A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled, Phase 2a Trial to Investigate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of Orally Administered Investigational Capsid Inhibitor Monotherapy in HIV-1 Infected Treatment-Naïve Adults
Phase: PHASE2
Conditions: HIV Infections
Sponsor: ViiV Healthcare

 
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CLINICAL STUDY PROTOCOL 
Primary Study 
Intervention(s) 
VH4004280 (also known as GSK4004280) 
VH4011499 (also known as GSK4011499) 
Other Study 
Interventions 
Not applicable 
Study Identifier 
218307 
EU CT Number 
2023-505350-18-00 
Approval Date 
08 May 2023 
Title 
A Randomized, Double-Blind (Sponsor Unblinded), Placebo-
Controlled, Phase 2a Trial to Investigate the Antiviral Effect, 
Safety, Tolerability and Pharmacokinetics of Orally Administered 
Investigational Capsid Inhibitor Monotherapy in HIV-1 Infected 
Treatment-Naïve Adults 
Compound 
Number/Name 
VH4004280 (also known as GSK4004280) 
VH4011499 (also known as GSK4011499)  
Brief Title 
Proof of concept treatment study of orally administered 
VH4004280 or VH4011499 in HIV-1 infected adults  
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 
In some countries, local law requires that the Clinical Trial 
sponsor is a local company legal entity. In these instances, the 
appropriate company to be identified as Sponsor must be agreed 
with the global ViiV Healthcare clinical team and signed off by 
the Senior Vice President, Head of Research & Development. 
This study is sponsored by ViiV Healthcare. GSK is supporting 
ViiV Healthcare in the conduct of this study. 
Sponsor 
signatory 
Scott McCallister, MD 
Vice President and Head, 
Physician Center of Excellence 
ViiV Healthcare 
VH medical monitor name and contact can be found in local study contact 
information document 
©2023 ViiV Healthcare and the GSK group of companies or its licensor. 

 
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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 
(VH) and GSK. 
• 
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 VH 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 VH/GSK and the express physical and/or digital 
informed consent of the participant and/or the participant’s LAR. 
• 
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 VH/GSK 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. VH/GSK will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
 

 
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Hence, I: 
• 
Agree to supply VH/GSK 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 VH/GSK may disclose any information about such ownership interests 
and financial ties to regulatory authorities. 
• 
Agree to provide VH/GSK with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 
 
Study identifier 
218307 
EU CT number 
2023-505350-18-00 
Approval date 
08 May 2023 
 
 
Title 
A Randomized, Double-Blind (Sponsor Unblinded), 
Placebo-Controlled, Phase 2a Trial to Investigate the 
Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of Orally Administered 
Investigational Capsid Inhibitor Monotherapy in 
HIV-1 Infected Treatment-Naïve Adults 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 
 

 
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TABLE OF CONTENTS 
 
PAGE 
LIST OF ABBREVIATIONS AND TRADEMARKS ........................................................... 9 
1. 
PROTOCOL SUMMARY ........................................................................................ 13 
1.1. 
Synopsis ..................................................................................................... 13 
1.2. 
Study design schematic .............................................................................. 16 
1.3. 
Schedule of activities (SoA) ........................................................................ 16 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study rationale ............................................................................................ 21 
2.2. 
Background ................................................................................................ 21 
2.2.1. 
Unmet Medical Need ................................................................... 21 
2.2.2. 
HIV-1 Capsid Inhibitors ................................................................ 22 
2.2.3. 
Clinical Studies with Orally Administered VH4004280 and 
VH4011499 .................................................................................. 23 
2.2.4. 
Further Non-clinical Data about VH4004280 and 
VH4011499 .................................................................................. 24 
................................................... 24 
2.3. 
Benefit/risk assessment .............................................................................. 25 
2.3.1. 
Risk assessment .......................................................................... 26 
2.3.2. 
Benefit assessment ..................................................................... 33 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 33 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 34 
4. 
STUDY DESIGN .................................................................................................... 38 
4.1. 
Overall design ............................................................................................. 38 
4.2. 
Scientific rationale for study design ............................................................. 39 
4.2.1. 
Participant input into design ......................................................... 39 
4.3. 
Justification for dose ................................................................................... 40 
4.4. 
End-of-study definition ................................................................................ 41 
5. 
STUDY POPULATION ........................................................................................... 41 
5.1. 
Inclusion Criteria ......................................................................................... 41 
5.2. 
Exclusion Criteria ........................................................................................ 42 
5.3. 
Lifestyle considerations ............................................................................... 47 
5.3.1. 
Meals and dietary restrictions ...................................................... 47 
5.3.2. 
Caffeine, alcohol, tobacco, marijuana/THC and illicit drug 
use............................................................................................... 47 
5.3.3. 
Activity ......................................................................................... 48 
5.4. 
Screen failures ............................................................................................ 48 
5.5. 
Criteria for temporarily delaying enrollment/randomization .......................... 48 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 49 
6.1. 
Study interventions administered ................................................................ 49 
6.2. 
Preparation, handling, storage, and accountability ...................................... 51 
6.3. 
Assignment to study intervention ................................................................ 51 
6.4. 
Blinding ....................................................................................................... 51 
6.5. 
Study intervention compliance .................................................................... 53 
6.6. 
Dose modification ....................................................................................... 53 
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6.7. 
Continued access to study intervention after the end of the study ............... 53 
6.8. 
Treatment of overdose ................................................................................ 53 
6.9. 
Prior and concomitant therapy .................................................................... 54 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 54 
7.1. 
Discontinuation of study intervention ........................................................... 54 
7.1.1. 
Liver chemistry stopping criteria ................................................... 55 
7.1.2. 
QTc stopping criteria .................................................................... 56 
7.1.3. 
Pregnancy ................................................................................... 56 
7.1.4. 
Temporary discontinuation ........................................................... 56 
7.1.5. 
Rechallenge ................................................................................. 56 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 57 
7.2.1. 
SARS-COV-2 Management Criteria ............................................. 57 
7.3. 
Lost to follow-up.......................................................................................... 58 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 58 
8.1. 
Administrative and baseline procedures ..................................................... 59 
8.1.1. 
Collection of demographic data .................................................... 59 
8.1.2. 
Medical/vaccination history .......................................................... 59 
8.2. 
Efficacy assessments ................................................................................. 59 
8.2.1. 
Quantitative HIV-1 RNA ............................................................... 59 
8.2.2. 
Lymphocyte Subsets by Flow Cytometry ..................................... 59 
8.3. 
Safety assessments .................................................................................... 60 
8.3.1. 
Physical examination ................................................................... 60 
8.3.2. 
Vital signs .................................................................................... 60 
8.3.3. 
Electrocardiograms ...................................................................... 60 
8.3.4. 
Clinical safety laboratory tests ..................................................... 61 
8.3.5. 
Pregnancy testing for participants of childbearing potential .......... 61 
8.3.6. 
Suicidal ideation and behavior risk monitoring ............................. 62 
8.3.7. 
Study Pausing Rules ................................................................... 62 
8.4. 
Adverse Events (AEs) and serious adverse events (SAEs) ........................ 63 
8.4.1. 
Time period and frequency for collecting AEs and SAEs ............. 63 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 64 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 64 
8.4.4. 
Regulatory reporting requirements for SAEs ................................ 64 
8.4.5. 
Pregnancy ................................................................................... 64 
8.4.6. 
CV and death events ................................................................... 65 
8.4.7. 
Disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs ..................................................... 66 
8.4.8. 
Contact information for reporting SAEs, pregnancies and 
study stopping criteria .................................................................. 66 
8.4.9. 
Participant card ............................................................................ 67 
8.5. 
Pharmacokinetics ....................................................................................... 67 
8.6. 
Pharmacodynamics .................................................................................... 68 
8.7. 
Genetics of the Participant .......................................................................... 68 
8.8. 
Biomarkers - Viral Genotyping and Phenotyping ......................................... 68 
8.9. 
Immunogenicity assessments ..................................................................... 69 
8.10. 
Health economics ....................................................................................... 69 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 69 
9.1. 
Statistical hypotheses ................................................................................. 69 

 
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9.2. 
Statistical hypotheses ................................................................................. 69 
9.3. 
Analysis sets ............................................................................................... 70 
9.4. 
Statistical analyses ..................................................................................... 70 
9.4.1. 
General considerations/definitions ............................................... 70 
9.4.2. 
Primary endpoint/estimand analysis ............................................. 71 
9.4.3. 
Secondary endpoints/estimands analyses ................................... 72 
9.4.4. 
Exploratory endpoints/estimands analysis ................................... 74 
9.5. 
Interim analyses .......................................................................................... 74 
9.6. 
Sample size determination .......................................................................... 75 
9.6.1. 
Sample Size Considerations ........................................................ 75 
9.6.2. 
Sample Size Sensitivity ................................................................ 75 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 77 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 77 
10.1.1. 
Regulatory and ethical considerations ......................................... 77 
10.1.2. 
Financial disclosure ..................................................................... 77 
10.1.3. 
Informed consent process ............................................................ 78 
10.1.4. 
Recruitment strategy .................................................................... 78 
10.1.5. 
Data protection ............................................................................ 78 
10.1.6. 
Committees structure ................................................................... 79 
10.1.7. 
Dissemination of clinical study data ............................................. 80 
10.1.8. 
Data quality assurance ................................................................ 80 
10.1.9. 
Source documents ....................................................................... 81 
10.1.10. Study and site start and closure ................................................... 82 
10.1.11. Publication policy ......................................................................... 82 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 83 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 85 
10.3.1. 
Definition of AE ............................................................................ 85 
10.3.2. 
Definition of SAE .......................................................................... 86 
10.3.3. 
Unsolicited AE. ............................................................................ 87 
10.3.4. 
Definition of CV events ................................................................ 88 
10.3.5. 
Definition of TEAE ....................................................................... 88 
10.3.6. 
Recording, assessment and follow-up of AEs, SAEs and 
pregnancies ................................................................................. 88 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 93 
10.4.1. 
Definitions .................................................................................... 93 
10.4.2. 
Contraception guidance ............................................................... 94 
10.5. 
Appendix 5: Genetics .................................................................................. 97 
10.6. 
Appendix 6: Liver safety: required actions and follow-up 
assessments ............................................................................................... 98 
10.7. 
Appendix 7: Division of AIDS table for grading the severity of adult 
and pediatric adverse events .................................................................... 101 
10.8. 
Appendix 8: CDC Classification for HIV-1 Infection ................................... 102 
10.9. 
Appendix 9: Permissible Procedures During COVID-19 Pandemic ........... 104 
10.10. Appendix 10: Country-specific requirements ............................................. 106 
10.10.1. Specific requirements for France ............................................... 106 
11. REFERENCES ..................................................................................................... 109 
 

 
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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities - screening and monotherapy period .................... 17 
Table 2 
Schedule of activities – follow-up period with open label standard 
of care and early discontinuation visit ..................................................... 19 
Table 3 
Study interventions administered ........................................................... 49 
Table 4 
VH4004280 study arms .......................................................................... 49 
Table 5 
VH4011499 study arms .......................................................................... 50 
Table 6 
Contact information for safety events questions and/or reporting ........... 66 
Table 7 
Intensive Pharmacokinetic Sampling Schedule on Day of Dosing .......... 67 
Table 8 
Expected precision (measured by the 95% CI width) of the 
estimated mean of maximum VLD in log10 scale for various 
assumptions of observed data variability for N=6 participants ................ 75 
Table 9 
Protocol-required Safety Laboratory Tests ............................................. 83 
Table 10 
DAIDS grading for an AE that is not specifically identified in the 
grading table ........................................................................................ 101 

 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design schematic ......................................................................... 38 
Figure 2 
Expected precision (measured by the 95% CI width) of the 
estimated mean of maximum VLD in log10 scale for various 
assumptions on observed data variability and sample size .................... 76 

 
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LIST OF ABBREVIATIONS AND TRADEMARKS 
Abbreviation 
Definition 
%CVb 
Between participant coefficient of variation expressed in 
percentage 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
Anti-HBc 
Negative status for hepatitis B core antibody 
Anti-HBs 
Negative status for hepatitis B surface antibody 
ARV 
Antiretroviral therapy  
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC(0-t) 
Area under the plasma concentration time curve from time 
zero to the last quantifiable time point 
AUC(0-24) 
Area under the plasma concentration vs time curve from time 
zero to 24 hours 
AUC(0-tlast) 
Area under the plasma concentration vs time curve from time 
zero hours to the time of last quantifiable concentration 
AUC(0-inf) 
Area under the plasma concentration vs time curve from time 
zero hours to infinity 
AUC(0-τ) 
Area under the plasma concentration vs time curve over a 
dosing interval from time of dosing to the time of the 
subsequent dose 
BLQ 
Below the limit of quantification 
CAI 
Capsid inhibitor 
cART 
Combination antiretroviral therapy 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
CIB 
Clinical investigator’s brochure 
CIOMS 
Council for international organizations of medical sciences 
Cmax 
Maximum observed plasma concentration 
CPK 
Creatine phosphokinase 
CPMS 
Clinical pharmacokinetics modeling and simulation 
CONSORT 
Consolidated standards of reporting trials 
CRF 
Case report form 
CSR 
Clinical study report 
DBL 
Database lock 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
EoS 
End of study 
F 
Bioavailability 
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Abbreviation 
Definition 
FDA 
Food and drug administration  
FSH 
Follicle stimulating hormone 
FTiH 
First-time-in-human 
FU 
Follow-up 
g 
gram 
g/L 
Gram per liter 
GCP 
Good clinical practice 
GCSP 
Global clinical safety and pharmacovigilance 
GERD 
Gastroesophageal reflux disease 
GLDH 
Glutamate dehydrogenase 
GSK 
GlaxoSmithKline 
h 
Hour 
Hb 
Hemoglobin 
HbcAb 
Hepatitis B core antibody 
HBV or HCV 
Hepatitis B or C virus 
HbsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health insurance portability and accountability act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IC90 
Concentration of drug required for 90% inhibition of the viral 
replication 
ICE 
Intercurrent events 
ICF 
Informed consent form 
ICH 
International council on harmonization 
IDSL 
Integrated data standards library 
ICSR 
Individual case safety reports 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IM 
Intramuscular 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
Kg 
Kilogram 
LAI 
Long acting injectable 
lbs 
Pounds 
m 
Meter 
MAD 
Multiple ascending dose 
Max 
Maximum 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
mg 
Milligram 

 
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Abbreviation 
Definition 
min 
Minute or minimum 
mL 
Milliliter 
mmHg 
millimeter of mercury 
MSDS 
Material safety data sheet 
ng 
Nanogram  
NOAEL 
No observed adverse effect level 
NQ 
Nonquantifiable 
PA 
Protein adjusted 
PLWH 
People living with HIV 
PK 
Pharmacokinetic 
POC 
Proof of concept 
POCBP 
Participant of childbearing potential 
POP PK 
Population pharmacokinetics 
PrEP 
Pre-exposure prophylaxis 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
Corrected QT interval 
QTcF 
QT Interval corrected for heart rate according to Fridericia’s 
formula 
QTLs 
Quality tolerance limits 
RBCs 
Red blood cells 
RNA 
Ribonucleic acid  
RHF 
Right-sided heart failure 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SOC 
Standard of care 
SRT 
Safety review team 
SUSARs 
Suspected unexpected serious adverse reactions 
t1/2 
Apparent terminal elimination phase half-life 
tmax 
Time to Cmax 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
VH 
ViiV Healthcare 
VLD 
Viral load decline 
VSLC 
ViiV safety and labelling committee 
WBC 
White blood cells 
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Abbreviation 
Definition 
WT 
Wild type 
 
TRADEMARK INFORMATION 
Trademarks of the ViiV Healthcare and 
GSK group of companies 
 
Trademarks not owned by the ViiV 
Healthcare and GSK group of 
companies 
NONE 
 
Cobas 
 
 
Phoenix 
 
 
WinNonlin 
 

 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled, Phase 2a Trial 
to Investigate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of Orally 
Administered Investigational Capsid Inhibitors in HIV-1 Infected Treatment-Naïve 
Adults 
Brief Title: 
Proof of concept treatment study of orally administered VH4004280 or VH4011499 in 
HIV-1 infected adults 
Rationale: (Refer to Section 2.1) 
VH4004280 and VH4011499 (also referred to as GSK4004280 and GSK4011499, 
respectively) are investigational CAI in early clinical development. They belong to a 
novel class of antiretroviral (ARV) agents targeting 
 
. Study 218307 is a proof of concept (POC), randomized double 
blind, placebo-controlled Phase 2a study to characterize the antiviral activity, 
safety/tolerability, PK, and the relationship between PK and antiviral activity of 
VH4004280 and VH4011499 monotherapy administered orally over 10 days, in HIV-1 
infected treatment-naïve adults. This study is being conducted following the availability 
of preliminary safety and PK clinical data from oral administration of these CAIs to 
healthy volunteers [TMF-15100069; TMF-14909676]. 
The purpose of this study is to evaluate the short-term safety and effect on reducing HIV-
1 RNA levels from baseline for each orally administered CAI. Two different doses of 
each CAI will be evaluated in Part 1 of the study and have been chosen based on 
modelling of prior data from 
 
 and prior pharmacokinetic 
data from the two ongoing Phase 1 healthy volunteer studies with orally dosed 
VH4004280 and VH4011499 (Studies 217058 and 218490, respectively). A third pre-
specified dose of one or both CAIs may be evaluated in Part 2 of the study and will be 
informed by an interim analysis of Part 1. 
The Phase 1 PK data support a 
 for 
VH4004280 and VH4011499, respectively, during the short monotherapy treatment 
period designed in this study. The chosen doses are intended to target exposures that are 
efficacious (short-term antiviral effect) and are well tolerated. On Day 11, after the last 
HIV-1 RNA collection, study participants will switch to open-label combination ART 
(cART) prescribed by the investigator and sourced as per local guidelines. Participants 
will continue in the study and be monitored through Day 39. 
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This study will facilitate an initial understanding of the antiviral activity and safety 
profile of both CAIs in an HIV positive ARV naïve 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 two ongoing Phase 1 studies 
with 
 and the single planned Phase 1 study with 
 
, will inform subsequent clinical trials and Phase 2b clinical development. 
Objectives, Endpoints, and Estimands: (Refer to Section 3) 
Objectives 
Endpoints 
Primary 
To evaluate the antiviral activity of orally 
administered VH4004280 and VH4011499 
monotherapy over 10 days in HIV-1 infected 
Treatment-Naïve (TN) participants 
Maximum change from baseline (Day 1) in plasma 
HIV-1 ribonucleic acid (RNA) through Day 11. 
Secondary 
To assess the safety and tolerability of orally 
administered VH4004280 and VH4011499 
• 
Incidence of adverse events (AEs), severity of 
AEs and AEs leading to study treatment 
discontinuation 
• 
Change from baseline and maximum toxicity 
grade increase from baseline for liver panel 
laboratory parameters (consisting of total and 
direct bilirubin, ALT, ALP and AST) 
To characterize the pharmacokinetic profiles of 
orally administered VH4004280 and VH4011499 
PK measures that include but are not limited to: 
• 
Maximum observed plasma drug concentration 
(Cmax), 
• 
Time to maximum observed plasma drug 
concentration (tmax), 
• 
Concentrations on Day 11 for VH4004280 and 
VH4011499. 
To determine the relationship between the 
exposure levels of orally administered 
VH4004280 and VH4011499 and change in 
plasma HIV-1 RNA 
VH4004280 and VH4011499 PK parameters with 
maximum change in plasma HIV-1 RNA from 
baseline through Day 11 
 
Overall Design: (Refer to Section 4.1) 
This is a Phase 2a, multi-center, randomized, double-blind (sponsor unblinded), placebo-
controlled (by each capsid inhibitor), proof of concept clinical study to evaluate the 
antiviral effect, safety, tolerability and PK/pharmacodynamics (PD) of orally 
administered VH4004280 and VH4011499 monotherapy over 10 days in ART naive 
HIV-1 viremic adults. 
Up to 42 treatment naïve participants with confirmed HIV-1 RNA ≥ 3,000 copies/mL and 
CD4 T-cell count ≥200 cells/µL will be recruited into this 2-part adaptive study. As per 
the study design schematic in Section 1.2, the first 14 participants screened and who are 
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found to meet all eligibility criteria will be randomly assigned on Day 1 to one of three 
placebo-controlled VH4004280 treatment groups (Part 1a: 6 active: 6 active: 2 placebo), 
followed by the next 14 participants randomly assigned on Day 1 to one of three placebo-
controlled VH4011499 treatment groups (Part 1b: 6 active: 6 active: 2 placebo). Each 
CAI will be evaluated as double-blind monotherapy for 10 days (primary endpoint). On 
Day 11, after the collection of the HIV-1 RNA sample, participants will start open-label 
standard-of-care combination antiretroviral therapy that is selected by the investigator 
and locally sourced. 
 
. 
As described in Section 9.2, an informal interim analysis will be conducted after 
9 participants (i.e., 4 participants per active arm and 1 placebo participant) from Part 1a 
have completed their Day 11 visit. A second informal interim analysis will be conducted 
after 9 participants (i.e., 4 participants per active arm and 1 placebo participant) from 
Part 1b have completed their Day 11 visit. The conduct of Part 2 is dependent on the 
results from Part 1 but if conducted, will evaluate a double-blind placebo controlled third 
pre-specified dose of one or both CAIs in up to an additional 14 participants [(Part 2a: 6 
active VH4004280:1 placebo) and/or (Part 2b: 6 active VH4011499:1 placebo)]. 
Total duration of study participation is approximately 45 to 66 days based on the 
following: 7 to 14 days, with a maximum of 28 days permitted in some cases for 
screening/qualification period, 10 days for treatment with the study intervention and 
assessment at all planned visits and 28 days for follow up visits including the final follow 
up visit. See Section 1.3 (Schedule of Assessments) for additional details of activities 
during screening, the monotherapy period and the standard of care period. 
Number of Participants: (Refer to Section 9.6) 
The sample size is based on feasibility and no formal calculation of power or sample size 
has been performed. 
Data and Safety Monitoring/Other Committee: (Refer to Section 10.1.6) 
A safety review team (SRT) is in place for each VH 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 studies of both CAIs. 
In addition to the investigator's management of their participant's safety, participant 
safety will be routinely monitored by the VH medical monitor and the GSK safety leads. 
Pertinent findings and conclusions are shared with the VH/GSK product SRT for periodic 
review of the overall benefit risk profile of the product and escalated, as needed for 
governance to ViiV’s Safety and Labelling Committee (VSLC). 
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1.2. 
Study design schematic 
 
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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Table 1 
Schedule of activities - screening and monotherapy period 
Clinical Procedures 
Screening1 
Monotherapy Treatment Period, Capsid Inhibitor (Double Blind) 
Day 1→Day 10 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Approximately 
7 to 14 days 
before Day 1 
Day 1 
Fixed visit. 
No window. 
Day 2 
Fixed visit. 
No window. 
Day 3, 4 or 5 
Conduct visit on 
Day 3, 4 or 5 
Day 6 
Fixed visit. 
No window. 
Day 7 
Fixed visit. 
No window. 
Day 8, 9 or 10 
Conduct visit on 
Day 8, 9 or 10 
Outpatient clinic visit2 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
Medical history, CDC classification 
X 
X 
 
 
 
 
 
Prior anti-retroviral therapy 
X 
X 
 
 
 
 
 
HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
HIV-1 capsid genotype/phenotype 
 
X 
X 
X 
X 
X 
X 
Lymphocyte T-cell subsets (CD4, CD8) 
X 
X 
 
 
 
 
 
Hepatitis B and C serologies 
X 
 
 
 
 
 
 
SARS CoV-2 point of care test 
 
X 
 
 
 
 
 
Physical exam3  
X 
X 
 
 
X 
 
 
Height, weight, BMI 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
C-SSRS administration (Baseline form) 
X 
 
X 
 
X 
 
 
12-lead ECG 
X 
X 
X 
 
 
 
X 
Safety labs (hematology, chemistry, urinalysis)4 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy (urine also on Day 1) for POCBP 
X 
X 
 
 
 
 
 
Plasma PK sampling5 
 
X 
X 
X 
X 
X 
X 

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Clinical Procedures 
Screening1 
Monotherapy Treatment Period, Capsid Inhibitor (Double Blind) 
Day 1→Day 10 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Approximately 
7 to 14 days 
before Day 1 
Day 1 
Fixed visit. 
No window. 
Day 2 
Fixed visit. 
No window. 
Day 3, 4 or 5 
Conduct visit on 
Day 3, 4 or 5 
Day 6 
Fixed visit. 
No window. 
Day 7 
Fixed visit. 
No window. 
Day 8, 9 or 10 
Conduct visit on 
Day 8, 9 or 10 
Plasma for storage6 
 
X 
X 
X 
X 
X 
X 
Pharmacogenetics (PGx) sample collection (if consented) 
 
X 
 
 
 
 
 
AE/SAE assessment7 
X 
X 
X 
X 
X 
X 
X 
HIV-associated conditions7 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
Interactive web response system for central randomization 
 
X 
 
 
 
 
 
VH4004280/placebo 
VH4011499/placebo 
1. 
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, the screening period may be extended up to 28 days to allow receipt of all screening results and/or to accommodate scheduling. 
2. 
The study requires 12 clinic visits. The visit schedule for each participant will be pre-planned and weekend, work schedules and clinic hours will be appropriately considered. At 
least one weekend clinic visit is required from Day 1 to Day 11.  
3. 
Complete Physical Exam performed at Screening and Day 39/Early Discontinuation. A symptom directed physical exam will be performed at all other noted visits. Any 
abnormalities to be recorded as AEs. SAEs are assessed from the time of consent. Non-serious AEs are assessed from the time of first dose. 
4. 
See Section 10.2 for details of clinical laboratory tests. Total bile acids (TBA), coagulation panel, and lipid panel (total cholesterol, HDL, LDL and triglycerides) required at Days 1, 
6, 11, 25, 39/Early Discontinuation. Other clinical chemistry, hematology and urinalysis done at every visit. Fasting bloodwork is required for the lipid panel. 
 
. 
5. 
. A single PK draw will be conducted at all other visits. 
Refer to Section 8.5 for the collection schedule, permitted collection windows and further details. 
6. 
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits. These samples will be used when needed, such as when samples are 
lost or where quantity is insufficient for testing. In the event samples are not used by study completion, they will be utilized for additional research on antiretroviral resistance 
and/or HIV-1 disease biology/host immune response (excluding any human genetic testing). 
7. 
The assessment of HIV-associated conditions and AEs/SAEs is conducted throughout the study. SAEs are assessed from the time of consent.  Non-serious AEs are assessed 
from the time of first dose. 
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Table 2 
Schedule of activities – follow-up period with open label standard of care and early discontinuation visit 
Clinical Procedures 
Follow-Up Phase 
Early 
Discontinuation6 
 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 125 
 
 
Day 11 
Fixed visit. No 
window. 
Day 18 
+/- 3 day window. 
Day 25 
+/- 3 day window 
Day 32 
+/- 3 day window 
Day 39 
+/- 3 day window  
 
Outpatient clinic visit 
X 
X 
X 
X 
X 
X 
HIV-1 RNA 
X 
Primary endpoint 
timepoint 
X 
X 
X 
X 
X 
HIV-1 capsid genotype/phenotype 
X 
X 
X 
X 
X 
X 
Lymphocyte T-cell subsets (CD4, CD8) 
X 
 
 
 
X 
X 
Physical exam2  
 
 
 
 
X 
X 
Height, weight, BMI 
X 
 
 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
C-SSRS administration (Since Last Visit 
form) 
X 
 
 
 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Safety labs (hematology, chemistry, 
urinalysis)3 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
X 
X 
X 
X 
X 
X 
Plasma PK single sample 
X 
X 
X 
X 
X 
X 
Plasma for storage 
X 
X 
X 
X 
X 
X 
AE/SAE assessment 
X 
X 
X 
X 
X 
X 
HIV-associated conditions 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
Standard of care cART1 
X 
X 
X 
X 
X 
X 
1. 
Standard of care cART will be chosen by the investigator and first dose will be directly observed at the end of the Day 11 visit. Choice of cART will be informed by local treatment 
guidelines, accessibility and locally run genotypic/phenotypic results (if available). 
2. 
Complete Physical Exam performed at Screening and Day 39/Early Discontinuation. A symptom directed physical exam will be performed at all other noted visits. Any 
abnormalities to be recorded as AEs. 
3. 
See Section 10.2 for details of clinical laboratory tests. Fasting bloodwork for the lipid panel is required at Days 1, 6, 11, 25, 39/Early Discontinuation. 

 
 
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4. 
Plasma samples for storage will be collected at each visit, 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 and consent is obtained for further research, then the stored samples may be utilized for 
additional research on antiretroviral resistance and/or HIV-1 disease biology/host immune response (excluding any human genetic testing). 
5. 
Additional follow-up visits/contacts beyond Day 39 are permitted if a participant experiences a safety event that requires follow-up monitoring. 
6. 
Early discontinuation assessments to be performed if a participant withdraws early from study. 

 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
VH4004280 and VH4011499 (also referred to as GSK4004280 and GSK4011499, 
respectively) are investigational CAIs in early clinical development. They belong to a 
novel class of ARV agents targeting 
 
. Study 218307 is a POC, randomized double blind, placebo-controlled Phase 2a 
study to characterize the antiviral activity, safety/tolerability, PK, and the relationship 
between PK and antiviral activity of VH4004280 and VH4011499 administered orally 
over 10 days, in HIV-1 infected treatment-naïve adults. This study is being conducted 
following the availability of preliminary safety and PK clinical data from oral 
administration of these CAIs to healthy volunteers [TMF-15100069; TMF-14909676]. 
The purpose of this study is to evaluate the short-term safety and effect on reducing 
HIV-1 RNA levels from baseline for each orally administered CAI. Two different doses 
of each CAI will be evaluated in Part 1 of the study and have been chosen based on 
 
 and prior pharmacokinetic 
data from the two ongoing Phase 1 healthy volunteer studies with orally dosed 
VH4004280 and VH4011499 (Studies 217058 and 218490, respectively). A third pre-
specified dose of one or both CAIs may be evaluated in Part 2 of the study and be 
informed by interim results from Part 1. 
The Phase 1 PK data support a 
 for 
VH4004280 and VH4011499, respectively, during the short monotherapy treatment 
period designed in this study. The chosen doses are intended to target exposures that are 
efficacious (short-term antiviral effect) and are well tolerated. On Day 11, after the last 
HIV-1 RNA collection, study participants will switch to open-label combination ART 
(cART) prescribed by the investigator and sourced as per local guidelines. Participants 
will continue in the study and be monitored through Day 39. 
This study will facilitate an initial understanding of the antiviral activity and safety 
profile of both CAIs in an HIV positive ARV naïve 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 two ongoing Phase 1 studies 
with 
 and the single planned Phase 1 study with 
 
, will inform subsequent clinical trials and Phase 2b clinical development 
2.2. 
Background 
2.2.1. 
Unmet Medical Need 
It is estimated that approximately 38 million people are currently living with HIV/AIDS 
globally. This worldwide epidemic continues to grow at a rate of 1.5 million new 
infections and causes 0.7 million deaths per year [UNAIDS, 2021]. The current paradigm 
in the treatment of HIV-1 involves life-long therapy with multiple ARVs. While HIV-1 
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medicines are effective, there is a need for developing more conveniently dosed and more 
conveniently dosed ARV regimens. 
2.2.2. 
HIV-1 Capsid Inhibitors 
ViiV has two investigational CAIs (VH4004280 and VH4011499) in early clinical 
development and which are 
 
 
 
 could provide comparable efficacy to currently available daily 
dosed regimens, be generally safe and well-tolerated, 
 
 
 
 
VH4004280 and VH4011499 belong to a novel class of ARV agents targeting a highly 
conserved region of the HIV-1 capsid protein. In-vitro experiments 
 
 
 
 
 
In cell culture, both compounds exhibited potent antiviral activity against a wide 
spectrum of HIV-1 isolates and subtypes and demonstrated no cross-resistance with 
different ARV classes. No major safety signals have been identified from the nonclinical 
toxicology studies. The drug-drug interaction potential of VH4004280 and VH4011499 
have been assessed in a series of in vitro studies. Based on the preliminary clinical drug-
drug interaction (DDI) analysis, both VH4004280 and VH4011499 had no effect on the 
 and thus both VH4004280 and VH4011499 
 
. However, the clinical risk 
of potential drug-drug interactions with VH4004280 and VH4011499 as victims is 
currently unknown. The potential to develop these compounds as long-acting medicines 
is further supported by the emerging preliminary safety and tolerability data and 
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favorable pharmacokinetic profile from the ongoing healthy volunteer Phase 1 clinical 
studies evaluating VH4004280 and VH4011499. 
2.2.3. 
Clinical Studies with Orally Administered VH4004280 and 
VH4011499 
The safety and pharmacokinetic profiles of orally administered VH4004280 and 
VH4011499 are being characterized in healthy volunteers in ongoing Studies 217058 and 
218490, respectively. Preliminary safety and PK results following oral administration of 
both CAIs have revealed no clinically significant findings and favorable pharmacokinetic 
profiles that support evaluation of both CAIs in this study following oral administration. 
2.2.3.1. 
Study 217058 - Oral FTIH VH4004280 
Study 217058 is an ongoing double-blind (sponsor unblinded), randomized, placebo-
controlled, single and multiple-ascending-dose Phase 1 and FTiH study to evaluate the 
safety, tolerability and pharmacokinetics of VH4004280, when 
 
 in healthy adult participants. The study is also designed 
to evaluate the DDI potential of VH4004280 and evaluate the safety, tolerability and PK 
of a VH4004280 
 in comparison with existing data from VH4004280 
 
Based on preliminary results, 41 participants and 18 participants have been enrolled in 
the single and MAD parts of the VH4004280 study, respectively. The study is currently 
ongoing and remains blinded (3:1 active to placebo random assignment to treatment). 
The pharmacokinetic profile of VH4004280 is being initially evaluated following single 
oral dose administration from 
 
. Based on the preliminary 
analysis, VH4004280 has a median 
 
 in concentration and a mean 
. VH4004280 showed a 
 
. There was an 
approximately 
 from Day 1 in Cmax and AUC0-tau, 
respectively following 
 Based on the 
preliminary clinical DDI analysis, VH4004280 
 and 
thus VH4004280 
 
Overall, there have been no clinically significant safety findings, serious adverse events 
(SAEs), deaths, pregnancies, trends in vital signs, laboratory parameters, ECG parameters 
nor discontinuations due to adverse events (AEs). More detailed information can be 
found in the CIBs [RPS-CLIN-048482; RPS-CLIN-056826]. 
2.2.3.2. 
Study 218490 - 
 FTIH VH4011499 
Study 218490 is an ongoing double-blind (sponsor unblinded), randomized, placebo-
controlled, single and multiple-ascending-dose Phase 1 and first time in human study to 
evaluate the safety, tolerability and pharmacokinetics of VH4011499, when administered 
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as a 
, in healthy adult participants. The study is 
also designed to evaluate the DDI potential of VH4011499 and evaluate the safety, 
tolerability and PK of a VH4011499 
 in comparison with existing data 
from VH4011499 
. 
Based on preliminary results, 32 participants and 19 participants have been enrolled in 
the single and MAD parts of the VH4011499 study, respectively. The study is currently 
ongoing and remains blinded (3:1 active to placebo random assignment to treatment.  
The pharmacokinetic profile of VH4011499 is being initially evaluated following single 
oral dose administration from 25 to 1875 mg 
 
. Based on the preliminary analysis, 
VH4011499 has a median 
 and a mean 
. 
VH4011499 showed a 
 in exposure from 
 
 There was an approximately 
 in Cmax 
and AUC0-tau, respectively following 
. 
Based on the preliminary clinical DDI analysis, VH4011499 had no effect on the 
 
 and thus VH4011499 
 
. 
Overall, there have been no clinically significant safety findings, deaths, SAEs 
considered related to treatment, pregnancies, trends in vital signs, laboratory parameters, 
ECG parameters nor discontinuations due to AEs. More detailed information can be 
found in the CIB [RPS-CLIN-056829]. 
2.2.4. 
Further Non-clinical Data about VH4004280 and VH4011499 
A detailed description of the non-clinical pharmacology, pharmacokinetics, toxicology, 
virology, and chemistry and manufacturing of VH4004280 and VH4011499 is provided 
in the respective CIBs [RPS-CLIN-048482; RPS-CLIN-026329; RPS-CLIN-047476; 
RPS-CLIN-046304; RPS-CLIN-056829; RPS-CLIN-056826]. 
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2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of VH4004280 and VH4011499 may be found in their 
respective CIBs [RPS-CLIN-048482; RPS-CLIN-026329; RPS-CLIN-047476; 
RPS-CLIN-046304; RPS-CLIN-056829; RPS-CLIN-056826]. 
In the ongoing Phase 1 oral studies in healthy volunteers with VH4004280 and 
VH4011499 (both blinded), no untoward safety signals have been identified from either 
the single ascending or multiple dose parts of the studies. In both studies, there have been 
no deaths, no trends in vital signs, laboratory or ECG parameters and no discontinuations 
due to AEs. There have been no SAEs in the VH4004280 study, and in the VH4011499 
study, there was one SAE (seriousness criteria: hospitalization) of Grade 2 chest pain, 
which occurred on Day 27 following a single dose of 
; results of ECG and cardiac 
enzyme tests were negative, and the event was considered by the investigator to be 
related to methamphetamine and unrelated to study treatment. 
The toxicity of VH4004280 and VH4011499 has been evaluated in 
 studies of up to 
4 weeks duration in rats and dogs, and 
 studies of up to 13 weeks duration 
using the
 of VH4004280 and 
VH4011499 in both rats and dogs. In the 
 studies with both compounds, there were 
no adverse findings in either rat or dog at all doses tested. 
In the 13-week 
 study in dogs with VH4004280 using the 
 
, there were no adverse findings up to the highest dose tested 
. In the 13-week 
 study in rats, the highest 
dose tested 
 was not considered tolerated due to clinical signs of 
suspected dehydration, along with lower body weights. The intermediate dose tested 
 was the NOAEL for VH4004280. 
In the 13 week 
 studies with VH4011499 using the 
 
, the NOAELs were considered to be greater than or equal to the highest 
 
doses tested in rats 
 and dogs 
 and the 
highest/only 
 doses tested in rats 
 and dogs 
 as 
there were no adverse findings in either species via either route.  There were decreases in 
body weight and/or food consumption following days of dosing in both species, but none 
were considered adverse as these were transient. 
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2.3.1. 
Risk assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug VH4004280 and/or VH4011499 
Drug-induced liver injury (and/or 
clinically significant liver 
chemistry elevations for 
VH4011499 only) 
Nonclinical 
In vitro, both VH4004280 and VH4011499 inhibited 
 with IC50 
values of 
 respectively, and the 
 
) with IC50 values of 
 
respectively. 
 can cause 
 
 can cause accumulation of 
 which may lead to 
. 
VH4004280: 
In the definitive 28-day 
 repeat dose dog study with VH4004280, 
minimally increased mean liver weights and increased total bile acids 
(1 animal) were seen at 
, however these were not 
associated with any microscopic liver findings. At the same dose, there 
were increases in fibrinogen concentrations in males (1.56X control) 
and females (1.55X control), and prolongation of activated partial 
thromboplastin time in females (1.87X control). In the 28-day repeat 
dose rat study with VH4004280, there were no weight changes and no 
microscopic findings in the liver. Additionally, there were no bilirubin 
changes in these studies. Whilst these changes could reflect possible 
hepatocellular and/or hepatobiliary injury, they were of low magnitude 
and without correlating histopathological findings.  
In the definitive 13-week VH4004280 
 rat 
study, treatment related minimal to mild hepatocellular vacuolation was 
Participants with current or history of liver 
disease, with coinfection with HBV or HCV or 
known hepatic or biliary abnormalities are 
excluded from participation in this study (refer to  
Section 5.2). 
Participants will be closely monitored for liver 
related AE and laboratory abnormalities, including 
serum total bile acids and coagulation 
parameters. 
Liver chemistry participant stopping criteria are 
defined (refer to Section 7.1.1). 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
observed in the highest dose group 
 
. This finding, not considered adverse, consisted of 
macro and microvesicles in the cytoplasm of centrilobular hepatocytes 
and correlated to pale discoloration of the liver in two males. Although a 
statistically significant increase in the mean relative (to body) liver 
weight occurred in males at this dose, this was largely considered 
related to body weight decrements. In addition, there were increases in 
total bilirubin (up to 2.38X control) and total bile acids (up to 2.90X 
control) at 
 on Days 28 and 85. There were no 
treatment-related changes in coagulation parameters in this study. 
There were no liver-related findings in the definitive 3-month 
VH4004280 
 dog study and no changes in coagulation 
parameters. 
VH4011499: 
In the definitive 13-week VH4011499 
 studies in rats and 
dogs, there were no adverse findings in the liver, including no 
increases in liver enzymes, total bile acids, bilirubin or coagulation 
parameters. 
In the definitive 28-day repeat dose 
dog study with VH4011499, at 
the highest dose/NOAEL 
, there were increases 
relative to pre-dose in alanine and aspartate aminotransferases (ALT 
increased by up to 11.3 fold in 4/6 dogs, AST increased by up to 3.0 
fold in 2/6 dogs) and glutamate dehydrogenase (GLDH increased by up 
to 6.2 fold in 4/6 dogs) with no histologic correlates in the liver and no 
changes in liver weight. No increases in bilirubin were observed. In the 
definitive 28-day repeat dose study in the rat (highest dose/NOAEL 
 there were no adverse effects of VH4011499, 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
including no increases in liver enzymes, total bile acids, bilirubin or 
coagulation parameters. 
Clinical (blinded data): 
No trends in liver or coagulation parameters have been observed in the 
ongoing Phase 1 oral clinical studies with VH4004280 or VH4011499. 
Increases in cholesterol and 
triglycerides 
Nonclinical 
VH4004280: 
In the definitive 28-day
 repeat dose toxicity studies with 
VH4004280, increases in mean serum total cholesterol concentration 
were observed in rats and dogs at the highest doses tested (
 
. Increased triglycerides were also noted 
in dogs at 
 In both species, there were no macroscopic 
or microscopic changes in the liver at any dose level. 
In the definitive 3-month VH4004280 
 rat 
study, increases in total cholesterol concentrations (up to 1.70X 
control) at 
 on Days 28 and 85 were observed. 
There were no increases in lipids in the definitive 3-month VH4004280 
 dog study. 
VH4011499: 
No increases in cholesterol or triglycerides were observed in the 
definitive 28-day 
 or 13-week 
 toxicity studies in dog 
and rat with VH4011499. 
Clinical (blinded data): 
Participants will be closely monitored for relevant 
AEs and laboratory abnormalities. Lipid panel is 
included in routine clinical laboratory tests as 
detailed in the SoA (Section 1.3). 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
No trends in lipid parameters have been observed in the ongoing 
Phase 1 oral clinical studies with VH4004280 or VH4011499. 
Hematology changes 
Nonclinical 
VH4004280: 
In the 28-day 
 dose dog study 
 
 increases in neutrophils and monocyte counts were 
observed. 
In the definitive 13-week VH4004280 
 rat 
study, treatment-related hematologic changes were observed at 
, and included increases in lymphocyte, neutrophil 
and/or white blood cell counts, decreases in hemoglobin concentration, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, increases in red blood cell counts, red cell distribution 
width concentration and/or in reticulocyte counts. There were no 
changes in hematology parameters in the definitive 13-week 
VH4004280 
 dog study. 
VH4011499: 
No changes in hematology parameters were observed in the definitive 
28 day 
 or 13-week 
 toxicity studies in dog and rat 
with VH4011499. 
Clinical (blinded data): 
 
No trends in hematology parameters have been observed in the 
ongoing Phase 1 oral clinical studies with VH4004280 or VH4011499. 
Participants will be closely monitored for relevant 
AEs and laboratory abnormalities. Hematology 
Panel is included in routine clinical laboratory 
tests as detailed in the SoA (Section 1.3). 
See Section 8.3.7 for clinical stopping criteria 
applicable to this potential risk. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Acute pulmonary injury (VH4004280 
only) 
Nonclinical 
In a single dose dose-range finding dog study with VH4004280 
 
, inflammatory changes were noted 
on lung histology. 
At 
 
histological findings in the lungs of 3/3 dogs included interstitial 
expansion containing primarily mononuclear cells and fibrin and 
multifocal mixed cell bronchioalveolar inflammation with alveolar 
infiltrates comprising vacuolated macrophages, neutrophils and few, 
non-vacuolated, mononuclear cells. In some regions, there was 
damage to the alveolar wall, evidenced by the presence of fibrin (free 
and phagocytized), hemorrhage and pneumocytes ranging from 
flattened to larger and vacuolated. These microscopic lung findings 
correlated to gross changes observed in the lung margins. At 
 
, there were no 
gross observations at necropsy and histologic changes in the lung 
consisted of minimal bronchioalveolar mixed cell inflammation in 2/3 
dogs. There were no microscopic findings in 3/3 dogs given 
 
 
There were no histological findings in the lung in the 28-day definitive 
rat and dog repeat dose studies (
 
) conducted with the VH4004280 
 formulation 
being used in Study 217058. 
There were no histological findings in the lung in the VH4004280 
definitive 
 13-week 
 in both rat (up to 
doses of 
 and dog 
 
 
Participants with current or history of respiratory 
disease are excluded from participation in this 
study (refer to Section 5.2). 
Participants will receive VH4004280 by the 
 
 
 
 and lower than those observed in 
 28-
day toxicity studies in both rat and dog, where 
there were no histologic findings in the lungs. 
Participants will be closely monitored for relevant 
AEs, vital signs and laboratory abnormalities. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
No similar findings have been observed in nonclinical studies with 
VH4011499. 
Effects on embryo-fetal development 
Nonclinical 
VH4004280: 
Rats and rabbits were given daily 
doses of VH4004280 in embryo-
fetal development studies. There were no effects on embryo-fetal 
development parameters or maternal toxicity in rats at up to 
 
 In rabbits, maternal toxicity (body weight losses and 
reductions in body weight gains) occurred at doses 
 in 
the absence of any effects on food consumption or clinical signs. At 
 maternal toxicity resulted in decreased fetal weights 
and skeletal variations (unossified sternebrae) but no malformations. 
Similar findings did not occur at lower doses, and these findings are 
related to maternal toxicity and not direct effects on embryo-fetal 
development. 
VH4011499: 
In embryo-fetal development studies, rats were given daily 
 doses 
and rabbits were given 
 of VH4011499. There were 
no effects on embryo-fetal development parameters or maternal toxicity 
in rats at up to 
  In rabbits, maternal toxicity (reduced 
body weight gains and food consumption) was noted at 
 
with no effects on embryo-fetal development parameters at doses up to 
 
Participants of childbearing potential (POCBP) 
must be using acceptable forms of birth control 
through to Day 39. POCBP will have pregnancy 
testing conducted prior to study intervention and 
during the study. 
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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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 should be dosed with caution 
if co-administered with VH4004280 from Day 1 
through Day 11. 
 should be dosed with caution if 
co-administered with VH4011499 or VH4004280 
from Day 1 through Day 11. 
 with 
 are not permitted from 
Day 1 through Day 11). 
Other (both VH4004280 and VH4011499) 
Emergence of resistance 
Short monotherapy period (10 days) followed 
immediately at the end of the Day 11 visit by 
initiation of cART. 
The dose and dose regimens selected are 
intended to rapidly achieve plasma 
concentrations that provide therapeutic benefit. 
The lowest starting dose that is pre-specified 
aims to target 
 
 is unlikely to occur under 
these conditions. 
 
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2.3.2. 
Benefit assessment 
This study in treatment naïve, HIV-1 infected but otherwise healthy participants is a 
short-term monotherapy design. There is no expected longer-term anti-HIV benefit to 
administration of VH4004280 or VH4011499 in this study. The monotherapy phase is 
10 days with frequent outpatient visits and a 4 week follow up period during which 
participants will continue to be closely monitored. On Day 11, after the collection of the 
HIV-1 RNA sample, participants will start open-label standard-of-care combination 
antiretroviral therapy that is selected by the investigator. 
2.3.3. 
Overall benefit-risk conclusion 
Considering the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with VH4004280 and VH4011499 are 
justified by the anticipated benefits that may be afforded to people living with HIV-1 
infection. 
 

 
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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Objectives 
Endpoints 
Primary 
To evaluate the antiviral activity of orally 
administered VH4004280 and VH4011499 
monotherapy over 10 days in HIV-1 infected 
Treatment-Naïve (TN) participants 
Maximum change from baseline (Day 1) in plasma 
HIV-1 ribonucleic acid (RNA) through Day 11. 
Secondary 
To assess the safety and tolerability of orally 
administered VH4004280 and VH4011499 
• 
Incidence of adverse events (AEs), severity of 
AEs and AEs leading to study treatment 
discontinuation 
• 
Change from baseline and maximum toxicity 
grade increase from baseline for liver panel 
laboratory parameters (consisting of total and 
direct bilirubin, ALT, ALP and AST) 
To characterize the pharmacokinetic profiles of 
orally administered VH4004280 and VH4011499 
PK measures that include but are not limited to: 
• 
Maximum observed plasma drug concentration 
(Cmax), 
• 
Time to maximum observed plasma drug 
concentration (tmax), 
• 
Concentrations on Day 11 for VH4004280 and 
VH4011499 
To determine the relationship between the 
exposure levels of orally administered 
VH4004280 and VH4011499 and change in 
plasma HIV-1 RNA 
VH4004280 and VH4011499 PK parameters with 
maximum change in plasma HIV-1 RNA from 
baseline through Day 11 
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Endpoints 
Estimand 
Population 
Treatment 
Summary Measure 
Intercurrent event (IE) / strategy / rationale 
Primary Objective: To evaluate the antiviral activity of orally administered VH4004280 and VH4011499 monotherapy over 10 days in HIV-1 infected Treatment-Naïve 
(TN) participants 
• 
Maximum 
change from 
baseline (Day 1) 
in plasma HIV-1 
ribonucleic acid 
(RNA) through 
Day 11. 
Overtly healthy 
(other than HIV-
1 infection) 
treatment naïve 
individuals 
VH4004280 or 
placebo single 
dose on Day 1 or 
VH4011499 or 
placebo single 
dose on Day 1 and 
Day 6 
Mean of maximum change 
from Baseline in log10 HIV-1 
RNA during Days 1-11  
Discontinuation of study treatment due to any reason: Treatment 
policy strategy, i.e., any HIV-1 RNA data available after study 
treatment discontinuation day + 1 and prior to starting SOC will be used 
in calculation of max VLD 
Use of SOC medication prior to Day 11: While on-treatment strategy, 
i.e., HIV-1 RNA collected after initiation of SoC, if for any reason this 
takes place prior to Day 11 will be excluded from calculation of max 
VLD 
Use of prohibited medication: Treatment policy strategy, i.e., any HIV-
1 RNA data available after use of prohibited medication will be used in 
calculation of max VLD 
Missed or partial doses of study treatment: Treatment policy strategy, 
i.e., HIV-1 RNA collected after missed or partial dose(s) will be used in 
calculation of max VLD 
Rationale: Interest is in evaluating efficacy irrespective of study 
treatment discontinuation or missed/partial doses, or use of prohibited 
medications, hence a treatment policy strategy is appropriate. Also, 
interest is to evaluate efficacy of VH4004280/VH4011499 monotherapy 
and not in combination with other antiretroviral medication hence a 
while on-treatment strategy is appropriate. 
Note: discontinuation or missed or partial doses of VH4004280 is not 
possible as only a single dose on Day 1 is administered, hence these 
IEs apply only to VH4011499 and to placebo matched for VH4011499. 
Secondary Objective: To assess the safety and tolerability of orally administered VH4004280 and VH4011499 

 
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Endpoints 
Estimand 
Population 
Treatment 
Summary Measure 
Intercurrent event (IE) / strategy / rationale 
• Incidence of 
adverse events 
(AEs), severity 
of AEs and AEs 
leading to study 
treatment 
discontinuation 
• Change from 
baseline and 
maximum 
toxicity grade 
increase from 
baseline for liver 
panel laboratory 
parameters 
Overtly healthy 
(other than HIV-
1 infection) 
treatment naïve 
individuals 
VH4004280 or 
placebo 
 
 
 
 or 
VH4011499 or 
placebo 
 
 
 
 
• AEs: 
o Number and 
percentage of 
participants with AEs 
o Number and 
percentage of 
participants with AEs 
by severity grade 
o Number and 
percentage of 
participants with 
AEs leading to 
study treatment 
discontinuation 
• Liver panel laboratory 
parameters 
o Summaries (mean, 
median, std, Q1, Q2, 
min, max) of change 
from baseline in liver 
Discontinuation of study treatment: Treatment policy strategy, i.e., all 
data to be used regardless of whether the study treatment 
discontinuation has occurred 
Use of SOC medication prior to Day 11: While on-treatment strategy, 
i.e., Safety data collected after initiation of SoC, if for any reason this 
takes place prior to Day 11 will be excluded from monotherapy Safety 
summaries 
Use of prohibited medication: Treatment policy strategy, i.e., all data 
to be used regardless of whether prohibited medication has been used 
Rationale: There is interest in evaluating and reporting monotherapy 
safety events from the monotherapy period and regardless of whether 
participants have completed monotherapy treatment or received 
prohibited medication  
Note: discontinuation of VH4004280 treatment is not possible as only a 
single dose on Day 1 is administered, hence this IE applies only to 
VH4011499 and to placebo matched for VH4011499. 
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Endpoints 
Estimand 
Population 
Treatment 
Summary Measure 
Intercurrent event (IE) / strategy / rationale 
panel laboratory 
parameters 
o Number and 
percentage of 
participants with 
maximum grade 
toxicity relative to 
Baseline 
Secondary Objective: To characterize the pharmacokinetic profiles of orally administered VH4004280 and VH4011499 
Concentration on 
Day 11 and PK 
parameters including 
o Cmax 
o tmax 
Overtly healthy 
(other than 
HIV-1 infection) 
treatment naïve 
individuals 
VH4004280 or 
placebo 
 
 
 
 or 
VH4011499 or 
placebo 
 
 
 
 
Summary statistics (e.g., 
arithmetic mean, median, std, 
minimum, maximum, 
geometric mean, sd (log), 
%CVb) 
Discontinuation of monotherapy treatment with VH4011499: While on-
treatment strategy, i.e., concentration values after study treatment 
discontinuation day + 1 will be excluded from analysis 
Use of prohibited medication: treatment policy strategy, i.e., all PK 
data to be used regardless of whether prohibited medication was used 
Rationale: Discontinuation of VH4011499 treatment may bias the 
evaluation of Pharmacokinetic behavior of VH4011499 as expected 
during and after the end of 10 days monotherapy period 
 
Note: discontinuation of VH4004280 treatment is not possible as only a 
single dose on Day 1 is administered 
 
 
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4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a Phase 2a, multi-center, randomized, double-blind (sponsor unblinded), placebo-
controlled (by each CAI), proof of concept clinical study to evaluate the antiviral effect, 
safety, tolerability, and PK/pharmacodynamics (PD) of 
 
 HIV-1 viremic adults. 
Up to 42 treatment naïve participants with confirmed HIV-1 RNA ≥ 3,000 copies/mL and 
CD4 T-cell count ≥200 cells/µL will be recruited into this 2-part adaptive study. As per 
Figure 1, the first 14 participants screened and who are found to meet all eligibility 
criteria will be randomly assigned on Day 1 to one of three placebo-controlled 
VH4004280 treatment groups (Part 1a: 6 active: 6 active: 2 placebo), followed by the 
next 14 participants randomly assigned on Day 1 to one of three placebo-controlled 
VH4011499 treatment groups (Part 1b: 6 active: 6 active: 2 placebo).  Each CAI will be 
evaluated as double-blind monotherapy for 10 days (primary endpoint). On Day 11, after 
the collection of the HIV-1 RNA sample, participants will start open-label standard-of-
care combination antiretroviral therapy that is selected by the investigator and locally 
sourced. Participants will be followed weekly through Day 39 to ensure that CAI drug 
concentrations have declined to BLQ. 
As described in 9.2, an informal interim analysis will be conducted after 9 participants 
(i.e., 4 participants per active arm and 1 placebo participant) from Part 1a have completed 
their Day 11 visit. A second informal interim analysis will be conducted after 9 
participants (i.e., 4 participants per active arm and 1 placebo participant) from Part 1b 
have completed their Day 11 visit. The conduct of Part 2 is dependent on the results from 
Part 1 but if conducted, will evaluate a double-blind placebo controlled third pre-
specified dose of one or both CAIs in up to an additional 14 participants [(Part 2a: 6 
active VH4004280:1 placebo) and/or (Part 2b: 6 active VH4011499:1 placebo)]. 
Figure 1 
Study design schematic 
 
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Total duration of study participation is approximately 45 to 66 days based on the 
following: 7 to 14 days, with a maximum of 28 days permitted in some cases for 
screening/qualification period, 10 days for treatment with the study intervention and 
assessment at all planned visits and 28 days for follow up visits including the final follow 
up visit. See Section 1.3 (Schedule of Assessments) for additional details of activities 
during screening, the monotherapy period and the standard of care period. This study 
includes the option of an additional 12 weeks post study VH/GSK reimbursement of 
locally sourced cART standard of care, as applicable. 
4.2. 
Scientific rationale for study design 
This is a Phase 2a, multi-center, randomized, double-blind (sponsor unblinded), placebo-
controlled, proof of concept clinical study to evaluate the antiviral effect, safety, 
tolerability, and PK/pharmacodynamics (PD) of orally administered VH4004280 and 
VH4011499 monotherapy over 10 days in approximately 42 ART naive HIV-1 viremic 
adults. 
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 each orally administered CAI. 
This study will facilitate an initial understanding of the antiviral activity and safety 
profile of both CAIs in an HIV positive ARV naïve 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 two ongoing Phase 1 studies 
with 
 and the single planned Phase 1 study with 
 
, 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 
of each CAI 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 each CAI and placebo. 
The two-part adaptive design will allow for interim evaluation of the exposure-antiviral 
response data to determine if evaluation of a third dose of one or both CAIs would be 
informative to properly characterize the exposure-antiviral relationship. If a third dose is 
not needed, then exposing additional participants to the investigational CAI can be 
avoided. 
4.2.1. 
Participant input into design 
Participants living with HIV-1 were not engaged in development of this short-term 
monotherapy proof-of-concept study design. 
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4.3. 
Justification for dose 
The VH4004280 and VH4011499 doses for investigation in this study are defined by 
emerging PK and safety data from the ongoing oral Phase 1 studies, preclinical potency 
data [RPS-CLIN-048482; RPS-CLIN-026329; RPS-CLIN-047476; RPS-CLIN-046304; 
RPS-CLIN-056829; RPS-CLIN-056826; TMF-14580566;  TMF-14086139; TMF-
14580566], and 
 
 
 
A therapeutic dose for VH4004280 and VH4011499 is proposed where majority of 
participants maintain, concentrations 
 
 
 
 
, that are expected to 
provide exposures that result in a near maximal change from baseline in plasma HIV-1 
RNA by Day 11. 
Thus, VH4004280 and VH4011499 doses in the current study aim to provide the 
following exposures through the 10-days monotherapy period:  
• 
 
 aimed to characterize the near maximal decline in 
HIV-1 RNA. 
• 
 
 aimed to 
characterize the near maximal decline in HIV-1 RNA. 
• Based on the interim analysis of exposures and response, a dose corresponding to 
10-days 
 
 
 aimed to confirm the 
maximal decline in HIV-1 RNA. 
A population pharmacokinetic (POP PK) analysis was conducted using preliminary data 
from the ongoing oral Phase 1 studies for VH4004280 and VH4011499 [TMF-15100069; 
TMF-14909676]. Based on the POP PK analysis, 
 
 
 Similarly, using a POP PK analysis for 
VH4011499, 
 
 
 
Thus, VH4004280 doses for the current study are expected to be 
 
 
 for Part 1 and a dose between approximately 
 
 will be selected for Part 2 
based on interim analysis. Similarly, VH4011499 doses for the current study are expected 
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to be 
 
 for Part 1 and a dose between 
approximately 
 
 
 will be selected for 
Part 2 based on interim analysis. VH4004280 and VH4011499 doses in Part 2 may be 
adjusted based on preliminary analyses of exposure and response from Part 1. 
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 39 End of Study (EOS) visit. The end of the study is defined as the date of the last 
visit of the last participant in the study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Up to 42 HIV-infected adults (treatment naive) 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. 
5.1. 
Inclusion Criteria 
Entry into screening nor meeting all eligibility criteria does not guarantee enrollment into 
the study. To manage the total study enrollment, VH/GSK at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time. 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
• Participant must be 18 to 65 years of age inclusive at the time of signing the 
informed consent. 
 
Type of Participant and Disease Characteristics 
2. Participants who are overtly healthy (other than HIV-1 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. Screening CD4+ T-cell count  cells/µL. 
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4. Documented HIV-1 infection and Screening plasma HIV-1 RNA 000 
copies/mL. A single repeat of this test is allowed within a single Screening period 
to determine eligibility. 
5. Treatment-naïve: Defined as no ARVs (in combination or monotherapy) received 
after the diagnosis of HIV-1 infection. Prior use of oral PreP is permitted and meets 
inclusion. Prior use of parenteral PreP is exclusionary. 
 
Weight 
6. Body weight 50.0 kg (110 lbs) for men and 45.0 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive - applies to males 
and females). 
 
Sex and Contraceptive/Barrier Requirements 
7. All participants participating in the study should be counseled on safer sexual 
practices including the use and benefit/risk of effective barrier methods (e.g. male 
condom) and on the risk of HIV transmission to an uninfected partner. 
 
Participants Male at birth: There are no contraceptive requirements for 
participants who were male at birth. 
 
Participants Female at birth: A participant who was female at birth is eligible to 
participate if they are not pregnant and not breastfeeding. Participant of 
childbearing potential (POCBP) must be using acceptable forms of birth control 
through to Day 39. The investigator is responsible for review of medical history, 
menstrual history, and recent sexual activity to decrease the risk for inclusion of a 
POCBP with an early undetected pregnancy. Refer to Section 10.4 for more details.  
 
Informed Consent 
8. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and stated in this protocol. 
 
Other Inclusions 
9. Participant must be willing and able to start locally accessible and commercially 
available cART on Study Day 11. The investigator will choose the standard of care 
cART according to local treatment guidelines, accessibility and locally run 
genotypic/phenotypic results (if available). 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 

 
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MEDICAL CONDITIONS 
1. Women who are breastfeeding or plan to become pregnant or breast feed during the 
study. 
2. Participants with acute 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. 
3. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 
3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic 
therapy during the study. Refer to Section 10.8 for more details. 
4. Untreated syphilis infection [positive rapid plasma reagin (RPR) at screen] without 
documentation of treatment.  Participants who have successfully completed 
treatment at least 7 days prior to Day 1 are eligible if recruitment is open. 
5. 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 VH medical monitor for inclusion of the 
participant prior to randomization. 
6. 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. 
7. 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; Any pre-existing physical or other psychiatric condition (including 
alcohol or drug abuse), which, in the opinion of the investigator (with or without 
psychiatric evaluation), could interfere with the participant’s ability to comply with 
the dosing schedule and protocol evaluations or which might compromise the 
safety of the participant. 
8. Any history of significant underlying psychiatric disorder, in the opinion of the 
investigator or VH medical monitor, including but not limited to schizophrenia, 
bipolar disorder with or without psychotic symptoms, other psychotic disorders, or 
schizotypal (personality) disorder; or a clinical assessment of suicidality based on 
the responses on the C-SSRS. 
9. Any history of major depressive disorder with or without suicidal features, or 
anxiety disorders, that required medical intervention (pharmacologic or not) such 
as hospitalization or other inpatient treatment and/or chronic (>6 months) 
outpatient treatment. Participants with other conditions such as adjustment disorder 
or dysthymia that have required shorter term medical therapy (<6 months) without 
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the VH medical monitor. 

 
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10. Any condition which, in the opinion of the investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study drugs or render the 
participant unable to take oral medication. 
11. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(except for Gilbert's syndrome or asymptomatic gallstones). 
12. A pre-existing condition, in the opinion of the investigator or VH medical monitor, 
that could interfere with normal gastrointestinal anatomy or motility (e.g., 
gastroesophageal reflux disease [GERD], gastric ulcers, gastritis, inflammatory 
bowel disease), hepatic and/or renal function, that could interfere with the 
absorption, metabolism, and/or excretion of the study interventions or render the 
participant unable to take oral study treatment. 
13. 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 VH 
medical monitor, will interfere with the safety for the individual participant. 
14. 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 
QTc interval (Fridericia’s) 
>450 msec 
>470 msec 
Note: 1A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by ECG or vitals 
within 30 minutes to verify eligibility. 2The QTc is the QT interval corrected for heart rate 
according to Fridericia’s formula (QTcF). It is either machine-read or manually over-read. The 
specific formula used to determine eligibility and discontinuation for an individual participant 
should be determined prior to initiation of the study. In other words, several different formulas 
cannot be used to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the study. 
 
15. To assess any potential impact on participant eligibility regarding safety, the 
investigator must refer to the CIBs 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. 
 
PRIOR/CONCOMITANT THERAPY 
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17. History of sensitivity to any of the study medications, or their components or drugs 
of their class, or a history of drug or other allergy that, in the opinion of the 
investigator or VH medical monitor, contraindicates their participation. 
18. Participants who require concomitant medications known to be associated with a 
prolonged QTc (see list from https://www.crediblemeds.org).  
19. Treatment with any of the following agents within 28 days of Screening: radiation 
therapy, cytotoxic chemotherapeutic agents, any systemic immune suppressant. 
20. Prior use of 
 for any reason is exclusionary. 
21. Participants receiving any protocol-prohibited medication and who are unwilling or 
unable to switch to an alternate medication. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
22. The participant has received an investigational HIV vaccine (immunotherapeutic or 
immunomodulatory). 
23. Exposure to an approved vaccine within 14 days prior to Day 1. 
24. Exposure to an investigational drug or experimental vaccine within either 28 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 
Day 1 if the investigator determines that the benefit-risk profile for that individual 
study participant is favorable. The use of other investigational SARS-CoV-2 
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 
25. Participation in the study would result in donation of blood or blood products in 
excess of 500 mL within 56 days. 
26. Exposure to more than four new investigational drugs or vaccines within 12 months 
prior to Day 1. 
27. 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 
investigational study intervention or any other type of medical research. 
 
DIAGNOSTIC ASSESSMENTS  
28. Presence of Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb) at screening  
• 
Evidence of Hepatitis B virus (HBV) infection based on the results of testing 
at Screening for Hepatitis B surface antigen (HBsAg). 
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• Participants who are negative for HBsAg should also be tested for Hepatitis B 
core antibody (anti-HBc), Hepatitis B surface antibody (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. 
• 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). 
29. 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) 
30. 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 
31. Positive SARS-CoV-2 polymerase chain reaction test, having signs and symptoms 
which in the opinion of the investigator are suggestive of COVID-19 (i.e., fever, 
cough etc.) on Day 1, or having contact with known COVID-19 positive person/s 
in the 14 days prior to Day 1. 
32. Creatinine clearance (eGFR) of < 50 mL/min/1.73 m2 via CKD-EPI method 
[Delgado, 2021]. 
33. Alanine aminotransferase (ALT) 1.5 x upper limit of normal (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. 
34. Any Grade 3-4 laboratory abnormality at Screening, except for a Grade 4 creatine 
phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, 
etc.) will exclude a participant from the study unless the investigator can provide a 
compelling explanation for the laboratory result(s) and has the assent of the 
sponsor. A single repeat of any lab abnormality is allowed within a single 
Screening period to determine eligibility. 
35. Any acute laboratory abnormality at screen which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound. 
36. Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening. A 
positive screen for marijuana/THC is not exclusionary. Refer to Section 5.3.2 for 
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OTHER EXCLUSIONS 
37. 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 white wine or 1.5 ounces (45 mL) of 80 proof distilled 
spirits. 
38. Regular use of drugs of abuse 
 
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, 6, 11, 25, and 39/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 
 and dosing. 
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 11 visit. Excessive consumption is 
defined as more than one glass of red wine or juice or one fruit per day, in combination. 
5.3.2. 
Caffeine, alcohol, tobacco, marijuana/THC and illicit drug use 
• During the study alcohol consumption will be limited to the following: An average 
weekly intake of <14 drinks for males or <7 drinks for females. One drink is 
equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine 
or 1.5 ounces (45 mL) of 80 proof distilled spirits. 
• No alcohol will be consumed for the intensive PK days (
 
 until after the final assessment of the day and release 
from the clinic. 
• No caffeine or xanthine containing products (e.g., coffee, tea, cola drinks, and 
chocolate) will be consumed for the intensive PK days (
 
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 until after the final assessment of the day and release 
from the clinic. 
• Only clinically minor to moderate use (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 
 
 until after the final assessment of the day and release from the 
clinic. 
• Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening is 
exclusionary. A positive screen for marijuana / THC is not exclusionary. Participants 
should refrain from the use of marijuana from Day 1 through the Day 11 visit. 
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 studies. 
5.4. 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled (i.e., 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 Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, any protocol deviations and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants should be assigned a new participant number. 
Previously assigned participant numbers are to be recorded in the participants’ eCRF. 
5.5. 
Criteria for temporarily delaying enrollment/randomization 
Refer to Section 7.1 for safety criteria that could temporarily pause further recruitment 
into the study. 
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6. 
STUDY INTERVENTIONS AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in Table 3 and includes 
VH4004280/placebo 
 and VH4011499/placebo 
. Study intervention does not 
include locally sourced open-label SOC that is first administered at the end of the Day 11 
visit and after final collection of the primary endpoint data (Day 11 plasma HIV-1 RNA 
sample). 
6.1. 
Study interventions administered 
Table 3 
Study interventions administered 
Intervention Label 
VH4004280
 
Matched placebo 
for VH4004280 
 
VH4011499 
 
Matched placebo 
for VH4011499 
 
Intervention Name 
VH4004280
  
Matched placebo 
for VH4004280 
 
VH4011499 
 
Matched placebo 
for VH4011499 
 
Intervention 
Description 
Type  
Drug 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Unit Dose Strengths 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo 
Experimental 
Placebo 
IMP and NIMP/AxMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Current Alias 
GSK4004280 
Not applicable 
GSK4011499 
Not applicable 
 
Table 4 
VH4004280 study arms 
Arm Title 
VH4004280 
VH4004280 
Placebo 
for 
VH4004280 
VH4004280 
Placebo for VH4004280 
Part 
Part 1a 
Part 1a 
Part 1a 
Part 2a 
Part 2a 
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Arm Title 
VH4004280 
VH4004280 
Placebo 
for 
VH4004280 
VH4004280 
Placebo for VH4004280 
Arm Type 
Experimental Experimental Placebo 
Experimental 
Placebo 
Regimen 
1 
2 
3 
4 
5 
1 Doses in Part 2 may be adjusted based on preliminary analyses of exposure and response data from Part 1. As a 
result, the dosing instructions and the placebo match in Part 2 would then be aligned to the specific dose regimen 
that is chosen. 
 
Table 5 
VH4011499 study arms 
Arm Title 
VH4011499 
VH4011499 
Placebo 
for 
VH4011499 
VH4011499 
Placebo for VH4011499 
Part 
Part 1b 
Part 1b 
Part 1b 
Part 2b 
Part 2b 
Arm Type 
Experimental Experimental Placebo 
Experimental 
Placebo 
Regimen  
6 
7 
8 
9 
10 
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1 Doses in Part 2 may be adjusted based on preliminary analyses of exposure and response data from Part 1. As a 
result, the dosing instructions and the placebo match in Part 2 would then be aligned to the specific dose regimen that 
is chosen. 
 
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 or authorized site staff are 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 VH/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. 
 
 
. Unused study intervention tablets in 
opened bottles may not be offered to the study participant beyond the expected dosing 
schedule as outlined in the SoA (Section 1.3) and may not be offered to any other person. 
6.4. 
Blinding 
This is a double-blind (sponsor unblinded) placebo-controlled study in which 
participants/investigators will not be unblinded to treatment (active capsid inhibitor drug 
or placebo) at the participant level. 
 
 
 
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There is a theoretical concern that investigators may deduce treatment assignment during 
the monotherapy period since they will have access to HIV-1 RNA results from the 
monotherapy period. However, since this study is a proof-of-concept clinical trial rather 
than a confirmatory trial, insufficient anti-viral effect over the monotherapy period cannot 
reliably predict placebo assignment. The monotherapy period is short which minimizes 
the likelihood of bias on subsequent endpoints during the monotherapy period. 
Knowledge of the treatment received during the monotherapy period is of little 
consequence within the SOC period and has no impact on the future conduct of the trial 
or assessment of study endpoints. 
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 
participant’s intervention assignment is unblinded, VH/GSK must be notified 
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. 
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 9.5 for more details about preservation of the blind during the conduct of 
the informal planned interim analyses. VH/GSK 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 one 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 VH/GSK policy. A participant may continue 
in the study if that participant’s intervention assignment is unblinded. 
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6.5. 
Study intervention compliance 
Participants will receive study intervention directly from qualified site staff and 
 
 The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
intervention. 
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 the investigational CAI (VH4004280 or VH4011499) after the end 
of the study is not permitted since therapeutic benefit has not yet been established. 
The investigator is responsible for ensuring consideration has been given to the poststudy 
care and treatment of the participant’s medical condition. The Sponsor recognizes some 
HIV-1 infected adults may encounter barriers to timely access to cART. Where it has 
been determined by the investigator to be an acceptable option, participants who have 
completed the study (i.e., Day 39 EOS which includes 10 days of double-blind 
monotherapy and 4 weeks of investigator chosen SOC) and are exercising reimbursement 
assistance from the Sponsor for their SOC, will have the option (but are not required) to 
receive up to an additional 3 months of reimbursement assistance post study. The 
investigator will choose the standard of care cART according to local treatment 
guidelines, accessibility and locally run genotypic/phenotypic results (if available).  
6.8. 
Treatment of overdose 
For this study, any dose of the CAI study intervention that exceeds the specified dose for 
that treatment group will be considered an overdose. In the event of an overdose, the 
investigator should: 
• Contact the VH medical monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until study intervention can no longer be detected systemically, as medically 
appropriate. 
• If requested by the VH medical monitor, obtain a plasma sample for PK analysis 
as soon as possible after the overdose. Intensive and single PK sampling is pre-
specified as per the SoA (Section 1.3) such that an additional PK sample in the 
event of overdose may not be needed. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
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Decisions regarding investigations and management will be made by the investigator in 
consultation with the VH medical monitor based on the clinical evaluation of the 
participant, although VH/GSK does not recommend specific treatment for an overdose. 
Refer to the approved product label for the cART standard of care for advice on 
overdose. 
6.9. 
Prior and concomitant therapy 
The VH medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. Any medication or vaccine (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along 
with reason for use, dates of administration including start and end dates, and dosage 
information including dose and frequency. 
• 
Acetaminophen/paracetamol at doses of ≤2 grams/day or nonsteroidal anti-
inflammatory drugs (NSAIDs) are permitted for use any time during the study and 
their use documented in the CRF. 
• 
No clinically significant interactions are expected following the start of any 
anticipated cART standard of care regimen on Day 11.  
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 
 
 
 
 
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Despite the study intervention being 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 cART standard of care on Day 11) 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 11 (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 7.1.1 (Liver chemistry stopping criteria), Section 7.1.2 (QTc stopping 
criteria) and Section 7.2.1 (SARS-CoV-2 management criteria). 
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 
 
Death 
 
Participant Reached Protocol-Defined 
Stopping Criteria 
Specify 
Lack of efficacy 
 
Lost to follow-up 
Physician Decision 
Specify 
Protocol Deviation 
Specify 
Withdrawal by Participant 
Specify 
Other 
Specify 
 
7.1.1. 
Liver chemistry stopping criteria 
Liver stopping and increased monitoring criteria have been designed to assure participant 
safety and evaluate liver event etiology, in alignment with the FDA premarketing clinical 
liver safety guidance: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-
induced-liver-injury-premarketing-clinical-evaluation 
If a participant meets the liver chemistry stopping criteria (i.e., ALT3xULN) further 
CAI dosing should be discontinued if applicable 
 
 and the participant will be monitored as detailed in 
Section 10.6. 
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 In the presence of abnormal liver chemistries that do 
not meet the protocol-specified liver chemistry stopping rule, the investigator may choose 
to discontinue further study treatment 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. 
7.1.2. 
QTc stopping criteria 
A participant that meets any of the bulleted criterion based on the average of triplicate 
ECG readings will have met a QTc stopping criterion. 
• 
QTcF >500 msec, 
• 
Change from baseline: QTcF >60 msec 
If a QTc stopping criteria is met or another clinically significant finding is identified, then 
the investigator in consultation with the VH medical monitor will determine if any 
change in participant management is needed and if the participant can continue the study 
intervention. Any new clinically relevant finding should be reported as an AE. 
Refer to Section 8.3.7 for information about study pausing criteria. 
7.1.3. 
Pregnancy 
Participants who become pregnant during the study should discontinue. Refer to 
Section 8.4.5 for further details. 
7.1.4. 
Temporary discontinuation 
Temporary discontinuation of either VH4004280/placebo or VH4011499/placebo is not 
allowed in this study. 
7.1.5. 
Rechallenge 
Rechallenge with either VH4004280/placebo or VH4011499/placebo is not allowed in 
this study. 
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7.2. 
Participant discontinuation/withdrawal from the study 
• A participant may withdraw from the study at any time at their own request for any 
reason (or without providing any reason) or may be withdrawn at any time at the 
discretion of the investigator for safety, behavioral, or compliance 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 cART 
standard of care on Day 11) 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, with the exception of SARS-CoV-2 scenarios as described in 
Section 7.2.1. If participants prematurely discontinue the study for non-safety reasons 
prior to Day 11 (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 contact participants who do not return for scheduled visits or 
follow-up and encourage protocol compliance. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). The SoA lists the data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• 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 records. 
• The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF. 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 (refer to Section 10.3.6). 
7.2.1. 
SARS-COV-2 Management Criteria 
A participant who is found to have SARS-CoV-2 infection during the study may proceed 
in the study at the discretion of the investigator and sponsor assuming the participant 
isolates according to current Centers for Disease Control and Prevention guidance and 
then has a repeat SARS-CoV-2 test that is negative. Otherwise, participants who are 
withdrawn from the study due to SARS-CoV-2 infection (including exposure to SARS-
CoV-2) may be replaced based upon the discretion of the sponsor and investigator. 

 
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Refer to Section 10.9 for further details regarding the conduct of the study when 
impacted by SARS-CoV-2 infections and/or exposures. 
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: 
1. 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. 
2. Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
3. Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
4. 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 
5. Study procedures and their timing are summarized in the Schedule of activities 
(SoA) (Section 1.3). Protocol waivers or exemptions are not allowed. 
6. Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
7. All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Participants who have signed informed 
consent but are not eligible to proceed should be recorded in the eCRF with a status 
of ‘screen failure’. 
8. 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 (Section 1.3). 

 
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9. 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. Refer to Section 10.10 for more information. 
10. The maximum amount of blood collected from each participant over the duration of 
any 56-day period will not exceed 500 mL. 
11. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
12. Pharmacokinetic results that could unblind the study will not be reported to 
investigative sites or other blinded personnel. 
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 intended 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. Also obtain the participant’s SARS-
CoV-2 vaccination history. 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 Laboratory 

 
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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. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
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 is symptom driven (with the exception of an expected 
respiratory system assessment at select visits) and may be targeted to include select 
system/organ assessments. 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 body mass index (BMI). 
8.3.2. 
Vital signs 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 
body temperature, single pulse rate, respiratory rate and blood pressure 
measurement. 
• 
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 (e.g., television, cell phones). 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 
Single 12-lead ECG tracings will be obtained as outlined in the SoA (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. 
Under certain circumstances the ECG should be repeated twice more (triplicate obtained) 
with recordings obtained as closely as possible in succession. Data from the average of 3 

 
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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), 
Refer to Section 7.1.2 for QTc stopping criteria for further details. 
8.3.4. 
Clinical safety laboratory tests 
• 
Refer to Section 10.2 for the list of clinical safety laboratory tests to be performed by 
the central laboratory in accordance with the Lab Manual and the SoA (Section 1.3). 
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 point of care SARS-CoV-2 validated test will be run locally to determine 
eligibility on Day 1. Sites should adhere to the manufacturers guidance for which 
samples are allowed (e.g., nasopharyngeal, oropharyngeal). 
• 
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. 
• 
All laboratory tests with values considered clinically significantly abnormal from 
dosing of the study intervention until the EoS visit (i.e., Day 39) should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or VH 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 
• 
Participants of childbearing potential (POCBP) must perform a pregnancy test before 
the administration of any dose of study intervention. 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. 
• 
Serum samples will be sent for pregnancy testing for the Screening Visit and all 
other timepoints. 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. 

 
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Additionally at the Day 1 Visit, a serum sample will be sent for pregnancy testing at 
the same time. 
• 
Refer to Section 8.4.5 for the information on study continuation for participants who 
become pregnant during the study. 
8.3.6. 
Suicidal ideation and behavior risk monitoring 
Participants with HIV infection occasionally may present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior).  In addition, there have been some 
reports of depression, suicidal ideation and behavior (particularly in patients with a 
pre‑existing history of depression or psychiatric illness) in some patients being treated 
with INIs, including DTG. Therefore, it is appropriate to monitor participants for 
suicidality before and during treatment. 
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior. It is recommended that the 
investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior. Participants presenting with new 
onset/treatment emergent depression should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the study 
medication may be required 
Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicidality Severity Rating Scale (C-SSRS). 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); all 
subsequent questioning is in relation to the last assessment. The eC-SSRS questionnaire 
is to be administered by a clinician at the timepoints in the SoA (Section 1.3). The 
eC-SSRS will be conducted electronically by computer. 
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the AE (non-serious or SAE) eCRF form 
on any participant 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. 
8.3.7. 
Study Pausing Rules 
Participant safety will be continuously monitored by the VH medical monitor and the 
GSK safety lead. 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 

 
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group, the ViiV Safety and Labelling Committee (VSLC) 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 following study pausing criteria would be applied per compound: 
• 
Any SAE, regardless of its severity, that is considered to be clinically significant and 
reasonably attributable to dosing with VH4004280 or VH4011499, in the opinion of 
the investigator or the Sponsor. 
• 
Any Grade 3 or higher rash or Grade 2 rash with evidence of systemic involvement 
that the investigator considers reasonably attributable to VH4004280 or VH4011499. 
• 
Any Grade 4 AE or laboratory abnormalities (with the exception of an asymptomatic 
Grade 4 lipid abnormalities or CPK increase) that the investigator considers 
reasonably attributable to VH4004280 or VH4011499. 
• 
Any participant meeting liver stopping criteria that the investigator considers 
reasonably attributable to VH4004280 or VH4011499. 
• 
Any participant meeting QTc stopping criteria that the investigator considers 
reasonably attributable to VH4004280 or VH4011499. 
8.4. 
Adverse Events (AEs) and serious adverse events (SAEs) 
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 (Section 6.9). This 
includes events reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
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. 
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. All 
AEs will be collected from the start of study intervention 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/pregnancies 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. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available 

 
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A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE reporting 
period defined in Section 8.4.1. 
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. 
Contacts for SAE reporting can be found in Section 8.4.8. 
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 
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 Section 10.3.6.6. 
• 
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 CIBs 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 
To be eligible to participate in the study, participants who were female at birth must not 
be pregnant (i.e., must have a negative pregnancy test) nor breastfeeding. In addition, 

 
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POCBP must be using acceptable forms of birth control from Screening through to Day 
39. The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy. Study intervention may only be administered if the screening 
pregnancy test (blood) and an additional pregnancy test on Day 1 (urine) are negative. 
Pregnancy testing for POCBP must be performed post baseline as per the SoA 
(Section 1.3). 
• 
Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until Day 39. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the 
necessary signed informed consent from the female partner) pregnancy. 
• 
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/pregnant female partner will be followed to determine the outcome 
of the pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the sponsor. See Section 8.4.1 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/pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
• 
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. 
8.4.6. 
CV and death events 
For any CV events detailed in Section 10.3 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 one week of receipt of a CV Event data query prompting its completion.  

 
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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 one 
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 10.8) 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 Disease Related Event on the SAE 
page rather than the HIV Associated Conditions eCRF. 
8.4.8. 
Contact information for reporting SAEs, pregnancies and study 
stopping criteria 
As per Section 10.3.6.7, 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 to report the event within 24 hours. Refer to 
Table 6 if you have questions. 
Table 6 
Contact information for safety events questions and/or reporting 
Safety Topic 
Contact 
Reporting SAEs and pregnancies 
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 pregnancies 
Contact the VH medical monitor 
Questions regarding any other safety event that 
may meet a safety stopping criteria 
Contact the VH medical monitor 

 
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8.4.9. 
Participant card 
The investigator must provide the participant with a “participant card” containing 
information about the clinical study. The participant 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 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 for 
, dosing and PK draws for 
intensive PK days. 
Table 7 
Intensive Pharmacokinetic Sampling Schedule on Day of Dosing 
 
Time of Event 
Window 
Time Relative to Dosing 
Hour:Minute 
Dosing 
Day 
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. 
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o Blood samples of approximately 2 mL will be collected and processed to 
plasma for measurement of plasma concentrations of study intervention. 
o The actual date and time (24-hour clock time) of each sample will be 
recorded. 
o 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 VH4004280 or 
VH4011499 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. 
8.6. 
Pharmacodynamics 
See Section 8.2  and Section 8.5 for relevant efficacy and PK assessments. 
8.7. 
Genetics of the Participant 
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected on 
Day 1 from participants who have consented to participate in the genetic analysis 
component of the study. Participation is optional. Participants who do not wish to 
participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Section 10.5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Laboratory 
Manual. 
8.8. 
Biomarkers - Viral Genotyping and Phenotyping 
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 11 will be batch tested for viral 
genotypic and phenotypic on treatment changes and/or resistance to the CAIs using the 

 
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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 cART. 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 assessments are not evaluated in this study. 
8.10. 
Health economics 
Health economic parameters are not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The SAP will be finalized prior to DBL 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 
secondary endpoints. If methods in the SAP differ from the methods described in the 
protocol, the SAP prevails. 
9.1. 
Statistical hypotheses 
The primary objective, as outlined in Section 3, 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 for each dose for both VH4004280 and VH4011499 CAIs.  
9.2. 
Statistical hypotheses 
The primary objective, as outlined in Section 3, 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 for each dose for both VH4004280 and VH4011499 CAIs.  

 
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9.3. 
Analysis sets 
Analysis Set 
Definition  
Screened  
• All participants who are screened for eligibility 
Randomized  
• All participants who are randomly assigned to study treatment (i.e., VH4004280, 
VH4011499 or placebo) in the study 
Safety 
• All randomized participants who take at least 1 partial or full dose of study treatment  
• Participants will be analyzed according to the treatment they actually received 
Full Analysis Set 
(FAS) 
• All randomized participants who received at least one full dose of study treatment 
• Data will be reported according to the randomized study intervention 
Per-Protocol (PP) 
• All participants in the full analysis set for whom there were no major protocol deviations 
that impact the primary analyses 
• Data will be reported according to the treatment actually received 
• Specific details of major protocol deviations that would exclude participants from the PP 
analysis set will be provided in the SAP 
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 treatment 
 
Further analysis sets may be defined in the SAP, as needed. 
9.4. 
Statistical analyses 
9.4.1. 
General considerations/definitions 
Data will be summarized by treatment (i.e., VH4004280, VH4011499, placebo matching 
VH4004280 and placebo matching VH4011499) 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, 
standard deviation (SD), median, interquartile range, minimum and maximum. For 

 
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PK data, geometric mean, SD of log-transformed data and geometric %CVb may 
also be used. 
• 
Categorical data: number and percentage of participants 
9.4.1.1. 
Protocol Deviations leading to exclusion from PP analysis set 
The SAP will describe the major protocol deviations that would exclude a participant 
from the Per Protocol analysis set. 
9.4.2. 
Primary endpoint/estimand analysis 
See Section 3 for definition of primary endpoint and estimand. 
9.4.2.1. 
Definition of endpoint/estimand 
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 
interpretation. 
9.4.2.2. 
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 by treatment (i.e., VH4004280, VH4011499, placebo matching VH4004280 
and placebo matching VH4011499) 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 treatment and dose level, in original and 
log10 scales. 
Descriptive statistics will be provided as described in Section 9.4.1. 
Handling of missing data and Intercurrent Events leading to exclusion of data 
Any missing HIV-1 RNA data (e.g., due to missed visits in the clinic, LFU 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.  

 
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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. 
9.4.2.3. 
Supplementary/supportive analysis/analyses 
A supplementary analysis will 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. 
9.4.3. 
Secondary endpoints/estimands analyses 
See Section 3 for definition of secondary endpoints and estimands. 
9.4.3.1. 
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.  
Analysis Method 
The number and proportion of participants with AEs will be tabulated overall and by 
severity grade, by treatment and dose level. The number and proportion of participants 
with AEs leading to discontinuation of VH4011499 or placebo matching VH4011499 
will also be tabulated by dose level of VH4011499 and placebo (matching VH4011499). 
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 (e.g., mean, median, std etc.) of 
change from Baseline values by visit will be presented by treatment and dose level. 
Number and percentage of participants with maximum toxicity grade increase from 
Baseline for liver panel parameters will be presented by treatment and dose level; this 
will be done separately for the monotherapy period and overall (i.e., monotherapy period 
plus SOC). 
Handling of missing data and Intercurrent Events leading to exclusion of data 
All available safety data will be considered in summaries of AEs and liver panel 
laboratory parameters within the respective period (e.g., monotherapy or monotherapy 
plus SOC) 
 
 or prohibited medication use has 
occurred. 
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No imputation will be performed for missed assessments while participants are on study 
or after study withdrawal. 
9.4.3.2. 
Pharmacokinetic analyses 
All pharmacokinetic analyses will be performed on the pharmacokinetic analysis set.  
Analysis Method 
Pharmacokinetic analysis will be the responsibility of the CPMS Department at GSK. 
Plasma VH4004280 and VH4011499 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. The various PK parameters will be 
inferred as data permits. 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 treatment (i.e., VH4004280 and 
VH4011499) and dose level. PK parameters will be summarized descriptively by 
treatment (i.e., VH4004280 and VH4011499) and dose level. Descriptive summaries will 
be used as described in Section 9.4.1. 
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. 
Handling of missing data and Intercurrent Events leading to exclusion of data 
Additional estimands for PK analyses may be specified in the SAP. 
No imputation will be performed for missed plasma concentrations and PK parameters 
while on study or after study withdrawal. 
9.4.3.3. 
Pharmacokinetic-Pharmacodynamic analyses 
Analysis Method 
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The relationship between selected PK parameters (e.g., concentrations on Day 11) 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. No imputation 
will be performed for missing data. 
9.4.4. 
Exploratory endpoints/estimands analysis 
Details on the analyses of exploratory endpoints and other analyses will be included in 
the SAP.  
9.5. 
Interim analyses 
An informal planned interim analysis will be conducted after 9 participants (i.e., 4 
participants per active arm and 1 placebo participant) from Part 1a have completed their 
Day 11 visit. A second informal planned interim analysis will be conducted after 9 
participants (i.e., 4 participants per active arm and 1 placebo participant) from Part 1b 
have completed their Day 11 visit. 
The planned interim analyses will evaluate the PK and pharmacodynamic (antiviral 
activity) of each respective capsid inhibitor and inform if a third pre-specified optional 
dosing arm for each capsid inhibitor will be evaluated in Part 2. Depending on the Part 1 
results, a higher dose, lower dose, or a dose between the two doses evaluated in Part 1 
will be evaluated in Part 2. It is also possible that Part 2 will not be conducted for one or 
both capsid inhibitors if the doses evaluated in Part 1 adequately describe the exposure- 
response of each capsid inhibitor. The interim results will also inform future clinical 
development of both compounds. 
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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 39 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.  
9.6. 
Sample size determination 
The sample size is based on feasibility and no formal calculation of power or sample size 
has been performed.  
9.6.1. 
Sample Size Considerations 
Based on data from the top two doses of the short-term monotherapy study of 
 
 we assumed the maximum viral load decline (VLD) from 
Baseline in log10 scale for individual participants follows a normal distribution.  
Assuming normality, the sample size of N=6 participants per intervention cohort allows 
estimation of the mean maximum VLD in log10 scale with precision shown on Table 8. 
Table 8 shows the expected precision of the estimated mean maximum VLD in log10 
scale measured by the 95% CI width for various observed data variability assumptions as 
reflected by the sample standard deviation (SD). 
Table 8 
 
9.6.2. 
Sample Size Sensitivity 
To evaluate study’s sensitivity to sample size we calculated the expected precision of the 
estimated mean of maximum VLD in log10 scale for a treatment intervention for various 
sample sizes. Figure 2 shows the expected precision, measured by the 95% CI width, of 
the estimated mean maximum VLD in log10 scale for various sample sizes for a 
CCI
CCI
CCI

 
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treatment intervention and various assumptions on the observed data variability (reflected 
by the sample SD). 
Figure 2 
CCI
CCI

 
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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. 
• Any 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, 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.  
If partners of male participants become pregnant during the study, consent will need to be 
obtained or notification given as per local regulation to the partner before collecting their 
PI (such as LMP and year of birth) or the PI of their baby (such as date of birth and sex) 
as part of safety follow-up. 
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; 

 
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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. 
• 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 VH/GSK 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. 
Committees structure 
Participant safety will be routinely monitored by the VH medical monitor and the GSK 
safety leads. Pertinent findings and conclusions are shared with the product’s Safety 
Review Team (SRT) for periodic review of the overall benefit risk profile of the product 
and escalated, as necessary to ViiV Healthcare’s Safety and Labelling Committee 
(VSLC). 
The SRT is in place for each VH product and is comprised 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 studies of both CAIs. 
ViiV Healthcare’s 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. 
ViiV Healthcare has transferred certain sponsor obligations (e.g., clinical operations, 
study intervention management, data management, statistics and programming, clinical 

 
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pharmacology and modelling and simulation, regulatory, pharmacovigilance, etc) to GSK 
and/or PPD 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. 
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 protocol summaries 
prior to study start and target results summaries submission within 12 months after 
the study end in all countries in the study. 
• 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 

 
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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 
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 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. 

 
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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. 
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. 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. 
Local safety laboratory results are only required if the investigator anticipates that the 
central laboratory results will not be available in time to support the administration of 
study intervention and/or to properly evaluate the participant. 
If a local safety sample is required, it is important that the sample for central analysis is 
obtained at the same time. If the central laboratory results significantly differ from the 
local results, then the local results will be transcribed into the eCRF (units, normal range 
and certification will need to be reported). If the central results corroborate the local 
results, then the local results will be retained in the source documents and not transcribed 
into the eCRF. Local genotypic/phenotypic nor HIV-1 RNA results should be entered 
into the eCRF. 
Table 9 
Protocol-required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Coagulation 
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
International normalized ratio (INR) 
Hematology  
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell (RBC) count 
RBC indices 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH)  
Percent reticulocytes 
White blood cell (WBC) count 
with differential 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
Amylase 
Lipase 
Creatine phosphokinase (CPK) 2 
Glucose 
Calcium 
Sodium 
Potassium 
Blood urea nitrogen (BUN) 
Creatinine3 

 
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Laboratory 
Assessments 
Parameters 
Total protein 
Total and direct bilirubin 
Alkaline phosphatase4 
Aspartate aminotransferase (AST or SGOT) 
Alanine aminotransferase (ALT or SGPT) 
Total Bile Acid (TBA) 
Lipid Panel 
(fasting) 
Triglycerides 
Total cholesterol 
Low-density lipoprotein (LDL) cholesterol 
High-density lipoprotein (HDL) cholesterol 
Routine 
Urinalysis 
Specific gravity 
Dipstick (pH, glucose, protein, blood, ketones, bilirubin, nitrite, leukocyte 
esterase) 
Microscopic examination (if blood or protein is abnormal) to include epithelial 
cells, RBCs, WBCs, casts, crystals and a culture (if positive, specify pathogen). 
Other Tests 
• Highly sensitive (serum or urine) human chorionic gonadotropin (hCG) 
pregnancy test participants female at birth 
• Follicle-stimulating hormone, if needed to demonstrate that a female is of 
nonchildbearing potential (See Section 10.4 ) 
• 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, hepatitis B surface antigen 
[HBsAg], Hepatitis B Core antibody (anti-HBc), 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) 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 10.6. 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 an 
expedited manner (excluding studies of hepatic impairment or cirrhosis). Laboratory analytes to be tested will 
include the routine liver panel and additional analytes [such as lactate dehydrogenase (LDH), gamma-glutamyl 
transferase (GGT), glutamate dehydrogenase (GLDH) and serum albumin]. 
2. 
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. 
3. Estimated serum creatinine clearance (using the Chronic Kidney Disease Epidemiology Collaboration CKD-
EPI method [Delgado, 2021]. 
4. 
at screening for eligibility determination ([creatinine clearance (eGFR) of < 50 mL/min/1.73 m2]. 
5. 
If alkaline phosphatase is elevated, consider fractionating. 
 

 
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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 
an AE or SAE. 
Events NOT Meeting the AE Definition  

 
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• 
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 8.4.9): 
• 
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 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 

 
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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 
the participant’s records. 

 
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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. 
• 
As AEs will not be solicited in this study, no list of solicited events is specified in 
this protocol. 
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. 

 
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• 
There may be instances when copies of medical records for certain cases are 
requested by VH/GSK. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to VH/GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
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 one of the following categories according to the DAIDS 
toxicity scales (refer to Section 10.7). 
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 one of the severity 
categories described in the functional DAIDS table shown in Section 10.7. 
Note: An event is defined as ‘serious’ when it meets at least one 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 CIBs 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. 

 
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• 
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 
assessment. 
• 
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. 
• 
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. 

 
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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 
histopathology. 
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 8.4.3). 
10.3.6.7. 
Reporting of SAE 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 VH/GSK non-IMP they will 

 
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report these events to VH/GSK or to the concerned competent authority 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. 
SAE Reporting to VH/GSK via Paper Data Collection Tool 
• 
Email 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 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. 

 
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10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Participant of childbearing potential 
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. 
Participants of nonchildbearing potential 
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. 
• Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH 
measurement >40 IU/L is required. 

 
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• 
Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception guidance 
10.4.2.1. 
Participants of childbearing potential 
Participants of childbearing potential must agree to use contraception/barrier as detailed 
below: 
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. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 
Highly Effective Methodsb That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
• oral 
• intravaginal 
• transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• 
injectable 
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 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational 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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10.4.2.2. 
Participants assigned as male at birth 
Male participants must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom and should also be advised that a female partner (if 
of child-bearing potential) to use a highly effective method of contraception with 
a failure rate of <1%. 
AND 
• Partner of child-bearing potential to use an additional highly effective 
contraceptive method (with a failure rate of <1%) that has a low user 
dependency or that is user dependent. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY FOR PARTNERS OF CHILD-
BEARING POTENTIAL INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 
Highly Effective Methodsb That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• 
injectable 
Sexual abstinence 
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 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 

 
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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: Genetics 
The potential use and analysis of DNA samples is explained as follows: 
• 
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to the 
CAI study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a [blood/saliva] sample will be collected 
for DNA analysis from consenting participants. 
• 
DNA samples will be used for research related to VH4004280, VH4011499 or HIV 
and related diseases. They may also be used to develop tests/assays, including 
diagnostic tests related to VH4004280, VH4011499, interventions of this drug class 
and/or HIV disease. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate). 
• 
Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to VH4004280, VH4011499 or study interventions of this 
class to understand the study disease or related conditions. 
• 
The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on VH4004280, VH4011499 or other 
CAIs of HIV-1 continues but no longer than 15 years or other period as per local 
requirements. 

 
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10.6. 
Appendix 6: Liver safety: required actions and follow-up 
assessments 
Phase 2a liver chemistry monitoring criteria have been designed to assure participant 
safety and to evaluate liver event etiology. In addition, see Section 8.3.7 (Clinical criteria 
for pausing and/or stopping the study). 
Phase 2a Liver Chemistry Monitoring/Stopping Criteria and Required Follow Up 
Assessments 
Liver Chemistry Monitoring/Stopping Criteria 
 
ALT-absolute 
ALT≥3xULN 
Report the following as an SAE1,2: 
• ALT≥3xULN AND total bilirubin2xULN (>35% direct bilirubin) or 
• ALT≥3xULN AND international normalized ratio (INR) >1.5 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue CAI study 
intervention, if applicable, and do not 
restart. 
• Report the event to VH medical monitor 
within 24 hours. Follow SAE reporting 
requirements if applicable.  
• Complete the liver event eCRF 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. 
• Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING). 
MONITORING: 
If ALT≥3xULN AND total bilirubin  2xULN 
or INR >1.5 
Make every attempt to carry out liver event 
follow-up assessments at the central 
laboratory as described below: 
• Viral hepatitis serology3 
• Syphilis screening 
• Drugs of abuse screen, including alcohol 
• Obtain international normalized ratio 
(INR)2 and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis within 60 hours of last dose 
or as soon as possible in relation to the 
most recent dose. Additional samples can 
be obtained as needed as dependent on 
the medical guidance4  
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 

 
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Liver Chemistry Monitoring/Stopping Criteria 
• Repeat liver chemistries (include ALT, 
aspartate transaminase [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, stabilise or return to 
within baseline. 
• A specialist or hepatology consultation is 
recommended. 
If ALT≥3xULN AND total bilirubin < 2xULN 
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. 
gamma-glutamyl transferase (GGT), 
glutamate dehydrogenase (GLDH) and 
serum albumin. 
• Fractionate bilirubin1 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 eCRF form. 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, recreational drugs, and other 
over the counter medications 
• Record alcohol use on the liver event 
alcohol intake eCRF 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 

 
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Liver Chemistry Monitoring/Stopping Criteria 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) and 
/or liver biopsy5 to evaluate liver disease; 
complete Liver Imaging and/or Liver 
Biopsy eCRF forms. 
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  3xULN and total bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving 
anticoagulants. 
3. 
Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; hepatitis E IgM 
antibody; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing) and. 
4. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of CAI 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. 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 laboratory manual. 
5. 
Liver biopsy may be considered and discussed with local specialists if available, for instance: 
o 
In participants when serology raises the possibility of autoimmune hepatitis (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. 

 
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10.7. 
Appendix 7: Division of AIDS table for grading the severity 
of adult and pediatric adverse events 
CORRECTED 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. 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
Table 10 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. 
Table 10 
DAIDS grading for an AE that is not specifically identified in the 
grading table 
 
For more information, please refer to the DAIDS grading table corrected version 2.1, July 
2017 [DAIDS, 2017]. 

 
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10.8. 
Appendix 8: 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  
• 
Candidiasis of oesophagus  

 
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• 
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 
oesophagitis (onset at age >1 month) 
• 
Histoplasmosis, disseminated or extrapulmonary  
• 
Isosporiasis, chronic intestinal (>1 month's duration)  
• 
Kaposi's sarcoma  
• 
Lymphoma, Burkitt's (or equivalent term)  
• 
Lymphoma, immunoblastic (or equivalent term)  
• 
Lymphoma, primary, of brain  
• 
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary  
• 
Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary  
• 
Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary 
• 
Pneumocystis jirovecii pneumonia  
• 
Pneumonia, recurrent 
• 
Progressive multifocal leukoencephalopathy  
• 
Salmonella septicaemia, recurrent  
• 
Toxoplasmosis of brain, onset at age >1 month  
• 
Wasting syndrome attributed to HIV. 
Source: [CDC, 2014] 

 
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10.9. 
Appendix 9: Permissible Procedures During COVID-19 
Pandemic 
Overall Rationale for this Appendix 
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
study intervention or other considerations if site personnel or study participants become 
infected with COVID-19. These challenges may lead to difficulties in meeting protocol-
specified procedures, including administering or using the study intervention or adhering 
to protocol-mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
These measures will remain in place until the site is able to resume normal working 
activities and may be re-instated as warranted. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, the 
investigator should consider specific public health guidance, the impact of any travel 
restrictions implemented by local/regional health authorities and local institutions, and 
individual benefit /risk when making enrollment and treatment decisions for trial 
participants. 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up however when not possible, for the duration of 
these special circumstances, the following measures may be implemented for enrolled 
participants. 
• 
Investigators should document in site files how restrictions related to COVID-19 led 
to the changes in study conduct and duration of those changes and indicate which 
trial participants were impacted and how those trial participants were impacted (as 
per the current local COVID-19 related regulatory guidance). 
• 
Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. 
• 
Participants previously deemed eligible during the screening period unable to attend 
within the allowable screening window due to COVID-19 may be rescreened. 
• 
A participant who is found to have SARS-CoV-2 infection during the study may 
proceed in the study at the discretion of the investigator and sponsor assuming the 
participant isolates according to current Centers for Disease Control and Prevention 
guidance and then has a repeat SARS-CoV-2 test that is negative. 

 
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• 
Participants who are withdrawn from the study due to COVID-19 infection 
(including exposure to COVID-19) may be replaced based upon the discretion of the 
sponsor and investigator. 
Vaccination for SARS-CoV-2 
Vaccination with an approved vaccine for SARS-CoV-2 is not permitted during the study 
but may occur at least 14 days prior to dosing on Day 1 or after Day 39/Early 
Discontinuation Visit. 
Data Management/Monitoring: 
• If on-site monitoring is no longer permitted, VH/GSK will consider remote Source 
Data Verification/Source Document Review (SDV/SDR) where permitted by the 
clinical site/institution. Remote SDV/SDR will be proposed to study sites to meet a 
patient and/or critical quality need, e.g., to assess participant safety or to ensure data 
integrity. In case of remote SDV/SDR, VH/GSK will work with the site to ensure 
participant privacy. 
• eCRF/CRF Final or Interim Sign off Process: The investigator is responsible for 
ensuring that the data within the eCRF casebook and any other data sources utilized 
during the study for each study participant is complete and consistent with source 
documents throughout the study (ICH GCP 4.9.1 4.9.2). The investigator may sign/re-
sign the eCRF from any computer/location by accessing the eCRF using his/her 
unique eCRF log-in credentials. The investigator may delegate this activity to another 
medically qualified and trained sub-investigator and this must be documented on the 
Delegation of Responsibilities (DoR) Log. It is recommended that the PI identifies a 
sub-investigator as a back-up for eCRF signatures. The sub-investigator must be 
appropriately trained on the protocol and eCRF requirements (with training 
documented), and the DoR log updated accordingly. 
• Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by VH/GSK. 
 
 

 
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10.10. 
Appendix 10: Country-specific requirements 
10.10.1. 
Specific requirements for France 
This appendix includes all applicable requirements of French Public Health Code / 
specific local GSK requirements and identifies, item per item, the mandatory 
modifications or additional information to the study protocol. 
1. Concerning the «SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA» 
The following vulnerable subject populations will be excluded of compensation for the 
inconvenience of participating in the study: minors, protected subjects, adult subjects not 
in condition to express their consent, subjects deprived of liberty, subjects receiving 
psychiatric cares, subjects hospitalized in a Health and Social Establishment for other 
purpose than the participation to the study. 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category (French Public Health Code L.1124-1). 
It is the investigator’s responsibility to ensure and to document (in the source document - 
subject notes) that the subject is affiliated to or beneficiary of a social security category. 
Subjects will be compensated for the inconvenience of participating in the study. The 
amount of compensation is stated in the Informed Consent Form. Subjects not completing 
the study for whatever reason could be compensated generally on a pro rata basis. 
According to French Public Health Code (L.1121-16 and R.1121-16), the following 
people must be registered in National File (“Fichier National”): 
• 
Healthy volunteer; 
• 
Subjects if the aim of the study is not linked to their disease; 
• 
Subjects on request of the Ethics Committee regarding study risks and 
constraints. 
The following details will be described: 
• 
Reference of the study 
• 
Surname and first name 
• 
Date and place of birth 
• 
Gender 
• 
Dates of beginning and termination of the study 
• 
Exclusion period during which the subject cannot participate to another study 
(French Public Health Code L.1121-12) 

 
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• 
The total amount of compensation, if any. 
The subjects’ registration in National File (“Fichier National”) should be documented in 
the source document - subject notes and monitored by the CRA. 
2. Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
• In section “Regulatory and Ethical Considerations, including the Informed 
Consent Process” of study protocol 
 Concerning the process for informing the subject and/or his/her legally 
authorized representative, the following text is added:  
French Patient Informed Consent is a document which summarizes the main 
features of the study and allows collection of the subject and/or his/her legally 
authorized representative written consent. It also contains a reference to the 
single scientific and ethical regulatory authorization. 
 Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
French Patient Informed Consent Form is in duplicate (triplicate for minor 
subject). 
The first page of the Patient Informed Consent Form is given to the 
investigator. The copy is kept by the patient or legally authorized 
representative. 
• Notification to the hospital director 
In accordance with Article R.1123-69 of the French Public Health Code, the 
Hospital Director is informed of the commitment to the trial in her/his 
establishment. The Hospital Director is supplied with the protocol and any 
information needed for the financial disposition, the name of the 
investigator(s), the number of sites involved in his establishment and the 
estimated time schedule of the trial. 
• Information to the hospital pharmacist 
In accordance with Article R.1123-70 of the French Public Health Code, the 
Hospital Pharmacist is informed of the commitment to the trial in her/his 
establishment. The Pharmacist is supplied with a copy of the protocol (which 
allows her/him to dispense the drug(s) of the trial according to the trial 
methodology), all information concerning the product(s) of the trial (e.g., 
included in the IB), the name of the investigator(s), the number of sites 
involved in her/his establishment and the estimated time schedule of the trial. 

 
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3. 
Concerning the “DATA MANAGEMENT” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacists if applicable, 
involved in this clinical trial, and data regarding the subjects recruited in this 
clinical trial (subject number, treatment number, subjects status with respect to the 
clinical trial, dates of visit, medical data) will be collected and computerized in 
VH/GSK data bases by VH/GSK or on its behalf, for reasons of follow up, 
clinical trial management and using the results of said clinical trial. According to 
the data privacy regulation, each of these people aforesaid has a right of access, 
correction and opposition on their own data through VH/GSK (Clinical 
Operations Department). 
• Ethnic Origin 
In accordance with the data privacy regulation, the ethnic origin, as any personal 
data, can only be collected if the collection of this data is strictly necessary and 
relevant for the purpose of the study. 
• Testing of Biological Samples 
In accordance with the French Public Health Code – article L1211-2, a biological 
sample without identified purpose at the time of the sample and subject’s 
preliminary information is not authorized. 
4. 
Concerning Data Privacy 
In accordance with the applicable data privacy regulation, personal data are 
processed in a manner that ensures appropriate security, including protection 
against unauthorized or unlawful processing and against accidental loss, 
destruction or damage, using appropriate technical or organizational measures. 
The processing is whether deemed to be compliant with one of the methodology 
of reference (MR-001) or has been the subject of a request for authorization to the 
CNIL. The investigator has, regarding the processing data related to her/him, a 
right of access, of rectification, erasure and of opposition with VH/GSK in 
accordance with the legal provisions. 
 
 

 
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11. 
REFERENCES 
CDC Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10. 
Claborn KR, Meier E, Miller MB, Leffingwell TR. A systematic review of treatment 
fatigue among HIV-infected patients prescribed antiretroviral therapy. Psychol Health 
Med. 2015;20(3):255-65. doi: 10.1080/13548506.2014.945601. Epub 2014 Aug 11. 
PMID: 25110152; PMCID: PMC4315727. 
Delgado, C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, 
Miller WG, Moxey-Mims MM, Roberts GV, St. Peter WL, Warfield C, Powe NR, A 
Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force 
on Reassessing the Inclusion of Race in Diagnosing Kidney Disease, American Journal 
of Kidney Diseases (2021), doi: https://doi.org/10.1053/j.ajkd.2021.08.003. 
GlaxoSmithKline Document Number TMF-14580566, Modeling and Simulation 
Analysis Report to predict the Pharmacokinetics of VH4011499 for FTIH Study, 
March 2022. 
GlaxoSmithKline Document Number TMF-14086139, Modeling and Simulation 
Analysis Report to predict the Pharmacokinetics of VH4004280 for FTIH Study, 
October 2021. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et.al 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035–1043. 
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UNAIDS [Internet] Global AIDS Epidemiological Estimates Update 2021. Available 
from https://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf 
and accessed via https://www.unaids.org/en/resources/fact-sheet 18 August 2021. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1. July 2017. 
VH4004280 Clinical Investigator's Brochure, VH Document No. RPS-CLIN-048482, 
13 February 2023. 
VH4004280 Supplement 01 to Clinical Investigator's Brochure, VH Document No. 
RPS-CLIN-056826, May 2023. 
VH4011499 Clinical Investigator's Brochure, VH Document No. RPS-CLIN-026329, 
07 April 2022. 
VH4011499 Supplement 01 to Clinical Investigator's Brochure, VH Document No. 
RPS-CLIN-047476, 28 November 2022. 
VH4011499 Supplement 02 to Clinical Investigator's Brochure, VH Document No. 
RPS-CLIN-046304, 16 February 2023. 
VH4011499 Supplement 03 to Clinical Investigator's Brochure, VH Document No. 
RPS-CLIN-056829, May 2023. 
ViiV Healthcare Protocol for Study 217058, First-Time-in-Human (FTIH) Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy 
Participants, VH Document No.TMF-15100069, Amendment 2, November 2022. 
ViiV Healthcare Protocol for Study 218490, First-Time-in-Human (FTIH) Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4011499 in Healthy 
Participants, VH Document No. TMF-14909676, Amendment 1, November 2022. 
CCI

Signature Page for  218307 TMF-16106355 v3.0
Signature Page for TMF-16106355 v3.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 08-May-2023 14:59:42 GMT+0000
PPD