Clinical trial NCT05163522
Conditions: HIV Infections
Keywords: First-time-in-human GSK4004280 VH4004280 HIV-1 capsid inhibitor Single ascending doses Multiple ascending doses
Sponsor: ViiV Healthcare
Start date: 2021-12-13; Completion date: 2023-06-21
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4004280 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD), Part 2 will investigate multiple ascending doses and drug-drug interaction (MAD/MAD DDI) Part 3 will investigate single dose relative bioavailability (RBA) of a new formulation of VH4004280.

Detailed description:

Arms: arm 1: Healthy participants were given a single oral dose of placebo on Day 1 and were followed up to approximately Day 49. arm 2: Healthy participants were given a single oral dose of 10 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49. arm 3: Healthy participants were given a single oral dose of 50 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49. arm 4: Healthy participants were given a single oral dose of 150 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49. arm 5: Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49. arm 6: Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49. arm 7: Healthy participants were given a dose of placebo once daily (QD) for a 14-day period and were followed up to approximately Day 63. arm 8: Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63. arm 9: Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63. arm 10: Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63. arm 11: Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.
Interventions: intervention 1: VH4004280 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: VH4004280 will be administered. intervention 2: Placebo will be administered. intervention 3: Midazolam will be administered

Protocol documents:
Prot_000.pdf: 
TMF- 15100069 
CONFIDENTIAL 
 
ViiV Healthcare group of companies 
 
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Protocol Amendment 02 
 
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Clinical Study Protocol template V16 dated 24-Jun-2021 
TITLE PAGE 
Protocol Title: A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled 
Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered 
VH4004280 in Healthy Participants. 
Protocol Number: 217058 / Amendment 02 
Compound Number 
or Name: 
GSK4004280 (Also known as VH4004280) 
Brief Title: VH4004280 First-Time-in-Human-Study. 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address (excluding US):  
ViiV Healthcare group of companies 
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, USA 
Telephone: +1 877-844-8872 
Regulatory Agency Identifying Number(s):  
Registry: IND 
ID: 156318  
Medical Monitor Name and Contact Information: found in the Study Reference 
Manual 
Sponsor Signatory  
Scott McCallister, MD 
Vice President and Head, Physician Center of Excellence 
ViiV Healthcare 
Approval Date: 17 Nov 2022 
Copyright 2022ViiV Healthcare and the GSK group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited.


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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. PPD Inc. and GlaxoSmithKline are 
supporting ViiV Healthcare in the conduct of this study.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
17 Nov 2022 
Amendment 1 
18 January 2022 
Original Protocol 
10 October 2021 
 
Amendment 02, 17 Nov 2022 
 
Overall Rationale for the Amendment: This amendment results from Sponsor 
decisions to include an evaluation of the VH4004280 tablet formulation for comparison 
with the existing VH4004280 PiB data and any potential perpetrator risks of DDIs 
associated with CYP3A4 inhibition and induction and OATP1B1/1B3 inhibition. An 
additional optional MAD dosing group (Optional MAD Dosing Group 4) is being added 
and MAD Dosing Group 3 is being required by the Sponsor in response to the inclusion 
of DDI evaluations. Part 3 of the study was included to evaluate the safety, tolerability 
and pharmacokinetics of the VH4004280 tablet formulation. Updates are also made 
following new non-clinical findings from definitive repeat dose toxicology studies of 
VH4004280 for up to 3 months duration with the 
 
 in rats and SC administration in dogs. As a result, the NOAEL has been 
updated as well. Additionally, revisions are also being added to reflect the decision to 
extend outpatient follow-up by two additional weekly visits as communicated in the 25 
March 2022 Protocol Administrative Letter. Lastly, updated study conduct guidance 
during the COVID-19 Pandemic and points of clarification have been incorporated 
throughout the protocol. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 (Synopsis) 
Updates supporting the addition of midazolam 
intervention as a sensitive CYP3A4 probe substrate and 
the evaluation of an endogenous biomarker 
(coproporphyrin I) as a OATP1B1/1B3 probe substrate in 
Part 2. Updates supporting the addition of a dosing group 
(Part 3) to evaluate a VH4004280 tablet formulation in 
comparison with existing data from VH4004280 PiB. 
 
Updates supporting the requirement of MAD Dosing 
Group 3 and the addition of an optional MAD Dosing 
Group (Optional MAD Dosing Group 4). 
Updated primary endpoint to define the “liver panel”. 
Liver panel includes total bilirubin, direct bilirubin, 
alkaline phosphatase, AST, and ALT. 
Revision to evaluate the 
potential perpetrator risks of 
VH4004280 associated with 
CYP3A4 inhibition and 
induction and OATP1B1/1B3 
inhibition. Revision to 
evaluate the safety, 
tolerability and PK properties 
of VH4004280 tablets 
compared to existing data 
from PiB. 
 
Sponsor decision to evaluate 
VH4004280 in three MAD 
dosing groups and potentially 
evaluate VH4004280 in an 
optional fourth MAD dosing 
group based on observed PK 
and safety data. 
Clarification for statistical 
analyses. 
Section 1.1 
(Synopsis); Section 4 
(Study Design); 
Section 7.4.2 (Clinical 
Criteria for Pausing 
and/or Stopping the 
Study)  
Clarifications and updates regarding the utilization of the 
SDEC to support the addition of a dosing group (Part 3) 
to evaluate a VH4004280 tablet formulation in 
comparison with existing data from VH4004280 PiB.  
Sponsor decision to utilize 
the SDEC to review data from 
Part 3.  
Section 1.2 (Schema); 
Section 2.1 (Study 
Rationale); Section 
4.1 (Overall Study 
Design); Section 4.2 
((Scientific Rationale 
for Study Design); 
Section 4.3.7 (Tablet 
PK (Part 3) Dose 
Selection); Section 
5.3. (Lifestyle 
Considerations) 
Updates supporting the addition of midazolam 
intervention as a sensitive CYP3A4 probe substrate and 
the evaluation of an endogenous biomarker 
(coproporphyrin I) as an OATP1B1/1B3 probe substrate 
in Part 2. Updates supporting the addition of dosing 
group (Part 3) to evaluate a VH4004280 tablet 
formulation in comparison with existing data from 
VH4004280 PiB. 
 
Updates supporting the requirement of MAD Dosing 
Group 3 and the addition of an optional MAD Dosing 
Group (Optional MAD Dosing Group 4). 
 
Revision to evaluate the 
potential perpetrator risks of 
VH4004280 associated with 
CYP3A4 inhibition and 
induction and OATP1B1/1B3 
inhibition. Revision to 
evaluate the safety, 
tolerability and PK properties 
of VH4004280 tablets 
compared to existing data 
from PiB. 
 
 Sponsor decision to evaluate 
VH4004280 in three MAD 
dosing groups and potentially 
evaluate VH4004280 in an 
optional fourth MAD dosing 
group based on observed PK 
and safety data. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 (Schedule 
of Activities (SOA) 
Updated to reflect the decision to extend outpatient 
follow-up by two additional weekly visits as 
communicated in the 25March2022 Protocol 
Administrative Letter.  
 
Updates supporting the addition of midazolam 
intervention as a sensitive CYP3A4 probe substrate and 
the evaluation of an endogenous biomarker 
(coproporphyrin I) as an OATP1B1/1B3 probe substrate 
in Part 2. Updates supporting the addition of a dosing 
group (Part 3) to evaluate a VH4004280 tablet 
formulation in comparison with existing data from 
VH4004280 PiB. 
 
Updates supporting the requirement of MAD Dosing 
Group 3 and the addition of an optional MAD Dosing 
Group (Optional MAD Dosing Group 4). 
Updates to the specify timing of SARS-Cov-2 testing 
prior to study drug dosing. 
Removal of Plasma Sample (metabolism) assessment in 
Part 2 (all dosing groups) at specific timepoints.  
 
Revisions and updates to 
SOA were based on 
emerging PK data indicating 
longer PK half-life than 
anticipated and following 
review of emerging safety 
data. 
 
Revision to evaluate the 
potential perpetrator risks of 
VH4004280 associated with 
CYP3A4 inhibition and 
induction and OATP1B1/1B3 
inhibition. Revision to 
evaluate the safety, 
tolerability and PK properties 
of VH4004280 tablets 
compared to existing data 
from PiB. 
 
Revision following updated 
Sponsor organizational 
guidance regarding healthy 
volunteer study conduct 
during the COVID-19 
pandemic. 
 
Sponsor decision to evaluate 
VH4004280 in three MAD 
dosing groups and potentially 
evaluate VH4004280 in an 
optional fourth MAD dosing 
group based on observed PK 
and safety data.  
 
Sponsor driven clarification 
as this sample collection was 
not needed at all previously 
marked timepoints.  
Section 2.3 
(Benefit/Risk 
Assessment) 
Updates to reflect non-clinical findings from definitive 
repeat dose toxicology studies of VH4004280 for up to 3 
months duration with the 
 
 in rats and SC administration in dogs. 
As a result, the NOAEL has been updated and is 
provided by the exposures observed following 
 
 in the 3-month rat 
study 
 
   
 
Updates to risk assessment summarizing new potential 
drug interactions risks with VH4004280 and midazolam 
introduced with the new study design. 
 
To provide new information of 
VH4004280. 
 
To align with conduct of the 
updated study design.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3 (Objectives 
and Endpoints) 
Updates to objectives and endpoints in alignment with 
conduct of the updated study design. 
 
Updated primary endpoint to define the “liver panel”. 
Liver panel includes total bilirubin, direct bilirubin, 
alkaline phosphatase, aspartate aminotransferase (AST), 
and alanine aminotransferase (ALT). 
Revision to evaluate the 
potential perpetrator risks of 
VH4004280 associated with 
CYP3A4 inhibition and 
induction and OATP1B1/1B3 
inhibition. Revision to 
evaluate the safety, 
tolerability and PK properties 
of VH4004280 tablets 
compared to existing data 
from PiB. 
 
Clarification for statistical 
analyses. 
Section 4 (Study 
Design) 
Updated to reflect the decision to extend outpatient 
follow-up by two additional weekly visits as 
communicated in the 25March2022 Protocol 
Administrative Letter 
Revisions and updates to 
follow-up duration were 
based on emerging PK data 
indicating longer PK half-life 
than anticipated and following 
review of emerging safety 
data 
Section 4.1.2 (Part 2 
(MAD); Section 4.3.4 
(Top Dose Rationale); 
Section 4.3.6 (Repeat 
Dosing Plan (Part 2)); 
Section 7.4.1 (PK 
Stopping Criteria for 
SAD and MAD) 
Updates to reflect non-clinical findings from definitive 
repeat dose toxicology studies of VH4004280 for up to 3 
months duration with the 
 
 in rats. As a result, the NOAEL has 
been updated and is provided by the exposures 
observed following 
 
 in the 3-month rat study 
 
   
 
Updates to reflect decision to include NOAEL as an 
additional, independent criterion for top dose 
determination in MAD (part 2) dose escalations. 
 
Sponsor driven decision to 
provide updated nonclinical 
toxicology information.   
 
Section 5.1 (Inclusion 
Criteria) 
Update to upper age limit for participants from 50 years 
of age to 55 years of age. 
 
Revision to inclusion criterion #3 to remove requirements 
around the timing of the SARs-CoV-2 PCR tests for 
eligibility. The criterion now reads, “Two consecutive 
negative SARs-CoV-2 PCR tests results are required 
prior to dosing.” 
Revision following updated 
Sponsor organizational 
guidance regarding healthy 
volunteer study conduct 
during the COVID-19 
pandemic. 
 
Revisions following review of 
emerging safety data and to 
support operational 
efficiencies. 
Section 5.2 (Exclusion 
Criteria) 
Revised exclusion criterion #9 to highlight examples of 
medications that are Cytochrome P450 enzyme inducers 
or inhibitors.  
 
Revised exclusion criterion #12 to provide a more 
conservative window of time regarding a participant’s 
past participation in another investigational study. 
 
Revised exclusion criterion #25 to include any 
sensitivities to the additional study intervention, 
midazolam.  
To support the updated study 
design.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4 (Screen 
Failures) 
Revised text to allow any individual who meets eligibility 
criteria is permitted to rescreen. 
 
To support operational 
efficiencies. 
Section 6 (Study 
Drug(s) and 
Concomitant Therapy) 
Updated to include details of midazolam for Part 2 (MAD) 
and VH4004280 tablets for Part 3 (Tablet PK). 
To support the updated study 
design. 
Section 6.7 
(Treatment of 
Overdose) 
Updated to reflect the decision to extend outpatient 
follow-up by two additional weekly visits as 
communicated in the 25March2022 Protocol 
Administrative Letter.  
 
The planned end of sampling 
updates based on emerging 
PK data indicating longer PK 
half-life than anticipated and 
following review of emerging 
safety data  
Section 7.1.3 (SARS-
CoV-2 Stopping 
Criteria) and Section 
10.8 (Appendix 8: 
Permissible 
Procedures During 
COVID-19 Pandemic) 
Revised the SARS-CoV-2 stopping criteria to allow for 
flexibility in how to manage the rest of a dosing group if a 
participant tests positive in the inpatient setting. It is no 
longer required to automatically discharge the rest of the 
dosing group if a participant tests positive in the inpatient 
setting. Decisions regarding the rest of the dosing group 
will be discussed with investigator and medical monitor. 
Revision to responsibly 
manage the ongoing study 
participation of COVID-19 
infected participants who are 
capable of completing the 
study and support operational 
efficiencies. 
Section 7.4.2.(Clinical 
Criteria for Pausing 
and/or Stopping the 
Study) 
Updated clinical pausing/stopping bulleted criteria. 
To align with organizational 
guidance updated in March 
2022.  
Section 8.1.2 (Vital 
Signs) 
Details of pulse oximetry included as part of risk 
mitigation strategy of midazolam dosing. 
 
Revised to qualify that temperature measurement should 
be according to site standard. 
Continuous pulse oximetry 
(15 minutes prior to 
midazolam dosing through 6 
hours post midazolam 
dosing) included to monitor 
for the respiratory effects of 
midazolam, on probe 
substrate drug dosing days. 
 
To permit flexibility observed 
at study site. 
Section 8.1.3.1 (12-
lead Safety ECGs)  
Revision to require repeat ECGs in triplicate in the case 
that the Investigator determines an ECG abnormality as 
clinically significant or is unable to determine the 
significance of abnormalities.  
 
 
Sponsor driven revision to 
allow more flexibility in study 
conduct and not require 
repeat ECGs in triplicate for 
abnormal readings that are 
determined as not clinically 
significant. 
Section 8.1.3.2. 
(Cardiodynamic 
Assessment (Clario)) 
Updated company name of the cardiodynamic 
assessment central reading vendor from eResearch 
Technology (eRT) to Clario. 
Update with current central 
reading vendor company 
name. 
Section 8.3 
(Pharmacokinetics) 
Section 8.5 
(Biomarkers) 
New information added regarding midazolam and 
coproporphyrin I sampling. 
To support the updated study 
design. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 9 (Statistical 
Considerations) 
Updated to include description of statistical analyses on 
new endpoints. 
A section on Bayesian simulation for dose escalation in 
MAD has been added.  
The Sample Size Determination section has been 
updated to provide expected precision of estimates for 
DDI evaluations and Part 3 for the chosen sample sizes. 
The potential for additional data cuts and analyses to 
instream dose escalation analyses to support regulatory 
needs publications or for other purposes has been 
added. 
To support the updated study 
design. 
Section 10.1.3 
(Informed Consent 
Process) 
Inclusion of text to further clarify that informed consent 
must be obtained from female partners of male 
participants if female partners become pregnant during 
the study. 
To provide further clarification 
of the informed consent 
process and data collection 
from female partners of male 
participants if female partners 
become pregnant during the 
study. 
Section 10.2 
(Appendix 2: Clinical 
Laboratory Tests) 
Revision to include creatine phosphokinase (CPK) to lab 
panel. 
To provide further clarification 
in study conduct. 
Section 10.9 
(Appendix 9: Protocol 
Amendment History) 
Relocated the Protocol Amendment Summary of 
Changes Table for the previous amendment 
(Amendment 01) to Appendix 9 for reference. 
For reference of overall 
rationale for protocol 
amendment 1 and summary 
of changes. 
Not applicable 
Other minor revisions that provide clarification. 
To provide further clarification 
in study conduct. 
 
 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 12 
1.1. 
Synopsis ..................................................................................................... 12 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study Rationale .......................................................................................... 31 
2.2. 
Background ................................................................................................ 31 
2.3. 
Benefit/Risk Assessment ............................................................................ 32 
2.3.1. 
Risk Assessment ......................................................................... 34 
2.3.2. 
Benefit Assessment ..................................................................... 38 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 38 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 39 
3.1. 
Estimands ................................................................................................... 40 
3.1.1. 
Primary Safety Estimands ............................................................ 40 
3.1.2. 
Primary Pharmacokinetic Estimand ............................................. 42 
4. 
STUDY DESIGN .................................................................................................... 43 
4.1. 
Overall Design ............................................................................................ 43 
4.1.1. 
Part 1 (SAD) ................................................................................ 43 
4.1.2. 
Part 2 (MAD) ................................................................................ 44 
4.1.3. 
Part 3 (Tablet PK) ........................................................................ 45 
4.1.4. 
Screening, Follow-up & Study Participation Duration ................... 45 
4.2. 
Scientific Rationale for Study Design .......................................................... 46 
4.3. 
Justification for Dose .................................................................................. 46 
4.3.1. 
Human Pharmacokinetics Prediction ........................................... 47 
4.3.2. 
Therapeutic Dose Rationale......................................................... 47 
4.3.3. 
Starting Dose Rationale in Part 1 (SAD) ...................................... 48 
4.3.4. 
Top Dose Rationale ..................................................................... 49 
4.3.5. 
Planned Doses and Safety Coverage (Part 1) ............................. 49 
4.3.6. 
Repeat Dosing Plan (Part 2) ........................................................ 50 
4.3.7. 
Tablet PK (Part 3) Dose Selection ............................................... 50 
4.4. 
Safety and Dose Escalation Committee ...................................................... 50 
4.5. 
End of Study Definition ............................................................................... 51 
5. 
STUDY POPULATION ........................................................................................... 52 
5.1. 
Inclusion Criteria ......................................................................................... 52 
5.2. 
Exclusion Criteria ........................................................................................ 54 
5.3. 
Lifestyle Considerations .............................................................................. 56 
5.3.1. 
Meals and Dietary Restrictions .................................................... 56 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 57 
5.3.3. 
Activity ......................................................................................... 57 
5.4. 
Screen Failures........................................................................................... 57 


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6. 
STUDY DRUG(S) AND CONCOMITANT THERAPY ............................................. 58 
6.1. 
Study drug(s) Administered ........................................................................ 58 
6.2. 
Preparation, Handling, Storage and Accountability ..................................... 60 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 60 
6.4. 
Study drug Compliance ............................................................................... 61 
6.5. 
Dose Modification ....................................................................................... 61 
6.6. 
Continued Access to Study drug after the End of the Study ........................ 61 
6.7. 
Treatment of Overdose ............................................................................... 61 
6.8. 
Concomitant Therapy.................................................................................. 62 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 63 
7.1. 
Participant Discontinuation of Study drug.................................................... 63 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 63 
7.1.2. 
QTc Stopping Criteria .................................................................. 64 
7.1.3. 
SARS-COV-2 Stopping Criteria ................................................... 64 
7.1.4. 
Temporary Discontinuation .......................................................... 64 
7.1.5. 
Rechallenge ................................................................................. 64 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 65 
7.3. 
Lost to Follow Up ........................................................................................ 65 
7.4. 
Study Pausing and/or Stopping Criteria ...................................................... 66 
7.4.1. 
PK Stopping Criteria for SAD and MAD ....................................... 66 
7.4.2. 
Clinical Criteria for Pausing and/or Stopping the Study ................ 66 
7.5. 
Site or Study Discontinuation ...................................................................... 67 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 68 
8.1. 
Safety Assessments ................................................................................... 68 
8.1.1. 
Physical Examinations ................................................................. 68 
8.1.2. 
Vital Signs .................................................................................... 68 
8.1.3. 
Electrocardiograms ...................................................................... 69 
8.1.4. 
Clinical Safety Laboratory Tests .................................................. 71 
8.2. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 72 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 72 
8.2.2. 
Method of Detecting AEs and SAEs ............................................. 73 
8.2.3. 
Follow-up of AEs and SAEs ......................................................... 73 
8.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 73 
8.2.5. 
Pregnancy ................................................................................... 73 
8.3. 
Pharmacokinetics ....................................................................................... 75 
8.4. 
Genetics ..................................................................................................... 76 
8.5. 
Biomarkers ................................................................................................. 76 
8.6. 
Immunogenicity Assessments ..................................................................... 76 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 77 
9.1. 
Statistical Hypotheses................................................................................. 77 
9.2. 
Analysis Sets .............................................................................................. 77 
9.3. 
Statistical Analyses ..................................................................................... 77 
9.3.1. 
General Considerations ............................................................... 77 
9.3.2. 
Primary Endpoints/Estimands Analyses ....................................... 78 
9.3.3. 
Safety Analyses ........................................................................... 80 
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9.3.5. 
Other Analyses ............................................................................ 81 
9.3.6. 
Safety and PK dose escalation analyses ..................................... 81 
9.4. 
Interim Analyses ......................................................................................... 87 
9.5. 
Final Analyses ............................................................................................ 87 
9.6. 
Sample Size Determination ........................................................................ 87 
9.6.1. 
Sample Size Sensitivity ................................................................ 88 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 90 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 90 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 90 
10.1.2. 
Financial Disclosure ..................................................................... 90 
10.1.3. 
Informed Consent Process .......................................................... 91 
10.1.4. 
Data Protection ............................................................................ 91 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 92 
10.1.6. 
Data Quality Assurance ............................................................... 92 
10.1.7. 
Source Documents ...................................................................... 93 
10.1.8. 
Study and Site Start and Closure ................................................. 94 
10.1.9. 
Publication Policy ......................................................................... 94 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 96 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 98 
10.3.1. 
Definition of AE ............................................................................ 98 
10.3.2. 
Definition of SAE .......................................................................... 99 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................. 100 
10.3.4. 
Reporting of SAE to VH/GSK ..................................................... 102 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 104 
10.4.1. 
Definitions: ................................................................................. 104 
10.4.2. 
Contraception Guidance for Male Participants and their 
Female Partners (if of child-bearing potential) ............................ 104 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 106 
10.6. 
Appendix 6: Abbreviations and Trademarks .............................................. 109 
10.7. 
Appendix 7: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, July 2017 ............................... 113 
10.8. 
Appendix 8: Permissible Procedures During COVID-19 Pandemic ........... 114 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 116 
11. REFERENCES ..................................................................................................... 119 
 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered 
VH4004280 in Healthy Participants. 
Brief Title: VH4004280 First-Time-in-Human-Study. 
Rationale: 
VH4004280 (also known as GSK4004280) belongs to a novel class of anti-retroviral 
(ARV) agents targeting a highly conserved region of the HIV-1 capsid protein. In-vitro 
experiments suggest its mechanism of action interferes with both the early (pre-
integration) and late (virus assembly) stages of the HIV-1 life cycle. There are currently 
no capsid inhibitors approved for the treatment of HIV infection in the US, although 
clinical efficacy and a generally favorable safety profile has been demonstrated in an 
investigational capsid inhibitor currently in development. In cell culture, VH4004280 
exhibits potent antiviral activity against a spectrum of HIV-1 isolates and subtypes. In 
MT-2 cells, a panel of 48 viruses with diverse CA sequences derived from different 
subtypes (A, CRF01_AE, B, C, F, and G) was inhibited with 50% effective concentration 
(EC50) values ranging from 0.08 nM to 0.92 nM and a median EC50 value of 0.27 nM 
(0.26 ng/mL). VH4004280 also displayed potent antiviral activity against multiple HIV-1 
strains and subtypes (A, CRF01_AE, CRF02_AG, B, C, D, E, F and G) in peripheral 
blood mononuclear cells (PBMCs). VH4004280 has demonstrated no cross-resistance 
with currently approved ARV classes. 
The overall objective of the ViiV CAI clinical development program is to develop 
investigational VH4004280 (also known as GSK4004280) as a long-acting novel 
medicine that can be administered via injection every month or longer 
 
. Either long-acting VH4004280-containing regimen 
would offer efficacy and safety comparable to currently available daily dosed ARV 
regimens yet improve both treatment adherence and quality of life through its less 
frequent dosing schedule. 
This FTIH study is designed to gain information on the safety, tolerability and PK 
properties of oral VH4004280 when administered as PiB. This study will also evaluate 
the safety, tolerability and PK properties of VH4004280 when administered as an oral 
tablet. The potential in-vitro based perpetrator risks of DDIs associated with CYP3A4 
inhibition and induction will also be evaluated by assessing the effect of VH4004280 on 
midazolam, a sensitive CYP3A4 probe substrate. The potential DDI risks associated with 
OATP1B1/1B3 inhibition will also be evaluated by assessing the effect of VH4004280 
on an endogenous biomarker as a probe (coproporphyrin I). Ultimately, this study will 
enable further clinical development of VH4004280, including a Phase 2a PoC study in 
CCI


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HIV-infected participants and a Phase 1 study of the long-acting injectable formulation of 
VH4004280.  
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single 
(Parts 1 and 3) and multiple (Part 2) doses of 
VH4004280 in healthy participants. 
• Incidence of adverse events (AEs), 
severity of AEs and proportion of 
participants who discontinue treatment 
due to AEs 
• Absolute values, change from baseline 
and maximum toxicity grade increase 
from baseline for liver panel laboratory 
parameters [consisting of total bilirubin, 
direct bilirubin, alkaline phosphatase, 
aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT)] 
To describe the plasma PK characteristics of 
VH4004280 in healthy participants following 
single (Part 1) and multiple (Part 2) doses. 
• Area under the plasma-concentration time 
curve (AUC): AUC(0-∞) for single dose 
and AUC(0-τ) for repeat dose 
• Maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(Tmax), and apparent terminal half-life 
(T1/2) will be calculated for each part (Part 
1 SAD and Part 2 MAD) as data in each 
part permits 
 
 
 


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Overall Design: 
This is a double-blind (sponsor unblinded), randomized, placebo-controlled, single and 
multiple-ascending-dose Phase 1 study to evaluate the safety, tolerability and 
pharmacokinetics of VH4004280, when administered as PiB formulation, in healthy adult 
participants. This study will also evaluate the DDI potential of VH4004280 for inhibition 
of OATP1B1/1B3 and changes in CYP3A activity, and evaluate the safety, tolerability 
and PK of a VH4004280 tablet formulation in comparison with existing data from 
VH4004280 PiB. All doses will be administered orally. This study will be executed in 3 
parts.  
In Part 1, the proposed dosing schedule is designed to investigate SAD of VH4004280 in 
up to 7 dosing groups. In Part 2, the proposed dosing schedule is designed to investigate 
MAD of VH4004280 administered daily, for 14 days in up to 4 dosing groups. A 
midazolam probe will be administered with VH4004280 or placebo in up to two dosing 
groups in Part 2 (MAD/DDI dosing group(s)) to examine the potential of VH4004280 to 
inhibit or induce CYP3A activity. The MAD/DDI dosing group(s) will also include the 
collection of endogenous biomarker (coproporphyrin I) samples before and following 
repeat dose administration of VH4004280 or placebo to investigate the potential of 
VH4004280 to inhibit OATP1B1/1B3. Review of available data from previous SAD and 
emerging MAD dosing groups will determine if the DDI potential of VH4004280 will be 
evaluated in one or two MAD dosing groups.   
Part 3 (Tablet PK) is an open-label, single dose-design to evaluate the safety, tolerability 
and PK properties of the tablet formulation of VH4004280, in comparison with existing 
data from VH4004280 PiB, in one dosing group. 
A SDEC will govern dose escalation decisions, including the determination of subsequent 
doses, based on emerging safety and pharmacokinetic data. The SDEC will also govern 
the total duration of dosing and follow-up, which may be altered if actual PK parameters 
differ significantly from predicted values. 
Number of Participants: 
A sufficient number of healthy adults will be screened to provide 8 participants for 
randomization (6:2 active: placebo) within each SAD dosing group. Within each MAD 
dosing group, up to 8 participants will be randomized (6:2 active: placebo). Within each 
MAD/DDI dosing group, up to 10 participants will be randomized (8:2 active: placebo). 
Overall, up to 56 participants (42 active: 14 placebo) will be included in Part 1. Up to 36 
participants (28 active: 8 placebo) will be included in Part 2, in the case that two 
MAD/DDI dosing groups are needed.  Up to 6 participants will be included (6 active) in 
Part 3 (Tablet PK). 
If participants prematurely discontinue the study, additional replacement participants may 
be enrolled at the discretion of the Sponsor. Assignment of replacement numbers will be 
detailed in the SRM. 
Note: Enrolled means a participant's agreement to participate in a clinical study following 
completion of the informed consent process, passed screening, and were randomized in 


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the study. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol. 
Intervention Groups and Duration: 
Study participants will have a screening visit within 30 days prior to the first dose of 
VH4004280 / PBO. 
In Part 1 (SAD), participants will receive a single dose of VH4004280 or PBO (6:2) on 
Day 1. Safety and PK assessments will be performed at timepoints specified in the SoA. 
Participants will remain in the clinic until completion of the Day 7 procedures and will 
return to the clinic on Days 14, 21, 28, 35, and 42 for follow up procedures and a final 
follow up visit on Day 49. 
In Part 2 (MAD) participants will receive doses of VH4004280 or PBO once daily for an 
anticipated 14-day period. Participants in non-DDI MAD dosing groups will receive daily 
doses of VH4004280 or PBO (6:2) on Day 1 through Day 14 and will remain in the clinic 
until completion of the Day 21 procedures and will return to the clinic on Days 28, 35, 
42, 49, and 56 for follow up procedures and a final follow up visit on Day 63. In 
MAD/DDI dosing group(s), participants will receive a single dose of midazolam on Days 
1, 2, and 15, and daily doses of VH4004280 or PBO (8:2) on Day 2 through to Day 15. A 
single dose of midazolam will be co-administered with a dose of VH4004280 or PBO on 
Days 2 and 15. Participants will remain in the clinic until completion of the Day 22 
procedures and will return to the clinic on Days 28, 35, 42, 49, and 56 for follow up 
procedures and a final follow up visit on Day 63. 
In Part 3 (Tablet PK), participants will receive a single dose of VH4004280 as a tablet 
formulation on Day 1. The dose of VH4004280 to be administered in Part 3 will be 
determined based on review of available data from previous dosing groups in Parts 1 
(SAD) and 2 (MAD) and predicted clinical doses. Participants will remain in the clinic 
until completion of the Day 7 procedures and will return to the clinic on Days 14, 21, 28, 
35, and 42 for follow up procedures and a final follow up visit on Day 49.  
Duration of participation through follow-up, determination of subsequent doses, dosing 
frequency and total duration of dosing may be altered if actual PK parameters differ 
significantly from predicted values (e.g., if half-life is significantly longer or shorter than 
the predicted). The duration of post dose follow-up will not exceed five half-lives. 
Safety and Dose Escalation Committee: Yes 
The study will utilize a Safety and Dose Escalation Committee SDEC which will include, 
at a minimum, the Sponsor medical monitor, clinical pharmacologist, and statistician to 
meet with the Investigator to make a dose escalation decision. Limited additional Sponsor 
representatives may be included on the SDEC. The decision to proceed to the next dose 
level of VH4004280 in both Part 1 (SAD) and Part 2 (MAD) will be made by the SDEC 
as outlined in the SDEC Charter, based on safety, tolerability and PK data obtained from 
the prior dose level(s). The study will also utilize a SDEC for instream reviews of 
emerging safety, tolerability and PK data during Part 3.


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Clinical Study Protocol template V16 dated 24-Jun-2021 
1.2. 
Schema 
 
Note: Actual doses (following Dosing Group 1) and the timing of transition from Part 1 (SAD) to Part 2 (MAD) will be informed by the 
emerging PK and safety data from previous dosing groups. Part 3 (Tablet PK) will be informed by available PK and safety data from 
previous dosing groups and predicted clinical doses 
.
CCI
CCI


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1.3. 
Schedule of Activities (SoA) 
The timing of planned study assessments may change during the course of the study 
based on emerging data/in-stream data review (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. These changes, if 
applicable will be determined at the discretion of the SDEC, the details of which are 
provided in the SDEC charter.  
Any changes in the timing of planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and 
approved by the relevant study team member and then archived in the sponsor and site 
study files but will not constitute a protocol amendment. 
The Competent Authority and IEC/IRB will be informed of any safety issues that 
constitute a substantial amendment and require alteration of the safety monitoring scheme 
or amendment of the ICF. The changes will be approved by the Competent Authority and 
the IEC/IRB before implementation. 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 1 
SCREENING AND FOLLOW UP/ EARLY DISCONTINUTION ASSESSMENTS (PART 1, PART 2, and PART 3) 
Procedure 
Screening 
(up to 30 days 
prior to Day 1)  
Follow-up/Early 
Discontinuation 
Visit (49 days 
post last dose)  
Notes 
Follow-up Visit to occur approximately 49 days after last study drug administration or 5 half-lives 
(as determined from Part 1 PK data). 
Outpatient Visit 
X 
X 
 
Informed Consent 
X 
 
 
Inclusion and Exclusion Criteria  
X  
 
Additional tests may be performed by the Investigator, as deemed necessary to determine 
eligibility (e.g., where safety or laboratory findings indicate). Tests will be conducted according 
to site specific standards. 
Demography 
X  
 
 
Medical History  
X 
 
 
Full Physical Examination (Including 
Height and Weight at the screening visit) 
X 
 
Additional examinations may be performed, or brief examinations made full examinations, by 
the Investigator, as deemed necessary (e.g., where safety or laboratory findings indicate). 
Brief Physical Examination and Weight 
 
X 
 
12-lead ECG  
X 
X 
Single ECGs will be used to determine participant eligibility at Screening. 
Vital signs 
X 
X 
 
Drug/alcohol/cotinine screen 
X 
 
 
HIV, Hep B and Hep C Screen 
X 
 
 
Clinical Laboratory assessments 
X 
X 
See Appendix 2 for details. Total bile acids and lipid panel at Follow-up/Early Discontinuation 
Visit, but not at Screening. 
Follicle-stimulating Hormone 
X 
 
As required in women to confirm postmenopausal status 
SAR-CoV-2 PCR test  
X 
 
Two consecutive SARS-CoV-2 PCR negative results are required prior to dosing. The tests 
should be performed on different days with the first test performed between Day -7 and Day -1 
and the second test performed pre-dose. 
 
Plasma pharmacokinetic sample 
 
X 
 
Adverse Event Review 
X 
X 
The collection of SAEs will be from the screening visit to the end of the study. The collection of 
non-serious AEs will be from the start of study intervention until the end of the study. 
Concomitant Medication Review 
X 
X 
 
 
 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 2 
Part 1 Single Ascending Dose (SAD) (All Dosing Groups) - Inpatient Days -1 to 7 
Procedure 
Day 
 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
 
Pre-
dose 
0 h 
0.5h 
1 h 
1.5 h 
2h 
3 h 
4h 
6 h 
8h 
10h 
12h 
24h 
48h 
72h 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Drug/alcohol/cotinine 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief Physical Exam1 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
Vital signs2 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X4 
  
X 
  
  
  
X 
  
  
  
X 
X  
X 
  
X 
  
X 
Cardiodynamic 
Assessment3 
  
X5 
<=============================================================>6 
  
  
  
  
  
Meals 
 
X 
  
See Section 5.3.1 
Clinical Laboratory 
Tests7,8,9 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X  
X 
SARS-CoV-2 PCR 
Test10 
X 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration11 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Clinical Study Protocol template V16 dated 24-Jun-2021 
Procedure 
Day 
Plasma Sample 
(pharmacokinetics)12 
  
X 
 g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample 
(metabolism)12 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Sample 
(metabolism)13 
  
X 
  
<===============================================================> 
  
  
  
  
  
Adverse Event Review 
<================================================================================================================> 
Concomitant 
Medication Review 
<================================================================================================================> 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
See Section 8.1.2 for details of Vital Sign measurements. On Day 1, all vitals should be measured pre-dose; only blood pressure and pulse rate are measured for all 
remaining Day 1 timepoints. 
3. 
See Section 8.1.3 for details of 12-lead ECGs and Cardiodynamic Assessment. 
4. 
At pre-dose a triplicate 12-lead ECG is required within 90 minutes of dosing. 
5. 
Three pre-dose ECG extractions prior to dosing on Day 1.  
6. 
Post-dose ECG extraction will coincide with plasma PK sample schedule up to 24h post-dose.  
7. 
See Appendix 2 for details of Clinical Laboratory Tests. 
8. 
Total Bile Acids (TBA) and Coagulation Panel required on Day -1, Day 2 and Day 7 only.  
9. 
Lipid Panel required on Day -1 and Day 7 only. 
10. Two consecutive SARS-CoV-2 PCR negative results are required prior to dosing. The tests should be performed on different days with the first test performed between Day -
7 and Day -1 and the second test performed pre-dose. Admission to unit may be done on Day -2 if necessary for SARS-CoV-2 PCR testing.  
11. In Part 1, VH4004280 will be administered as a PiB. 
12. See Section 8.3 for further details for plasma PK and metabolite sample collection. One whole blood sample of sufficient volume will be processed into two aliquots of 
plasma: one to measure concentrations of VH4004280 and the other to characterize related metabolites. 
13. A urine sample will be collected pre-dose (40 mL) within 1 h prior to dosing and from time 0 up to 24 h post dosing. Details of urine collection and processing are detailed in 
the SRM. 
 
 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 3 
Part 1 SAD (All Dosing Groups) Outpatient Visit Days 14, 21, 28, 35, 42, and 49 
 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
See Section 8.1.2 for details of Vital Sign measurements. 
3. 
See Section 8.1.3 for details of 12-lead ECGs. 
4. 
See Appendix 2 for details of Clinical Laboratory Tests. 
5. 
Total Bile Acids, Coagulation Panel and Lipid Panel to be included in each weekly clinical laboratory test.  
6. 
See Section 8.3  for further details for plasma PK sample collection. One whole blood sample of sufficient volume will be processed to measure concentrations of 
VH4004280. 
7. 
In the event terminal half-life is longer than predicted, PK and laboratory assessment will occur every 7 days until an estimated 5 half-lives have elapsed. 
8. 
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at the Day 49 Visit, these procedures and those listed in Table 1 for Follow-
up/Early Discontinuation Visit are the same. 
 
 
Procedure 
Day 
14 
21 
28 
35 
42 
497,8 
Visit Window 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Test4,5  
X 
X 
X 
X 
X 
X 
Plasma sample (pharmacokinetics) 6 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
<=======================================================================================>  
Concomitant Medication Review 
<=======================================================================================>  


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Table 4 
Part 2 Multiple Ascending Dose (MAD) - Inpatient Days -1 to 21 
Procedure 
Day 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Discharge from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Drug/alcohol/cotinine screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SARS-CoV-2 PCR Test1 
X 
X  
  
  
  
  
  
 X 
  
  
  
  
  
  
 X 
  
  
  
  
  
  
X  
Brief Physical Exam2 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
Vital Signs 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG4 
X 
X8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
  
  
X 
  
X 
X 
Cardiodynamic Assessment4 
  
<===>5,6 
  
  
  
  
  
  
  
  
  
  
  
<===>6,7 
  
  
  
  
  
  
Meals 
  
See Section 5.3.1 
Clinical Laboratory Test10,11,12 
X 
  
X 
  
  
X 
  
X 
  
  
  
X 
  
  
X 
  
  
  
  
  
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug Administration13 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Plasma Sample (Pharmacokinetics)14   
X15 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X15 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample (metabolism)14 
  
X15 
X16 
 
  
  
  
  
  
  
  
  
  
  
X15 
X 
  
  
  
  
  
  
Urine Sample (metabolism)17 
  
<===> 
  
  
  
  
  
  
  
  
  
  
  
<=====> 
  
  
  
  
  
  
Bile Sample (EnteroTracker)18 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
Adverse Event Review 
<=====================================================================================================> 
Concomitant Medication Review 
<=====================================================================================================> 
1. 
Two consecutive SARS-CoV-2 PCR negative results are required prior to dosing. The tests should be performed on different days with the first test performed between Day -
7 and Day -1 and the second test performed pre-dose. Admission to unit may be done on Day -2 if necessary for SARS-CoV-2 PCR testing.  
2. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
3. 
Pre-dose and 1h, 3h, 6h and 12h. All vitals should be measured pre-dose; only blood pressure and pulse rate are measured for all remaining daily timepoints. 
4. 
See Section 8.1.3 for details of 12-lead ECGs and Cardiodynamic assessment. 
5. 
Three pre-dose ECG extractions prior to dosing on Day 1.  
6. 
Post-dose ECG extraction will coincide with plasma PK sample schedule up to 24h post-dose.  
7. 
Single pre-dose ECG extraction prior to dosing on Day 14. 
8. 
Dose administration day ECGs will be collected at pre-dose and 3, 6, 9 and 12-hours post-dose. 
9. 
Pre-dose triplicate ECG is required on Day 1 within 90 minutes of dosing. 
10. See Appendix 2 for details of Clinical Laboratory Tests. 
11. Total Bile Acids (TBA) and PT/PTT required on Day -1, Day 2, Day 7, Day 14 and Day 21 only. 
12. Lipid Panel required on Day -1, Day 7, Day 14 and Day 21 only. 
13. In Part 2, VH4004280 will be administered as a PiB. 
14. See Section 8.3 for further details for plasma PK and metabolite sample collection. One whole blood sample of sufficient volume will be processed into two aliquots of 
plasma: one to measure concentrations of VH4004280 and the other to characterize related metabolites. Blood samples drawn Day 15 and onward should be collected on an 
approximately 24-hour cycle (i.e., 24 hours post dose, 48 hours post dose, 72 hours post dose, etc). 
15. At pre-dose, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, 10 h and 12h. Plasma sample (pharmacokinetics) collection time points may be optimized based on emerging data from SAD. 
16. At pre-dose only. 
17. On Day 1 a urine sample will be collected pre-dose (40 mL) within 1 h prior to dosing and from time 0 up to 24 h post dosing. On Day 14 urine will be collected from time 0 to 
24h post dosing. Details of urine collection and processing are detailed in the SRM. 
18. Part 2 only: the EnteroTracker will be swallowed 2 h post-dose. After 6 h post dose the string will be removed. Details of bile collection and processing are detailed in the 
SRM. See Section 8.3 for further details. 
 
 


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Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 5 
Part 2 MAD - Outpatient Visit Days 28, 35, 42, 49, 56, and 63 
Procedure 
Day 
28 
35 
42 
49 
56 
634,5 
Visit Window 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Test3 
X 
X 
X 
X 
X 
X 
Plasma sample (pharmacokinetics) 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
<==============================================================================================> 
Concomitant Medication Review 
<==============================================================================================> 
 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
See Section 8.1.3 for details of 12-lead ECGs.  
3. 
See Appendix 2 for details of Clinical Laboratory Tests. Total Bile Acids, PT/PTT and Lipid Panel required in each weekly clinical laboratory test. 
4. 
In the event terminal half-life is longer than predicted, PK and laboratory assessment will occur every 7 days until an estimated 5 half-lives have elapsed. 
5. 
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at Day 63 Visit, these procedures and those listed in Table 1 for Follow-up/Early 
Discontinuation Visit (~49 days post last dose) are the same. 
 
 


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Table 6 
Part 2 MAD/ Drug-Drug Interaction (DDI) - Inpatient Days -1 to 22 
Procedure 
Day 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
Discharge from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
Drug/alcohol/cotinine screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
SARS-CoV-2 PCR Test1 
X 
X  
  
  
  
  
  
 X 
  
  
  
  
  
  
 X 
  
  
  
  
  
  
 
X 
Brief Physical Exam2 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
 
X 
  
  
  
  
  
 
X 
Vital Signs 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG4 
X 
X5,6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
  
  
X 
  
X 
X 
X 
Meals 
  
See Section 5.3.1 
Clinical Laboratory Test7,8,9 
X 
  
 
X 
  
 
X  
 
X  
  
  
 
X 
  
 
X  
  
  
  
  
  
 
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Drug Administration10 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
 
Midazolam Administration11 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pulse oximetry12 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Plasma Sample (VH4004280 
Pharmacokinetics)13 
  
  
X14 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X15 
X14 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample (VH4004280 
metabolism)13 
  
  
X14 
X15 
  
  
  
  
  
  
  
  
  
  
 
X14 
X  
  
  
  
  
  
 
Plasma Sample (Midazolam and 1-
hydroxymidazolam 
Pharmacokinetics)16 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Plasma Sample (coproporphyrin I)17  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Urine Sample (VH4004280 
metabolism)18 
  
 
<===> 
  
  
  
  
  
  
  
  
  
  
 
<===> 
  
  
  
  
  
 
Bile Sample (EnteroTracker)19 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 X 
  
  
  
  
  
  
  
 
Adverse Event Review 
<===============================================================================> 


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Procedure 
Day 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Concomitant Medication Review 
<===============================================================================> 
1. 
Two consecutive SARS-CoV-2 PCR negative results are required prior to dosing. The tests should be performed on different days with the first test performed between Day -
7 and Day -1 and the second test performed pre-dose. Admission to unit may be done on Day -2 if necessary for SARS-CoV-2 PCR testing.  
2. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
3. 
Pre-dose and 1h, 3h, 6h and 12h. All vitals should be measured pre-dose; only blood pressure and pulse rate are measured for all remaining daily timepoints. 
4. 
See Section 8.1.3 for details of 12-lead ECGs and Cardiodynamic assessment. 
5. 
Dose administration day ECGs will be collected at pre-dose and 3, 6, 9 and 12-hours post-dose. 
6. 
Pre-dose triplicate ECG is required on Day 1 within 90 minutes of dosing. 
7. 
See Appendix 2 for details of Clinical Laboratory Tests. 
8. 
Total Bile Acids (TBA) and PT/PTT required on Day -1, Day 3, Day 8, Day 15 and Day 22 only. 
9. 
Lipid Panel required on Day -1, Day 8, Day 15 and Day 22 only. 
10. In Part 2, VH4004280 will be administered as a PiB. 
11. Midazolam will be co-administered with VH4004280 on Day 2 and Day 15. 
12. Continuous pulse oximetry monitoring will begin within 15 minutes of dosing with midazolam and will continue until 6 hours post midazolam dosing. Pulse oximetry will be 
recorded pre-dose and 0.25, 0.75, 1, 2, 3, 4, 5 and 6 h post dose.  
13. See Section 8.3 for further details for plasma PK and metabolite sample collection. One whole blood sample of sufficient volume will be processed into two aliquots of 
plasma: one to measure concentrations of VH4004280 and the other to characterize related metabolites. Blood samples drawn Day 15 and onward should be collected on an 
approximately 24-hour cycle (i.e., 24 hours post dose, 48 hours post dose, 72 hours post dose, etc). 
14. At pre-dose, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, 10 h and 12h. Plasma sample (pharmacokinetics) collection time points may be optimized based on emerging data from SAD. 
15. At pre-dose only. 
16. Plasma PK samples for midazolam and 1-hydroxymidazolam will be collected pre-dose (within 15 mins prior to dosing) and 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, 10 h, 12h, and 24h 
post midazolam dose on Day 1 and Day 15. On Day 2, plasma PK samples for midazolam and 1-hydroxymidazolam will be collected 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12h, 
and 24h post midazolam dose. The 24 h post Day 1 dose collection will be pre-dose on Day 2.  
17. Plasma PK samples for coproporphyrin I will be collected pre-dose of midazolam (within 15 mins prior to dosing) and 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, 10 h, 12h, and 24h post 
midazolam dose on Day 1 and Day 15.  
18. On Day 2 a urine sample will be collected pre-dose (40 mL) within 1 h prior to dosing and from time 0 up to 24 h post dosing. On Day 15 urine will be collected from time 0 to 
24h post dosing. Details of urine collection and processing are detailed in the SRM. 
19. Part 2 only: the EnteroTracker will be swallowed 2 h post-dose. After 6 h post dose the string will be removed. Details of bile collection and processing are detailed in the 
SRM. See Section 8.3 for further details.  
 
 


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Table 7 
Part 2 MAD/DDI - Outpatient Visit Days 28, 35, 42, 49, 56, and 63 
Procedure 
Day 
28 
35 
42 
49 
56 
634,5 
Visit Window 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Test3 
X 
X 
X 
X 
X 
X 
Plasma sample (VH4004280 
pharmacokinetics) 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
<==============================================================================================> 
Concomitant Medication Review 
<==============================================================================================> 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
See Section 8.1.3 for details of 12-lead ECGs.  
3. 
See Appendix 2 for details of Clinical Laboratory Tests. Total Bile Acids, PT/PTT and Lipid Panel required in each weekly clinical laboratory test. 
4. 
In the event terminal half-life is longer than predicted, PK and laboratory assessment will occur every 7 days until an estimated 5 half-lives have elapsed. 
5. 
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at Day 63 Visit, these procedures and those listed in Table 1 for Follow-up/Early 
Discontinuation Visit (~49 days post last dose) are the same. 
 
 


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Table 8 
Part 3 Tablet PK - Inpatient Days -1 to 7 
Procedure 
Day 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
Pre-
dose 
0 h 
0.5h 
1 h 
1.5 h 
2h 
3 h 
4h 
6 h 
8h 
10h 
12h 
24h 
48h 
72h 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Drug/alcohol/cotinine 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief Physical Exam1 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
Vital signs2 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X4 
  
X 
  
  
  
X 
  
  
  
X 
X  
X 
  
X 
  
X 
Meals 
 
X 
  
See Section 5.3.1 
Clinical Laboratory 
Tests5,6,7 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X  
X 
SARS-CoV-2 PCR 
Test8 
X 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration9 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Plasma Sample 
(pharmacokinetics)10 
  
X 
 g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
<================================================================================================================> 
Concomitant 
Medication Review 
<================================================================================================================> 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 


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2. 
See Section 8.1.2 for details of Vital Sign measurements. On Day 1, all vitals should be measured pre-dose; only blood pressure and pulse rate are measured for all 
remaining Day 1 timepoints. 
3. 
See Section 8.1.3 for details of 12-lead ECGs. 
4. 
At pre-dose a triplicate 12-lead ECG is required within 90 minutes of dosing. 
5. 
See Appendix 2 for details of Clinical Laboratory Tests. 
6. 
Total Bile Acids (TBA) and Coagulation Panel required on Day -1, Day 2 and Day 7 only.  
7. 
Lipid Panel required on Day -1 and Day 7 only. 
8. 
Two consecutive SARS-CoV-2 PCR negative results are required prior to dosing. The tests should be performed on different days with the first test performed between Day -
7 and Day -1 and the second test performed pre-dose. Admission to unit may be done on Day -2 if necessary for SARS-CoV-2 PCR testing.  
9. 
In Part 3, VH4004280 will be administered as a tablet. 
10. See Section 8.3 for further details for plasma PK and metabolite sample collection. One whole blood sample of sufficient volume will be processed into two aliquots of 
plasma: one to measure concentrations of VH4004280 and the other to characterize related metabolites. 
 
 


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Table 9 
Part 3 Tablet PK - Outpatient Visit Days 14, 21, 28, 35, 42, and 49 
1. 
See Section 8.1.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
See Section 8.1.2 for details of Vital Sign measurements. 
3. 
See Section 8.1.3 for details of 12-lead ECGs. 
4. 
See Appendix 2 for details of Clinical Laboratory Tests. 
5. 
Total Bile Acids, Coagulation Panel and Lipid Panel to be included in each weekly clinical laboratory test.  
6. 
See Section 8.3 for further details for plasma PK sample collection. One whole blood sample of sufficient volume will be processed to measure concentrations of VH4004280. 
7. 
In the event terminal half-life is longer than predicted, PK and laboratory assessment will occur every 7 days until an estimated 5 half-lives have elapsed. 
8. 
For participants with no ongoing AEs or Vital Sign/Laboratory measures of clinical concern at the Day 49 Visit, these procedures and those listed in Table 1 for Follow-
up/Early Discontinuation Visit are the same. 
Procedure 
Day 
14 
21 
28 
35 
42 
497,8 
Visit Window 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Test4,5  
X 
X 
X 
X 
X 
X 
Plasma sample (pharmacokinetics) 6 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
<=======================================================================================>  
Concomitant Medication Review 
<=======================================================================================>  


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2. 
INTRODUCTION 
VH4004280 (also referred to as GSK4004280) belongs to a novel class of ARV agents 
targeting a highly conserved region of the HIV-1 capsid protein. Investigational 
VH4004280 is being developed for people living with HIV-1 to be part of a long-acting 
ARV treatment regimen that is either conveniently dosed parenterally every 3 months 
(Q3 monthly) or longer or that serves as a component of a once-weekly oral treatment 
regimen. 
2.1. 
Study Rationale 
This is a double-blind, randomized, placebo-controlled, FTIH study in a combined single-
ascending (Part 1) and multiple-ascending (Part 2) dose design to assess the tolerability, 
safety and pharmacokinetics of orally administered VH4004280 in healthy participants. 
This study is designed to evaluate: the safety, tolerability, and PK properties of 
VH4004280 when administered as single and multiple ascending dosing with the 
powder-in-a-bottle (PiB) formulation; the safety, tolerability and PK properties of the 
VH4004280 tablet formulation; and any effect of VH4004280 on the activity of CYP3A 
using midazolam as a probe and on OATP1B1/1B3 using an endogenous biomarker as a 
probe (coproporphyrin I). The data gathered in this study will inform further evaluation 
of VH4004280 in people living with HIV-1 
 
2.2. 
Background 
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 
medicines are effective, there is an opportunity for developing more conveniently dosed 
and better tolerated ARV regimens. Long-acting injectable versions of drugs are being 
developed to improve convenience by extending the dosing interval from every day to 
every month or longer. These therapeutic options hold great promise for future treatment 
and represent an emerging paradigm for the treatment and prevention of HIV-1 infection. 
An all long-acting ARV regimen that is dosed every month or longer offers many 
potential advantages over daily dosed regimens, including: improved ARV adherence, 
improved treatment satisfaction, and minimizing the patient’s daily reminder of their HIV 
status.  
VH4004280 belongs to a novel class of ARV agents targeting a highly conserved region 
of the HIV-1 capsid protein. In-vitro experiments suggest its mechanism of action 
interferes with both the early (pre-integration) and late (virus assembly) stages of the 
HIV-1 life cycle. There are currently no capsid inhibitors approved for the treatment of 
HIV infection, although clinical efficacy and a generally favorable safety profile has been 
demonstrated by an investigational capsid inhibitor currently in development [Gupta, 
2021;Molina, 2021]. In cell culture, VH4004280 exhibits potent antiviral activity against 
a spectrum of HIV-1 isolates and subtypes. In MT-2 cells, a panel of 48 viruses with 
diverse CA sequences derived from different subtypes (A, CRF01_AE, B, C, F, and G) 
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was inhibited with 50% effective concentration (EC50) values ranging from 0.08 nM to 
0.92 nM and a median EC50 value of 0.27 nM (0.26 ng/mL). VH4004280 also displayed 
potent antiviral activity against multiple HIV-1 strains and subtypes (A, CRF01_AE, 
CRF02_AG, B, C, D, E, F and G) in peripheral blood mononuclear cells (PBMCs). 
VH4004280 has demonstrated no cross-resistance with currently approved ARV classes, 
including integrase strand transfer inhibitors, nucleoside reverse transcriptase inhibitors, 
non-nucleoside reverse transcriptase inhibitors and protease inhibitors. 
Nonclinical studies support a favorable toxicity and safety profile for VH4004280 and 
suggest the potential of VH4004280 as a long-acting medicine [GSK Document Number 
RPS-CLIN-014478]. The drug-drug interaction potential of VH4004280 has been 
conducted in a series of in vitro studies [GSK Document Number RPS-CLIN-014478]. 
As the clinical risk of significant drug-drug interactions with VH4004280 as a perpetrator 
or a victim is currently unknown, participants in the first clinical study with VH4004280 
must abstain from taking concomitant medications unless, in the opinion of the 
investigator and sponsor, the medication will not interact with VH4004280. 
The purpose of this FTIH study with VH4004280 (via powder-in-bottle) is to initially 
characterize the tolerability, safety, and pharmacokinetics of VH4004280. The drug 
concentrations obtained from oral administration of VH4004280 in both the single 
ascending dose and repeat ascending dose parts of this study will help inform subsequent 
development of long-acting VH4004280.  
A detailed description of the nonclinical pharmacology, pharmacokinetics, toxicology, 
virology, and the chemistry and manufacturing of VH4004280 is provided in the Clinical 
Investigator’s Brochure [GSK Document Number RPS-CLIN-014478] and Investigator’s 
Brochure supplement [GSK Document Number RPS-CLIN-043688]. 
2.3. 
Benefit/Risk Assessment 
VH4004280 has been studied in repeat dose oral toxicology studies up to 28 days 
duration in rats and dogs, and for up to 3 months duration in repeat dose toxicology 
studies with the 
 
 in rats and SC administration in dogs. 
In the definitive (GLP) 3-month rat study with the 
 of VH4004280 
, clinical observations at a dose of 
 included hunched 
posture, decreased activity, decreased body weight and suspected dehydration, which 
required supportive measures and were thus considered adverse. Non-adverse findings in 
the liver (minimal to mild vacuolation) were observed at 
. In the 
definitive 3-month dog study with the 
 of VH4004280, there were no 
similar clinical observations and no liver-related findings at doses 
 
. As the exposure to VH4004280 was higher and of longer duration in these 
definitive 3-month injectable rat and dog studies compared to the 28-day oral studies 
(described below), the NOAEL has been updated and is provided by the exposures 
observed following 
 in the 3-month rat study 
 
 
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Repeat dose oral studies of 28 days duration in rats and dogs demonstrated no significant 
safety findings at the highest doses tested 
 in rats and 
 in 
dogs). Clinical pathology and liver weight changes were of generally low magnitude, 
were not associated with correlating microscopic findings or clinical sequelae and were 
all considered to be non-adverse. In addition, there were no significant findings in 
definitive non-clinical studies conducted to assess genotoxicity, safety pharmacology and 
phototoxicity. 
Minimal, mixed-cellular, bronchioalveolar inflammation was identified on lung histology 
from dogs dosed in a dose-range finding study exploring 
 
. Notably, there were no histologic 
changes in the lungs of either rats or dogs 
 
 in the definitive 3-month studies with the same 
 
. In addition, there were no histologic changes in the lungs of either rats 
or dogs 
 in the 28-day 
repeat dose 
 definitive toxicity studies conducted with the VH4004280 
 
 being used in Study 217058.  The proposed maximum 
 doses to be used 
in this clinical study are predicted to result in exposures below the established 
 
  
Midazolam Probe (Part 2, MAD/DDI dosing group(s)): Based on in vitro data, there is 
potential for inhibition of CYP3A by VH4004280 leading to increased midazolam 
exposures and a deeper and more prolonged CNS suppression. There is also potential for 
induction of CYP3A by VH4004280 leading to decreased midazolam exposures. To 
allow for accurate assessment of PK as a result of either CYP3A inhibition or induction 
while minimizing the risk of serious CNS suppression, a 5 mg oral dose of midazolam 
has been selected for this study. Of note, many drug interaction studies with potent 
CYP3A inhibitors (e.g., azole antifungals including ketoconazole) have been conducted 
with midazolam doses as high as 15 mg [Backman, 1998; Olkkola, 1994]. Though some 
of these studies have reported deeper or longer sedation, no serious adverse events have 
been reported. Additionally, during dosing with midazolam in the present study, close 
observation for signs of CNS suppression as well as pulse oxygenation monitoring and 
timed respiratory rate will be implemented, and flumazenil will be readily available. 
[Rogers, 2002].  
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of VH4004280 may be found in the Clinical 
Investigator’s Brochure [GSK Document Number RPS-CLIN-014478] and Investigator’s 
Brochure supplement [GSK Document Number RPS-CLIN-043688]. 
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2.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug(s) VH4004280 
Drug-induced liver injury  
In vitro, 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. In the 28-day repeat dose rat study, 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 3-month VH4004280 
 rat study, 
treatment related minimal to mild hepatocellular vacuolation was 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. 
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 (see 
Exclusion Criteria, Section 5.2). 
Participants will be closely monitored 
for liver related AE and laboratory 
abnormalities, including serum total 
bile acids and coagulation parameters. 
Sentinel dosing is included (see 
Section 4.1). 
Liver chemistry participant stopping 
criteria are defined (see Section 7.1.1). 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug(s) VH4004280 
Increases in cholesterol and 
triglycerides 
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. 
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. 
Hematology changes 
In the 28-day dog study 
), increases in neutrophils 
and monocyte counts were observed 
In the definitive 3-month 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 3 month VH4004280
 dog study. 
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. 
Sentinel dosing is included (see 
Section 4.1). 
See Section 7.4.2 for clinical stopping 
criteria applicable to this potential risk. 
Acute pulmonary injury 
In a single dose dose-range finding dog study 
 
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, 
Participants with current or history of 
respiratory disease are excluded from 
participation in this study (see 
Exclusion Criteria, Section 5.2).  
Participants will receive VH4004280 
by the 
 route at doses predicted to 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug(s) VH4004280 
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 
 in the 
same study. 
There were no histological findings in the lung in the 28-day definitive rat and dog 
repeat dose studies 
 
conducted with the VH4004280 
 being used in Study 217058. 
 
There were no histological findings in the lung in the VH4004280 definitive
3 
month 
 studies in both rat 
 
 and dog 
 
  
result in low exposures compared to 
findings in the
dog study 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. 
Sentinel dosing is included (see 
Section 4.1). 
 
Drug Interactions (inhibition of 
OATP1B1/1B3) 
In vitro, VH4004280 is a OAT1B1/1B3 inhibitor. The potential clinical impact will be 
investigated in this study using the biomarker coproporphyrin. 
Co-medications, including 
OATP1B1/1B3 substrates, are 
prohibited in FTIH. 
Drug Interactions (inhibition and 
induction of CYP3A4) 
In vitro, VH4004280 is a CYP3A4 inducer and a CYP3A4 inhibitor. The potential 
clinical impact will be investigated in this study using midazolam as a probe 
substrate for CYP3A4.  
 
Co-medications, including CYP3A4 
substrates, are prohibited in FTIH. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug(s) VH4004280 
Midazolam 
Respiratory depression and 
transient drowsiness 
Midazolam may cause respiratory depression and transient drowsiness. 
Screening: Eligible participants will be 
overtly healthy as determined by a 
medical professional based on medical 
evaluation. On Treatment: Participants 
will be housed throughout study 
conduct to ensure rapid diagnosis and 
management of any potential event. 
To monitor for the respiratory effects of 
midazolam, continuous pulse oximetry 
and timed respiratory rate will be 
measured on probe substrate drug 
dosing days (See SoA, Section 1.3). 
To allow for accurate assessment of 
PK as a result of either CYP3A 
inhibition or induction while minimizing 
the risk of serious CNS suppression, a 
5 mg oral dose of midazolam has been 
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2.3.2. 
Benefit Assessment 
This is a study in healthy participants and as such there is no expected benefit to 
administration of VH4004280. Participation in this study may contribute to the process of 
developing new therapies for HIV. There may be benefit to individual participants from 
the medical evaluations and assessments that could identify conditions that the participant 
was previously unaware. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Potential risks identified with VH4004280 based on non-clinical oral studies were drug-
induced liver injury and increases in cholesterol and triglycerides at 50-125X predicted 
clinical efficacious AUC0-24 and Cmax. Increases in cholesterol, triglycerides, and liver-
related laboratory parameters in animals were not accompanied by histopathological 
changes in the liver and all findings were considered non-adverse. The protocol will 
exclude participants from the study with any pre-existing liver disease and all participants 
will be closely monitored for liver related AEs and laboratory abnormalities, with 
additional monitoring of total bile acids and more frequent monitoring of lipids. The 
proposed oral doses to be used in this clinical study are predicted to result in exposures 
below the established No Adverse Effect Level 
)  
In addition, consistent with Sponsor guidance for early phase studies, this study will be 
conducted in a hospital-based/adjacent clinical research unit with prior experience 
conducting first-time-in-human-trials, sufficient overnight facilities and immediate 
emergency care capabilities. 
ViiV Healthcare has assessed this study for any risks that may be posed to participants 
taking part. The proposed risk assessment and management plan for the study has been 
developed in accordance with the tenets of FDA and EMEA guidance on strategies to 
identify and mitigate risks for FTIH clinical trials with investigational medicinal 
products. 
More detailed information about the known and expected benefits and risks of 
VH4004280 can be found in the Clinical Investigator’s Brochure [GSK Document 
Number RPS-CLIN-014478] and Investigator’s Brochure supplement [GSK Document 
Number RPS-CLIN-043688].  
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3. 
Objectives, Endpoints and Estimands 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single 
(Parts 1 and 3) and multiple (Part 2) doses of 
VH4004280 in healthy participants. 
• Incidence of adverse events (AEs), 
severity of AEs and proportion of 
participants who discontinue treatment 
due to AEs 
• Absolute values, change from baseline 
and maximum toxicity grade increase 
from baseline for liver panel laboratory 
parameters [consists of total bilirubin, 
direct bilirubin, alkaline phosphatase, 
aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT)] 
To describe the plasma PK characteristics of 
VH4004280 in healthy participants following 
single (Part 1) and multiple (Part 2) doses. 
• Area under the plasma-concentration 
time curve (AUC): AUC(0-∞) for single 
dose and AUC(0-τ) for repeat dose 
• Maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(Tmax), and apparent terminal half-life 
(T1/2) will be calculated for each part 
(Part 1 SAD and Part 2 MAD) as data in 
each part permits 
Safety 
To further assess the safety and tolerability of 
single (Parts 1 and 3) and multiple (Part 2) 
doses of VH4004280 in healthy participants. 
• Post baseline values and changes over 
time of vital signs and ECG parameters 
• Absolute values, change from baseline 
and maximum toxicity grade increase 
from baseline for hematology, coagulation 
and remaining chemistry panels 
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Objectives 
Endpoints 
 
3.1. Estimands 
3.1.1. 
Primary Safety Estimands 
The primary Safety estimands aim to assess the proportion of participants with Adverse 
Events (including severity), proportion of participants with AEs leading to 
discontinuation of study treatment and provide summaries of absolute values and change 
from Baseline in liver panel laboratory parameters as well as maximum toxicity grade 
increase from Baseline in healthy volunteers receiving VH4004280 or placebo. 
The primary Safety estimands are described by the following attributes: 
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Population 
Safety analysis set 
Treatment 
Part 1: single oral dose of VH4004280 PiB or placebo 
Part 2: multiple oral doses (once daily) of VH4004280 or 
placebo, with a midazolam probe administered on Day 1, Day 2, 
and Day 15 in DDI dosing group(s)  
Part 3: single oral dose of VH4004280 tablet  
 
 
 
ICEs 
Discontinuation of study treatment due to any reason, will be 
addressed with treatment policy strategy in Part 2 
(discontinuation of study treatment can’t occur in Parts 1 and 3 
as participants will receive only 1 dose). The occurrence of the 
ICE is considered irrelevant in defining the treatment effect of 
interest. All safety data will be included in the analysis up to the 
end of the follow-up period irrespective of the occurrence of this 
ICE. 
 
 
Endpoints 
• Incidence and severity of AEs 
• Incidence of AEs leading to discontinuation of study 
treatment 
• Absolute values and change from Baseline in liver panel 
laboratory parameters 
• Liver panel laboratory parameters maximum grade increase 
post-Baseline relative to Baseline 
 
 
 
 
 
Summary Measure 
• Number and percentage in each treatment arm (i.e., 
VH4004280 for each dosing group or placebo collectively 
from all dosing groups) for AEs and AEs leading to study 
treatment withdrawal 
• Summaries (e.g., mean, median, std etc.) of absolute values 
and change from Baseline values by visit and treatment arm 
(i.e., VH4004280 for each dosing group or placebo 
collectively from all dosing groups) in liver panel laboratory 
parameters. 
• Number and percentage of participants with maximum grade 
increase relative to Baseline in liver panel laboratory 
• parameters by treatment arm. 
 


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Rationale for primary Safety estimands: 
This attempts to estimate safety effects likely to be attributable to the drug irrespective of 
whether the participant completed the treatment. Further details of the analyses of 
primary safety endpoints will be provided in the SAP. 
3.1.2. 
Primary Pharmacokinetic Estimand 
The primary Pharmacokinetic estimand aims to assess summary statistics (e.g. geometric 
mean, median, %CV etc.) of PK parameters in healthy participants following a single oral 
dose of VH4004280 PiB in Part 1 and multiple oral doses (once daily) of VH4004280 in 
Part 2, while on and post treatment and in the absence of intake of non-permitted 
concomitant medication (see Section 6.8). 
The primary Pharmacokinetic estimand is described by the following attributes: 
Population 
VH280 Pharmacokinetic analysis set 
Treatment 
Part 1: single oral dose of VH4004280 PiB 
Part 2: multiple oral doses (once daily) of VH4004280 with a 
midazolam probe administered on Day 1, Day 2, and Day 15 in 
DDI dosing group(s)  
ICEs 
Study treatment discontinuation in part 2 will be addressed with 
while on-treatment strategy. Further details will be provided in 
the SAP. 
Endpoints 
• 
Part 1: AUC(0-inf), Cmax, tmax, t1/2 
• Part 2: AUC(0-τ), Cmax, tmax, t1/2 at Day 14 (for dosing 
groups without midazolam administration) or at Day 15 (for 
dosing groups with midazolam administration) 
Summary Measure 
• Summary statistics (e.g. geometric mean, geometric %CV, 
arithmetic mean, median, std, min, max etc.) by dosing group 
 
Rationale for primary PK estimand: 
Discontinuation of study treatment may bias the evaluation of pharmacokinetic behavior 
of study treatment. Further details of the analyses of primary pharmacokinetic endpoints 
will be provided in the SAP. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1, 3-Part, double-blind (sponsor unblinded), randomized, placebo-
controlled, single and multiple-ascending-dose study to evaluate the safety, tolerability 
and pharmacokinetics of VH4004280 in healthy participants. The purpose of this study is 
to evaluate: the safety, tolerability, and PK properties of VH4004280 when administered 
as single and multiple ascending dosing with PiB; the safety, tolerability and PK 
properties of the VH4004280 tablet formulation; and any effect of VH4004280 on the 
activity of CYP3A using midazolam as a probe and on OATP1B1/1B3 using an 
endogenous biomarker as a probe (coproporphyrin I). Approximately 98 healthy 
participants are planned to be randomized, in Part 1 (SAD, n=56), Part 2 (MAD, n=36), 
and Part 3 (Tablet PK, n=6) from a single center in the US.  
All dosing and 7 day post last-dose follow-up will be conducted in a hospital 
based/adjacent inpatient clinical trial unit. A final follow up visit will take place 
approximately 49-days post final dose in Part 1 (SAD), Part 2 (MAD), and Part 3 (Tablet 
PK), as indicated in the Schedule of Activities (SoA), Section 1.3. 
 
 
 
 
Part 1 (SAD) will investigate single doses of VH4004280 from the starting dose up to a 
maximum safe dose that provides adequate dose information for future dosing 
requirements in the VH4004280 development program and does not exceed the NOAEL.  
A summary of overall study design for Parts 1 and 2, including proposed doses, sample 
size and order, is presented in Table 10 (Part 1 SAD) and Table 11 (Part 2 MAD). 
4.1.1. 
Part 1 (SAD) 
Part 1 (SAD) will be conducted in up to 7 separate dosing groups. Each participant will 
be randomized to receive a single dose of blinded VH4004280 or blinded PBO (in a 6:2, 
active: PBO ratio) administered orally. Details of the starting dose and dose escalation 
can be found in Section 4.3.3 and Section 4.3.5, respectively. Dose escalation decisions, 
including the determination of subsequent doses to be administered in Part 1, will be 
determined by the SDEC, see Section 4.4 but will be constrained by any emerging safety 
or tolerability concerns and to a maximum 5x dose increase between consecutive dosing 
groups (e.g., dosing group 2 and dosing group 3) where predicted VH4004280 
concentrations would not exceed mean NOAEL criteria. 
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Table 10 
Part 1 SAD 
SAD 
(6 active:2 PBO) 
Dosing Group 
Predicted Dose1 
(mg) 
Target fold coverage 
of NOAEL2 
1 
2 
Dose Group 2 
3 
Dose Group 3 
4 
Dose Group 4 
5 
Dose Group 5 
6 (optional expansion group)3 
 
7 (optional expansion group)3 
 
1. 
Doses beyond group 1 will be decided by the SDEC based on emerging PK and safety data from prior 
dosing groups. 
2. 
Calculated using 
. Target fold coverage can be revised based on emerging data. 
3. 
Dosing groups 6 and 7 are optional expansion groups of up to a maximum dose whose predicted 
VH4004280 concentrations would not exceed mean NOAEL criteria or other predefined limits or to repeat a 
previous dose level, if required. 
At the start of each SAD dosing group, 2 of the total number of participants will serve as 
sentinel participants, with one receiving blinded VH4004280 and the other receiving 
blinded PBO. The investigator may stagger dose administration time as needed for 
sentinel participants. Sentinel participants will be followed clinically for 24 hours 
following dose administration to monitor for emergence of adverse events. Following this 
period, if there are no safety concerns, in the judgement of the PI, on review of 24-hour 
safety data (including but not limited to vital signs, ECGs, available laboratory tests and 
adverse events) for sentinel participants, the remaining 6 participants will be 
subsequently dosed with blinded VH4004280 or blinded PBO, according to the 
randomization schedule. The PI may stagger dose administration time for remaining 
dosing group participants as needed. The 24-hour clinical observation period for sentinel 
participants and dose administration in subsequent participants may be reduced following 
completion of dosing group 1, if there are no safety or tolerability concerns.  
The proposed dosing schedule is designed to investigate single doses of VH4004280 in 
Part 1 and then, at a suitable cross-over point, begin repeated once-daily dosing of 
VH4004280 in Part 2. 
4.1.2. 
Part 2 (MAD) 
The starting dose in Part 2 (MAD) will be identified after preliminary PK data are 
evaluated in Part 1 (SAD). Part 2 (MAD) will be conducted in up to 4 ascending repeat-
dose groups. Each participant will be randomized to receive a QD dose of blinded 
VH4004280 or blinded PBO administered orally for 14 days. Participants in non-DDI 
MAD dosing groups will receive daily doses of VH4004280 or PBO (6:2) on Day 1 
through Day 14. In up to two dosing groups in Part 2 (MAD/DDI dosing group(s)), 
participants will receive a single dose of midazolam on Days 1, 2, and 15, and daily doses 
of VH4004280 or PBO (8:2) on Day 2 through to Day 15. A single dose of midazolam 
will be co-administered with a dose of VH4004280 or PBO on Days 2 and 15. The 
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MAD/DDI dosing group(s) will also include the collection of endogenous biomarker 
(coproporphyrin I) samples before and following repeat dose administration of 
VH4004280 or PBO to investigate the potential of VH4004280 to inhibit OATP1B1/1B3. 
Review of available data from previous dosing groups in Parts 1 and 2 will determine if 
the DDI potential of VH4004280 will be evaluated in one or two dosing groups.   
For Part 2, doses will be escalated such that the predicted mean plasma exposure at the 
next dose level will not exceed the mean plasma
 See Section 4.3 for 
further details on dose predictions. 
Table 11 
Part 2 MAD 
MAD 
(6 or 8 active: 2 PBO)1 
Once daily (QD) dose for 14 days2 
Dosing Group 
Predicted Dose2 
 
1 
> anticipated therapeutic dose 
2 
Up to maximum NOAEL 
exposure and not exceeding 
the permitted top dose  
3 
4 (Optional expansion group)3 
As required 
1. 
Dosing groups requiring midazolam dosing to evaluate the DDI potential of VH4004280 will enroll 10 
participants (8 active: 2 placebo). All other dosing groups will enroll 8 participants (6 active: 2 placebo). 
2. 
Actual doses will be decided based on emerging PK and safety data from prior dosing groups in Part 1 and 
Part 2. 
3. 
Dosing Group 4 is an optional expansion group as required. 
Details of the starting dose and dose escalation can be found in Section 4.3.6. Dose 
escalation decisions, including the determination of subsequent doses, dosing frequency 
and total duration of dosing to be administered in Part 2, will be determined by the SDEC 
(see Section 4.4). 
4.1.3. 
Part 3 (Tablet PK) 
Part 3 (Tablet PK) is an open-label,single-dose design to evaluate the safety, tolerability 
and PK properties of the tablet formulation of VH4004280, in comparison with existing 
data from VH4004280 PiB, in one dosing group of 6 participants. All participants will 
receive a single dose of the VH4004280 tablet on Day 1 and will remain in the clinic 
until completion of the Day 7 procedures. They will return to the clinic on Days 14, 21, 
28, 35, and 42 for follow up procedures and a final follow up visit on Day 49.  
 
Details of the VH4004280 tablet dose can be found in Section 4.3.7. While there is only 
one dosing group in Part 3, the study will utilize a SDEC for instream review of emerging 
PK and safety data. 
 
4.1.4. 
Screening, Follow-up & Study Participation Duration 
Participants in all parts of the study will have a screening visit within 30 days prior to 
their first dose and a final follow up visit approximately 49-days following final dose in 
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Part 1 (SAD), Part 2 (MAD), and Part 3 (Tablet PK). Duration of study participation 
(from the Screening Visit to the final post-dosing Follow-up Visit) will be approximately 
11 weeks for participants in Part 1 (SAD) and Part 3 (Tablet PK), and approximately 13 
weeks for participants in Part 2 (MAD).  
Duration of study participation may change, if actual PK parameters differ significantly 
from the predicted base case values (e.g. if half-life is significantly longer or shorter than 
the predicted); but will not exceed five half-lives. 
Participants will not be replaced if the reason for discontinuation from the study is due to 
a safety concern. If participants prematurely discontinue the study for non-safety reasons 
or intolerance to ingestion of the study drug (i.e., vomiting the solution shortly after 
ingestion), 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. 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. 
 
4.2. 
Scientific Rationale for Study Design 
This FTIH study, conducted in healthy adult participants, is designed to assess the safety, 
tolerability, and PK of an oral powder formulation of VH4004280, an investigational 
HIV-1 capsid inhibitor. The data gathered within this FTIH study will inform subsequent 
clinical trials, including a follow-on Phase 2a POC study in HIV-1-infected participants. 
Clinical development plans for the VH4004280 compound, include studies with 
parenterally administered (subcutaneous and intramuscular) versions of the molecule.
 
.  Part 3 (Tablet PK) is 
planned to evaluate the VH4004280 tablet formulation for comparison with the existing 
VH4004280 PiB data and will inform subsequent clinical trials.  
All doses of VH4004280 in this oral FTIH study will be administered in the fed state (see 
Section 5.3.1 for details of moderate fat/calorie meal) with dosing starting after 5 minutes 
of completing a standardized moderate fat/calorie meal, unless otherwise indicated. 
In Part 2 (MAD), doses will exceed the anticipated effective dose in a daily oral regimen 
in order to study exposures that may occur in future clinical studies with alternative 
routes, formulations and dosing durations. This will be done without exceeding the 
NOAEL established in nonclinical toxicology studies. 
4.3. 
Justification for Dose 
This section describes the analyses conducted to estimate human VH4004280 PK profile, 
and to predict starting, top and therapeutic doses required to maintain plasma 
concentrations at levels expected to produce pharmacologic activity in humans. 
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4.3.1. 
Human Pharmacokinetics Prediction 
The pharmacokinetics of VH4004280 in human was estimated using several approaches 
to determine a range of starting, therapeutic and top doses to achieve the objectives of 
this study. The methods utilized were allometry, PBPK, FDA guidance on human 
equivalent dose and the analysis of data from a molecule in the clinic with the same 
pharmacology. The following approaches were used to anticipate VH4004280 clinical 
PK and/or estimate a safe starting dose. The details each method is described in the 
Human Prediction Report [GSK Document Number TMF-14086139]. 
4.3.2. 
Therapeutic Dose Rationale 
Steady-state trough concentrations are typically the PK parameter of interest for efficacy 
for other antiretroviral classes such as protease inhibitors and integrase inhibitors.
 
 
 
As detailed in Section 4.3.1, estimates of concentration at the end of a dosing interval at 
steady state (Cτ) from the allometric scaling resulted in a dose of 
 that 
are expected to achieve 
 
. The PBPK and evaluation of existing clinical data used the same 
efficacy thresholds and the estimated doses are reported in Table 12. 
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Table 12 
Estimated efficacious dose using different approaches (F= 9%) 
Approach 
Estimate 
Allometry 
PBPK1 
Existing clinical data 
1Doses from PBPK model achieving efficacious threshold are based on 
 
4.3.3. 
Starting Dose Rationale in Part 1 (SAD) 
The proposed starting dose of VH4004280 in part 1 (SAD) is 
 which is a fraction 
of all the estimated efficacious doses. A conservative assessment of the PK predictions 
and therapeutic doses was chosen to estimate the starting dose. The PK estimated from 
allometry was used in conjunction with the NOAEL to estimate and justify the starting 
dose. 
A starting dose, to be used in SAD (Part 1) Cohort 1, aims to 
 
 
 
 
 
  
 
 
. Further details are 
provided in Human Prediction Report [GSK Document Number TMF-14086139]. 
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The estimated starting dose using different approaches is summarized in Table 13. 
Considering the output from all estimation methods, a 10 mg dose was selected as a 
starting dose for this study. 
Table 13 
Estimated starting dose using different approaches 
Starting Dose Estimation Approach 
Estimate 
Allometry 
PBPK1 
Existing clinical data 
MRSD 
1Dose from PBPK model are based on 
 
4.3.4. 
Top Dose Rationale 
The top dose is defined as the highest dose where the predicted mean plasma exposures at 
that dose level (either SAD or MAD) approaches but does not exceed the mean 
 
 
The top dose will be 
reviewed based on the emerging human PK data from the initial low dose cohorts 
studied. 
4.3.5. 
Planned Doses and Safety Coverage (Part 1) 
Dose escalations in Part 1 (SAD) will be governed in real-time by PK and safety stopping 
criteria (see Section 7.4.1 and Section 7.4.2). Doses following the first dose will be 
curtailed by responses to any safety, tolerance or other data, and predicted not to exceed 
mean NOAEL, and within a maximum 5x dose increase. 
Based on the assumptions described above and PK predictions made with the allometry 
model using bioavailability value of 9%, possible dose escalations are illustrated below in 
Table 14. Following the review and evaluation of emerging available PK and safety data, 
the dose elevations and maximum SAD dose will be revised. The proposed number of 
cohorts for Part 1 (SAD) is 5 with a further 2 for possible expansion.  
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Table 14 
Comparison of predicted human pharmacokinetics and NOAEL 
pharmacokinetics in rats for SAD dosing (Part 1) 
Model-predicted 
human doses  
PK Parameters (Geometric mean) of Model-
predicted human doses 
Safety Coverage (ratio of 
human and rat PK 
parameters)  
Dose 
(mg) 
Dose 
(mg/kg) 
Cmax 
(ng/mL) 
C24 
(ng/mL) 
AUC0-24 
(ng*h/mL) 
AUC0-inf 
(ng*h/mL) 
Fold-
Dose 
(mg/kg)1 
Fold-
Cmax2 
Fold-
AUC3 
4.3.6. 
Repeat Dosing Plan (Part 2) 
The planned dosing regimen for Part 2 is QD (24h dosing intervals) for 14 days, judged 
sufficient to evaluate accumulation, repeat dosing PK and be able to evaluate future 
steady state exposures.  
Part 2 (MAD) will be conducted in up to 4 ascending repeat-dose groups and each 
escalation is expected to be within 3x exposure increase. The top dose in MAD is defined 
as the highest dose where the predicted mean plasma exposures at that dose level 
approaches but does 
 
Dose escalation in the MAD will be governed by both MAD PK and safety stopping 
criteria (see Section 7.4.1 and Section 7.4.2). 
 
4.3.7. 
Tablet PK (Part 3) Dose Selection  
In Part 3, the safety, tolerability and PK of theVH4004280 tablet formulation will be 
evaluated in comparison with existing data from VH4004280 PiB.  A tablet dose will be 
determined as a reasonable representative dose for this assessment, based on review of 
available data from previous dosing groups in Parts 1 (SAD) and 2 (MAD) and predicted 
clinical doses. 
4.4. 
Safety and Dose Escalation Committee 
The study will utilize a SDEC which will include, at a minimum, the Sponsor medical 
monitor, clinical pharmacologist, and statistician to meet with the Investigator to make a 
dose escalation decision. Limited additional Sponsor representatives may be included on 
the SDEC. The SDEC will evaluate available data including but not limited to: AEs, vital 
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signs, clinical laboratory findings, ECG parameters and PK data. In most cases the SDEC 
will meet when data are available for the entire dosing group through at least Day 7 
assessments in Part 1 and at least Day 21 assessments in Part 2; however, there is 
allowance for the SDEC to meet when data are available for fewer participants in a 
dosing group (that is, at least 4 participants on active drug). The study will also utilize a 
SDEC for instream review of emerging PK and safety data in Part 3. In Part 3, the SDEC 
will plan meet when data are available for the entire dosing group through at least Day 7 
assessments. Limited data may be available for withdrawn participants. The blinding of 
personnel is discussed in Section 6.3. The construct and function of the SDEC will be 
documented in a charter. 
4.5. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study. A participant is considered to have completed the study if he/she has completed 
the entire dosing period and post dosing follow-up period, including the final follow up 
visit, as detailed in the SoA (Section 1.3). 
 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent. 
 
TYPE OF PARTICIPANT  
2. Participants who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and cardiac 
monitoring.  
3. Two consecutive SARs-CoV-2 PCR negative tests are required prior to dosing. 
 
WEIGHT 
4. Body weight within 50kg – 100kg and body mass index (BMI) within the range 
19-30kg/m2 (inclusive). 
 


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SEX AND CONTRACEPTIVE/BARRIER REQUIREMENTS 
5. Male or female of non-childbearing potential 
a. Male Participants: 
Male participants (male sex assigned at birth) are eligible to participate if they 
agree to the following during the study drug period and for a period of 50 days, 
corresponding to time needed to eliminate study drug(s) (e.g. 5 terminal half-lives 
estimated to a maximum of approximately 10 days) plus an additional 90 days (a 
spermatogenesis cycle) after the last dose of study drug: 
Refrain from donating semen 
Plus either:  
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent OR 
Agree to use a male condom and female partner of child-bearing potential 
to use an additional highly effective contraceptive method with a failure 
rate of <1% as described in Appendix 4. 
 
b. Female Participants: 
A female participant (female sex assigned at birth) is eligible to participate 
if: 
She is a woman of nonchildbearing potential (WONCBP), as defined in 
Section 10.4 Contraception and Barrier Guidance, and is not pregnant, 
nor breastfeeding. There is no requirement for female study participants 
to use a highly effective method of contraception since, to be eligible, 
they must be of nonchildbearing potential. 
 
INFORMED CONSENT 
6. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
 
 
 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, neurological or psychiatric disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study drug or interfering with the interpretation 
of data. The investigator may contact the Sponsor medical monitor to discuss the 
inclusion of participants who have a history of specific conditions that are not 
expected to interfere with their participation in the study. 
2. Abnormal blood pressure as determined by the investigator. 
3. Symptomatic herpes zoster within 3 months prior to screening 
4. Evidence of active or latent tuberculosis (TB) as documented by medical history, 
examination, and TB skin testing. A chest x-ray is not required but may be done at 
the discretion of the investigator. 
 
NOTE: Either a positive tuberculin skin test (TST; defined as a skin induration ≥5 
mm at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other 
vaccination history) or a positive (not indeterminate) TB test such as 
QuantiFERON-TB Gold Plus test, The choice to perform a TST or a 
QuantiFERON-TB Gold Plus test will be made by the investigator according to 
local licensing and standard of care. The QuantiFERON-TB Gold Plus test can 
only be used in countries where it is licensed, and the use of this test is dependent 
on previous treatment(s). This test may not be suitable if previous treatment(s) 
produced significant immunosuppression. 
5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
6. Breast cancer within the past 10 years. 
7. Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
8. QT interval corrected for heart rate according to Fridericia’s formula (QTcF) >450 
msec. 
 
PRIOR/CONCOMITANT THERAPY 
9. Past or intended use of over-the-counter or prescription medication [including 
Cytochrome P450 enzyme inducers or inhibitors, vitamins, herbal and dietary 
supplements (including St. John’s Wort)] within 7 days (or 14 days if the drug is a 


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PRIOR/CONCOMITANT THERAPY 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to dosing and 
for the duration of the study, unless in the opinion of the Investigator and Sponsor, 
the medication will not interfere with the study medications, procedures, or 
compromise participant safety. Specific medications listed in Section 6.8 may be 
allowed. 
10. Live vaccine(s) within 1 month prior to screening, or plans to receive such 
vaccines during the study. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
11. Exposure to more than 4 new investigational products within 12 months prior to 
the first dosing day. 
12. Current enrollment or past participation in another investigational study in which 
an investigational intervention (eg, drug, human blood product, monoclonal 
antibody, vaccine, invasive device) was administered within 1 month prior to 
screening or 5 half-lives (whichever is longer). This includes excluding a 
participant for exposure to an experimental drug, human blood product, 
monoclonal antibody, or vaccine (which does not have emergency, conditional, or 
standard market authorization) for SARS-CoV-2 within 1 month prior to 
screening. Note: Consult with the Sponsor medical monitor if clarification is 
needed. 
13. Participation in the study would result in loss of blood or blood products in excess 
of 500 mL over a 56-day period. 
14. Current enrollment or past participation in this clinical study. 
 
DIAGNOSTIC ASSESSMENTS  
15. ALT >1.5xULN. A single repeat test is allowed within a single screening period to 
determine eligibility. 
16. Total bilirubin >1.5xULN (isolated total bilirubin >1.5xULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%). A single repeat test is allowed 
within a single screening period to determine eligibility. 
17. Estimated serum creatinine clearance (using Chronic Kidney Disease 
Epidemiology Collaboration equation) <60 mL/min. 
18. History of or current infection with hepatitis B or hepatitis C. 
19. 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) within 14 days of inpatient admission, or having contact with known 
COVID-19 positive person/s in the 14 days prior to inpatient admission. 


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20. Positive pre-study drug/alcohol screen. 
21. Positive HIV antibody test. 
22. Cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening. 
 
OTHER EXCLUSIONS 
23. Regular alcohol consumption within 6 months prior to the study defined as:  
 
An average weekly intake of >14 units for males or >7 units for females. One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass 
(125 ml) of wine or 1 (25 ml) measure of spirits. 
24. Regular use of known drugs of abuse. 
25. Sensitivity to the study drug, or components thereof, midazolam (For Part 2, 
MAD/DDI dosing group(s)), excipients contained therein, benzodiazepines, or 
drug or other allergy that, in the opinion of the investigator or Sponsor medical 
monitor, contraindicates participation in the study. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the 
start of study drug until after the final dose. 
No water is allowed for 2 hours after dosing, with the exception of water consumed for 
dosing. Water is allowed ad libitum at all other times. 
All doses of VH4004280 in Part 1 (SAD), Part 2 (MAD), and Part 3 (Tablet PK) will be 
administered in the fed state (moderate fat/calorie). Participants will fast for at least 9.5 
hours prior to dosing and will start eating their standardized moderate fat meal 30 
minutes prior to the start of dosing. Participants will consume their meal in up to 25 
minutes (leaving at least 5 minutes between the end of the meal and the start of dosing). 
The standardized moderate fat meal will contain approximately 600 calories, 30% of 
which are from fat. 
In Part 2 (MAD) (Day 13 or Day 14 only), participants will undergo biliary metabolism 
testing using the EnteroTracker for analysis of VH4004280 and its metabolites. 
Participants will receive a food cue to stimulate gall bladder emptying at approximately 3 
hours after swallowing the Entero-Tracker (i.e. 5 hours post dose). A high fat food item 
will be consumed 1 hr prior to removal of the string (examples: sausage sandwich or 
cream cheese [2 tablespoons] on a bagel). The EnteroTracker will be removed 6 hours 
post dose. 
All other meals will be provided as per the sites own standards. 


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5.3.2. 
Caffeine, Alcohol, and Tobacco 
During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours 
before the start of dosing (with VH4004280 or midazolam depending on the dosing 
group) until 2 weeks after discharge from the inpatient unit. Participants also should 
abstain from ingesting caffeine-or xanthine-containing products 24 hours prior to all 
remaining outpatient study visits until the end of that visit. 
Use of alcohol or tobacco products will not be allowed from screening until after the final 
follow-up 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 (e.g., watching television, reading). 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical 
study is not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, any protocol deviations and any SAEs. 
Any individual who meets eligibility criteria is permitted to rescreen. 
With one exception, individuals who do not meet the criteria for participation in this 
study (screen failure) may not be rescreened. Participants previously deemed eligible 
during the screening period unable to attend within the allowable screening window due 
to COVID-19 may be rescreened. 
 


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6. 
STUDY DRUG(S) AND CONCOMITANT THERAPY 
Study drug is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The active investigational interventions used in this study are 
VH4004280 PiB and VH4004280 tablet.  
6.1. 
Study drug(s) Administered 
 
Table 15 
Study drug(s) Administered 
Intervention on 
Label 
VH4004280      
PiB 
Placebo         
PiB 
VH4004280  
Tablet 
Midazolam 
Dose 
Formulation 
PiB for 
reconstitution with 
50 mL of vehicle 
 
 
 
 
 
50 mL of vehicle 
 
 
 
 
 
VH4004280 
Tablet 
Oral syrup 
Unit Dose 
Strength(s) 
Oral Suspension 
of VH4004280 
Not Applicable 
25 mg and 100 
mg 
2 mg/mL  
Dosage Level(s) 
Starting dose 
single dose of 10 
mg, subsequent 
doses to be 
determined at 
dose escalation 
meetings. 
To match active. 
Dose to be 
determined 
following review of 
available data 
from Parts 1 and 
2. 
5mg 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Dosing 
Instruction 
Each dose to be 
reconstituted with 
50 mL vehicle 
followed by 
additional rinses 
with Sterile Water 
for Irrigation 
Dose with food 
[moderate 
fat/calorie meal]. 
Full dosing 
instructions will be 
Each dose to be 
reconstituted with 
50 mL vehicle 
followed by 
additional rinses 
with Sterile Water 
for Irrigation 
Dose with food 
[moderate 
fat/calorie meal]. 
Full dosing 
instructions will be 
Tablet(s) to be 
taken with water 
(~240 mL). 
Dose with food 
[moderate 
fat/calorie meal]. 
Full dosing 
instructions will be 
provided in the 
SRM. 
 
Dosing 
instructions will be 
provided in the 
SRM. 
CCI
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Intervention on 
Label 
VH4004280      
PiB 
Placebo         
PiB 
VH4004280  
Tablet 
Midazolam 
provided in the 
SRM. 
provided in the 
SRM. 
Use 
Clinical 
investigation 
Placebo   control 
Clinical 
investigation 
Clinical 
investigation 
Sourcing 
VH4004280 
 
 
 
 
 are provided 
centrally by the 
sponsor 
Sterile Water for 
irrigation provided 
by the site. 
VH4004280 
 
 
 
 
 are provided 
centrally by the 
sponsor 
Sterile Water for 
irrigation provided 
by the site. 
Provided in bulk 
by the Sponsor 
Provided locally 
by the study site, 
subsidiary, or 
designee. 
 
Packaging and 
Labelling 
Study drug will be 
provided in amber 
glass bottle with 
child resistant 
caps. Each bottle 
will be covered to 
obscure the 
appearance of the 
study drug. Each 
bottle will be 
labelled as 
required per 
country 
requirement. 
Study drug will be 
provided in amber 
glass bottle with 
child resistant 
caps. Each bottle 
will be covered to 
obscure the 
appearance of the 
study drug. Each 
bottle will be 
labelled as 
required per 
country 
requirement. 
Study Intervention 
will be provided in 
bulk by Sponsor. 
The investigator 
will package in 
glass or high-
density 
polyethylene 
bottles. Each 
bottle will be 
labelled as 
required per 
country 
requirement. 
Clinical site 
purchased 
commercial 
product. 
 
 
 
CCI
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6.2. 
Preparation, Handling, Storage and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study drug. 
Only participants enrolled in the study may receive study drug and only authorized site 
staff may supply or administer study drug. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized 
site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drug are 
provided in the Study Reference Manual.  
Under normal conditions of handling and administration, study drug is not expected to 
pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or 
skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Sponsor medical monitor and/or VH/GSK 
study contact. 
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. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be randomized, according to the randomization schedule generated 
prior to the study by the Biostatistics Department at GSK using validated internal 
software. Each participant in Part 1 and Part 2 will be dispensed blinded study drug, 
labelled with his/her unique randomization number, throughout the study. Each 
participant scheduled to receive study drug will receive a treatment allocation number 
when randomized.  
For Part 1 and Part 2, this will be double-blinded with participants and the site staff 
blinded. The site pharmacy will be unblinded. For dose escalation, the statistician will 
have access to unblinded data. Limited additional Sponsor representatives (such as the 
unblinded Clinical Research Associate) may have access to unblinded data. The Sponsor 
will present data at SDEC meetings in a blinded fashion when interacting with site staff. 
Other Sponsor staff will remain blinded unless unblinding becomes necessary. 
 
The blind may be broken if, in the opinion of the Investigator, it is in the participant’s 
best interest for the investigator to know the study treatment assignment. The Sponsor 
study team must be notified before the blind is broken unless identification of the study 
treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the participant’s 
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breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
The unblinded Clinical Research Associate, and in the event of a Quality Assurance 
audit, the auditor(s), will be allowed access to unblinded study treatment records at the 
site to verify that randomization/dispensing has been done accurately. 
A participant will be withdrawn if the participant’s intervention code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF. 
GSK’s GCSP 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 GSK 
policy. 
6.4. 
Study drug Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff.  
Participants will receive study drug directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents. The dose of study drug 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 drug. Study site staff will examine each 
participant’s mouth to ensure that the study drug was ingested. 
6.5. 
Dose Modification 
The decision to proceed to the next dose level of VH4004280 in both Part 1 (SAD) and 
Part 2 (MAD) will be made by the SDEC as outlined in the SDEC Charter, based on 
safety, tolerability and PK data obtained from the prior dose level(s).  
6.6. 
Continued Access to Study drug after the End of the Study 
This study will enrol healthy participants only, therefore, no additional treatment from the 
Sponsor, including treatment with VH4004280, will be provided after study completion. 
6.7. 
Treatment of Overdose 
ViiV Healthcare does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
• Contact the Sponsor medical monitor immediately. 
• Closely monitor the participant for AE/SAE and laboratory abnormalities to the 
planned end of sampling (at least 49 days after the last dose) or until VH4004280 can 


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no longer be detected systemically (if the follow-up monitoring is extended based on 
emerging data). 
• Obtain a plasma sample for PK analysis immediately and through 7 days if requested 
by the Sponsor medical monitor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Sponsor medical monitor, based on the clinical evaluation of the 
participant. No dose modifications are permitted without prior discussion and consent 
from the SDEC. 
6.8. 
Concomitant Therapy 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) within 7 days or 5 half-
lives (whichever is longer) before the start of study drug until completion of the follow-
up visit, unless, in the opinion of the investigator and sponsor, the medication will not 
interfere with the study.  
Permitted medication(s): 
• Paracetamol/Acetaminophen, at doses of ≤ 2 grams/day, is permitted for use any time 
during the study. 
• In the event of irritation from ECG leads, up to 2.5% topical hydrocortisone may be 
used at the discretion of the investigator 
• Vaccination with an approved vaccine for SARS-CoV-2 prior to or during study 
participation (see SRM for detailed guidance on acceptable timing for vaccination) 
• Other concomitant medications may be considered on a case-by-case basis by the 
investigator in consultation with the Sponsor medical monitor. 
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 reviewed with the Study Sponsor 
Medical Monitor. The following details should be recorded: 
• reason for use 
• dates of administration including start and end dates 
dosage information including dose and frequency 
 


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7. 
DISCONTINUATION OF STUDY DRUG AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Participant Discontinuation of Study drug 
In rare instances, it may be necessary for a participant to permanently discontinue study 
drug. If study drug is permanently discontinued, the participant will not remain in the 
study. See the SoA (Section 1.3) for data to be collected at the time of discontinuation of 
study drug and follow-up and for any further evaluations that need to be completed. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study drug for abnormal liver tests is required when: 
a participant meets one of the conditions outlined in the algorithm or  
 in the presence of abnormal liver chemistry not meeting protocol-specified stopping 
rules, if the investigator believes that it is in the best interest of the participant.  
 
Study drug will be discontinued for a participant if liver chemistry stopping criteria are 
met: 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 
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7.1.2. 
QTc Stopping Criteria 
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study drug. See Section 8.1.3. 
QTcF >500 msec, 
Change from baseline: QTc >60 msec 
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QTcF ≤60 msec) after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
7.1.3. 
SARS-COV-2 Stopping Criteria 
A participant must be withdrawn from study drug and discontinued from the study if 
he/she is found to have SARS-CoV-2 infection during an inpatient stay. The management 
of all other inpatient participants within the same dosing group should be discussed by 
the investigator and the medical monitor. Individuals who have not been exposed to the 
virus will be permitted to remain in the clinic and fulfil their inpatient stay. Individuals 
who have been exposed will be discharged home regardless of whether they are 
symptomatic. Individuals who are discharged home may still be able to continue in the 
study at the discretion of the investigator and medical monitor assuming the participant 
adheres to current Centers for Disease Control and Prevention guidance for exposure and 
assuming the participant continues to have a negative SARS-CoV-2 test status. 
  
Participants who test positive during the outpatient phase of the trial 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. 
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. 
7.1.4. 
Temporary Discontinuation 
Temporary discontinuation of study drug for a study participant in this study is not 
allowed. 
7.1.5. 
Rechallenge 
Study treatment restart or rechallenge in this study is not allowed. 


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7.1.5.1. 
Study drug Restart or Rechallenge after liver stopping criteria met 
Study drug restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study are not allowed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
 
Participants will not be replaced if the reason for discontinuation from the study is due to 
a safety concern. If participants prematurely discontinue the study for non-safety reasons 
or intolerance to ingestion of the study drug (i.e., vomiting the solution shortly after 
ingestion), 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. 
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) for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed. 
The participant will be permanently discontinued from the study drug and the study at 
that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 


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equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
7.4. 
Study Pausing and/or Stopping Criteria 
7.4.2. 
Clinical Criteria for Pausing and/or Stopping the Study 
Cumulative safety parameters and all available pharmacokinetic parameters from 
previous dosing cohorts will be fully assessed by the SDEC before selecting the 
subsequent dose to be used within the next dosing cohort in Parts 1 and 2. Any trends 
toward drug-related laboratory changes or other safety events will be fully evaluated. The 
decision to dose-escalate will be based on the nature, severity, and frequency of any 
safety and/or tolerability observations. The decision to dose-escalate may be delayed to 
allow the collection of additional safety data, if clinically indicated. While there is only 
one dosing group in Part 3, the study will utilize the SDEC for instream review of 
emerging data. All available safety parameters and pharmacokinetic parameters through 
at least Day 7 will be fully assessed by the SDEC and any trends toward drug-related 
laboratory changes or other safety events will be fully evaluated.  
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If the following number of participants, within the ongoing cohort of active participants, 
develops clinically significant changes in safety parameters or significant AEs thought to 
be drug related, the dose escalation will be paused until all of the cumulative safety data 
are reviewed by the SDEC and the ViiV Safety and Labelling Committee (VSLC). The 
VSLC is comprised of senior representatives from various departments, including clinical 
development, toxicology, pharmacovigilance, epidemiology, and medical affairs. 
• Death of one participant, regardless of causality assessment. 
• One participant experiences a Grade 4 AE or an SAE (of any grade) that the 
Investigator considers reasonably attributable to VH4004280. 
• Two participants (within the same dosing group) experience a ≥Grade 3 AE of the 
same type that the Investigator considers reasonably attributable to VH4004280 and 
which leads to a decision to withdraw from the study (by Investigator or subject 
request). 
• Two participants (within the same dosing group) have ≥Grade 2 intensity rash with 
systemic symptoms (e.g. fever, liver transaminase elevation and/or eosinophilia) that 
the Investigator considers reasonably attributable to VH4004280. 
• Two participants (within the same dosing group) have a Grade 4 laboratory 
abnormality of the same type (regardless of causality assessment) or a Grade 3 
laboratory abnormality of the same type which the Investigator considers reasonably 
attributable to VH4004280. Excluded from this are asymptomatic changes in lipid 
panel or creatine kinase changes with an alternative aetiology. 
• Two participants (within the same dosing group) meeting liver stopping criteria (see 
Section 7.1.1) 
• Two participants (within the same dosing group) with confirmed QTcF >500 msec or 
a change from baseline of QTcF >60 msec 
• One sentinel participant (who received VH4004280) meeting any individual stopping 
criteria (see Section 7.1). 
• Two participants (within the same dosing group) with clinically significant 
arrhythmias (Investigator judgment). 
 
7.5. 
Site or Study Discontinuation 
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1). 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
Protocol waivers or exemptions are not allowed  
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study drug. 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Results that could unblind the study will not be reported to the investigative site or other 
blinded personnel until the study has been unblinded. 
The maximum amount of blood collected from each participant over the duration of 56 
days, including any extra assessments that may be required, will not exceed 500 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.1.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded. 
A brief/targeted physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
8.1.2. 
Vital Signs 
Single temperature, pulse rate, respiratory rate, and blood pressure will be assessed. Body 
temperature measurements should be assessed according to site standard and should be 
measured at the same anatomical location throughout the study. Pulse oximetry will be 
assessed following each dose of midazolam (in Part 2, MAD/DDI dosing group(s)(See 
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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. 
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). 
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. If 
abnormalities in pulse or blood pressure are noted, repeat recordings should be measured 
in triplicate, at least 1 minute apart. The average of the 3 readings will be recorded on the 
CRF. 
 
8.1.3. 
Electrocardiograms 
8.1.3.1. 
12-lead Safety ECGs 
12-lead ECG recordings will be obtained after the participant has been in a semi-supine 
position for at least 5 minutes using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Participant eligibility will be 
based upon triplicate ECG recordings. Single recordings will be made at all other time 
points. 
Single 12-lead ECG 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. Refer to Section 7.1.2 for QTc withdrawal criteria and additional QTc readings 
that may be necessary. 
If the Investigator determines an ECG abnormality as clinically significant or is unable to 
determine the significance of abnormalities relating to rate, rhythm or intervals (including 
prolongation of the QT interval), then ECGs should be repeated in triplicate with 
recordings over a 5-minute time period. Refer to Section 7.1.2 QTc Stopping Criteria for 
QTc withdrawal criteria and additional QTc readings that may be necessary. 
When triplicate ECGs are required, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart. 
Safety ECGs may be printed from the Holter device. ECG parameters from safety ECGs 
will not be collected unless as part of an observed adverse event. 
 
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8.1.4. 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. 
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The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 35 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or Sponsor medical monitor.  
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. 
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). 
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). 
8.2. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AEs or SAEs can be found in Section 10.3. 
The definitions of unsolicited and solicited adverse events can be found in Section 10.3. 
AEs will be reported by the participant. 
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 all AEs that are serious, considered related to any study drug (including 
midazolam) or the study, or that caused the participant to discontinue the study (Section 
7).  
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. 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All SAEs will be collected from the signing of the ICF until the final follow-up visit 
specified in the SoA (Section 1.3).  
All AEs will be collected from the start of intervention until the final follow-up visit.  
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded as medical history/current medical conditions not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 


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investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
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, at any time 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 drug or study participation, the investigator must 
promptly notify the sponsor. 
8.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  
8.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Section 10.3. 
8.2.4. 
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 towards the safety of participants and the safety of 
a study drug under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
8.2.5. 
Pregnancy 
Details of all pregnancies in female partners of male participants will be collected after 
the start of study drug and until 140 days after the last dose taken by the male participant.  
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the pregnancy. The 
site must obtain the necessary signed informed consent from the female partner. While 
pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 


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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 pregnant partner will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the status of the mother and child, and 
the information will be forwarded to GSK. 
Any post-study pregnancy-related SAE considered reasonably related to the study drug by 
the investigator will be reported to the sponsor as described in Section 8.2.4. While the 
investigator is not obligated to actively seek this information in former study participants 
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8.3. 
Pharmacokinetics 
Blood Sample Collection  
Whole blood PK and metabolite samples will be collected for measurement of plasma 
concentrations of VH4004280 (1 mL) and to assess for VH4004280-related material (2 
mL for most timepoints, 5 mL for 12 h and 24 h post-dose) at the timepoints specified in 
the SoA (Section 1.3). 
In Part 2, whole blood PK samples will also be collected for the measurement of plasma 
concentrations of midazolam and 1-hydroxymidazolam (2 mL) at the timepoints specified 
in the SoA (Section 1.3). 
One whole blood sample of sufficient volume (typically 3 mL whole blood, but will be 6 
mL at 12 and 24 h post-dose timepoints, where applicable) will be processed into two 
aliquots of plasma: one to measure concentrations of VH4004280 and the other to 
characterize related metabolites. These samples may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. 
Approximately 25-55 blood samples are planned to be collected to evaluate PK 
objectives for each part of the study. Additional samples may be collected during the 
study if warranted and agreed upon between the investigator and the sponsor. The timing 
of sampling may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Note: PK blood samples drawn after the last dose should be collected on an 
approximately 24-hour cycle (i.e., 24 hours post last dose, 48 hours post last dose, 72 
hours post last dose, etc). 
PK samples will be analysed using an appropriately validated assay method by or under 
the supervision of the sponsor. 
The metabolite analyses will be conducted and reported separately from the main study 
report. 
Urine Sample Collection 
Urine metabolite samples will be collected at the time-points listed in the SoA 
(Section 1.3) and assayed for VH4004280-related material. Details of urine sample 
processing, storage and shipping procedures are provided in the SRM. The metabolite 
analyses will be conducted and reported separately from the main study report. 
 
Entero-Tracker: Bile Sample Collection  
Duodenal bile metabolite samples will be collected on Day 13 or Day 14 in Part 2 (MAD) 
dosing groups only. Collection of samples should be performed for each ascending MAD 
dosing group. Only the samples from the highest dosing group will be assayed for 
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Bile fluid is recovered on a highly absorbent nylon line which is contained within a 
weighted gelatine capsule. The line unwinds after capsule swallowing as the capsule 
dissolves in the stomach and the line then passes into the duodenum. During withdrawal, 
the weighted section of the capsule separates from the line and passes in the stool. 
Additional details of the bile Entero-Tracker sample collection, processing, storage and 
shipping procedures are provided in the SRM. The metabolite analyses will be conducted 
and reported separate from the main study report. 
8.4. 
Genetics 
Genetics are not evaluated in this study. 
8.5. 
Biomarkers 
The OATP1B1/1B3 biomarker coproporphyrin I will be investigated in this study.  
Whole blood PK samples will also be collected for the measurement of plasma 
concentrations of coproporphyrin I (2 mL) at the timepoints specified in the SoA (Section 
1.3).  Samples will be analyzed using an appropriately validated method under the 
supervision of the sponsor. 
8.6. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
 
 


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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 
safety endpoints. 
9.1. 
Statistical Hypotheses 
The primary objectives of this study are to assess the safety and tolerability of 
VH4004280 in healthy participants following single (Parts 1 and 3) and multiple (Part 2) 
doses and describe the plasma pharmacokinetic characteristics of VH4004280 following 
single (Part 1) and multiple (Part 2) doses.  
No formal statistical hypotheses are to be tested. Point estimates and corresponding 
confidence intervals will be constructed for any comparisons of interest (test:reference). 
9.2. 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
Analysis set 
Description 
Screened  
All participants who were screened for eligibility. 
Enrolled 
All participants who signed the ICF, passed screening and 
were randomized in the study. 
Safety 
All enrolled participants who take at least 1 full or partial dose 
of study treatment.Participants will be analysed according to 
the treatment they actually received. 
VH280 PK  
All participants in the Safety analysis set who have taken at 
least one full dose with at least one non-missing VH4004280 
PK assessment. (Nonquantifiable values will be considered as 
non-missing values). 
Further analysis sets may be defined in the SAP. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations 
In each part of the study, data will be summarised by dosing group for VH4004280 and 
collectively from all dosing groups for placebo, unless otherwise specified. 
For all endpoints, except for ECG, the baseline value will be the latest pre-dose 
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dose ECGs for each dosing group will be performed in triplicate. In such case of triplicate 
measurement for pre-dose, the average will be used as baseline. 
Continuous and categorical variables will be summarized using the following descriptive 
statistics, unless otherwise specified: 
• 
Continuous data: n (number of subjects used for the summary), arithmetic mean, 
SD, median, interquartile range, minimum and maximum. For PK parameters, geometric 
mean, SD of log-transformed data and geometric %CVb may also be used. 
• 
Categorical data: number and percentage of participants in each category. 
Confidence intervals for PK analyses will use 90% confidence levels, unless otherwise 
specified. 
9.3.2. 
Primary Endpoints/Estimands Analyses 
9.3.2.1. 
Safety Analyses 
All primary safety analyses will be performed on the Safety analysis set.  
Primary Endpoints 
Statistical Analysis Methods 
AEs 
In each part, the number and proportion of participants reporting AEs 
will be tabulated by dosing group for VH4004280 and collectively for 
placebo. AEs will also be tabulated by severity and relationship to 
study drug. AEs will be tabulated using MedDRA preferred terms. For 
the calculations in these tables, each participant’s AEs will be 
counted once under the 
maximum severity or the strongest relationship to study product.  
For part 2, AEs leading to study treatment withdrawal will also be 
summarized. In Parts 1 and 3, discontinuation of study treatment 
can’t occur as participants receive only 1 dose of study treatment. 
AEs will be summarized separately for each part of the study.   
Liver panel laboratory 
parameters 
In each part, data for liver panel parameters will be summarised by 
dosing group for VH4004280 and collectively for placebo and by visit. 
Summary statistics (e.g. mean, median, SD) for change from 
baseline and summaries of maximum grade increase relative to 
Baseline will also be presented.  
Liver panel laboratory parameters will be summarised separately for 
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Intercurrent Events 
The intercurrent events mentioned in Section 3 along with the corresponding strategies 
will be considered during the analysis. 
Study treatment discontinuation: 
All available AE and liver panel data with respect to study treatment discontinuation will 
be used in AE summaries and summaries of liver panel data, respectively. 
See Section 3 for a definition of primary safety estimands. More details on the primary 
safety analyses will be included in the SAP. 
9.3.2.2. 
Pharmacokinetic Analyses 
All primary pharmacokinetic analyses will be performed on the VH280 Pharmacokinetic 
population. 
Plasma VH4004280 concentration-time data will be analyzed by non-compartmental 
methods with WinNonlin 8.1 or higher, Phoenix (Pharsight Corporation) or comparable 
software. Calculations for the final analysis, will be based on the actual sampling times 
recorded during the study. The various analyses will be conducted as data permits. 
Individual plasma PK parameters for each participant and dosing group will be 
determined, including but not limited to: 
• Part 1 (single dose PiB): AUC(0-inf), Cmax, tmax, t1/2. 
• Part 2 (repeated once daily [QD] dose) dosing groups without midazolam 
administration:  
o Day 1 (first Dose): Cmax, tmax 
o Day 14 (last Dose): AUC(0-t), Cmax, tmax, t1/2  
• Part 2 (repeated once daily [QD] dose) dosing groups with midazolam administration:  
o Day 2 (first Dose): Cmax, tmax 
o Day 15 (last Dose): AUC(0-t), Cmax, tmax, t1/2 
For a full list of the definition of pharmacokinetic parameters refer to Section 10.6. 
Plasma VH4004280 concentrations will be presented in graphical and/or tabular form and 
will be summarized descriptively by dose. Plasma VH4004280 concentrations and PK 
parameters data will be summarized by dosing group and listed by participant within each 
part of the study. Descriptive summaries will be used as described in Section 9.3.1. More 
details will be provided in the SAP.  
Intercurrent Events 
The intercurrent events mentioned in Section 3 along with the corresponding strategies 
will be considered during the analysis. 
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Only serum concentration data available up to the time of study treatment discontinuation 
will be used in descriptive concentration data summaries and in derivation of PK 
parameters. 
Any missing PK data due to study withdrawal will remain missing.  
See Section 3 for a definition of primary PK estimands. More details on the primary PK 
analyses will be included in the SAP.  
9.3.3. 
Safety Analyses 
All safety analyses will be performed on the Safety analysis set. Within each part, 
summary statistics (e.g. mean, median, std etc.) of absolute values and change from 
Baseline values by visit and treatment arm (i.e. VH4004280 or placebo) will be presented 
for vital signs (e.g. blood pressure etc.), ECG (e.g. QTc, PR, QRS interval), coagulation 
(e.g. PT, PTT, INR), hematology and remaining chemistry laboratory parameters. 
Proportion of participants with maximum toxicity grade increase from Baseline will be 
presented by treatment arm for coagulation, hematology and remaining chemistry 
laboratory parameters. Details will be provided in the SAP.  
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9.3.5. 
Other Analyses 
In Part 1 (and in Part 2, if data permits), dose proportionality will be assessed by the 
power model for PK parameters. 
In Part 2, accumulation ratios will be evaluated by determining the ratio of last dose (i.e. 
Day 14 for dosing groups 1 and 4, and Day 15 for MAD/DDI dosing group(s))) to first 
dose (i.e. Day 1 for dosing groups 1 and 4, and Day 2 for MAD/DDI dosing group(s)) on 
Cmax, AUC(0-τ) and Cτ PK parameters. 
In Part 2, attainment of steady-state will be assessed by estimating the slope of pre-dose 
trough concentrations using at least the last 3 pre-dose concentrations. 
In Part 3, the loge-transformed PK parameters (for VH4004280 tablet and for 
VH4004280 PiB from the same dose in Part 1) will be analyzed as data permits using a 
mixed effect model with a fixed effect term for tablet vs. PiB. Participant will be treated 
as a random effect in the model. Point estimates and 90% CIs for the ratios of tablet vs. 
PiB in PK parameters will be provided. Additional details will be provided in the SAP. 
Special statistical and data analysis considerations may be warranted in the event that the 
COVID-19 or related epidemics or natural disasters may affect the study and data 
integrity. To the extent possible, these will be described in the SAP. 
9.3.6. 
Safety and PK dose escalation analyses 
Refer to Section 4.4 for information on the dose escalation procedure. Further details 
about instream data review and the Safety and Dose Escalation Committee and process 
will be recorded in a Dose Escalation Plan.  
9.3.6.1. 
Bayesian dose escalation analyses 
In the SAD part of the study, beginning with the second dose and for each subsequent 
dose, the Bayesian probability of any participant to exceed the 
 
 at the subsequent dosing group will be calculated using PK data of 
participants who received VH4004280 in the previous dosing groups as appropriate. 
Observations on placebo are excluded. This probability, together with safety and 
tolerability data of the preceding dosing groups, will be used to help selection of the next 
dose. The Bayesian probability of exceeding the Cmax NOAEL threshold can be 
calculated for additional potential doses to aid in dose selection, if necessary. 
The Bayesian probability will be based on Whitehead’s model shown below. [Whitehead, 
2001] using non-informative prior for model parameters. 
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𝑦𝑖= 𝜃1 + 𝜃2𝑑𝑖+ 𝜖𝑖 
Where 𝑦𝑖 is log-PK of the 𝑖-th participant, 𝑑𝑖 is the log-dose administered to the 𝑖-th 
participant. 𝜃1 and 𝜃2 are population intercept and slope, respectively, and 𝜖𝑖 is the 
random error of the 𝑖-th participant.  
For the prediction of the second dose in Part 1 and Part 2, 𝜃2 will be assumed to equal 1 
(representing a dose proportionality assumption). This will allow for the estimation of the 
remaining parameters of the model using data from only one dose level. After the second 
dose, 𝜃2 will be estimated by the data. 
 
In the MAD part, the probability for either the maximum of Cmax or maximum of AUC0-24 
across all participants in the next dose to exceed the MAD PK stopping criteria (see 
Section 7.4.1) will be calculated using similar Bayesian methodology. 
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9.4. 
Interim Analyses 
There will be no formal interim analysis. 
Preliminary safety, tolerability, and available PK data will be reviewed internally prior to 
each dose escalation and prior to initiation of Parts 2 and 3. Dose escalation can only 
occur after the SDEC has found that the safety and PK profiles are supportive to proceed 
with the evaluation of the next higher dose level (see Section 6.5). 
Additional data cuts and analyses may be conducted to support regulatory needs, 
publications or for other purposes, if needed. Criteria for data quality for data released for 
these purposes will be described in the study data management plan. 
9.5. 
Final Analyses 
Final analyses will be performed after the completion of the study and final datasets 
authorization. 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by participant, treatment and day; summaries will be 
presented by treatment, day, and time. 
More details will be included in the SAP. 
9.6. 
Sample Size Determination 
Sample size for all parts of the study is based on feasibility and no formal calculation of 
power or sample size has been performed.  
Parts 1 and 2 
A sample size of approximately 6-8 active and 2 placebo participants per dosing group 
should be sufficient to provide useful estimates of both inter- and intra- participant 
variability for VH4004280 PK parameters and initial safety assessment. 
Although the sample size is not based on statistical criteria, general probabilities can be 
determined for the likelihood of observing AEs. With 6 or 8 active participants per 
dosing group, if the true rate of an adverse event is 5%, the chance of seeing at least 1 
participant with the adverse event for a given dosing group is 26% or 34%, respectively. 
Similarly, if the true adverse event rate is 20%, the chance of seeing at least 1 participant 
with the adverse event for a given dosing group is 74% or 83%, respectively. 
For Part 2, for dosing groups in which midazolam is administered, with a sample size of 8 
active participants, assuming a geometric CVw for midazolam of 15% (estimated from 
study 213052; GSK Document Number 2019N422949_01) for AUC(0-∞), the expected 
precision of the estimated ratio of midazolam AUC(0-∞) for midazolam + VH4004280 
vs. midazolam will be as follows:  
 


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Drug 
CVw 
Half-width 
(log-scale) 
Ratio 
90% CI 
Midazolam 
15% 
0.141 
0.9 
(0.781, 1.037) 
1.0 
(0.868, 1.152) 
1.1 
(0.955, 1.267) 
 
Part 3 
To investigate the tablet PK, a sample size of 6 active participants will be used in the 
dosing group using tablet formulation in Part 3. 
The median of between-subject variability (geometric CVb) in VH4004280 PK 
parameters from the PiB administration across the first 5 dosing groups in SAD in this 
study were 27% and 32% for Cmax and AUC(0-∞), respectively. 
Assuming a between-subject geometric coefficient of variation (CVb) of 30% and a 
sample size of 6 active participants per group (i.e. PiB, tablet), it is estimated that the half 
width of the 90% CI for the formulation difference on the log-scale will be within 0.31 of 
the PK parameter (e.g. Cmax, AUC(0-∞)) point estimate. If the point estimate of the ratio of 
geometric means of PK parameters is assumed to be 1, then the 90% CI of the ratio will 
be approximately (0.74, 1.36). 
 
9.6.1. 
Sample Size Sensitivity 
Part 2 (dosing groups with midazolam administration) 
A sensitivity analysis assuming a higher within-subject variability, CVw of 25% for 
midazolam AUC(0-∞) and a sample size of 10 active participants was conducted. Table 18  
below shows the expected precision of the estimated ratio of AUC(0-∞) of midazolam for 
midazolam+VH400280 vs. midazolam. 
Table 18 
Part 2 - MAD/DDI dosing group sample size sensitivity 
Drug 
N 
CVw 
Half-width 
(log-scale) 
Ratio 
90% CI 
Midazolam 
8 
15% 
0.141 
0.9 
(0.781, 1.037) 
1.0 
(0.868, 1.152) 
1.1 
(0.955, 1.267) 
25% 
0.233 
0.9 
(0.713, 1.136) 
1.0 
(0.792, 1.263) 
1.1 
(0.871, 1.389) 
10 
15% 
0.122 
0.9 
(0.796, 1.017) 
1.0 
(0.885, 1.130) 
1.1 
(0.973, 1.243) 
25% 
0.202 
0.9 
(0.735, 1.101) 
1.0 
(0.817, 1.224) 
1.1 
(0.899, 1.346) 


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The precision of the estimated ratio (i.e. 90% CI width) of midazolam AUC(0-∞) 
midazolam +VH4004280 vs. midazolam increases only by ~14% when increasing the 
sample size from 8 to 10 participants in the VH4004280 arm. 
Part 3 
A sensitivity analysis assuming a higher between-subject variability, CVb of 40% for PK 
parameters (e.g. Cmax, AUC(0-∞)) and a sample size of 10 active participants for the tablet 
formulation was conducted. Table 19 below shows the expected 90% CI of the ratio of 
geometric means for various assumed estimated ratios as an example. 
Table 19 
Part 3 sample size sensitivity 
NPiB 
NTablet 
CVb 
Ratio 
Estimated 90% CI 
6 
6 
0.30 
0.9 
(0.662, 1.224) 
1 
(0.736, 1.360) 
1.1 
(0.809, 1.496) 
0.40 
0.9 
(0.601, 1.347) 
1 
(0.668, 1.497) 
1.1 
(0.735, 1.646) 
10 
0.30 
0.9 
(0.689, 1.175) 
1 
(0.766, 1.306) 
1.1 
(0.842, 1.437) 
0.40 
0.9 
(0.634, 1.278) 
1 
(0.704, 1.420) 
1.1 
(0.775, 1.562) 
 
The precision of the estimated ratio (i.e. 90% CI width) of PK parameters between 
VH4004280 tablet and VH4004280 PiB increases only by ~13% when increasing the 
sample size from 6 to 10 active participants in the VH4004280 tablet cohort. 
 


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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: 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
Applicable ICH Good Clinical Practice (GCP) guidelines 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, 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 amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
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: 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable)), European Medical Device Regulation 2017/745 for clinical 
device research (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 his/her representative will explain the nature of the study, including 
the risk and benefits, to the participant and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protect requirements, where 
applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the participant.  
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 
personal information such as last menstrual period and year of birth, or the personal 
information of their baby such as date of birth and sex as part of safety follow-up.  
If follow-up information from a treating physician or other licensed medical practitioner 
is required for a medical device incident with an AE/SAE involving an associated 
person(s), the Associated Person Safety Reporting Information and Authorization Letter 
must be signed by the associated person to obtain consent. 
VH/GSK (alone or working with others) may use participant’s coded study data and 
samples and other information to carry out this study; understand the results of this study; 
learn more about VH4004280 or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the the study drug 
approved for medical use or approved for payment coverage. 
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
10.1.4. 
 Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  


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The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent.  
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a VH/GSK site or other mutually-
agreeable location. 
VH/GSK will also provide all investigators who participated in the study with a summary 
of the study results and will tell the investigators what treatment their patients’ received. 
The investigator(s) is/are encouraged to share the summary results with the study 
participants, as appropriate. 
Under the framework of the SHARE initiative, 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. Requests for access 
may be made through www.clinicalstudydatarequest.com. 
VH/GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
The procedures and timing for public disclosure of the protocol and results summary and 
for development of a manuscript for publication for this study will be in accordance with 
VH/GSK Policy. 
VH/GSK intends to make anonymized patient-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 
10.1.6. 
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.  
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Quality tolerance limits (QTLs) will be pre-defined in the QTL report to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These pre-defined parameters will be monitored during and at the end of the study and all 
deviations from the QTLs and remedial actions taken will be summarized in the clinical 
study report. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy 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), 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. Detailed information about study data collection and 
management process including systems used can be found in the study Data Management 
Plan or equivalent CRO document. 
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 Clinical Study 
Report (CSR)/ equivalent summary unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in Source Data 
Acknowledgment. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  


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10.1.8. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
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 drug 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 of participants (evaluated after a reasonable amount of time) 
by the investigator 
If the study is prematurely terminated or 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 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 
10.1.9. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in (Table 20) will be performed by the local 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. 
 
Table 20 
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 count 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH)  
Percent reticulocytes 
White blood cell 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 
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 


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Laboratory 
Assessments 
Parameters 
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) 
Other Screening 
Tests 
SARS-CoV-2 polymerase chain reaction test 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only) 
Alcohol, cotinine, and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody).  
NOTES : 
 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Section 10.5 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). 
 
Recommend repeat testing if creatine phosphokinase 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. 
 
Estimated serum creatinine clearance (using Chronic Kidney Disease Epidemiology Collaboration equation) at 
screening for eligibility determination. 
 
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 drug, whether or not considered related to the study 
drug. 
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 drug. 
 
Definition of Unsolicited and Solicited AE 
• 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 participant 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. 
• 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. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant.  
 
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 drug administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug or a concomitant medication. Overdose per se will not be reported as an 


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Events Meeting the AE Definition 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments 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). 
• 
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. 
 
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 other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 


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An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
• 
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 
f. 
Is a suspected transmission of any infectious agent via an authorized 
medicinal product 
g. 
Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% direct 
bilirubin) or international normalized ratio (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. 
Recording and Follow-Up of AE and SAE 
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, 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 VH/GSK required form. 


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AE and SAE Recording 
• 
There may be instances when copies of medical records for certain cases are 
requested by VH/GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to VH/GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• Every AE and SAE reported during the trial should be evaluated by the investigator 
and graded in the eCRF according to the DAIDS toxicity scales. 
Note: Grade 4 DAIDS toxicity grades for laboratory parameters that are 
asymptomatic would not necessarily be considered SAEs, a clinical correlation 
would be necessary. 
• 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 
following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study drug 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 drug 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 


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Assessment of Causality 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to VH/GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to VH/GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
VH/GSK to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide VH/GSK with a copy of any 
postmortem findings including histopathology.  
• 
New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information. 
 
10.3.4. 
Reporting of SAE to VH/GSK 
SAE Reporting to VH/GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to VH/GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next SAE Reporting to VH/GSK via Paper Data Collection 
Tool) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 


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SAE Reporting to VH/GSK via Electronic Data Collection Tool 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next table on SAE Reporting to VH/GSK via Paper Data Collection 
Tool) or to the Sponsor medical monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to VH/GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the Sponsor medical monitor or the SAE 
coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
As per Section 5.1(Inclusion Criteria) of the protocol a female participant (female sex 
assigned at birth) is eligible to participate in this study if she is a woman of 
nonchildbearing potential (WONCBP). There is no requirement for female study 
participants to use a highly effective method of contraception since, to be eligible, they 
must be of nonchildbearing potential. 
10.4.1. 
Definitions: 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
Documented hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
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. 
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 for Male Participants and their Female 
Partners (if of child-bearing potential) 
Male participants must agree to use contraception/barrier as detailed below: 
Agree to use a male condom and should also be advised of the benefit for a female 
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a condom may break or leak when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
AND 
Female 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 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 drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly 
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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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
 
Phase 1 Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology  
 
Phase 1 Liver Chemistry Stopping Criteria and Required Follow Up Assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND total bilirubin2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, report as an SAE1,2. 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
Immediately discontinue study drug 
Report the event to GSK within 24 hours 
Complete the liver event form and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
Perform liver event follow up assessments as 
described in the Follow Up Assessment 
column. 
Do not restart or rechallenge participant with 
study drug  
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 
Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours 
Viral hepatitis serology3 
Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show downward 
trend 
Obtain blood sample for pharmacokinetic (PK) 
analysis, one sample will be obtain as soon 
as possible in relation to the most recent 
dose. Another sample can be obtained as 
needed as dependent on the medical 
guidance4  
Obtain serum creatine phosphokinase (CPK), 
lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT), 
glutamate dehydrogenase (GLDH) and serum 
albumin. 
Fractionate bilirubin, if total bilirubin 2xULN 
Obtain complete blood count with differential 
to assess eosinophilia 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the liver event form 


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Liver Chemistry Stopping Criteria  
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 
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 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. 
Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) and /or 
liver biopsy to evaluate liver disease; 
complete Liver Imaging form. 
Liver biopsy may be considered and 
discussed with local specialists if available, for 
instance: 
In participants when serology raises the 
possibility of autoimmune hepatitis (AIH) 
In participants when suspected DILI 
progresses or fails to resolve on withdrawal of 
study drug 
In participants with acute or chronic atypical 
presentation. 
If liver biopsy is conducted, then complete 
liver biopsy form 
 
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.  
 
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 
 
Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing) and hepatitis E IgM antibody  
 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study drug prior to PK 
blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best approximation. If 


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the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.  
 


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10.6. 
Appendix 6: Abbreviations and Trademarks 
z 
Apparent Elimination Rate Constant 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARV 
Antiretroviral therapy  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration-Time Curve 
AUC(0-∞) 
Area Under the Plasma Concentration Time Curve from Time Zero 
to Infinity 
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 = 0 
hours to time = 24 hours 
AUC(0-
tlast) 
Area under the plasma concentration vs time curve from time = 0 
hours to the last evaluable timepoint 
AUC(0-inf) 
Area under the plasma concentration vs time curve from time = 0 
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 
BCG 
Bacillus Calmette-Guerin 
C24 
Concentration at 24h Post-Dose 
CAI 
Capsid Inhibitor 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
Apparent Oral Clearance 
Cmax 
Maximum Observed Plasma Concentration 
Clast 
Concentration in a concentration time course 
CPK 
Creatine phosphokinase 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
Cτ 
Concentration at the end of the dosing interval at steady state 
CV 
Coefficient of Variation 
CVw 
Inter-Participant Coefficient of Variation 
CVb 
Between participant coefficient of variation 
CYP 
Cytochrome P450 
DBL 
Database lock 
DDI 
Drug-Drug Interaction 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ER 
Extended Release 
CCI


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EU 
European Union 
F 
Bioavailability 
FDA 
Food and Drug Administration  
FSH 
Follicle Stimulating Hormone 
FTIH 
First-time-in-human 
FTR  
Fostemsavir 
g 
gram 
g/L 
Gram Per Litre 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GLP 
Good Laboratory Practice 
GMR 
Geometric Mean Ratio 
GSK 
GlaxoSmithKline 
h 
Hour 
Hb 
Hemoglobin 
HBV or 
HCV 
Hepatitis B or C virus 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HED 
Human Equivalent Dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPLC 
High Performance Liquid Chromatography 
HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
ICE 
Intercurrent events 
ICF 
Informed Consent Form 
ICH 
International Council On Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
INR 
International Normalised Ratio 
IRB 
Institutional Review Boards 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IVIVT 
In Vitro/In Vivo Translation  
Kg 
Kilogram 
m 
Metre 
MAD 
Multiple Ascending Dose 
MCH 
Mean Corpuscular Haemoglobin 
MCV 
Mean Corpuscular Volume 
MDZ 
midazolam 
mg 
Milligram 
min 
Minute 
mL 
Millilitre 
CCI


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mmHg 
millimetre of Mercury 
MRSD 
Maximum Recommended Starting Dose 
MSDS 
Material Safety Data Sheet 
ng 
Nanogram  
NOAEL 
No observed adverse effect level 
NQ 
Nonquantifiable 
PBPK 
Physiologically based pharmacokinetic 
PI 
Principal Investigator 
PiB 
Powder-in-a-bottle 
PK 
Pharmacokinetic 
PoC 
Proof of Concept 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PVR 
Pulmonary Vascular Resistance 
QTc 
Corrected QT Interval 
QTcF 
QT Interval Corrected for Heart Rate According to Fridericia’s 
Formula 
QTLs 
Quality tolerance limits 
RAP 
Reporting and Analysis Plan 
RNA 
Ribonucleic Acid  
RHF 
Right-Sided Heart Failure 
RNA 
Ribonucleic Acid 
R(AUC(0-
τ)) 
The accumulation ratio of AUC(0-inf): the ratio of AUC(0-inf) 
measured after the first dose and last dose in a multiple dose series 
R(Cmax) 
The accumulation ratio of Cmax: the ratio of Cmax measured after the 
first dose and last dose in a multiple dose series 
R(Cτ) 
The accumulation ratio of Cτ: the ratio of Cτ measured after the first 
dose and last dose in a multiple dose series 
SAD 
Single Ascending Dose 
SAP 
Statistical analysis plan 
SARS-CoV-
2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Standard Deviation 
SDEC 
Safety and Dose Escalation Committee 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2 
Apparent Terminal Elimination Phase Half-Life 
Tmax 
Time to Cmax 
TB 
Tuberculosis 
TQT 
Thorough QT 
TST 
Tuberculin skin test 
ULN 
Upper Limit of Normal 
CCI


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US 
United States 
VSLC 
ViiV Safety and Labelling Committee 
Vz/F 
Apparent Oral Volume of Distribution 
WBC 
White Blood Cells 
WONCBP 
Woman of Non-Childbearing Potential 
 
Trademark Information 
Trademarks of the ViiV Healthcare and 
GlaxoSmithKline group of companies 
 
Trademarks not owned by the ViiV 
Healthcare and GlaxoSmithKline group 
of companies 
None 
 
EnteroTracker 
 
 
WinNonlin 
 


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10.7. 
Appendix 7: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, July 2017 
VERSION 2.1, July 2017 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
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 
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5 
For more information, please refer to the DAIDS grading table Version 2.1, July 2017 at 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). 


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10.8. 
Appendix 8: 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 drug 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 drug 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.  
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you 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 drug, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants.  
Clinical investigators should document in site files and the eCRF 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 must be withdrawn from study drug and discontinued from the study if 
he/she is found to have SARS-CoV-2 infection during an inpatient stay. The management 
of all other inpatient participants within the same dosing group should be discussed by 
the investigator and the medical monitor. Individuals who have not been exposed to the 
virus will be permitted to remain in the clinic and fulfil their inpatient stay. Individuals 
who have been exposed will be discharged home regardless of whether they are 


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symptomatic. Individuals who are discharged home may still be able to continue in the 
study at the discretion of the investigator and medical monitor assuming the participant 
adheres to current Centers for Disease Control and Prevention guidance for exposure and 
assuming the participant continues to have a negative SARS-CoV-2 test status. 
 Participants who test positive during the outpatient phase of the trial 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. 
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. 
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 Principal Investigator (PI) 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 PI may sign/re-
sign the eCRF from any computer/location by accessing InForm (or other eDC platform) 
using his/her unique eCRF log-in credentials. The PI 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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10.9. 
Appendix 9: Protocol Amendment History 
Amendment 01, 18 January 2022 
Overall Rationale for the Amendment: This amendment results from the FDA “Study 
May Proceed” letter for IND Opening (Number 156318, Reference ID 4897085) dated 01 
December 2021. FDA recommended 6 clinical revisions/clarifications to the protocol, 
listed below. An additional revision to the potential risks with VH4004280 is also being 
added by the Sponsor in response to emerging non-clinical data. Lastly, points of 
clarification have been incorporated throughout the protocol. 
 
 


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Summary of changes table of previous amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 2 (Clinical 
Laboratory Tests) 
Revised laboratory clinical chemistry panel to include 
addition of amylase and lipase to monitor for potential 
pancreatitis events. This is a general precaution, since 
there are no pre-clinical data with VH4004280 that 
suggest toxicity to the pancreas. 
FDA recommended change, 
Clinical item #6 
Section 2.3 
(Benefit/Risk 
Assessment) 
Updated the potential risk section with the potential risk 
of acute pulmonary injury that was identified from a non-
GLP dog study exploring high doses of a 
 
 of VH4004280 
 
. The proposed 
 doses to be used in 
this clinical study are predicted to result in exposures 
 below the established No 
Adverse Effect Level 
 
 and below exposures where the lung 
inflammation was observed in dogs receiving 
 
VH4004280 
 
. 
Sponsor driven revision 
based on emerging non-
clinical safety finding. There 
are no resulting changes to 
the conduct or safety 
monitoring of participants 
Section 3 (Objectives 
and Endpoints) and 
Section 1.1 (Synopsis) 
Clarified what “part” refers to in the primary 
pharmacokinetic endpoint section. 
FDA requested clarification 
Clinical item #7 
Section 4.4 (Safety 
and Dose Escalation 
Committee) 
Clarified that in most cases the SDEC will meet when 
data are available for the entire dosing group (rather than 
just 4 participants on active) through at least Day 7 
assessments in Part 1 and at least Day 21 assessments 
in Part 2. The protocol retains the allowance for the 
SDEC to meet when data are available for fewer 
participants in a dosing group (that is, at least 4 
participants on active drug). 
FDA recommended change, 
Clinical item #8 
Section 5.2 (Exclusion 
Criteria) 
Clarified the “chemical entities” text in exclusion criterion 
#11 to “investigational products”, such that the criterion 
now reads, “Exposure to more than 4 new investigational 
products within 12 months prior to the first dosing day”. 
FDA requested clarification, 
Clinical item #9 
Section 5.1 (Inclusion 
Criteria) and Appendix 
4 (Contraceptive and 
Barrier Guidance) 
Clarified that female participants do not need to adhere 
to the birth control measures outlined in the protocol as, 
by definition of inclusion, are women of non-childbearing 
potential. As already noted in the protocol, the birth 
control measures outlined in the protocol for females is 
only relevant for female partners of male study 
participants. 
FDA requested clarification, 
Clinical item #10 
Section 5.2 (Exclusion 
Criteria) 
Revised the hepatitis exclusion criteria to exclude 
participants with a history of hepatitis B and hepatitis C 
infection, to the already existing exclusion of active 
infections. As a result, three exclusion criteria (#18, #19 
and #20) were consolidated into one exclusion criterion 
(#18) which now reads, “History of or current infection 
with hepatitis B or hepatitis C“ 
FDA recommended change, 
Clinical items #11. 
Section 5.3.1 (Meals 
and Dietary 
Restrictions) 
Clarified that the meal will be given 30 minutes ahead of 
the start of dosing, the meal should be consumed within 
25 minutes, and the EnteroTracker is removed 6 hours 
after dose. 
 
Sponsor driven clarifications 
Section 7.1.3 (SARS-
CoV-2 Stopping 
Revised the SARS-CoV-2 stopping criteria to 
differentiate how to manage the participant who tests 
Sponsor driven revision to 
responsibly manage the 
CCI
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Criteria) and Appendix 
7 (Permissible 
Procedures During 
COVID-19 Pandemic) 
positive in the inpatient vs the outpatient setting. A 
participant must be withdrawn from study drug and 
discontinued from the study if he/she is found to have 
SARS-CoV-2 infection during an inpatient stay. If the 
participant is found to have SARS-CoV-2 infection while 
an outpatient, then the participant 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.  
ongoing study participation of 
COVID-19 infected 
participants who are capable 
of completing the study. 
Not applicable 
Other minor revisions that provide clarification. 
Sponsor driven clarifications 


TMF- 15100069 
CONFIDENTIAL 
 
 
 
217058 
 
 
Protocol Amendment 02 
 
119 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
11. 
REFERENCES 
Backman JT, Kivistö KT, Olkkola KT, et al. The area under the plasma concentration-
time curve for oral midazolam is 400-fold larger during treatment with itraconazole than 
with rifampicin. Eur J Clin Pharmacol 1998; 54:53-8. 
 
 
 
 
 
GlaxoSmithKline Document Number RPS-CLIN-014478, VH4004280 Investigator's 
Brochure, Version 00, October 2021. 
GlaxoSmithKline Document Number RPS-CLIN-043688, VH4004280 Supplemental 
Investigator's Brochure, Version 01, October 2022.  
GlaxoSmithKline Document Number TMF-14086139, Modeling and Simulation 
Analysis Report to predict the Pharmacokinetics of VH4004280 for FTIH Study, October 
2021 
GlaxoSmithKline Document Number 2019N422949_01. Effects of GSK3640254 on the 
Single-Dose Pharmacokinetics of Probe Substrates (Caffeine, Metoprolol, Montelukast, 
Flurbiprofen, Omeprazole, Midazolam, Digoxin, and Pravastatin) in Healthy Subjects. 2 
Jun 2020. 
Guidance for Industry estimating the maximum safe starting dose in initial clinical trials 
for therapeutics in adult healthy volunteers. FDA/CDER, July 2005 
Gupta S, et al. Long-acting subcutaneous lenacapavir dosed every 6 months as part of a 
combination regimen in treatment-naïve people with HIV: Interim 28-week results of a 
randomized, open-label, Phase 2 induction-maintenance study (CALIBRATE), IAS 2021, 
18-21 July, Berlin, Germany, Poster OALB0302, Accessed via 
https://www.ias2021.org/the-programme/ 18 August 2021. 
Molina J, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 
heavily treatment experienced people with HIV; week 26 results (CAPELLA), IAS 2021, 
18–21 July, Berlin, Germany. Oral OALX01LB02, Accessed via 
https://www.ias2021.org/the-programme/ 18 August 2021. 
 
Olkkola KT, Backamn JT, Neuvonen PJ. Midazolam should be avoided in patients 
receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 
1994; 55:481-5. 
Rogers JF, Morrison AL, Nafziger AN, et al. Flumazenil reduces midazolam-induced 
cognitive impairment without altering pharmacokinetics.  Clin Pharmacol Ther. 2002 
Dec;72(6):711-7 
CCI


TMF- 15100069 
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217058 
 
 
Protocol Amendment 02 
 
120 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
UNAIDS [Internet] Global AIDS Epidemiological Estimates Update 2021 [cited on 18 
August 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. 
Whitehead J, Patterson S, Webber D, et al. Easy-to-implement Bayesian methods for 
dose-escalation studies in healthy volunteers. Biostatistics. 2001 Mar;2(1):47-61. 
 


Signature Page for  217058 TMF-15100069 v1.0
Signature Page for TMF-15100069 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 17-Nov-2022 14:02:31 GMT+0000
PPD

SAP_001.pdf: 
 Statistical Analysis Plan Amendment 3
Study ID: 217058 
Official Title of the Study: A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study 
to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4004280 in Healthy 
Participants. 
NCT Number: NCT05163522 
Date of Document: 9 December 2022 


CONFIDENTIAL 
ViiV Healthcare group of companies 
Statistical Analysis Plan 217058 
1 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A Randomized, Double-Blind (Sponsor Unblinded), Placebo-
Controlled Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Orally Administered VH4004280 in 
Healthy Participants. 
Study Number: 
217058 
Compound Number: GSK4004280 (Also known as VH4004280) 
Abbreviated Title: 
VH4004280 First-Time-in-Human-Study 
Sponsor Name: ViiV Healthcare UK Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
IND 
156318 
Copyright 2022 the ViiV Healthcare group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


CONFIDENTIAL 
 
2 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 5 
1.2. 
Objectives, Estimands and Endpoints ........................................................... 5 
1.2.1. 
Estimands ...................................................................................... 8 
1.3. 
Study Design .............................................................................................. 12 
2. 
STATISTICAL HYPOTHESES ............................................................................... 13 
2.1. 
Multiplicity Adjustment ................................................................................ 13 
3. 
ANALYSIS SETS ................................................................................................... 14 
4. 
STATISTICAL ANALYSES ..................................................................................... 15 
4.1. 
General Considerations .............................................................................. 15 
4.1.1. 
General Methodology .................................................................. 15 
4.1.2. 
Baseline Definition ....................................................................... 16 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 16 
4.2.1. 
Definition of endpoint(s)/estimands .............................................. 17 
4.2.2. 
Main analytical approach of primary Safety analyses ................... 17 
4.2.3. 
Main analytical approach of primary PK (VH4004280) 
analyses ...................................................................................... 20 
4.3. 
Safety Analyses .......................................................................................... 22 
4.3.1. 
Safety endpoint(s) ........................................................................ 22 
4.5. 
Other Analyses ........................................................................................... 29 
4.5.1. 
Subgroup Analyses ...................................................................... 29 
4.5.2. 
Other Pharmacokinetic Analyses ................................................. 29 
4.6. 
Interim Analyses ......................................................................................... 32 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 33 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 34 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 34 
6.1.1. 
Participant Disposition ................................................................. 34 
6.1.2. 
Protocol Deviations ...................................................................... 34 
6.1.3. 
Demographic and Baseline Characteristics .................................. 35 
6.1.4. 
Concomitant Medications and Current Medical Conditions .......... 35 
6.1.5. 
Subject Disposition & Study Treatment Discontinuation ............... 35 
6.1.6. 
Protocol Deviations ...................................................................... 35 
6.1.7. 
Additional COVID-19 Assessments .............................................. 35 
6.2. 
Appendix 2 Abbreviations and Trademarks ................................................. 37 
6.2.1. 
Abbreviations ............................................................................... 37 
Trademarks ................................................................................................ 37 
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7. 
REFERENCES ....................................................................................................... 38 


CONFIDENTIAL 
 
 
4 
 
VERSION HISTORY 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
1 
10 Dec 2021 
Version 1  
(18 Oct 2021) 
Not 
Applicable 
Original version 
2 
09 Dec 2022 
Amendment 02 
(17 NOV 2022) 
Protocol 
amendment 
Describe the 
data analyses of 
additional dosing 
groups in 
MAD/DDI (in 
part 2) and study 
part 3. Add 
Urinalysis data 
outputs 
 


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5 
 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report (CSR) for Study 217058. Details of the planned final analyses are provided.  
Descriptive study population analyses, such as summary of demographic and baseline 
characteristics, and additional details with regards to data handling conventions and the 
list of tables, figures and listings and specification of data displays are provided in the 
Output and Programming Specification (OPS) document.  
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There are no changes from the originally planned statistical analysis specified in the 
protocol amendment 02 (Dated: 17-NOV-2022). 
1.2. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of 
single (Part 1 and 3) and multiple (Part 2) 
doses of VH4004280 in healthy 
participants. 
• Incidence of adverse events (AEs), 
severity of AEs and proportion of 
participants who discontinue 
treatment due to AEs  
• Absolute values, change from 
baseline and maximum toxicity grade 
increase from baseline for liver panel 
laboratory parameters [consists of 
total bilirubin, direct bilirubin, 
alkaline phosphatase, aspartate 
aminotransferase (AST), and alanine 
aminotransferase (ALT)] 
To describe the plasma PK characteristics 
of VH4004280 in healthy participants 
following single (Part 1) and multiple (Part 
2) doses. 
• Area under the plasma-concentration 
time curve (AUC): AUC(0-∞) for single 
dose and AUC(0-τ) for repeat dose. 
• Maximum observed plasma drug 
concentration (Cmax), time to 
maximum observed plasma drug 
concentration (Tmax), and apparent 
terminal half-life (T1/2) will be 
calculated for each part (Part 1 SAD 
and Part 2 MAD) as data in each part 
permits. 


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6 
 
Objectives 
Endpoints 
Safety 
To further assess the safety and tolerability 
of single (Parts 1 and 3) and multiple (Part 
2) doses of VH4004280 in healthy 
participants. 
• Post baseline values and changes over 
time of vital signs and ECG 
parameters  
• Absolute values, change from 
baseline and maximum toxicity grade 
increase from baseline for 
hematology, coagulation and 
remaining chemistry panels  
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Objectives 
Endpoints 
 
 
 
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1.2.1. 
Estimands 
Table 1 
Estimands 
Objective 
Estimand 
Variable/Endpoint 
Population & Summary Measure 
Intercurrent event (IE) strategy & rationale 
Primary Objective 1: 
To assess  
the safety and 
tolerability of single 
(Part 1 and 3) and 
multiple (Part 2) 
doses of VH4004280 
in healthy 
participants. 
• Incidence of AEs overall and by 
severity grade 
• Incidence of AEs leading to 
discontinuation of study treatment1 
o Absolute values and change from 
Baseline in liver panel laboratory 
parameters 
o Liver panel laboratory parameters 
maximum grade increase post-
Baseline relative to Baseline for 
gradable parameters or worst-case 
post-baseline changes from 
baseline with respect to normal 
range for any non-gradable lab 
parameters 
Safety analysis set 
• Number and percentage in each 
treatment arm2  
o Summaries (e.g. mean, median, 
std etc.) of absolute values and 
change from Baseline values by 
visit and treatment arm1 in liver 
panel laboratory parameters. 
o Number and percentage of 
participants with maximum grade 
increase relative to Baseline in 
gradable liver panel laboratory 
parameters by treatment arm1, or 
number and percentage of 
participants with worst-case post-
baseline changes from baseline 
with respect to normal range for 
any non-gradable lab parameters  
IE Strategy: 
Discontinuation of study treatment: treatment 
policy strategy for part 2 (discontinuation of 
study treatment can’t occur in parts 1 and 3 as 
participants receive only 1 dose). All available 
AE, liver panel data will be used. No imputation 
will be done for missing data. 
For parts 1 and 3 no relevant intercurrent events 
are anticipated.  
Rationale: 
Interest lies to estimate safety effects likely to be 
attributable to VH4004280 irrespective of 
whether the participant completed the treatment. 
Primary Objective 2: 
o Part 1:  
▪ 
VH4004280 PK Concentrations,  
VH280 Pharmacokinetic analysis set 
IE Strategy: 


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9 
 
Objective 
Estimand 
Variable/Endpoint 
Population & Summary Measure 
Intercurrent event (IE) strategy & rationale 
To describe the 
plasma 
pharmacokinetic 
(PK) characteristics 
of VH4004280 (PiB) 
in healthy 
participants following 
single (Part 1) and 
multiple (Part 2) 
doses. 
▪ 
VH4004280 PK parameters: 
AUC(0-24), AUC(0-tlast), AUC(0-∞), 
Cmax, C24, Tmax, T1/2, Clast, Tlast, 
and %AUCex 
o Part 2:  
▪ 
VH4004280 PK Concentrations, 
▪ 
VH4004280 PK parameters: 
− 
First Dose (Day 1 or 2): 
Cmax, tmax and any other PK 
parameters included in 
SDTM.PP 
− 
Last dose (Day 14 or 15): 
AUC(0-τ), Cmax, Tmax, 
T1/2and any other PK 
parameters included in 
SDTM.PP 
o Part 1: 
PK Concentrations & parameters: 
Summary statistics (e.g. geometric 
mean, median, mean, std, %CV, 
min, max etc.) by visit (only for 
concentrations) and dosing group. 
o Part 2: 
PK Concentrations & parameters: 
Summary statistics (e.g. geometric 
mean, median, mean, std, %CV, 
min, max etc.) by visit (only for 
concentrations) and dosing group. 
 
Discontinuation of VH4004280 administration 
in part 2 will be addressed with while on-
treatment strategy. No imputation will be done 
for missing data.  
For part 1 no relevant intercurrent events are 
anticipated.  
Rationale: 
Discontinuation of VH4004280 may bias the 
evaluation of Pharmacokinetic behavior of 
VH4004280 (PiB). 
Safety Objective: 
To further assess the 
safety and tolerability 
of single (Part 1) and 
multiple (Part 2) 
doses of VH4004280 
in healthy 
participants. 
• Absolute values and change from 
Baseline in vital signs and ECG 
parameters 
o Absolute values and change from 
Baseline and maximum grade 
increase post-Baseline relative to 
Baseline for gradable lab 
Safety analysis set 
• Summaries (e.g. mean, median, 
std etc.) of absolute values and 
change from Baseline values by 
visit and treatment arm2  
o Summaries (e.g. mean, median, 
std etc.) of absolute values and 
IE Strategy: 
Discontinuation of study treatment: treatment 
policy strategy for part 2 (discontinuation of 
study treatment can’t occur in parts 1 and 3 as 
participants receive only 1 dose). All available 
data will be used. No imputation will be done 
for missing data. 


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10 
 
Objective 
Estimand 
Variable/Endpoint 
Population & Summary Measure 
Intercurrent event (IE) strategy & rationale 
hematology, coagulation and 
remaining chemistry parameters, or 
worst-case post-baseline changes 
from baseline with respect to 
normal range for non-gradable lab 
parameters including urinalysis 
 
change from Baseline by visit and 
treatment arm, and number and 
percentage of participants with 
maximum grade increase relative 
to Baseline by treatment arm2 for 
gradable lab parameters, or 
number and percentage of 
participants with worst-case post-
baseline changes from baseline 
with respect to normal range for 
non-gradable lab parameters 
For parts 1 and 3 no relevant intercurrent events 
are anticipated.  
Rationale: 
Interest lies to estimate safety effects likely to be 
attributable to VH4004280 irrespective of 
whether the participant completed the treatment. 
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11 
 
Objective 
Estimand 
Variable/Endpoint 
Population & Summary Measure 
Intercurrent event (IE) strategy & rationale 
1In part 1 study treatment is VH4004280 or placebo, in part 2 is VH4004280 with or without midazolam or placebo and in part 3 is VH4004280 
2Data summaries will be presented for each dosing group for VH4004280 and collectively from all dosing groups for placebo, within each part of the study
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12 
 
1.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
Phase 1, First Time in Human study in healthy participants 
• 
Randomized, Placebo-Controlled (for parts 1 and 2), dose-escalation 
study  
• 
Double-Blind (Sponsor Unblinded) 
• 
A screening visit within 30 days prior to their first dose 
• 
Follow-up period will be approximately 11 weeks (inpatient Days -1 to 7) 
for participants in Part 1 (SAD) and Part 3 and approximately 13 weeks 
(inpatient Days -1 to 21) for participants in Part 2 (MAD) 
• 
Participants within each dosing group in Part 1 (SAD) will receive a 
single dose of VH4004280 (PiB) or placebo on Day 1, participants within 
each dosing group in part 2 will receive one dose daily of VH4224280 
(PiB) or placebo for 14 days (Days 1-14) and participants in Part 3 will 
receive a single dose of VH4004280 (tablet) 
• 
Estimated last follow-up visit is on Day 49 for part 1 (SAD) and part 3 
and Day 63 for part 2 (MAD) 
• 
Primary analysis will be at the End of Study (EoS) 
Study 
intervention 
Assignment 
Part 1 (SAD): It will be conducted in up to 7 ascending separate dosing 
groups. Within each dosing group,  8 participants will be randomized to 
receive a single dose of blinded VH4004280 (PiB) or blinded PBO (in a 6:2, 
active:PBO ratio) administered orally. At the start of each SAD dosing group, 
2 of the total number of participants will serve as sentinel participants, with 
one receiving blinded VH4004280 and the other receiving blinded PBO. The 
proposed dosing schedule is designed to investigate single doses of 


CONFIDENTIAL 
 
13 
 
Overview of Study Design and Key Features 
VH4004280 PiB in Part 1 and then, at a suitable cross-over point, begin 
repeated once-daily dosing of VH4004280 PiB in Part 2. 
Part 2 (MAD): It will be conducted in up to 4 ascending separate dosing 
groups. The starting dose in Part 2 (MAD) will be identified after preliminary 
PK data are evaluated in Part 1 (SAD). Within each dosing group each 
participant will be randomized to receive a once-daily (QD) dose of blinded 
VH4004280 (PiB) or blinded PBO (6:2) administered orally for 14 days. In up 
to two dosing groups (MAD/DDI dosing groups), participants will receive a 
single dose of midazolam on Days 1, 2 and 15 and daily doses of VH4004280 
(PiB) or placebo (8:2) on Day 2 through to Day 15. A single dose of 
midazolam will be co-administered with a dose of VH4004280 (PiB) or PBO 
on Days 2 and 15. The MAD/DDI dosing group(s) will also include the 
collection of endogenous biomarker (coproporphyrin I) samples before and 
following repeat dose administration of VH4004280 (PiB) or PBO to 
investigate the potential of VH4004280 to inhibit OATP1B1/1B3. 
Part 3 (Tablet PK): It will be conducted in 1 dosing group. Participants will 
receive a single dose of VH4004280 tablet on Day 1 and will remain in the 
clinic until completion of the Day 7 procedures. They will return to the clinic 
on Days 14, 21, 28, 35, and 42 for follow up procedures and a final follow up 
visit on Day 49. The dose to be administered in Part 3 will be determined 
based on review of available data from previous dosing groups in Parts 
1 (SAD) and 2 (MAD) and predicted clinical doses. 
Interim 
Analysis 
There will be no formal interim analysis. However, all preliminary safety, 
tolerability, and available pharmacokinetic data (including data from the 
dosing group in part 3) will be reviewed internally by the Safety and Dose 
Escalation Committee prior to each dose escalation and according to the dose 
escalation charter. Dose escalation can only occur after SDEC has found that 
the safety and PK profiles are supportive to proceed with the evaluation of the 
next dose level (see protocol Section 4.4 Safety and Dose Escalation 
Committee). 
 
2. 
STATISTICAL HYPOTHESES  
No formal statistical hypotheses are to be tested. Study objective will be evaluated 
through descriptive summaries.  
2.1. 
Multiplicity Adjustment 
No adjustment for multiplicity will be made.  
 


CONFIDENTIAL 
 
14 
 
3. 
ANALYSIS SETS 
Table 2 
Analysis Sets 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
All participants who were screened for 
eligibility. 
Study Population 
Enrolled 
• All participants who signed the Informed 
Consent Form (ICF), passed screening and 
randomized in the study 
• Note screening failures (who never passed 
screening even if rescreened) and 
participants screened but never enrolled 
into the study (Met eligibility but not 
needed) are excluded from the Enrolled 
analysis set as they did not enter the study. 
Study Population 
Safety 
• All enrolled participants who take at least 
one full or partial dose of study treatment 
(i.e. VH4004280 or midazolam or placebo) 
• For VH4004280 PiB, participants who have 
taken either a full or part (i.e. 
 of 
solution) dose will be included in the Safety 
analysis set 
• Participants will be analysed according to 
the treatment they actually received. 
• Study 
Population 
• Safety 
VH280 
Pharmacokinetic 
(PK) 
• All participants in the Safety analysis set 
who had at least one dose of VH4004280 
tablet or have ingested at least one full dose 
(i.e. 
) of VH4004280 PiB and who 
had at least one non-missing VH4004280 
PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing 
values). 
• Data will be reported according to the 
actual study intervention. 
PK 
MDZ 
Pharmacokinetic 
• All participants in the Enrolled analysis set 
who received at least one dose of 
midazolam and have at least 1 non-missing 
midazolam or 1-hydroxymidazolam PK 
assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• Data will be reported according to the 
actual study intervention. 
PK 
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15 
 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
CP-1 
Pharmacokinetic 
• All participants in the Enrolled analysis set 
who have at least 1 non-missing 
Coproporphyrin I PK assessment (Non-
quantifiable [NQ] values will be considered 
as non-missing values). 
• Data will be reported according to the 
actual study intervention. 
PK 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
If participants prematurely discontinue the study for non-safety reasons or intolerance to 
ingestion of the study drug (i.e., vomiting the solution shortly after ingestion), 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. 
Confidence intervals for PK analyses will use 90% confidence levels, unless otherwise 
specified.  
Unless, otherwise specified, summary tables will provide the following descriptive 
statistics: 
• Continuous data: n (number of subjects used for data summary), arithmetic mean, 
standard deviation (SD), median, interquartile range, minimum and maximum. For 
PK parameters, geometric mean, SD of log-transformed data and geometric %CVb 
may also be used. 
• Categorical data: number and percentage of participants in each category. 
PK values collected outside analysis visit windows (see OPS) will be excluded from the 
summaries (applies to both Tables and Figures) but will be included in listings. Figures 
with subject level information will include all values (i.e. irrespective of being 
within/outside of visit windows). Lab values from any laboratory will be included in data 
summaries. 
Within each part of the study, data will be summarised by dosing group for VH4004280 
and collectively from all dosing groups for placebo, unless otherwise specified.  
 
. Only selected listings 
required by regulatory agencies will be created in static fashion. See OPS for the list of 
selected listings.  
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16 
 
4.1.2. 
Baseline Definition 
For all endpoints, except for ECG, the baseline value will be the latest assessment with a 
non-missing value, including those from unscheduled visits, prior to either VH4004280 
or midazolam administration. If time is not collected, Day 1 assessments are assumed to 
be taken prior to first dose (of either VH4004280 or midazolam) and used as baseline. 
Day 1 pre-dose ECGs for each dosing group will be performed in triplicate. In such case 
of triplicate measurement for pre-dose, the average will be used as baseline. In case one 
of the three assessments is missing, the average of the two available assessments will be 
used as baseline. In all other cases (e.g. when a single Day 1 pre-dose assessment is 
available, or Day 1 assessment is completely missing) the last pre-dose ECG assessment 
will be used as baseline.  
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.2. 
Primary Endpoint(s) Analyses 
Adverse 
Events 
(AEs) 
The number and proportion of participants reporting AEs will be 
tabulated by dosing group for VH4004280 and collectively for Placebo. 
AEs will also be tabulated by severity grade and relationship to study 
drug. AEs will be tabulated using MedDRA preferred terms. For the 
calculations in these tables, each participant’s AEs will be counted once 
under the maximum severity or relationship to study product. 
For part 2, AEs leading to study treatment (i.e. VH4004280 or 
midazolam or placebo) withdrawal will also be summarized by dosing 
group for VH4004280 and collectively for Placebo). In parts 1 and 3, 
discontinuation of study treatment can’t occur as participants receive 
only 1 dose of study treatment. 
The analyses will be repeated for each part of the study. 
Liver panel 
laboratory 
parameters 
Liver panel data will be summarised by dosing group for VH4004280 
and collectively for Placebo and by visit. Summary statistics (e.g. mean, 
median, std) for absolute values and change from baseline. Summaries 
of maximum grade increase relative to Baseline for graded lab 
parameters or summaries of worst-case post-baseline changes from 
baseline with respect to normal range for any non-gradable lab 
parameters will be presented.  
The analyses will be repeated for each part of the study. 
PK for 
VH4004280 
PiB 
Summary statistics (e.g. geometric mean, median, %CV etc.) will be 
provided for the VH4004280 Pharmacokinetic concentrations and 
parameters per dosing group for VH4004280 in each part of the study. 
The analyses will be repeated for each part of the study. 


CONFIDENTIAL 
 
17 
 
4.2.1. 
Definition of endpoint(s)/estimands 
• Adverse Events:  
o 
Number and percentage of participants with AEs 
• Liver panel laboratory parameters (i.e. ALP, ALT, AST, total and direct 
bilirubin): 
o 
Absolute values 
o 
change from Baseline 
o 
Number and percentage of participants with maximum grade increase 
relative to Baseline (for DAIDS-graded lab parameters) 
o 
Number and percentage of participants with worst-case post-baseline 
changes from baseline with respect to normal range (for any non-gradable 
lab parameters) 
• PK:  
o 
Part 1: AUC(0-24), AUC(0-tlast), AUC(0-∞), Cmax, C24, Tmax, T1/2, Clast, Tlast, 
%AUCex and CL/F 
o 
Part 2 dosing groups without midazolam administration:  
— Day 1 (first dose):  Cmax, tmax and any other PK parameters 
included in SDTM.PP 
— Day 14 (last dose): AUC(0-τ), Cmax, Tmax, T1/2 and any other PK 
parameters included in SDTM.PP 
—  
o 
Part 2 dosing groups with midazolam administration:  
— Day 2 (first dose):  Cmax, tmax and any other PK parameters 
included in SDTM.PP 
— Day 15 (last dose): AUC(0-τ), Cmax, Tmax, T1/2 and any other PK 
parameters included in SDTM.PP 
For definition of estimands see Table 1. 
4.2.2. 
Main analytical approach of primary Safety analyses 
All primary safety analyses (i.e. AEs and liver panel lab parameter analyses) will be 
based on the Safety analysis set. 
4.2.2.1. 
Adverse Events Analyses 
AEs will be coded to the preferred term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA) using the latest version at time of database release. AEs 
will be graded by the investigator according to the Division of AIDS (DAIDS) Criteria 
Version 2.1. 
Analyses of adverse events (AEs), Serious AEs (SAEs), AEs leading to study treatment 
withdrawal and other significant AEs will be based on GSK Core Data Standards.  
Summaries will be produced using all follow-up data from Day 1 (inclusive) available at 
the time of analysis. AEs occurring while participants received any study intervention 


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(i.e.VH400280 or Midazolam or placebo) and post study intervention (e.g. after 
participants stopped VH400280 or/and midazolam) will be summarised collectively. The 
following categories and subcategories of AEs will be summarised for each dosing group 
of VH4004280 and Placebo (collectively from all dosing groups) for each part of the 
study: 
• AEs 
o Overall 
o By Maximum Grade 
• AEs leading to withdrawal from study in part 1 
• AEs leading to permanent discontinuation of study treatment (VH4004280 or 
midazolam or placebo) in part 2 or withdrawal from study 
• Drug-related AEs 
o Overall 
o By Maximum Grade 
• Drug-related Non-serious AEs 
• Common (≥5%) non-Serious AEs 
• SAEs 
• Drug-related SAEs 
Each summary display will contain the number and percentage of participants with the 
AE. 
The Common (≥5%) non-Serious AEs display will include also the number of events of 
the AE. 
AEs will be displayed by 
- Column: Treatment arm or intensity. 
- Row: in descending order by SOC and PT, or PT only, as applicable 
A listing of reasons for considering as a SAE will be provided. 
For MAD/DDI dosing groups in part 2, summaries of AE tables will include AEs from 
Day 1 (when participants are on midazolam only) and from all subsequent days (when 
participants are on VH4004280 + midazolam, or VH4004280 only or receiving no 
treatment after the completion of VH4004280 and midazolam administration). No 
distinction between summaries of AEs recorded on Day 1 (midazolam only) and 
summaries of AEs from subsequent days will be provided. AEs with onset on Day 1 will 
be available through subject-level data 
 (SAEs will also be available in 
the SAE listing; see OPS). 
Tables of drug related AEs occurring in the part 2 MAD/DDI dosing groups will include 
AEs related to either VH4004280 or midazolam, as recorded in eCRF (there will be no 
distinction between AEs related to VH4004280 or related to midazolam).  
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary) and graded by the investigator according to the DAIDS 
(Version 2.1) grading table.  
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All planned AE displays are provided in the OPS document. 
4.2.2.2. 
Liver panel laboratory analyses 
The ADLB dataset will be used, which contains the data that is available at a particular 
timepoint, with no imputation for missing values. For each part of the study the following 
analyses on the liver panel laboratory parameters (i.e. ALP, ALT, AST, total and direct 
bilirubin) will be performed. 
Absolute and change from baseline values for liver panel laboratory parameters will be 
summarised by dosing group of VH4004280 and Placebo (collectively from all dosing 
groups) at every assessed time point.  
Laboratory toxicities will be graded according to the Division of AIDS (DAIDS) Criteria 
Version 2.1.  
For liver panel lab tests that are gradable by DAIDS (e.g. ALT, AST), summaries of 
worst-case grade increase from baseline grade will be provided. These summaries will 
display the number and percentage of participants with a maximum post-baseline grade 
increase from their baseline grade (e.g. for participants with maximum increase from 
Baseline to grade 4 the number and percentage of them will be displayed, same for 
increase to grade 3, 2 and 1). Also, maximum increase subtotals (i.e. max increase in 
grade to any grade between 1 and 4, max increase to grade 2-4 or max increase to grade 
3-4) will be included. The grade increases are determined by comparing the baseline 
grade to the worst case post-baseline grade (e.g., Increase to Grade 1, Increase to Grade 2 
etc.) and maximum grade increase subtotals (e.g., Increase to Grades 1 to 4, Increase to 
Grades 2 to 4, Increase to Grades 3 to 4). The grading subtotals are determined by adding 
the counts for each worst case grade change within the subtotal category, e.g., ‘Increase 
to Grades 1 to 4’ is a subtotal of all worst case increases to Grade 1, to Grade 2, to Grade 
3, and to Grade 4. Participants with missing baseline value are to be assumed to have a 
Grade 0 at baseline.  The determination of the worst case during the post-baseline period 
takes into account both planned and unscheduled assessments.   
For any liver panel lab tests that are not gradable by DAIDS (e.g. total protein), 
summaries of worst-case post-baseline changes from baseline with respect to normal 
range will be generated by treatment. The change categories are: to low, to normal or no 
change, and to high. The categorization is determined by comparing the baseline category 
to the worst case post-baseline category. The determination of the worst case post-
baseline takes into account both planned and unscheduled assessments. If a subject has 
both a decrease ‘To Low’ and an increase ‘To High’, then the subject is counted in both 
the ‘To Low’ and ‘To High’ categories.  If a subject was High at baseline and decreases 
to Low during the time interval, then the subject is counted in the ‘To Low’ category. If 
the low or high category (compared to normal) is not applicable for a liver lab parameter, 
then it will be excluded from the display.  
Liver panel data for participants with at least one abnormal lab value will be included in 
the listing of chemistry laboratory parameters.  
More details of all planned displays are provided in the OPS document. 


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4.2.3. 
Main analytical approach of primary PK (VH4004280) analyses 
Pharmacokinetic parameters for VH4004280 will be calculated by standard non-
compartmental analysis according to current working practices and using the currently 
supported version of WinNonlin. All calculations of non-compartmental parameters for 
the final analysis will be based on actual sampling times. For the calculation of the Area 
under the concentration-time curve (AUC), the linear trapezoidal method will be 
employed for all incremental trapezoids arising from increasing concentrations and the 
logarithmic trapezoidal method will be used for those arising from decreasing 
concentrations (i.e., Linear Up/Log Down calculation method in Phoenix WinNonlin 
Professional). A minimum number of three data points (not including Cmax) should be 
used in calculating λz. The pharmacokinetic parameters described in Table 3 will be 
determined from the plasma concentration-time data, as data permits and they will be 
included in the final SDTM datasets. As per the PK Estimand definition in Table 1, in 
case of discontinuation of VH4004280 administration in part 2 of the study, only serum 
VH4004280 concentration data up to the time of discontinuation of VH4004280 will be 
used in derivation of VH4004280 PK parameters. 
Table 3 
Definition of primary PK parameters 
Study Part 
PK 
parameter 
Definition 
Part 1 
AUC(0-∞) 
Area under the plasma concentration time curve 
from time zero to infinity calculated as  
AUC(0-∞) = AUC(0-t) + Clast /λz 
Part 2 
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 
Part 1 & 2 
%AUCex 
Percentage of AUC(0-∞) obtained by extrapolation 
calculated as  
%AUCex= [AUC(0-∞)- AUC(0-t)]/AUC(0-∞) x 100 
Part 1 & 2 
Cmax 
Maximum observed plasma concentration 
Part 1 & 2 
Tmax 
Time to first occurrence of Cmax 
Part 1 & 2 
T1/2 
Apparent terminal elimination phase half-life 
calculated as loge 2/λz where λz terminal phase rate-
constant estimated by linear regression of 
logarithmically transformed concentration versus 
time data. 
Part 1 & 2 
AUC(0-24) 
Area under the plasma concentration vs time curve 
from time = 0 hours to time = 24 hours 


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Study Part 
PK 
parameter 
Definition 
Part 1 & 2 
AUC(0-tlast) 
Area under the plasma concentration vs time curve 
from time = 0 hours to the last observed quantifiable 
concentration 
Part 1 & 2 
C24 
Concentration at 24h Post-Dose 
Part 1 & 2 
Clast 
Last observed quantifiable concentration in a 
concentration time course 
Part 2 
Cτ 
Concentration at the end of the dosing interval at 
steady state 
Part 1 & 2 
Tlast 
Time of the last observed quantifiable concentration 
in a concentration time course 
Part 1 & 2 
CL/F 
Apparent Clearance following oral administration 
Note: Additional Parameters may be included as required 
All primary pharmacokinetic analyses will be performed on the VH280 Pharmacokinetic 
analysis set. 
4.2.3.1. 
Summaries of PK concentration values and PK parameters 
In each part of the study, each pharmacokinetic concentration for VH4004280 at every 
scheduled time point will be summarized, as long as it’s been collected within the PK 
sampling windows. PK concentrations sampled outside the PK sampling windows will be 
included in listings and in subject level figures but will not be included in summaries. 
The PK sampling windows are included in the OPS. The 95% confidence interval for the 
mean will be displayed. 
All derived VH4004280 PK parameters will be summarised for each dosing group using 
descriptive statistics. The following summary measures will be used: geometric mean, 
95% CI of geometric mean, standard deviation of the loge-transformed data (SD logs), 
between subject geometric coefficient of variation (%CVb), arithmetic mean, 95% CI of 
arithmetic mean, sd, median, minimum, maximum. 
In Part 2 of the study, PK concentrations or PK parameters derived after discontinuation 
of study treatment will be excluded from data summaries in accordance with the “while 
on-treatment” strategy for IE as described in Section 1.2.1. 
In Part 2 of the study, if a participant does not take the full dose (i.e. 
) of study 
treatment or miss a dose, any PK concentrations and PK parameters inferred within 24h 
from the partial or missed dose may be excluded from data summaries and statistical 
analyses, as appropriate.  
The following figures will be produced:  
• A by-subject graph of the concentration data over time, on linear and semi-
logarithmic scales.  
• Separate graphs of the mean and median concentration data over time, on linear 
and semi-logarithmic scales by dosing-group. 
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• Individual and box plot of PK parameters by dosing group 
A by-subject listing of pharmacokinetic concentration values at each time point will be 
produced. All PK parameters will also be listed.  
4.3. 
Safety Analyses 
4.3.1. 
Safety endpoint(s) 
Vital Signs 
Post Baseline values and change from Baseline for vital signs 
(e.g. blood pressure) will be summarised by treatment (i.e. for 
each dosing group for VH4004280 and collectively for 
Placebo) and visit for each part of the study. 
Proportion of participants with worst case post-Baseline vital 
signs relative to Baseline will be presented. 
ECG 
Post Baseline values and change from Baseline for ECG 
parameters (e.g. QTc, PR, QRS) will be summarised by 
treatment (i.e. for each dosing group for VH4004280 and 
collectively for Placebo) and visit for each part of the study. 
Proportion of participants with increase in QTc relative to 
Baseline will be presented. 
Hematology, 
coagulation, 
urinalysis and 
remaining chemistry 
panel laboratory 
parameters 
Post Baseline values and change from Baseline for 
hematology, coagulation (e.g. PT, PTT, INR), urinalysis and 
remaining chemistry laboratory parameters will be 
summarised by treatment (i.e. for each dosing group for 
VH4004280 and collectively for Placebo) and visit for each 
part of the study. 
Summaries of maximum grade increase relative to Baseline 
for graded lab parameters or summaries of worst-case post-
baseline changes from baseline with respect to normal range 
for non-gradable lab parameters will be presented. 
4.3.1.1. 
Definition of endpoint(s)/estimands 
Refer to Table 1 in Safety Objective section. 
4.3.1.2. 
Main analytical approach 
All safety analyses will be performed on the Safety analysis set. The following analyses 
will be performed for each part of the study. 
Vital Signs 
Values of vital signs (temperature, systolic and diastolic blood pressure, pulse rate, 
respiratory rate and pulse oximetry) and change from baseline will be summarized by 
scheduled visit and treatment.  


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The number of participants with worst case vital sign results relative to Potential Clinical 
Importance (PCI) criteria which are post-baseline relative to baseline will be summarized 
by treatment. The change categories for PCI criteria are: To Low, To w/in Range or No 
Change, To High. The categorization is determined by comparing the baseline category 
to the worst case post-baseline category. The determination of the worst case post-
baseline takes into account both planned and unscheduled assessments. Participants with 
missing baseline value are to be assumed to have within range baseline value.    
All vital signs data for participants with at least one value of potential clinical importance 
will be included in a listing.  
PCI values for vital signs and all vital signs displays are included in the OPS.  
ECG 
Values of ECG parameters (heart rate, PR, QRS, QT, and QTc intervals) and change 
from baseline will be summarized by scheduled visit and treatment.  
A summary of the number and percentage of participants with ECG findings will be 
summarized by treatment and planned time. The ECG findings to be summarized are the 
ECG interpretation and clinical significance (yes/no) of abnormal ECGs. 
The number and percentage of participants with maximum QTc values (i.e., worst case) 
post-baseline relative to baseline will be summarized by ECG parameter (e.g., QTcF 
Interval, Aggregate), treatment, planned time, and category (the standard categories are: 
no change or post-baseline increase to <=450 msec, any increase to >450 msec, increase 
>450 to <=480 msec, increase >480 to <=500 msec, and increase >500 msec). The 
maximum value category is determined by comparing the baseline value category to the 
worst case post-baseline value category for each subject.  The determination of the worst 
case post-baseline takes into account both planned and unscheduled assessments.   
Participants will be summarized (i.e. number of participants and percentage) by a 
categorization of their maximum increase in QTc value (e.g., QTcF Interval, Aggregate) 
(i.e., worst case) post-baseline relative to baseline. The standard categories for the worst 
case shifts of QTc in msec are:  Increase <=30 msec, Increase of 31-60 msec, and 
Increase of >60 msec change from baseline in QTc interval. Participants with missing 
baseline values are excluded from the display.    
A figure plotting the baseline QTc and the worst-case post-baseline values will be 
produced. The figure will have reference lines at 480 and 500 msec for both the ordinate 
and the abscissa axes. There will be diagonal reference lines at equality (i.e. a 45-degree 
line), at equality plus 30 msec, and at equality plus 60 msec. 
All ECG data for participants with a value of potential clinical importance will be 
included in a listing.  
 PCI values for ECG and all ECG displays are included in the OPS.  
 


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Hematology, coagulation, urinalysis and remaining chemistry lab parameters 
The ADLB dataset will be used, which contains the data that is available at a particular 
timepoint, with no imputation for missing values.  
Absolute and change from baseline values for hematology, coagulation, urinalysis (e.g. 
specific gravity) and remaining (non-primary) chemistry laboratory parameters will be 
summarised by treatment at every assessed time point. For urinalysis parameters assessed 
with the dipstick method (categorical parameters), number and percentage of participants 
in each outcome category will be summarised at every assessed time point.  
For graded lab parameters by DAIDS, the number of participants with laboratory results 
will be summarized by laboratory test, treatment and maximum grade increase. The 
maximum grade increase categories and maximum increase subtotals will be included in 
the display (same as for liver lab parameters in Section 4.2.2.2). There are some lab 
parameters which are graded for both low values and high values. Summaries of these lab 
tests will be differentiated by term, e.g. sodium will be summarized as “hyponatremia” 
and “hypernatremia”, calcium as “hyperkalemia” and “hypokalemia” etc. Check Section 
4.2.2.2 for more details (analysis is the same as for graded liver panel lab parameters). 
For lab parameters which are not graded by DAIDS, the number of participants with 
worst case laboratory results relative to normal range criteria which are post-baseline 
relative to baseline will be summarized by laboratory test and category. Check Section 
4.2.2.2 for more details (analysis is the same as for non-graded liver panel lab 
parameters). 
For urinalysis parameters assessed with the dipstick method, summaries of worst-case 
post-baseline relative to Baseline will be created. The categories for which summaries 
(i.e. number and percentage of participants) will be provided are based on the actual 
values within the data, e.g. ‘No Change/Decreased’, ‘Increase to TRACE’, ‘Increase to 
1+ or Increase to +’, ‘Increase to 1+ or to 1/4 G/DL’, etc.   ‘Decreased’ indicates a 
“lesser” result including change to a negative result.  The categorization is determined by 
comparing the baseline category to the worst case post-baseline category. The 
determination of the worst case post-baseline takes into account both planned and 
unscheduled assessments. Subjects with a missing baseline value are to be assumed to 
have a negative baseline value.    
Listings of hematology, coagulation, urinalysis and chemistry laboratory data will be 
created. The hematology, coagulation and chemistry listings will include only 
participants with at least one abnormal lab value (i.e. DAIDS grade ≥1 or outside normal 
range) in any lab parameter within each lab data category. The urinalysis listing will 
include only participants with at least one abnormal value (i.e. outside normal range) for 
specific gravity or pH or if there is an increase from Baseline in Protein or in Occult 
Blood or if microscopy is performed. All lab parameters at all visits will be listed for the 
participants included in the listing.   
All displays on hematology, coagulation, urinalysis and chemistry laboratory parameters 
are included in the OPS.  


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4.3.2. 
Other Safety Analyses 
Other safety analyses will be based on the Safety Analysis Set, unless otherwise 
specified. 
4.3.2.1. 
Extent of Exposure 
For parts 1 and 3 of the study each participant receives a single dose. Therefore, no 
summaries of extent of exposure or cumulative dose will be generated for parts 1 and 3.  
Extend of exposure to VH4004280 or placebo will be summarised for part 2. Number of 
days of exposure will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
For MAD/DDI dosing groups in part 2, treatment start and stop dates refer to 
VH4004280 or placebo; administration of midazolam is not considered in calculation of 
exposure.  
Participants who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure. 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly. 
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4.5. 
Other Analyses 
4.5.1. 
Subgroup Analyses 
No subgroup analyses are planned. 
4.5.2. 
Other Pharmacokinetic Analyses 
All other pharmacokinetic analyses will be performed on the VH280 Pharmacokinetic 
analysis set. 
For other pharmacokinetic statistical analyses on part 2:  
• PK parameters derived after discontinuation of study treatment will be excluded 
from statistical analyses in accordance with the “while on-treatment” strategy for 
IE as described in Section 1.2.1.   
• If a participant does not take the full dose (i.e. 
) of VH4004280 or miss a 
dose, any PK concentrations and PK parameters inferred within 24h from the 
partial or missed dose may be excluded from the statistical analyses, as 
appropriate.  
4.5.2.1. 
Dose Proportionality Assessment 
Dose proportionality will be assessed in Part 1 of the study. If required, dose 
proportionality may be assessed in Part 2 of the study.  
Power Model 
The analysis will be based on selected available PK parameters. No imputation will be 
done for missing PK parameters for any participant.  
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Endpoint / Variables 
• For SAD part: AUC(0-∞) (AUC0-t may be used if required), Cmax 
• For MAD part: 
o First dose (Day 1 or 2): Cmax, AUC0-24 
o Last dose (Day 14 or 15): Cmax, AUC(0-24), AUC(0-t) 
Model Specification 
• Dose proportionality of VH4004280 PK parameters will be assessed using the 
following power model: 
𝑦= 𝛼∗𝑑𝑜𝑠𝑒𝛽 
where y denotes the PK parameter being analyzed and dose denotes the dose 
administered to a subject. 
• Dose proportionality implies that β = 1 and it will be assessed by estimating β along 
with its confidence interval. 
• β will be estimated by regressing the loge transformed PK parameter on the loge dose 
as shown below: 
 𝑙𝑜𝑔𝑒𝑦= 𝑙𝑜𝑔𝑒𝛼+ 𝛽𝑙𝑜𝑔𝑒𝑑𝑜𝑠𝑒 
• Data from all available doses in each part of the study will be considered.  
Model Results Presentation 
Table: Estimates of slope 𝛽 will be reported in a Table along with corresponding 90% 
confidence intervals.  
Figure: Comparative plots will be provided showing individual subject values by 
treatment (dose) for each of the PK parameters, together with the predicted PK 
parameter value from the Power Model. 
 
ANOVA method 
If power model does not show dose proportionality, dose proportionality may be assessed 
by an analysis of variance (ANOVA) model.  
The PK parameter (e.g. AUC(0-∞), Cmax) will be dose-normalised prior to loge-
transformation by multiplying by reference dose / dose. Dose-normalised PK parameters 
will be analysed separately using a fixed effects ANOVA model for treatment (dose). 
Point estimates for the adjusted means on the loge scale, the mean difference between 
each dose (test) and the reference dose and associated 90% confidence interval will be 
constructed using the residual variance. The point estimate and confidence interval will 
then be exponentially back-transformed to obtain adjusted (least square) geometric means 
for each treatment (dose), and point estimates and associated 90% confidence intervals 
for the ratio test/reference. The reference dose will be chosen based on the lowest 
clinically relevant dose over which PK can be adequately described, with each other dose 
as the test doses in the construction of the ratio µ(test)/µ(reference). 
Plots will be provided showing individual subject dose-normalised PK parameters versus 
dose and will also include the geometric mean and 95% CI for each dose.  


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Plots will also be provided showing the adjusted geometric mean ratio of test to reference 
treatment (dose) for PK parameters together with 90% confidence interval. 
4.5.2.2. 
Estimation of Accumulation Ratios in MAD 
Accumulation ratios will be estimated in Part 2. These are defined as the ratio of last dose 
(Day 14 or 15) to first dose (Day 1 or 2) PK parameters as follows: 
𝑅(𝐴𝑈𝐶(0−𝜏)) =
𝐴𝑈𝐶(0−𝜏) on Day 14
𝐴𝑈𝐶(0−𝜏) on Day 1 , 
𝑅(𝐶𝑚𝑎𝑥) =
𝐶𝑚𝑎𝑥 on Day 14
𝐶𝑚𝑎𝑥 on Day 1 , 
𝑅(𝐶𝜏) =
𝐶𝜏 on Day 14
𝐶𝜏 on Day 1 , 
The analysis will be based on the available AUC(0-τ), Cmax and Cτ PK parameters. No 
imputation will be done for such missing PK parameters for any participant.  
To estimate the accumulation ratios for each dose in part 2, a mixed-effects ANOVA 
model will be used on the loge-transformed PK parameters (AUC(0-τ), Cmax and Cτ), with a 
random intercept (for each participant) and fixed effects for the day. Day will be treated 
as a categorical variable in the model. The Kenward & Roger (KR2) degrees of freedom 
approach will be used [Kenward & Roger, 2009]. The accumulation ratio of VH4004280 
will be estimated by calculating the ratio of the geometric least squares (GLS) means of 
PK parameters between last dose (Day 14 or 15) and first dose (Day 1 or 2) and the 
corresponding 90% CI. The GLS means of AUC(0-τ), Cmax and Cτ on first dose (Day 1 or 
2) and last dose (Day 14 or 15), along with the estimated accumulation ratio and its 90% 
CI will be displayed.  
4.5.2.3. 
Assessment of attainment of steady state in MAD 
To estimate the attainment of steady state for each dose in part 2, a mixed-effects 
ANCOVA model will be used on the loge-transformed C0 and Cτ, with a random 
intercept (for each participant) and fixed effect for the day. Day will be treated as a 
continuous variable in the model. The Kenward & Roger (KR2) degrees of freedom 
approach will be used [Kenward & Roger, 2009]. Achievement of plasma VH4004280 
steady state will be assessed by visual inspection of plots of C0 (from days 2 through 14 
or from days 3 through 15) and Cτ (from day 15 or 16) by day and by calculating the 
point estimate and 90% CI of the slope of the linear regression of C0 and Cτ versus day 
for Days 2-15 or for 3-16. To claim that steady state is reached, the pre-dose 
concentration slope estimate should be close to zero or the 90% CI for the slope estimate 
should include zero.  
The same analysis will be repeated by dropping one earlier day at time until at least the 
last 3 pre-dose concentrations remain. The results will be presented in the same table. 


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In addition, as mentioned above, C0 on Day 2 through 14 or Day 3 through 15 for the 
part 2 MAD/DDI dosing groups and Cτ on day 15 or 16 (for MAD/DDI) will be plotted 
versus day by dose. 
For each of the statistical models in Section 4.5.2.1 –Section 4.5.2.3, distributional 
assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values 
(i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.  
If there are any departures from model assumptions, alternative models or data 
transformations may be explored. 
4.6. 
Interim Analyses 
There will be no formal interim analysis. However, all preliminary safety, tolerability, 
and available pharmacokinetic data (including data from the dosing group in part 3) will 
be reviewed internally by the Safety and Dose Escalation Committee (see protocol 
Section 4.4) prior to each dose escalation and according to the dose escalation charter. 
Safety (AEs, vital signs, clinical laboratory findings, ECG) and PK data will be reviewed 
by the PI and ViiV/GSK study team after completion of each dose level. Dose escalation 
can only occur after PI and ViiV/GSK study team has found that the safety and PK 
profiles are supportive to proceed with the evaluation of the next dose level. 
Additional data cuts and analyses may be conducted to support regulatory needs, 
publications or for other purposes, if needed. Criteria for data quality for data released for 
these purposes will be described in the study data management plan. 
At each dose, the Bayesian probability of any individual exceeding the Cmax threshold in 
Part 1 and the Bayesian probability of any individual exceeding either the Cmax or 
AUC(0-24) (on day 14) threshold in Part 2, among the individuals planned to receive the 
next dose will be calculated. This probability, together with safety, tolerability and other 
PK data will be used by SDEC for dose escalation. The Bayesian probability will be 
based on Whitehead’s model shown below [Whitehead, 2001] using non-informative 
prior for model parameters. 
𝑦𝑖= 𝜃1 + 𝜃2 𝑑𝑖+ 𝜖𝑖 
Where yi is log-PK of i-th participant, di is the log-dose administered to the i-th 
participant. θ1 and θ2 are population intercept and slope, respectively, and 𝜖𝑖 is the 
random error of the i -th participant. 
For the prediction of the second dose in Part 1 and Part 2, 𝜃2 will be assumed to equal 1 
(representing a dose proportionality assumption). This will allow for the estimation of the 
remaining parameters of the model using data from only one dose level. After the second 
dose, 𝜃2 will be estimated by the data. 


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5. 
SAMPLE SIZE DETERMINATION 
Sample size for all parts of the study is based on feasibility and no formal calculation of 
power or sample size has been performed. A sample size of approximately 6-8 active and 
2 placebo participants per dosing group should be sufficient to provide useful estimates 
of both inter- and intra- participant variability for VH4004280 PK parameters and initial 
safety assessment. 
Although the sample size is not based on statistical criteria, general probabilities can be 
determined for the likelihood of observing AEs. With 6 or 8 active participants per 
dosing group, if the true rate of an adverse event is 5%, the chance of seeing at least 1 
participant with the adverse event for a given dosing group is 26% or 34%, respectively. 
Similarly, if the true adverse event rate is 20%, the chance of seeing at least 1 participant 
with the adverse event for a given dosing group is 74% or 83%, respectively. 
For further details on sample size and sample size sensitivity see Section 9.6 in the 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
The study population analyses will be based on the Safety analysis set, unless otherwise 
specified.  
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are included in the OPS. 
6.1.1. 
Participant Disposition 
A summary of the number of participants who enrolled or failed screening will be 
provided. A summary of the number and percentage of participants who failed screening 
overall and by screen failure reason will be provided.  
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized.  
For part 2, a summary of study intervention status will be provided. This display will 
show the number and percentage of participants who have completed the scheduled study 
intervention or have discontinued study intervention prematurely, as well as primary 
reasons for discontinuation of study intervention. In parts 1 and 3, study treatment 
discontinuation is not possible as participants receive only 1 dose of study treatment.  
The number and percentage of participants who withdrew from the study due to an AE 
will be summarised by the outcome (fatal versus non-fatal) of the AE. 
 
6.1.2. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance to the Protocol Deviation Management Plan. These protocol deviations will 
be reviewed to identify those considered as important as follows: 
o 
Data will be reviewed prior to unblinding and freezing the database for each part of 
the study to ensure all important deviations (where possible without knowing the 
study intervention details) are captured and categorised in the protocol deviations 
dataset.  
o 
This dataset will be the basis for the summaries and listings of important protocol 
deviations. 
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A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
summary will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
6.1.3. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, race, height and weight 
at Baseline will be summarized with descriptive statistics. In addition, the following age 
categories will be summarized: 18-64, 65-84 and >=85 based on the Enrolled Analysis 
Set. 
All Demographic characteristics listings are described in the OPS. 
6.1.4. 
Concomitant Medications and Current Medical Conditions 
Concomitant medications will be coded using both the GSK Drug and WHO Drug 
dictionaries. A listing of concomitant medications based on GSK Drug dictionary will be 
produced.  
Medical occurrences beginning after obtaining informed consent but before the start of 
study drug will be recorded as current medical conditions, not as AEs, 
 
 
6.1.5. 
Subject Disposition & Study Treatment Discontinuation 
Tables “Summary of Subject Status and Subject Disposition for the Study Conclusion 
Record” and “Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment” will be repeated, with the reason for study withdrawal and study treatment 
discontinuation, respectively, categorized as due to the COVID-19 pandemic, or non-due 
to the COVID-19 pandemic based on information collected on the COVID-19 Pandemic 
Study Impact eCRF page. The summaries will be based on GSK Core Data Standards and 
details are provided in the OPS. 
6.1.6. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced of important protocol deviations related to COVID-19, and important 
protocol deviations not related to COVID-19. PDs related to COVID-19 pandemic will 
have the standard text “COVID-19: ” as prefix. Important protocol deviations related to 
COVID-19 will be included in the Listing of Important protocol deviations.  
The listing of important protocol deviations will be based on GSK Core Data Standards 
and details are provided in the OPS. 
6.1.7. 
Additional COVID-19 Assessments 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
Numbers of participants with a suspected, probable or confirmed COVID-19 infection 
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among participants with a COVID-19 reported Adverse Event, and of COVID-19 test 
results will be summarized. 
COVID-19 tables will be based on GSK Core Data Standards. 
 
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6.2. 
Appendix 2 Abbreviations and Trademarks 
6.2.1. 
Abbreviations 
AE 
Adverse Event  
CP-1 
Coproporphyrin I 
DAIDS 
Division of AIDS 
DDI 
Drug-Drug Interaction 
ECG 
Electrocardiogram 
MAD 
Multiple Ascending Dose 
MDZ 
Midazolam 
PCI 
Potential Clinical Importance 
PK 
Pharmacokinetic(s) 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
VH 
ViiV Healthcare group of companies 
 
 
Trademarks 
Trademarks of ViiV Healthcare  
 
Trademarks not owned by ViiV 
Healthcare  
None 
 
WinNonlin 
 
 
 
 
 
 
 
 


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7. 
REFERENCES 
Whitehead J, Patterson S, Webber D, Francis S, Zhou Y. Easy-to-implement Bayesian 
methods for dose-escalation studies in healthy volunteers. Biostatistics. 2001 
Mar;2(1):47-61. 
Kenward, M. G., and Roger, J. H. (2009). “An Improved Approximation to the Precision 
of Fixed Effects from Restricted Maximum Likelihood.” Computational Statistics and 
Data Analysis 53:2583–2595. 
 


Signature Page for  217058 TMF-14129623 v2.0
Signature Page for TMF-14129623 v2.0
Reason for signing: Approved
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Date of signature: 09-Dec-2022 14:43:20 GMT+0000
PPD