excluded from PK data summaries, as instructed by 
CPMS prior to final database lock.  
The following figures will be produced:  
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• A by-subject graph of the concentration data over time, on linear and semi-
logarithmic scales  
• Graph of geometric mean of concentration data over time, on linear and semi-
logarithmic scales  
• Individual and box plot of PK parameters  
 
Listings of PK concentration and PK parameter values will be produced. 
4.3.2.4. 
PD and PK/PD analyses 
Pharmacokinetic-pharmacodynamic analyses will be the responsibility of the CPMS 
Department at GSK. The relationship between selected PK parameters (e.g., 
concentrations on Day 10) and selected PD parameters (e.g., maximum change from 
baseline in log10 plasma HIV-1 RNA) will be explored separately by CPMS. These 
analyses will be described in a separate CPMS report. 
4.3.2.5. 
Virology analyses 
Genotypic assessments will be analyzed separately by the study virologist. These 
analyses will be performed after SAC, when the genotypic data become available. 
4.3.2.6. 
Immunology analyses 
Change from baseline in CD4+, CD8+ and CD4+/CD8+ (if collected) will be 
summarized descriptively at every assessment visit. Visits up to Day 10 (inclusive) will 
exclude any values assessed under SoC, if SoC starts earlier for any reason. 
To further explore the relationship between VH4524184 exposures and CD4+ T-cell 
counts, a scatter plot of change from baseline on Day 10 (within the monotherapy period) 
in CD4+ counts and Cmax after each administration, AUC0-10 and C10 will be created for 
all participants receiving active drug. A LOWESS line will be included in the scatter plot.  
Further analyses may be conducted post SAC if any signals or trends are identified in this 
univariate analysis. 
4.4. 
Tertiary Endpoints Analyses 
4.4.1. 
Vital Signs 
Post-baseline values of vital signs (temperature, systolic and diastolic blood pressure, 
pulse rate and respiratory rate) and change from baseline over time will be summarized 
by assessment visit.  
The number of participants with worst case vital sign results relative to Potential Clinical 
Importance (PCI) criteria which are post-baseline relative to baseline will be summarized. 


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The change categories for PCI criteria are: To Low, To w/in Range or No Change, To 
High. The categorization is determined by comparing the baseline category to the worst 
case post-baseline category. The determination of the worst case post-baseline takes into 
account both planned and unscheduled assessments. Participants with missing baseline 
value are to be assumed to have a within range baseline value.  
This summary will be produced while participants are under the monotherapy period, as 
well as overall (i.e. monotherapy + follow-up). 
All vital signs data for participants with at least one value of potential clinical importance 
will be included inRAPIDO DV. PCI values for vital signs are defined in section 6.2.1.  
4.4.2. 
ECG 
If multiple ECG records are available for a visit/timepoint (e.g. in case of triplicate ECG), 
then the average for continuous ECG variables and the worst case for categorical will be 
used for data summaries for that visit/timepoint. 
Post-baseline values of ECG parameters (heart rate, PR, QRS, QT, and QTc intervals) 
and change from baseline will be summarized by assessment visit. 
The number and percentage of participants with ECG findings will be summarized by 
assessment visit. The ECG findings to be summarized are the ECG interpretation and 
clinical significance (yes/no) of abnormal ECGs. All ECG data for participants with a 
value of potential clinical importance occurring during either the monotherapy or follow-
up period will be included in RAPIDO DV. PCI values for ECG parameters are defined 
in section 6.2.1. 
4.4.3. 
Suicidality Scores 
Baseline suicidality data assessed electronically via the C-SSRS questionnaire will be 
summarised. Number and percentage of participant with suicidal ideation or behaviour 
during lifetime and currently (i.e. within the past 2 months of screening) will be 
presented.  
Participant-level suicidality data will be available via RAPIDO DV. 
4.4.4. 
Hematology, coagulation, urinalysis and remaining chemistry lab 
parameters 
Post-baseline values, change from baseline and maximum toxicity grade increase from 
baseline for hematology, coagulation, urinalysis and remaining chemistry panels will 
follow the same approach as liver panel laboratory analyses, detailed in section 4.3.2.2.  
There are some lab parameters which are graded for both low values and high values. 
Summaries of these lab tests will be differentiated by term, e.g. sodium will be 


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summarized as “hyponatremia” and “hypernatremia”, calcium as “hyperkalemia” and 
“hypokalemia” etc. 
For urinalysis parameters assessed with the dipstick method, summaries of worst-case 
post-baseline relative to baseline will be created. The categories for which summaries 
(i.e. number and percentage of participants) will be provided are based on the actual 
values within the data, e.g. ‘No Change/Decreased’, ‘Increase to TRACE’, ‘Increase to 
1+ or Increase to +’, ‘Increase to 1+ or to 1/4 G/DL’, etc. ‘Decreased’ indicates a “lesser” 
result including change to a negative result. The categorization is determined by 
comparing the baseline category to the worst-case post-baseline category. The 
determination of the worst-case post-baseline takes into account both planned and 
unscheduled assessments. Subjects with a missing baseline value are to be assumed to 
have a negative baseline value. 
These summaries will be produced while participants are under the monotherapy period, 
as well as overall (i.e. monotherapy + follow-up). 
A listing of hematology, coagulation and chemistry laboratory data will be created. For 
each laboratory category (i.e. chemistry, hematology etc.), the listing will include 
participants with at least one abnormal lab value (i.e. DAIDS grade ≥1 for graded 
parameters or outside normal range for non-graded) during either the monotherapy or the 
follow-up period in any lab parameter within a lab category. All data for all lab 
parameters within the lab category in which an abnormal value was observed will be 
included in the listing; no lab parameters from another lab category in which no abnormal 
values were observed will be included (e.g. if a participant has an abnormal ALT value 
then all data from all chemistry lab parameters will be included in the listing and none of 
the lab parameters from hematology and coagulation).  
A listing of urinalysis data will be created. The urinalysis listing will include only 
participants with at least one abnormal value (i.e. outside normal range) for specific 
gravity or pH or if there is an increase from Baseline in Protein or in Occult Blood or if 
microscopy is performed, during either the monotherapy or the follow-up period. 
4.5. 
Other Safety Analyses 
Other safety analyses will be based on the Safety Analysis Set, unless otherwise 
specified. 
4.5.1. 
Extent of Exposure 
Extent of exposure in cumulative actual dose (mg) will be summarized and exposure will 
be listed for all participants. 


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4.6. 
Other Analyses 
4.6.1. 
Subgroup analyses 
No subgroup analyses are planned. 
4.6.2. 
Other pharmacokinetic analyses 
All other pharmacokinetic analyses will be performed on the Pharmacokinetic analysis 
set and will follow the IE strategies outlined for the secondary PK objective in section 
1.1.  
4.6.2.1. 
Dose proportionality assessment  
Dose proportionality may be assessed following guidance from CPMS prior to final 
database lock.   
Power Model 
The analysis will be based on selected available PK parameters. No imputation will be 
done for missing PK parameters for any participant. 
Endpoint / Variables 
AUC(0-t) and Cmax, as the data permit, at first, second, and third dose, separately 
 
Model Specification 
• Power model  
 𝑦= 𝛼∗𝑑𝑜𝑠𝑒𝛽 
where y denotes the PK parameter being analyzed and dose denotes the dose administered 
to a subject.  
• Dose proportionality implies that 𝛽= 1 and will be assessed by estimating 𝛽 along with its 
confidence interval by regressing the loge transformed PK parameter on the loge dose as 
shown below:  
log𝑒𝑦= log𝑒𝛼+ 𝛽log𝑒𝑑𝑜𝑠𝑒 
Model Checking & Diagnostics 
• Distributional assumptions underlying the statistical analyses will be assessed by visual 
inspection of residual plots. Normality will be examined by normal probability plots, while 
homogeneity of variance will be assessed by plotting the residuals against the predicted 
values for the model. 
• If there are any important departures from the distributional assumptions, alternative models 
may be explored using appropriately transformed data. 
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• Estimates of slope 𝛽 will be reported along with corresponding 90% CIs. If the CI contains 1 
then we shall assume Dose Proportionality to hold. 
 
ANOVA Method 
If power model does not show dose proportionality, dose proportionality may be assessed 
by an analysis of variance (ANOVA) model.  
PK parameters will be dose-normalised prior to loge-transformed by multiplying by 
reference dose / dose. Dose-normalised PK parameters will be analysed separately using 
a fixed effects ANOVA model for dose. Point estimates for the adjusted means on the 
loge scale, the mean difference between each dose (test) and the reference dose and 
associated 90% confidence interval will be constructed using the residual variance. The 
point estimate and confidence interval will then be exponentially back-transformed to 
obtain adjusted (least square) geometric means for each dose, and point estimates and 
associated 90% confidence intervals for the ratio test/reference. The reference dose will 
be chosen based on the lowest clinically relevant dose over which PK can be adequately 
described, with each other dose as the test doses in the construction of the ratio 
µ(test)/µ(reference). 
4.6.2.2. 
Estimation of Accumulation Ratios 
Accumulation ratios may be estimated for Cmax following guidance from CPMS prior to 
final database lock. These are defined as the ratio of PK parameters from last 
administration to first administration on Day 1, as follows:  
𝑅(𝐶𝑚𝑎𝑥) = 𝐶𝑚𝑎𝑥 𝑜𝑛 𝐷𝑎𝑦 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛
𝐶𝑚𝑎𝑥 𝑜𝑛 𝐷𝑎𝑦 1
 
To estimate the accumulation ratios for each dose level, a mixed effects ANOVA model 
will be used on the loge-transformed Cmax. Participant will be treated as a random effect 
in the model, while day will be treated as fixed effect categorical variable. The Kenward 
& Roger (KR2) degrees of freedom approach will be used [Kenward & Roger, 2009]. 
The accumulation ratio will be estimated by calculating the ratio of the geometric least 
squares means of PK parameters between last administration (e.g. 
) and 
first administration (Day 1) and the corresponding 90% CI. No imputation will be done 
for missing PK parameters. 
Model assumptions for the analyses outlined in sections 4.6.2.1 and 4.6.2.2 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 warranted, alternative models or data transformations may 
be explored.  
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4.7. 
Interim Analyses 
An informal planned interim analysis will be conducted after all participants in Part 1 
have completed their monotherapy period.  
The planned interim analysis will evaluate the PK and pharmacodynamic (antiviral 
activity) of VH4524184 and inform the need for Part 2, as well as future clinical 
development of VH4524184.  
Any safety outputs provided at the interim analysis will summarise data by dosing levels, 
with placebo participants grouped with active participants at the corresponding dose 
level. In other words, safety data summaries will be blinded to study intervention, but not 
to dose level. Any ‘by visit’ outputs could include data from the follow-up period, if 
available.  
The tables, figures and listings that will be provided at the planned interim analysis are 
described in the OPS. 
Additional interim analyses may be performed during the course of the study to inform 
internal decision-making activities and/or support regulatory requests. No changes to the 
conduct of the study will be implemented as a result of these analyses.  
4.8. 
Final Analyses 
The final EoS analysis will be conducted after the completion of the study (i.e., when all 
participants complete the follow-up period with the Day 38 visit) and final datasets 
authorization. At the EoS analysis all primary, secondary and tertiary objectives will be 
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evaluated with two exceptions: the analysis of (i) viral resistance and (ii) 
pharmacogenetics (if done), may be evaluated at a later stage and each of these outcomes 
will be reported separately. 
4.9. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 29 September 2023). 
5. 
SAMPLE SIZE DETERMINATION 
The sample size is based on feasibility and no formal calculation of power or sample size 
has been performed. 
Further details on sample size considerations are included in protocol section 9.5.1. 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the Safety 
Analysis Set.  
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
will be based on GSK Core Data Standards. Details of the planned displays are included 
in the OPS. 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who enrolled or failed 
screening will be provided. For screen failures, the number and percentage of participants 
overall and by screen failure reason will be also provided. 
A summary of the number and percentage of participants who entered, completed, are 
ongoing or withdrew from study at each study period (i.e. Monotherapy, Follow-Up) will 
be provided. A participant will be considered to have completed the Monotherapy period 
if they have completed Day 10 visit and have not started SoC prior to Day 10. If a 
participant has started SoC treatment prior to Day 10 visit and has performed Day 10 
visit, he/she will be classified as having ‘Not Completed’ the Monotherapy phase. A 
participant is considered to have entered the Follow-Up period if there is a recorded 
concomitant antiretroviral treatment start date.  
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from study will be provided. Reasons for study 


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withdrawal will be summarized. A participant is considered to have completed the study 
if he/she has a “Completed” status in the Study Conclusion eCRF page.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the scheduled study 
intervention or have discontinued study intervention prematurely, as well as primary 
reasons for discontinuation of study intervention.  
The number and percentage of participants who withdrew from study due to an AE will 
be summarised by the outcome (fatal versus non-fatal) of the AE.  
A listing of reasons for study withdrawal will be provided. 
Participant-level disposition information will be available via RAPIDO DV. 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, race, height/weight and 
BMI at baseline will be summarized with descriptive statistics. In addition, the following 
age categories will be summarized: 18-64, 65-84 and >=85 based on the Enrolled 
Analysis Set. 
Demographic data will be listed.  
Other baseline characteristics data such as medical history and CDC HIV-1 classification 
will be available at the participant-level via RAPIDO DV. Participant-level HIV-1 
associated conditions and pregnancy data will also be available via RAPIDO DV. 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations (where possible without knowing the study intervention details) 
are captured and categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 


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Participant-level protocol deviations which result in exclusion from the Per Protocol 
analysis set will be available via RAPIDO DV.  
• 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
deviations leading to analysis population exclusions are captured and categorised in 
the protocol deviations ADaM dataset (note these exclusions are not captured in the 
SDTM dataset). 
6.1.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using both the GSK Drug and WHO 
Drug dictionaries. However, the listing of concomitant medications will be based on GSK 
Drug dictionary only.  
6.1.5. 
Medical Conditions 
Medical occurrences beginning after obtaining informed consent but before the start of 
study intervention will be recorded as medical history/current medical conditions, not as 
AEs, and will be available via RAPIDO DV. 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
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). A high or low 
abnormal laboratory value is not necessarily of clinical concern.  
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 
as specified in the protocol.  
In addition, the following criteria will be used to flag potential clinical importance: 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval (QTcF) 
msec 
< 320 
> 450 (Males) 
> 470 (Females) 


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*On-treatment triplicate averaged QTcF value > 60 msec over baseline regardless of sex 
 
Note: PCI values for Respiratory Rate & Temperature are not applicable. 
6.2.2. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Screening is defined as time prior to the first dose of study intervention. 
Monotherapy is defined as the time from first dose of study intervention (Day 1) to the 
start of standard of care ART (Day 10) 
• 
If time of assessment or study intervention is not collected, Day 1 assessments other 
than AEs are considered to have occurred prior to study intervention dose and 
therefore considered part of the Pre-Intervention period, whereas AEs with Day 1 
onset are considered to have occurred after study intervention dose and are therefore 
considered part of the Monotherapy period. 
Follow-up is defined as any time after the transition to standard of care ART on Day 10.  
• 
If time of assessment or time of SoC initiation is not collected, Day 10 assessments 
other than AEs are considered to have occurred prior to SOC initiation and therefore 
considered part of the Monotherapy period, whereas AEs with Day 10 onset are 
considered to have occurred after SOC initiation and are therefore considered part of 
the Follow-up period. 
For concomitant medications, study periods will be defined as follows (please note that 
the screening period is used interchangeably with pre-treatment in descriptions): 
 
Change from Baseline 
Increase from baseline QTc 
Msec 
> 60* 
Vital Sign Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Systolic Blood Pressure 
mmHg 
< 85 
> 140 
Diastolic Blood Pressure 
mmHg 
< 45 
> 90 
Heart Rate 
bpm 
< 45 (Males) 
< 50 (Females) 
> 100 


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6.2.3. 
Study Day and Reference Dates 
The study day is calculated as below: 
• 
Assessment Date = Missing               
→ Study Day = Missing  
• 
Assessment Date < Study Intervention Start Date  


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→ Study Day = Assessment Date – Study Intervention Start Date 
• 
Assessment Data ≥ Study Intervention Start Date 
→ Study Day = Assessment Date – Study Intervention Start Date + 1     
6.2.4. 
Assessment Window  
For data summaries by visit, the nominal visit description will be used. Unscheduled and 
withdrawal visit data will be slotted into a target visit based on visit window defined in 
the table below. Within each study period, if there are multiple assessments within the 
same window, the following hierarchy will determine which assessment will be used:  
1. The assessment that is closest to the target day.  
2. If there are multiple assessments equidistant from the target day, then:  
a. For continuous parameters, the average of the values will be used  
b. For categorical parameters, the worst assessment will be used 
CCI


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6.2.5. 
Multiple measurements at One Analysis Time Point 
If ECG has been assessed more than once (e.g. in triplicate) at an analysis time point, the 
average of the available ECG measurements will be calculated and summary statistics 
will be based on the calculated average. This applies to both baseline and post baseline 
assessments.  
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from a central lab will be taken over the test from a local lab. If multiple assessments 
are taken from the same type of lab on a study day, the worst case will be used. 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary variables 
for sorting data in listings only. In addition, partial dates may be imputed for ‘slotting’ 
data to study phases or for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., time 
since diagnosis). In addition, imputed dates are not used for deriving the last contact 
date in overall survival analysis dataset. 
Adverse Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
CCI


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Element 
Reporting Detail 
Missing start day 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of study 
intervention start date, then 
− 
If stop date contains a full date and stop date is earlier 
than study intervention start date, then set start date= 
1st of month. 
− 
Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start date, 
then 
− 
If stop date contains a full date and stop date is earlier 
than study intervention start date, then set start date = 
January 1. 
− 
Else set start date = study intervention start date.       
Else set start date = January 1. 
Missing end day  
A '28/29/30/31' will be used for the day (dependent on the month 
and year). 
Missing end day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
Concomitant 
Medications/Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
Missing start day 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of study 
intervention start date, then 


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Element 
Reporting Detail 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set start 
date= 1st of month. 
− 
Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start date, 
then 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set start 
date = January 1. 
− 
Else set start date = study. intervention start date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the 
month. 
Completely missing 
start/end date 
No imputation 
6.2.7. 
Trademarks 
Trademarks of the GlaxoSmithKline / 
ViiV Healthcare Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline / ViiV Healthcare 
Group of Companies 
RAPIDO DV 
 
WinNonlin 


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7. 
REFERENCES 
Kenward, M. G., and Roger, J. H. (2009). “An Improved Approximation to the  
Precision of Fixed Effects from Restricted Maximum Likelihood.” Computational  
Statistics and Data Analysis 53:2583–2595.