Conditions: HIV Infections
Keywords: GSK4011499 VH4011499 First-time-in-human HIV-1 capsid inhibitor Single ascending doses Multiple ascending doses Drug-drug Interaction
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 73
Healthy volunteers: yes

Brief summary:
This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4011499 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD) and Part 2 will investigate multiple ascending doses (MAD). Part 3 will investigate single dose of a new formulation of VH4011499. The transition from SAD to MAD will be based on the assessment of the Safety and Dose Escalation Committee.

Detailed description:

Arms:
arm 1: Healthy participants were given a single dose of placebo on Day 1 and were followed up until Day 28. arm 2: Healthy participants were given a single dose of 25 mg VH4011499 on Day 1 and were followed up until Day 28. arm 3: Healthy participants were given a single dose of 125 mg VH4011499 on Day 1 and were followed up until Day 28. arm 4: Healthy participants were given a single dose of 200 mg VH4011499 on Day 1 and were followed up until Day 28. arm 5: Healthy participants were given a single dose of 625 mg VH4011499 on Day 1 and were followed up until Day 28. arm 6: Healthy participants were given a single dose of 1875 mg VH4011499 on Day 1 and were followed up until Day 28. arm 7: Healthy participants were given a dose of placebo once daily for a 14-day period and were followed up until Day 42. arm 8: Healthy participants were given a dose of VH4011499 200 mg PiB once daily for a 14-day period and were followed up until Day 42. arm 9: Healthy participants were given a dose of VH4011499 300 mg once daily and a single dose of Midazolam on Days 1, 2, and 15, and were followed up until Day 42. arm 10: Healthy participants were given a dose of VH4011499 400 mg PiB once daily for a 14-day period and were followed up until Day 42. arm 11: Healthy participants were given a dose of VH4011499 200 mg tablet on Day 1 and were followed up until Day 28.

Interventions: intervention 1: VH4011499 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: VH4011499 will be administered. intervention 2: Placebo will be administered. intervention 3: Midazolam will be administered

Protocol document:
Prot_000.pdf: 
 
 
  


TMF-14909676 
CONFIDENTIAL 
ViiV Healthcare group of companies 
218490 
   Protocol Amendment 01 
 
1  
Clinical Study Protocol template V17 dated 24-Jan-2022 
TITLE PAGE 
Protocol Title: A Randomized, Double-Blind (Sponsor Unblinded), Placebo-
Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally 
Administered VH4011499 in Healthy Participants. 
Protocol Number: 218490 / Amendment 01 
Compound 
Number or Name: 
GSK4011499 (also known as VH4011499) 
Brief Title: VH4011499 First-Time-in-Human-Study 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address: 
 
    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 
 
This study is sponsored by ViiV Healthcare. GSK is supporting ViiV Healthcare in the 
conduct of this study. 
 
Regulatory Agency Identifying Number(s): Regulatory Agency identifying 
number(s) as appropriate 
 
Registry: IND 
ID: 159876 
 
Sponsor Signatory 
 
Scott McCallister, MD 
Vice President and Head, Physician Center of Excellence 
ViiV Healthcare 
 
Approval Date: 14 Nov 2022 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual 
 
©2022 ViiV Healthcare and the GSK group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
14 Nov 2022 
Original Protocol 
13 April 2022 
 
Amendment 01 14 Nov 2022 
 
Overall Rationale for the Amendment: This amendment results from the FDA “Study 
May Proceed” letter for IND Opening (Number 159876, Reference ID 4981945) dated 
13-MAY-2022, wherein the FDA recommended that the inclusion of women of 
childbearing potential be considered but require the use of highly effective forms of 
contraception, excluding modalities that may have potential DDIs. Additionally, this 
amendment results from Sponsor decisions to include an evaluation of the VH4011499 
tablet formulation for comparison with the existing VH4011499 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 VH4011499 tablet 
formulation. Lastly, points of clarification have been incorporated throughout the 
protocol. 
 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
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 VH4011499 tablet 
formulation in comparison with existing data from 
VH4011499 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 VH4011499 associated 
with CYP3A4 inhibition and 
induction and 
OATP1B1/1B3 inhibition. 
Revision to evaluate the 
safety, tolerability and PK 
properties of VH4011499 
tablets compared to 
existing data from PiB.  
 
Sponsor decision to 
evaluate VH4011499 in 
three MAD dosing groups 
and to potentially evaluate 
VH4011499 in an additional 
MAD dosing group based 
on observed PK and safety 
data. 
 
Clarification for statistical 
analyses. 
Section 1.1 (Synopsis); 
Section 4.1.3 (Part 3 
(Tablet PK)); 7.4.2 
(Clinical Criteria for 
Pausing and/or 
Stopping the Study); 
10.1.5 (Committees 
Structure (Safety and 
Dose Escalation 
Committee)) 
Clarifications and updates regarding the utilization of 
the SDEC to support the addition of a dosing group 
(Part 3) to evaluate a VH4011499 tablet formulation in 
comparison with existing data from VH4011499 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 a OATP1B1/1B3 probe substrate 
in Part 2. Updates supporting the addition of a dosing 
group (Part 3) to evaluate a VH4011499 tablet 
formulation in comparison with existing data from 
VH4011499 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 VH4011499 associated 
with CYP3A4 inhibition and 
induction and 
OATP1B1/1B3 inhibition. 
Revision to evaluate the 
safety, tolerability and PK 
properties of VH4011499 
tablets compared to 
existing data from PiB. 
 
Sponsor decision evaluate 
VH4011499 in three MAD 
dosing groups and to 
potentially evaluate 
VH4011499 in an additional 
MAD dosing group based 
on observed PK and safety 
data. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
Section # and Name 
Description of Change 
Brief Rationale  
Section 1.3 (Schedule of 
Activities (SOA)) 
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 VH4011499 tablet 
formulation in comparison with existing data from 
VH4011499 PiB. 
 
Updates supporting the requirement of MAD Dosing 
Group 3 and the addition of an optional MAD Dosing 
Group (Optional MAD Dosing Group 4). 
 
Inclusion of pregnancy testing throughout the study. 
 
Removal of a Plasma Sample (metabolism) 
assessment in Part 2 (all dosing groups) at specific 
timepoints.  
Revision to evaluate the 
potential perpetrator risks 
of VH4011499 associated 
with CYP3A4 inhibition and 
induction and 
OATP1B1/1B3 inhibition. 
Revision to evaluate the 
safety, tolerability and PK 
properties of VH4011499 
tablets compared to 
existing data from PiB. 
 
Sponsor decision to 
evaluate VH4011499 in 
three MAD dosing groups 
and to potentially evaluate 
VH4011499 in an additional 
MAD dosing group based 
on observed PK and safety 
data. 
 
FDA Recommended 
Change, Clinical item #1. 
 
Sponsor driven clarification 
as this sample collection 
was not needed at all 
previously marked 
timepoints.  
Section 2.3 
(Benefit/Risk 
Assessment) 
Updates to risk assessment summarizing new potential 
drug-drug interaction risks with VH4011499 and 
midazolam introduced with the new study design. 
To align with conduct of the 
updated study design.  
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, AST, and ALT. 
 
Revision to evaluate the 
potential perpetrator risks 
of VH4011499 associated 
with CYP3A4 inhibition and 
induction and 
OATP1B1/1B3 inhibition. 
Revision to evaluate the 
safety, tolerability and PK 
properties of VH4011499 
tablets compared to 
existing data from PiB. 
 
Clarification for statistical 
analyses. 
Section 4.1.2 (Part 2 
(MAD)); Section 4.3.3 
(Top Dose Rationale); 
Section 4.3.6 (Repeat 
Dosing Plan (Part 2)) 
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 
amend dose escalation 
criteria. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
Section # and Name 
Description of Change 
Brief Rationale  
Section 5.1 (Inclusion 
Criteria); Section 8.2.5 
(Pregnancy Testing); 
Section 8.3.5 
(Pregnancy); Section 
10.4 (Appendix 4: 
Contraceptive and 
Barrier Guidance) 
Updated to support the inclusion of WOCBP with the 
requirement that they use low user-dependency, highly 
effective (<1% failure rate) methods of contraception 
(IUD/IUS) or have bilateral tubal occlusion). 
FDA Recommended 
Change, Clinical item #1.  
 
Section 5.1 (Inclusion 
Criteria) 
 
Revised inclusion criterion #5 to remove the option for 
male participants to agree to use a male condom and 
should also be advised of the benefit for a female 
partner of child-bearing potential to use a highly 
effective method of contraception.  
 
 
 
Sponsor decision to take a 
more conservative 
approach and require 
highly effective 
contraception use in female 
partners of child-bearing 
potential of male 
participants and to rectify a 
discrepancy between 
inclusion criteria #5 and 
Appendix 4. 
Section 5.2 (Exclusion 
Criteria) 
Revised exclusion criterion #7 to highlight examples of 
medications that are Cytochrome P450 enzyme 
inducers or inhibitors.  
 
Revised exclusion criterion #23 to include any 
sensitivities to the additional study intervention, 
midazolam.  
To support the updated 
study design.  
Section 6 (Study 
Drug(s) and 
Concomitant Therapy) 
Updated to include details of midazolam for Part 2 
(MAD) and VH4011499 tablets for Part 3 (Tablet PK). 
To support the updated 
study design. 
Section 7.4.1 (PK 
Stopping Criteria for 
SAD and MAD) 
Updates to reflect decision to include NOAEL as an 
additional, independent criterion for top dose 
determination in MAD (Part 2) dose escalations 
 
Updates to use the most current NOAEL parameters for 
VH4011499 ((which are based on emerging non-clinical 
GLP toxicity data and defined in the SDEC charter) at 
the time of any dose escalation decision.  
Sponsor driven decision to 
amend dose escalation 
criteria.  
 
Sponsor driven decision to 
include protocol flexibility to 
adopt the most current 
NOAEL parameters at the 
time of any dose escalation 
decision. 
Section 8.2.2 (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. 


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Section # and Name 
Description of Change 
Brief Rationale  
Section 8.2.3.1 (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 8.4 
(Pharmacokinetics); 
Section 8.6 
(Biomarkers) 
New information added regarding midazolam and 
coproporphyrin I sampling. 
To support the updated 
study design. 
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. 
Sample Size Determination section has been updated 
to provide expected precision of estimates for DDI 
evaluations and Part 3 for the chosen sample sizes. 
To support the updated 
study design. 
Section 10.1.3 
(Informed Consent 
Process) 
Inclusion of text to further clarify that in the case of an 
unexpected pregnancy in female participants, 
participants will be informed that personal information 
of the baby will be collected as part of safety follow-up.  
 
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 and partners will be informed that personal 
information of the baby will be collected as part of 
safety follow-up. 
To provide further 
clarification of the informed 
consent process and data 
collection in the case of 
unexpected pregnancy in 
female participants or 
female partners of male 
participants. 
Not applicable 
Other minor revisions that provide clarification. 
To provide further 
clarification in study 
conduct. 
 
 
 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS ................................................................................................... 7 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
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 ......................................................................... 33 
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 .............................................. 41 
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) ........................................................................ 46 
4.1.4. 
Screening, Follow-up & Study Participation Duration .................... 46 
4.2. 
Scientific Rationale for Study Design ........................................................... 47 
4.3. 
Justification for Dose ................................................................................... 47 
4.3.1. 
Human Pharmacokinetics Prediction ............................................ 48 
4.3.2. 
Starting Dose Rationale in Part 1 (SAD) ....................................... 48 
4.3.3. 
Top Dose Rationale ..................................................................... 49 
4.3.4. 
Anticipated Therapeutic Dose Rationale....................................... 49 
4.3.5. 
Planned Doses and Safety Coverage (Part 1) .............................. 50 
4.3.6. 
Repeat Dosing Plan (Part 2) ........................................................ 51 
4.3.7. 
Tablet PK (Part 3) Dose Selection ............................................... 51 
4.4. 
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 ................................................... 56 
5.3.3. 
Activity ......................................................................................... 57 
5.4. 
Screen Failures ........................................................................................... 57 
5.5. 
Criteria for Temporarily Delaying ................................................................. 57 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 58 


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6.1. 
Study Intervention(s) Administered .............................................................. 58 
6.2. 
Preparation, Handling, Storage and Accountability ...................................... 60 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................ 60 
6.4. 
Study Intervention Compliance .................................................................... 61 
6.5. 
Dose Modification ....................................................................................... 61 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 62 
6.7. 
Treatment of Overdose ............................................................................... 62 
6.8. 
Concomitant Therapy .................................................................................. 62 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 64 
7.1. 
Discontinuation of Study Intervention ........................................................... 64 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................. 64 
7.1.2. 
QTc Stopping Criteria ................................................................... 65 
7.1.3. 
SARS-COV-2 Stopping Criteria .................................................... 65 
7.1.4. 
Temporary Discontinuation .......................................................... 66 
7.1.5. 
Rechallenge ................................................................................. 66 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 66 
7.3. 
Lost to Follow Up ........................................................................................ 67 
7.4. 
Study Pausing and/or Stopping Criteria ....................................................... 67 
7.4.1. 
PK Stopping Criteria for SAD and MAD ........................................ 67 
7.4.2. 
Clinical Criteria for Pausing and/or Stopping the Study ................ 68 
7.5. 
Site or Study Discontinuation ...................................................................... 69 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 70 
8.1. 
Efficacy and/or Immunogenicity Assessments ............................................. 70 
8.2. 
Safety Assessments ................................................................................... 70 
8.2.1. 
Physical Examinations ................................................................. 70 
8.2.2. 
Vital Signs .................................................................................... 71 
8.2.3. 
Electrocardiograms ...................................................................... 71 
8.2.4. 
Clinical Safety Laboratory Tests ................................................... 72 
8.2.5. 
Pregnancy Testing ....................................................................... 72 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 73 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 73 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 74 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 74 
8.3.4. 
Regulatory Reporting Requirements for SAEs .............................. 74 
8.3.5. 
Pregnancy ................................................................................... 75 
8.3.6. 
Adverse Events of Special Interest ............................................... 75 
8.4. 
Pharmacokinetics ....................................................................................... 75 
8.5. 
Genetics ..................................................................................................... 77 
8.6. 
Biomarkers ................................................................................................. 77 
8.7. 
Immunogenicity Assessments ..................................................................... 77 
8.8. 
Medical Resource Utilization and Health Economics .................................... 77 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 78 
9.1. 
Statistical Hypotheses................................................................................. 78 
9.2. 
Analysis Sets............................................................................................... 78 
9.3. 
Statistical Analyses ..................................................................................... 78 
9.3.1. 
General Considerations ............................................................... 78 


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9.3.2. 
Primary Endpoint(s)/Estimands(s) Analysis .................................. 79 
9.3.3. 
Safety Analyses ........................................................................... 81 
................................................................. 81 
9.3.5. 
Other Analysis ............................................................................. 82 
9.3.6. 
Safety and PK dose escalation analyses ...................................... 83 
9.4. 
Interim Analysis ........................................................................................... 88 
9.5. 
Final Analyses ............................................................................................ 88 
9.6. 
Sample Size Determination ......................................................................... 88 
9.6.1. 
Sample Size Sensitivity ................................................................ 89 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 91 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 91 
10.1.1. 
Regulatory and Ethical Considerations ......................................... 91 
10.1.2. 
Financial Disclosure ..................................................................... 92 
10.1.3. 
Informed Consent Process ........................................................... 92 
10.1.4. 
Data Protection ............................................................................ 93 
10.1.5. 
Committees Structure (Safety and Dose Escalation 
Committee) .................................................................................. 93 
10.1.6. 
Dissemination of Clinical Study Data ............................................ 94 
10.1.7. 
Data Quality Assurance ............................................................... 94 
10.1.8. 
Source Documents ...................................................................... 95 
10.1.9. 
Study and Site Start and Closure ................................................. 95 
10.1.10. Publication Policy ......................................................................... 96 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................... 97 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 99 
10.3.1. 
Definition of AE ............................................................................ 99 
10.3.2. 
Definition of SAE ........................................................................ 100 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................. 102 
10.3.4. 
Reporting of SAE to VH/GSK ..................................................... 104 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ...................................... 105 
10.4.1. 
Woman of Nonchildbearing Potential (WONCBP)....................... 105 
10.4.2. 
Woman of Childbearing Potential (WOCBP) .............................. 106 
10.4.3. 
Contraception Guidance ............................................................. 106 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................. 109 
10.6. 
Appendix 6: Abbreviations and Trademarks ............................................... 112 
10.7. 
Appendix 7: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, July 2017 ................................ 116 
10.8. 
Appendix 8: Permissible Procedures During COVID-19 Pandemic ............ 117 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 119 
11. REFERENCES ..................................................................................................... 120 
 
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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  
VH4011499 in Healthy Participants. 
Brief Title: 
VH4011499 First-Time-in-Human-Study. 
Rationale: 
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. The current paradigm in the treatment 
of HIV-1 involves life-long therapy with multiple ARVs. This dependency on medical 
therapy requires a need for continuous improvement on the durability, tolerability and 
convenience of all ARV classes. 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. 
 
The overall objective of the ViiV CAI clinical development program is to develop 
investigational VH4011499 (also known as GSK4011499) as a long-acting novel 
medicine that can be administered via injection every month or longer 
 
 Either long-acting VH4011499-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. Of note, VH4011499 is ViiV's second capsid inhibitor in 
clinical development and is preceded by VH4004280 which is currently in Phase 1. 
 
VH4011499 belongs to a novel class of ARV agents targeting a highly conserved region 
of the HIV-1 capsid protein. In-vitro experiments suggest its primary antiviral mechanism 
of action is derived from inhibition of a replication step early in the viral replication cycle 
prior to integration of the HIV-1 provirus into the host cell chromatin. VH4011499 also 
possesses a less potent late antiviral activity, reducing production of infectious virions 
from virus-producing cells. 
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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 in an investigational capsid inhibitor currently in development. In cell 
culture, VH4011499 exhibited potent antiviral activity against a wide spectrum of HIV-
1 isolates and subtypes and also demonstrated no cross-resistance with currently 
approved ARV classes. The potential to develop VH4011499 as a long-acting medicine 
is further supported by nonclinical studies (including rat and dog studies up to 28 days) 
that show a favorable toxicity, safety and PK profile for VH4011499. 
 
This FTIH study is designed to gain information on the safety, tolerability and PK 
properties of oral VH4011499 when administered as PiB. This study will also evaluate 
the safety, tolerability and PK properties of VH4011499 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 VH4011499 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 
VH4011499 on an endogenous biomarker as a probe (coproporphyrin I). This study will 
enable further clinical development of VH4011499, including a Phase 2a PoC study in 
HIV-infected participants and a Phase 1 study of the long-acting injectable formulation 
of VH4011499. 
 
 


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12  
Clinical Study Protocol template V17 dated 24-Jan-2022 
Objectives and Endpoints and Estimands: 
 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single 
(Parts 1 and 3) and multiple (Part 2) doses of 
VH4011499 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 
VH4011499 in healthy participants following 
single (Part 1) and multiple (Part 2) doses. 
• 
Area under the plasma-concentration time 
curve (AUC): AUC(0-inf) for single dose 
and AUC(0-t) 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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Clinical Study Protocol template V17 dated 24-Jan-2022 
Overall Design: 
 
Brief Summary: 
 
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 VH4011499, when administered as a PiB formulation, in 
healthy adult participants. This study will also evaluate the DDI potential of 
VH4011499 for inhibition of OATP1B1/1B3 and changes in CYP3A activity, and 
evaluate the safety, tolerability and PK of a VH4011499 tablet formulation in 
comparison with existing data from VH4011499 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 VH4011499 
in up to 6 dosing groups. In Part 2, the proposed dosing schedule is designed to 
investigate MAD of VH4011499 administered daily, for 14 days in up to 4 dosing 
groups. A midazolam probe will be administered with VH4011499 or placebo in up to 
two dosing groups in Part 2 (MAD/DDI dosing group(s)) to examine the potential of 
VH4011499 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 VH4011499 or placebo to investigate the 
potential of VH4011499 to inhibit OATP1B1/1B3. Review of available data from 
previous SAD and emerging MAD dosing groups will determine if the DDI potential of 
VH4011499 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 VH4011499, in comparison 
with existing data from VH4011499 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 (such as half-life) 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 48 participants (36 active:12 placebo) will be included in Part 1. and 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 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. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
 
Note: Enrolled means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed 
consent process, passed screening and were randomized in 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.  
 
Intervention Groups and Duration: 
 
Study participants will have a screening visit within 30 days prior to the first dose of 
VH4011499 / PBO. 
 
In Part 1 (SAD), participants will receive a single dose of VH4011499 or placebo (6:2) 
on Day 1. Sentinel dosing is included. 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 
and 21 for follow up procedures and a final follow up visit on Day 28. 
 
In Part 2 (MAD) participants will receive doses of VH4011499 or PBO once daily for 
an anticipated 14-day period. Participants in non-DDI MAD dosing groups will receive 
daily doses of VH4011499 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 and 35 for follow up procedures and a final follow up visit on Day 42. In 
MAD/DDI dosing group(s), participants will receive a single dose of midazolam on 
Days 1, 2, and 15, and daily doses of VH4011499 or PBO (8:2) on Day 2 through to 
Day 15. A single dose of midazolam will be co-administered with a dose of 
VH4011499 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 and 35 
for follow up procedures and a final follow up visit on Day 42.  
 
In Part 3 (Tablet PK), participants will receive a single dose of VH4011499 as a tablet 
formulation on Day 1. The dose of VH4011499 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 and 
21 for follow up procedures and a final follow up visit on Day 28. 
 
If actual PK parameters differ significantly from predicted values (e.g., if half-life is 
significantly longer or shorter than the predicted), then the duration of in clinic stay, 
duration of post last dose follow-up, determination of subsequent doses, dosing 
frequency and total duration of dosing may be altered. The duration of post dose 
follow-up is not intended to exceed five half-lives. 
Data Monitoring/ Other Committee: Yes 
 
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 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
on the SDEC. The decision to proceed to the next dose level of VH4011499 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 V17 dated 24-Jan-2022 
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


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Clinical Study Protocol template V17 dated 24-Jan-2022 
1.3. 
Schedule of Activities (SoA) 
i. 
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. 
ii. 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. 
iii. 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. 
iv. For further detail on Assessments and Procedures see Section 8. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
Table 1 
SCREENING AND EARLY DISCONTINUTION ASSESSMENTS (PART 1, PART 2, and PART 3) 
 
Procedure 
Screening 
(up to 30 days prior to 
Day 1) 
Early 
Discontinuation 
from Study Visit 
Notes 
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: Clinical Laboratory Tests for details. Total bile acids at Early 
Discontinuation Visit. Fasting lipid panel at screening and at Early Discontinuation Visit. 
Pregnancy Test 
X 
X 
Highly sensitive serum hCG pregnancy test. 
Follicle-stimulating Hormone 
X 
As required in women to confirm postmenopausal status. 
SAR-CoV-2 PCR test 
X1 
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 
Not required if no study drug administered. 
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 V17 dated 24-Jan-2022 
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 
96h 
120h 
144h 
Admission to Unit 
X9 
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 
<=============================================================>5 
Meals 
X 
See Section 
5.3.1 
Clinical Laboratory 
Tests6,7,8 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 PCR 
Test9 
X9 
X9 
X 
Pregnancy Test10 
 
X 
X 
Randomization 
X 
Drug administration11 
X 
Plasma Sample 
(pharmacokinetics)12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
Procedure 
Day 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
Pre- 
dose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
12 h 
24 h 
48 h 
72 h 
96 h 
120h 
144h 
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. 
Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
Day 1 measured pre-dose; only blood pressure and pulse rate are measured for all remaining Day 1 timepoints. 
3. 
See Section 8.2.3 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. Post-dose ECG extraction will coincide with plasma PK sample schedule up to 24h post-dose. 
6. 
See Appendix 2: Clinical Laboratory Tests for details of Clinical Laboratory Tests. 
7. 
Total Bile Acids (TBA) and Coagulation Panel required on Day -1, Day 2 and Day 7 only. 
8. 
Lipid Panel required on Day -1 and Day 7 only. 
9. 
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. 
10. See Section 8.2.5. Serum or urine pregnancy testing to be performed within 24 hours of dosing on Day 1.  
11. In Part 1, VH4011499 will be administered as a PiB. 
12. PK blood samples drawn post-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) 
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 V17 dated 24-Jan-2022 
Table 3 
Part 1 SAD (All Dosing Groups) - Outpatient Visit Days 14, 21 and 28 
Procedure 
Day 
14 
21 
288 
Visit Window 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
Vital signs2 
X 
X 
X 
12-lead ECG3 
X 
X 
X 
Clinical Laboratory Test4,5 
X 
X 
X 
Pregnancy Test6 
X 
X 
X 
Plasma sample (pharmacokinetics)7 
X 
X 
X 
Adverse Event Review 
<=================================================================> 
Concomitant Medication Review 
<=================================================================> 
1. 
See Section 8.2.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. Weight will be measured 
on Day 28. 
2. 
See Section 8.2.2 for details of Vital Sign measurements. 
3. 
See Section 8.2.3 for details of 12-lead ECGs. 
4. 
See Appendix 2: Clinical Laboratory Tests 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 8.2.5. Serum or urine pregnancy testing to be performed. 
7. 
See Section 8.4 for further details for plasma PK sample collection. One whole blood sample of sufficient volume will be processed to measure concentrations of 
VH4011499. 
8. 
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. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
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 
X1 
Discharge from Unit 
X 
Drug/alcohol/cotinine screen 
X 
SARS-CoV-2 PCR Test1 
X1 
X1 
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 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
Cardiodynamic Assessment4 
<===>6 
<===>6 
Meals 
See Section 5.3.1 
Clinical Laboratory Test7,8,9 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test10 
 
X 
 
 
 
 
 
 
Randomization 
X 
Drug Administration11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample (Pharmacokinetics)12 
X
13 
X
14 
X
14 
X
14 
X
14 
X
14 
X
14 
X
14 
X
14 
X
14 
X
13 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample (metabolism)12 
X
13 
X
14 
 
X
13 
X 
Urine Sample (metabolism)15 
<===> 
<=====> 
Bile Sample (EnteroTracker)16 
X 
Adverse Event Review 
<=================================================================================================================> 
Concomitant Medication Review 
<=================================================================================================================> 
 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
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 8.2.1 for details of brief physical examination. 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.8.2.3 for details of 12-lead ECGs and cardiodynamic assessment (Holter monitoring). 
5. 
Pre-dose triplicate ECG is required on Day 1 within 90 minutes of dosing. Dose administration day ECGs will be collected at pre-dose and 3, 6, 9 and 12-hours post-dose. 
6. 
Three pre-dose ECG extractions prior to dosing on Day 1. Post-dose ECG extraction will coincide with plasma PK sample schedule up to 24h post-dose. Single pre-
dose ECG extraction prior to dosing on Day 14. 
7. 
See Appendix 2: Clinical Laboratory Tests for details of Clinical Laboratory Tests. 
8. 
Total Bile Acids (TBA) and PT/PTT required on Day -1, Day 2, Day 7, Day 14 and Day 21 only. 
9. 
Lipid Panel required on Day -1, Day 7, Day 14 and Day 21 only.  
10. See Section 8.2.5. Serum or urine pregnancy testing to be performed within 24 hours of dosing on Day 1.  
11. In Part 2, VH4011499 will be administered as a PiB. 
12. See Section 8.4. 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). 
13. 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. 
14. At pre-dose only. 
15. 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. 
16. The EnteroTracker will be swallowed 2.5 h post-dose. A small food cue will be provided at 5.25 post dose and the string will be removed at 6.5 h post dose. Details of 
bile collection and processing are detailed in the SRM. See Section 8.4for further detail. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
Table 5 
Part 2 MAD - Outpatient Visit Days 28, 35 and 42 
 
Procedure 
Day 
28 
35 
425 
Visit Window 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
Vital signs 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
Clinical Laboratory Test3 
X 
X 
X 
Pregnancy Test4 
X 
X 
X 
Plasma sample (pharmacokinetics) 
X 
X 
X 
Adverse Event Review 
<===========================================================================> 
Concomitant Medication Review 
<===========================================================================> 
1. 
See Section 8.2.1 Brief physical exams may be made full physical exams at the discretion of the investigator. Weight will be measured on Day 42. 
2. 
See Section 8.2.3 for details of 12-lead ECGs. 
3. 
See Appendix 2: Clinical Laboratory Tests for details of Clinical Laboratory Tests. Total Bile Acids, PT/PTT and Lipid Panel required in each weekly clinical laboratory 
test.  
4. 
See Section 8.2.5. Serum or urine pregnancy testing to be performed. 
5. 
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. 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
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 
X1 
Discharge from Unit 
 
X 
Drug/alcohol/cotinine screen 
X 
 
SARS-CoV-2 PCR Test1 
X1 
X1 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
Meals 
See Section 5.3.1 
Clinical Laboratory Test6,7,8 
X  
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
Pregnancy Test9 
 
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 (VH4011499 
Pharmacokinetics)13 
 
 
X14 
X15 
X15 
X15 
X15 
 
X15 
 
X15 
 
X15 
X15 
X15 
X14 
X 
X 
X 
X 
X 
X 
X 
Plasma Sample (VH4011499 
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 


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Clinical Study Protocol template V17 dated 24-Jan-2022 
 
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 
Urine Sample (VH4011499 
metabolism)18 
 
<=====> 
 
 
 
 
 
 
 
 
 
 
 
<=====> 
Bile Sample (EnteroTracker)19 
 
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 8.2.1 for details of brief physical examination. 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 8.2.3 for details of 12-lead ECGs and cardiodynamic assessment (Holter monitoring). 
5. 
Pre-dose triplicate ECG required on Day 1 within 90 minutes of dosing. Dose administration day ECGs will be collected pre-dose and 3, 6, 9 and 12-hours post-dose. 
6. 
See Appendix 2: Clinical Laboratory Tests for details of Clinical Laboratory Tests. 
7. 
Total Bile Acids (TBA) and PT/PTT required on Day -1, Day 3, Day 8, Day 15 and Day 22 only. 
8. 
Lipid Panel required on Day -1, Day 8, Day 15 and Day 22 only.  
9. 
See Section 8.2.5. Serum or urine pregnancy testing to be performed within 24 hours of dosing on Day 1. 
10. In Part 2, VH4011499 will be administered as a PiB. 
11. Midazolam will be co-administered with VH4011499 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 8.4. 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. 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, 6 h, 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, 6 h, 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. The EnteroTracker will be swallowed 2.5 h post-dose. A small food cue will be provided at 5.25 post dose and the string will be removed at 6.5 h post dose. Details of 
bile collection and processing are detailed in the SRM. See Section 8.4 for further details. 


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Table 7 
Part 2 MAD/ DDI - Outpatient Visit Days 28, 35 and 42 
Procedure 
Day 
28 
35 
425 
Visit Window 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
Vital signs 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
Clinical Laboratory Test3 
X 
X 
X 
Pregnancy Test4 
X 
X 
X 
Plasma sample (VH4011499 pharmacokinetics) 
X 
X 
X 
Adverse Event Review 
<=====================================================================================> 
Concomitant Medication Review 
<=====================================================================================> 
1. 
See Section 8.2.1 Brief physical exams may be made full physical exams at the discretion of the investigator. Weight will be measured on Day 42. 
2. 
See Section 8.2.3 for details of 12-lead ECGs. 
3. 
See Appendix 2: Clinical Laboratory Tests Clinical Laboratory Tests for details of Clinical Laboratory Tests. Total Bile Acids, PT/PTT and Lipid Panel required in each 
weekly clinical laboratory test.  
4. 
See Section 8.2.5. Serum or urine pregnancy testing to be performed. 
5. 
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. 


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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 
96h 
120h 
144h 
Admission to Unit 
X9 
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 
X8 
X8 
X 
Pregnancy Test9 
 
X 
 
Randomization 
X 
Drug administration10 
X 
Plasma Sample 
(pharmacokinetics)11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Procedure 
Day 
Day 
-1 
Day 1 
2 
3 
4 
5 
6 
7 
Pre- 
dose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
12 h 
24 h 
48 h 
72 h 
96 h 
120h 
144h 
Adverse Event Review 
<=========================================================================================================================> 
Concomitant Medication 
Review 
<=========================================================================================================================> 
1. 
Brief physical exams may be made full physical exams at the discretion of the investigator. 
2. 
Day 1 measured pre-dose; only blood pressure and pulse rate are measured for all remaining Day 1 timepoints. 
3. 
See Section 8.2.3 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: Clinical Laboratory Tests 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. 
See Section 8.2.5. Serum or urine pregnancy testing to be performed within 24 hours of dosing on Day 1.  
10. In Part 3, VH4011499 will be administered as a tablet. 
11. PK blood samples drawn post-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, 
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Table 9 
Part 3 Tablet PK - Outpatient Visit Days 14, 21 and 28 
Procedure 
Day 
14 
21 
288 
Visit Window 
±1 day 
±1 day 
±1 day 
Brief Physical Exam1 
X 
X 
X 
Vital signs2 
X 
X 
X 
12-lead ECG3 
X 
X 
X 
Clinical Laboratory Test4,5 
X 
X 
X 
Pregnancy Test6 
X 
X 
X 
Plasma sample (pharmacokinetics)7 
X 
X 
X 
Adverse Event Review 
<==================================================================> 
Concomitant Medication Review 
<==================================================================> 
1. 
See Section 8.2.1 for details of brief physical exam. Brief physical exams may be made full physical exams at the discretion of the investigator. Weight will be measured 
on Day 28. 
2. 
See Section 8.2.2 for details of Vital Sign measurements. 
3. 
See Section 8.2.3 for details of 12-lead ECGs. 
4. 
See Appendix 2: Clinical Laboratory Tests 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 8.2.5. Serum or urine pregnancy testing to be performed. 
7. 
See Section 8.4 for further details for plasma PK sample collection. One whole blood sample of sufficient volume will be processed to measure concentrations of 
VH4011499. 
8. 
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. 


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2. 
INTRODUCTION 
VH4011499 (also referred to as GSK4011499) belongs to a novel class of ARV agents 
targeting a highly conserved region of the HIV-1 capsid protein. 
Investigational VH4011499 is being developed for people living with HIV-1 to be part of 
a long-acting ARV treatment regimen. The purpose of this FTIH study with VH4011499 
(via powder-in-bottle) is to initially characterize the tolerability, safety, and 
pharmacokinetics of VH4011499. The drug concentrations obtained from oral 
administration of VH4011499 in both the single ascending dose and repeat ascending 
dose parts of this study will help inform subsequent development of long-acting 
VH4011499. 
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 VH4011499 in healthy participants. 
This study is designed to evaluate: the safety, tolerability, and PK properties of 
VH4011499 when administered as single and multiple ascending dosing with the PiB 
formulation; the safety, tolerability and PK properties of the VH4011499 tablet 
formulation; and any effect of VH4011499 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 
VH4011499 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. 
 
VH4011499 belongs to a novel class of ARV agents targeting a highly conserved region 
of the HIV-1 capsid protein. In-vitro experiments suggest its primary antiviral mechanism 
of action is derived from inhibition of a replication step early in the viral replication cycle 
prior to integration of the HIV-1 provirus into the host cell chromatin. VH4011499 also 
possesses a less potent late antiviral activity, reducing production of infectious virions 
from virus-producing cells [GSK Document Number RPS-CLIN-026329]. Of note, 
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VH4011499 is ViiV's second capsid inhibitor in clinical development and is preceded by 
VH4004280 which is currently in Phase 1 [ViiV Healthcare Protocol for Study 217058, 
2022]. 
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 
in an investigational capsid inhibitor currently in development [Gupta, 2022; Oguagu, 
2022]. In cell culture, VH4011499 exhibited potent antiviral activity against a wide 
spectrum of HIV-1 isolates and subtypes and also demonstrated no cross-resistance with 
currently approved ARV classes [GSK Document Number RPS-CLIN- 026329]. The 
potential to develop VH4011499 as a long-acting medicine is further supported by 
nonclinical studies (including rat and dog studies up to 28 days) that show a favorable 
toxicity, safety and pharmacokinetic profile for VH4011499 [GSK Document Number 
RPS-CLIN-026329]. 
 
A detailed description of the non-clinical pharmacology, pharmacokinetics, toxicology, 
virology, and the chemistry and manufacturing of VH4011499 is provided in the Clinical 
Investigator’s Brochure [GSK Document Number RPS-CLIN-026329]. 
 
2.3. 
Benefit/Risk Assessment 
In the definitive (GLP) 28-day repeat dose oral studies in rats and dogs with VH4011499 
, increases in liver enzymes (up 
to 11.3-fold pre-treatment levels at a mean 
 
) were observed in dogs at the highest dose tested, which 
was also considered the NOAEL in this study. There were no histologic correlates in the 
liver and no changes in liver weight in the dogs, and no adverse findings in the definitive 
rat study up to the highest dose and NOAEL of 
. There were no 
significant findings in GLP non-clinical studies conducted to assess genotoxicity, safety 
pharmacology and phototoxicity. 
 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of VH4011499 may be found in the Clinical Investigator’s 
Brochure [GSK Document Number RPS-CLIN-026329]. 
 
Midazolam Probe (Part 2, MAD/DDI dosing group(s)): Based on in vitro data, there is 
potential for inhibition of CYP3A by VH4011499 leading to increased midazolam 
exposures and a deeper and more prolonged CNS suppression. There is also potential for 
induction of CYP3A by VH4011499 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 2022]. 
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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) VH4011499 
Drug-induced liver 
injury and/or 
clinically significant 
liver chemistry 
elevations 
VH4011499: 
In vitro, VH4011499 
 
 
 
 
In the definitive 28-day repeat dose dog study with VH4011499, at the 
 there were increases relative to 
predose in alanine and aspartate aminotransferases (ALT increased by up to 
11.3 fold in 4/6 dogs, AST increased by up to 3.0 fold in 2/6 dogs) and 
GLDH increased by up to 6.2 fold in 4/6 dogs with no histologic correlates 
in the liver and no changes in liver weight. No increases in bilirubin were 
observed. In the definitive 28-day repeat dose study in the rat (
 
), there were no adverse effects of 
VH4011499, including no increases in liver enzymes, total bile acids or 
bilirubin. 
VH4004280: 
In vitro, VH4004280 
 
. In the definitive 28 
day repeat dose dog study, 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 
Participants with current or 
history of liver disease, 
history of or current 
infection 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. 
Sentinel dosing is included 
(see Section 4.1). 
Liver chemistry participant 
stopping criteria are defined 
(see Section 7.1.1.). 
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hepatobiliary injury, they were of low magnitude and without correlating 
histopathological findings. 
Increases in 
cholesterol and 
triglycerides 
VH4011499: 
No increases in cholesterol or triglycerides and no macroscopic or 
microscopic findings in the liver were observed in the definitive 28 day 
repeat dose toxicity studies in dog and rat with VH4001499. 
VH4004280: 
In the definitive 28 day repeat dose toxicity studies with VH4004280, 
increases in mean serum total cholesterol concentration were observed in 
rats and dogs at the highest doses tested (
 
. Increased triglycerides were also noted in dogs at 
 
. In both species, there were no macroscopic or microscopic 
changes in the liver at any dose level. 
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. 
Increases in WBC and 
activated PTT  
 
VH4011499: 
No increases in WBC or PTT were observed in the definitive 28 day repeat 
dose toxicity studies in dog and rat with VH4001499. 
VH4004280: 
In the 28-day definitive dog study (
) 
with VH4004280, increases in neutrophils and monocyte counts were 
observed, together with an increase in activated partial thromboplastin time.  
Participants will be closely 
monitored for relevant AEs 
and laboratory 
abnormalities. 
Hematology Panel and 
Coagulation Panel are 
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. 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug(s) VH4011499  
Drug Interactions 
(inhibition of 
OATP1B1/1B3) 
In vitro, VH4011499 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, VH4011499 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. Midazolam may cause respiratory 
depression and transient drowsiness. 
Co-medications, including 
CYP3A4 substrates, are 
prohibited in FTIH. 
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, 


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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 5mg oral dose 
of midazolam has been 
selected for this study. 


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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 VH4011499. 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 
 
In non-clinical oral studies, increases in liver enzymes were observed, which were not 
accompanied by macroscopic or microscopic findings or weight changes in the liver. The 
increased liver enzymes in animals was observed at systemic exposures that were 244- 
692 times higher than the predicted clinical efficacious AUC(0-24) and Cmax. 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 lipids. 
 
In addition, consistent with Sponsor guidance for early phase studies, this study will be 
conducted in one or more clinical research units with prior experience conducting first- 
time-in-human-trials, sufficient overnight facilities and immediate emergency care 
capabilities. Moreover, part 1 (SAD) must be conducted in a hospital based/adjacent 
inpatient clinical trial unit 
 
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 
VH4011499 can be found in the Clinical Investigator’s Brochure [GSK Document 
Number RPS-CLIN-026329]. 
 
 


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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 
VH4011499 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 
VH4011499 in healthy participants following 
single (Part 1) and multiple (Part 2) doses. 
• 
Area under the plasma-concentration time 
curve (AUC): AUC0-inf for single dose 
and AUC(0-t) 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 VH4011499 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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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 VH4011499 or placebo. 
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The primary Safety estimands are described by the following attributes: 
 
 
Population 
Safety analysis set 
Treatment 
Part 1: single oral dose of VH4011499 PiB or placebo 
Part 2: multiple oral doses (once daily) of VH4011499 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 VH4011499 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 or 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., VH4011499 
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., 
VH4011499 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. 
 
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 VH4011499 PiB in Part 1 and multiple oral doses (once daily) of VH4011499 in 


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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 
VH499 Pharmacokinetic analysis set 
Treatment 
Part 1: single oral dose of VH4011499 PiB 
Part 2: multiple oral doses (once daily) of VH4011499 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 in healthy participants. The purpose 
of this study is to evaluate: the safety, tolerability, and PK properties of VH4011499 when 
administered as single and multiple ascending dosing with the PiB; the safety, tolerability and 
PK properties of the VH4011499 tablet formulation; and any effect of VH4011499 on the 
activity of CYP3A using midazolam as a probe and on OATP1B1/1B3 using an endogenous 
biomarker as a probe (coproporphyrin I). Approximately 90 healthy participants are 
planned to be randomized, in Part 1 (SAD, n=48), Part 2 (MAD, n=36), and Part 3 
(Tablet PK, n=6) from one or more centers in the US. 
 
All dosing and 7 day post last-dose in clinic follow-up will be conducted in clinical trial 
units with experience in conducting first-time-in-human studies with sufficient overnight 
facilities and immediate emergency care capabilities. Moreover, Part 1 (SAD) must be 
conducted in a hospital based/adjacent inpatient clinical trial unit. A final follow up 
outpatient visit will take place approximately 28-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. The 28-day post final dose follow-up assumes a potential maximum half-life 
of 3-5 days for VH4011499. While the estimated half-life prior to starting the study is 13 
hours, the actual half-life will be defined as data emerge from the study. The study is 
designed to ensure adequate PK follow-up for all participants. The follow-up duration 
may be altered if the actual half-life is significantly longer or shorter than predicted. 
 
If actual PK parameters differ significantly from predicted values (e.g. if half-life is 
significantly longer or shorter than the predicted), then the duration of in clinic stay, 
duration of post last dose follow-up, determination of subsequent doses, dosing frequency 
and total duration of dosing may be altered. The duration of post dose follow-up is not 
intended to exceed five half-lives. 
 
Part 1 (SAD) will investigate single doses of VH4011499 from the starting dose up to a 
maximum safe dose that provides adequate dose information for future dosing 
requirements in the VH4011499 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 6 separate dosing groups. Each participant will 
be randomized to receive a single dose of blinded VH4011499 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 4.3.2 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 10.1.5 but will be constrained by any emerging 


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safety or tolerability concerns and to a maximum 5x the predicted exposure increase 
between consecutive dosing groups (e.g., dosing group 2 and dosing group 3) where 
predicted VH4011499 concentrations would not exceed mean NOAEL criteria. 
 
Table 10 
Part 1 SAD 
 
SAD 
(6 active:2 placebo) 
Dosing Group 
Predicted Dose1 (mg) 
1 
25 mg 
2 
Dose Group 2 
3 
Dose Group 3 
4 
Dose Group 4 
5 (optional expansion group)3 
As required 
 
6 (optional expansion group)3 
As required 
 
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 the rat 
 NOAEL dose. Target fold coverage can be revised based on emerging 
data. 
3. 
Dosing groups 5 and 6 are optional expansion groups used to dose escalate up to a maximum 
dose whose predicted VH4011499 concentrations would not exceed mean NOAEL criteria or 
other predefined limits, to repeat a previous dose level, or to dose de-escalate. 
At the start of each SAD dosing group, 2 of the total number of participants will serve as 
sentinel participants, with one receiving blinded VH4011499 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 VH4011499 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 VH4011499 in 
Part 1 and then, at a suitable cross-over point, begin repeated once-daily dosing of 
VH4011499 in Part 2. 
 
4.1.2. 
Part 2 (MAD) 
 
Part 2 (MAD) will be conducted in up to 4 ascending repeat-dose groups. Each 
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participant will be randomized to receive a QD dose of blinded VH4011499 or blinded 
PBO administered orally for 14 days. Participants in non-DDI MAD dosing groups will 
receive daily doses of VH4011499 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 VH4011499 or PBO (8:2) on 
Day 2 through to Day 15. A single dose of midazolam will be co-administered with a dose 
of VH4011499 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 VH4011499 or PBO to investigate the potential of 
VH4011499 to inhibit OATP1B1/1B3. Review of available data from previous SAD and 
emerging MAD dosing groups will determine if the DDI potential of VH4011499 will be 
evaluated in one or two MAD dosing groups.  
 
The starting dose in Part 2 (MAD) will be identified after preliminary PK data are 
evaluated in Part 1 (SAD).  
 
For both Parts 1 and 2, doses will be escalated such that the predicted mean plasma 
exposure at the next dose level will not exceed the mean plasma Cmax and AUC  
observed at the NOAEL exposures defined in Section 4.3.3. See Section 4.3 for further 
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Table 11 
Part 2 MAD 
 
MAD 
(6 or 8 active: 2 placebo)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 VH4011499 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 Groups 3 and 4 are optional expansion groups used to dose escalate of up to a maximum 
dose (whose predicted VH4011499 concentrations would not exceed the permitted top dose based 
on emerging data and safety cover), to repeat a previous dose level, or to dose de-escalate. 
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 10.1.5). 
 
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 VH4011499, in comparison with existing 
data from VH4011499 PiB, in one dosing group of 6 participants. All participants will 
receive a single dose of the VH4011499 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 and 
21 for follow up procedures and a final follow up visit on Day 28.  
 
Details of the VH4011499 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 28-days following final dose in 
Part 1 (SAD), Part 2 (MAD), and Part 3 (Tablet PK). Duration of study participation 


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(from the Screening Visit to the final post-dosing Follow-up Visit) will be approximately 
8 weeks for participants in Part 1 (SAD) and Part 3 (Tablet PK), and approximately 10 
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). 
 
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 (e.g., vomiting the solution shortly after 
ingestion and/or intentionally choosing to not ingest the full dose because of participant 
preference issues such as taste or smell), 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 VH4011499, 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 VH4011499 compound, include studies with 
parenterally administered (subcutaneous and intramuscular) versions of the molecule.  
 
 Part 3 (Tablet PK) is 
planned to evaluate the VH4011499 tablet formulation for comparison with the existing 
VH4011499 PiB data and will inform subsequent clinical trials. 
 
All doses of VH4011499 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 of the study (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 non-clinical toxicology studies. 
 
4.3. 
Justification for Dose 
This section describes the analyses conducted to estimate human VH4011499 PK profile, 
and to predict starting, top and anticipated therapeutic doses required to maintain plasma 
concentrations at levels expected to produce pharmacologic activity in HIV-1 infected 
subjects. 
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4.3.1. 
Human Pharmacokinetics Prediction 
 
The pharmacokinetics of VH4011499 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 maximum safe 
starting dose and the analysis of data from lenacapavir, a molecule in the clinic with the 
same pharmacology. These approaches were used to anticipate VH4011499 clinical PK 
and/or estimate a safe starting dose. The details of each method are described in the 
Human Prediction Report [GSK Document Number TMF-14580566]. 
 
4.3.2. 
Starting Dose Rationale in Part 1 (SAD) 
 
The proposed starting dose was based on a range of approaches including the anticipated 
therapeutic dose predictions and MRSD assessments. Guidance for Industry estimating 
the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy 
volunteers. FDA/CDER, July 2005. 
 
The NOAEL doses identified from the 28-day GLP rat and dog studies were 
 
 and 
, respectively. The
 
 based on the respective rat and dog 
NOAEL doses. A 10-fold safety factor on the HEDs yields an approximate MRSD of 
. 
 
The estimated starting doses using allometry and additional approaches are summarized 
in Table 12. 
 
Table 12 
Estimated starting dose using different approaches 
 
Starting Dose Estimation 
Approach 
Estimate 
Allometry 
PBPK1 
Existing clinical data 
MRSD 
1Dose from PBPK model are based on 
 
 
 
The resulting starting dose of VH4011499 in part 1 (SAD) is 25 mg. This reflects a 
mitigation of any potential safety risks (e.g., elevated liver chemistries) to the clinical 
study participants, since this is the first time that VH4011499 will be dosed in man and 
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safety outcomes are uncertain. 
 
The predicted exposures (based on an allometric PK model) of the proposed starting dose 
of 25 mg for 
 
are shown in Table 13. 
 
Table 13 
Projected exposure for the single starting dose of 
 
 
 
Dose 
(mg) 
Predicted PK Parameters 
Median (90%PI) 
Safety Coverage 
Cmax 
(ng/ml) 
C24 
(ng/ml) 
AUC0-inf 
(ng*h/ml) 
Fold- 
Dose 
(mg/kg)1 
Fold- 
Cmax2 
Fold- 
AUC3 
25 
25 
1Fold dose = NOAEL dose in Rat (
) /Proposed Dose in human mg/kg 
2Fold Cmax = NOAEL Cmax in rats (
)/ Cmax 
3Fold AUC = NOAEL AUC(0-24) in rats (
)/ AUC0-inf 
 
4.3.3. 
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 NOAEL 
exposures (
). For both 
Parts 1 and 2, the predicted mean plasma exposure at the top dose levels will not exceed 
the mean plasma Cmax and AUC observed at the NOAEL exposures. 
 
The predicted top dose of 
 administered as a single dose is estimated to provide a 
median plasma 
 
 
. And the top dose will be reviewed based on the 
emerging human PK data from the initial low dosing groups studied. 
 
4.3.4. 
Anticipated 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. A 
therapeutic dose is proposed as where 
 
 
 
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Estimates of concentration at the end of a dosing interval at steady state (Cτ) from 
allometric scaling resulted in a dose range 
 
. This dose range is expected to 
 
. The PBPK and evaluation of existing clinical 
data used the same efficacy thresholds and the estimated doses are reported in Table 14 
Using clinical LEN data as a relative benchmark, an equivalent VH4011499 maintenance 
dose is estimated to be 
 based on the
. 
 
 
Table 14 
Estimated therapeutic dose using different approaches 
 
Approach 
Estimate 
Allometry 
PBPK1 
Existing clinical data 
1Doses from PBPK model achieving efficacious threshold are based on 
 
 
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 exposure increase. De-escalation of a dose or 
repeat of a dose level is permitted, if needed. 
 
Based on the assumptions described above and PK predictions made with the allometry 
model, possible dose escalations are illustrated below in Table 15. These dose elevations 
and maximum SAD dose will be revised based on emerging PK and safety data. The 
proposed number of cohorts for Part 1 (SAD) is 4 with a further 2 for possible expansions 
 
 
Table 15 
Comparison of predicted human pharmacokinetics and NOAEL 
pharmacokinetics in rats for SAD dosing (Part 1) 
 
 
Model-predicted 
human doses 
PK Parameters (Median Range) of Model- 
predicted human doses2 
Safety Coverage (ratio of 
human and rat PK 
parameters) 
Dose1 
(mg) 
Dose 
(mg/kg) 
Cmax 
(ng/mL) 
C24 
(ng/mL) 
AUC(0-24) 
(ng*h/mL) 
AUC(0-
inf) 
(ng*h/mL) 
Fold- 
Dose 
(mg/kg)3 
Fold- 
Cmax 4 
Fold- 
AUC5 
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25 
125 
600 
1200 
2000 
1 Doses beyond group 1 will be decided by the Safety and Dose Escalation Committee 
based on emerging PK and safety data from prior dosing groups. 
2 Median range of the parameter were predicted 
. 
3Fold dose = NOAEL dose in Rat (
 /Proposed Dose in human mg/kg 
4Fold Cmax = NOAEL Cmax in rats (
)/Predicted human Cmax 
5Fold AUC = NOAEL AUC(0-24) in rats (
)/Predicted Human AUC(0-inf) 
 
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 is defined as the 
highest dose where the predicted mean plasma exposures at that dose level approaches 
but does not exceed the mean NOAEL exposures (
 
). 
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 the VH4011499 tablet formulation will be 
evaluated in comparison with existing data from VH4011499 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. 
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 results are required prior to dosing. 
 
 
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 118 days 
(28-day post dose follow-up period plus an additional 90-day 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 
 
 
WEIGHT 
4. Body weight > 50kg and body mass index (BMI) within the range 19-32kg/m2 
(inclusive). 
 


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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%, with low user dependency or that are user dependent, as 
described in Appendix 4: Contraceptive and Barrier Guidance 
b. Female Participants: 
a. 
A female participant (female sex assigned at birth) is eligible to participate 
if: 
• She is a 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 considered WONCBP to use 
a highly effective method of contraception since, to be eligible, they 
must be of nonchildbearing potential. 
OR 
• She is a woman of childbearing potential (WOCBP) as defined in 
Section 10.4 Contraception and Barrier Guidance, and is using a 
contraceptive method that is highly effective (with a failure rate of <1% 
per year), with low user dependency, [as described in Appendix 4: 
Contraceptive and Barrier Guidance] during the study intervention 
period and for at least 58 days (e.g., 28- day post dose follow-up period 
plus 30 days (a menstrual cycle) after the last dose of study 
intervention. Highly effective, low user-dependency (with a failure rate 
of <1% per year) are limited to intrauterine devices/systems or bilateral 
tubal occlusion ≥3 months prior to screening.  
o A WOCBP must have a negative highly sensitive pregnancy test 
(serum as required by local regulations) within 24 hours before the 
first dose of study intervention (with VH4011499 or midazolam 
depending on the dosing group) (see Section 8.2.5: Pregnancy 
Testing). 
o Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.2.5 Pregnancy Testing. 
o The investigator is responsible for review of medical history, 
menstrual history, and recent sexual activity to decrease the risk for 
inclusion of a woman with an early undetected pregnancy. 
 
 
INFORMED CONSENT 
6. 
Capable of giving signed informed consent as described in Section 10 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: 
 
 
 
 
 
 
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. 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. 
4. Breast cancer within the past 10 years. 
5. Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
6. QT interval corrected for heart rate according to Fridericia’s formula (QTcF) 
>450 msec. 
MEDICAL CONDITIONS 
7. 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 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. 
8. Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines 
during the study. 
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DIAGNOSTIC ASSESSMENTS 
13. ALT >1.5xULN. A single repeat test is allowed within a single screening period 
to determine eligibility. 
14. 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. 
15. Estimated serum creatinine clearance (using Chronic Kidney Disease 
Epidemiology Collaboration equation) <60 mL/min. 
16. History of or current infection with hepatitis B or hepatitis C. 
17. 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. 
18. Positive pre-study drug/alcohol screen. 
19. Positive HIV antibody test. 
20. Cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening. 
9. Exposure to more than 4 new investigational products within 12 months prior to 
the first dosing day. 
10. Current enrollment or past participation in another investigational study in which 
an investigational intervention (e.g., 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 who has been exposed with 1 month prior to screening 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. Note: Consult with the Sponsor medical monitor if 
clarification is needed. 
11. Participation in the study would result in loss of blood or blood products in excess 
of 500 mL over a 56-day period. 
12. Previously dosed in this clinical study. 
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OTHER EXCLUSIONS 
21. 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. 
22. Regular use of known drugs of abuse. 
23. 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 VH4011499 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 8 
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 VH4011499 and its metabolites. 
Participants will receive a food cue to stimulate gall bladder emptying at approximately 
5.25 hours post dose. Examples of the high fat food item include sausage sandwich or 
cream cheese [2 tablespoons] on a bagel. The EnteroTracker will be removed 6.5 hours 
post dose. 
All other meals will be provided as per the sites own standards. 
 
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 


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24 hours before the start of dosing (with VH4011499 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. 
 
5.5. 
Criteria for Temporarily Delaying 
Not applicable. 
 
 


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6. 
 STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention 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 
VH4011499 PiB and VH4011499 tablet. 
 
6.1. 
Study Intervention(s) Administered 
 
Table 16 
Study intervention(s) Administered 
Intervention on 
Label 
VH4011499     
PiB 
Placebo       
PiB 
VH4011499 
Tablet 
Midazolam 
Dose 
Formulation 
PiB for 
reconstitution 
with 50 mL of 
vehicle (0.5% 
w/v 
50 mL of 
vehicle (0.5% 
w/v 
VH4011499 
tablet 
Oral syrup 
Unit Dose 
Strength(s) 
Oral 
Suspension of 
VH4011499 
Not 
 Applicable 
25 mg and  
100 mg 
2 mg/mL 
Dosage 
Level(s) 
Starting single 
dose of 25 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/ 
Injection 
 
Each dose to be 
reconstituted 
with 50 mL 
vehicle followed 
by additional 
rinses with 
Sterile Water for 
Irrigation/ 
Injection 
 
Tablet(s) to be 
taken with water 
(~240 mL). 
 
Dose with food 
[moderate 
fat/calorie 
meal]. 
 
Full dosing 
Dosing 
instructions will 
be provided in 
the SRM. 
CCI
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Intervention on 
Label 
VH4011499     
PiB 
Placebo       
PiB 
VH4011499 
Tablet 
Midazolam 
Dose with food 
[moderate 
fat/calorie 
meal]. 
 
Full dosing 
instructions will 
be provided in 
the SRM. 
Dose with food 
[moderate 
fat/calorie 
meal]. 
 
Full dosing 
instructions will 
be provided in 
the SRM. 
instructions will 
be provided in 
the SRM. 
 
Use 
Clinical 
investigation 
Placebo control 
Clinical 
investigation 
Clinical 
investigation 
 
 
Sourcing 
VH4011499 
Active Powder, 
 
 
 are 
provided 
centrally by the 
sponsor 
Sterile Water for 
irrigation/ 
injection 
provided by the 
site. 
 
 
 are 
provided 
centrally by the 
sponsor 
Sterile Water for 
irrigation/ 
injection 
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. 
 
 
 
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6.2. 
Preparation, Handling, Storage and Accountability 
• The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study 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, prepare, 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. 
 
Parts 1 and 2 will be partially blinded. The blinding strategy is structured to ensure that 
no one who is involved in the management of individual participants is unblinded to 
treatment at the participant level. 
 
• Participants will be blinded to their treatment. 
• Site staff will be blinded with the exception of the unblinded pharmacist who will 
prepare the study drug. 
• The Sponsor will be blinded with the exception of the statistician and clinical 
pharmacologist who will have access to unblinded data. The Sponsor’s unblinded 


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Clinical Research Associate, and in the event of a Quality Assurance audit, the 
auditor(s), will be allowed access to unblinded study drug records at the site to verify 
that randomization/dispensing has been done accurately. The Sponsor will present 
data at SDEC meetings in a fashion that preserves the blinding of individual 
participants. Other Sponsor staff will remain blinded unless unblinding becomes 
absolutely 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 
condition. In this case, the Sponsor study team must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
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 Intervention 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 VH4011499 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). 
 
 


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6.6. 
Continued Access to Study Intervention after the End of the 
Study 
This study will enrol healthy participants only, therefore, no additional treatment from the 
Sponsor, including treatment with VH4011499, 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 21 days after the last dose) or until VH4011499 can 
no longer be detected systemically (if the follow-up monitoring is extended based on 
emerging data). 
• Obtain a plasma sample for PK analysis immediately if requested by the Sponsor 
medical monitor (determined on a case-by-case basis). Additional PK samples over 
time may be requested. 
• 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 
The drug-drug interaction potential of VH4011499 has been evaluated in a series of in 
vitro studies [GSK Document Number RPS-CLIN-026329]. As the clinical risk of 
significant drug-drug interactions with VH4011499 as a perpetrator or a victim is 
currently unknown, participants in this study must abstain from taking concomitant 
medications. To this end, 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 interact with VH4011499 and 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 


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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 INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1: 
Regulatory, Ethical, and Study Oversight Considerations 
 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
drug. If study drug is permanently discontinued, every attempt will be made to continue 
follow-up data collection for the participant, assuming that the participant continues to 
provide consent to participate in the study. In most cases, the SoA should continue to be 
followed for participants that have discontinued study drug. The investigator should 
discuss each specific case with the medical monitor and agree which post dose 
assessments will not be performed (e.g., intensive PK and ECGs on Day 14 or Day 15 
and bile collection on Day 13 or Day 14 may become less informative and therefore not 
done). 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 
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Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal. 
 
Refer to Appendix 5: Liver Safety: Required Actions and Follow-up Assessments for 
required Liver Safety Actions and Follow up Assessments. 
 
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 8.2.3. 
 
• 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 


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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 the 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. 
 
7.1.5.1. 
Study Intervention 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 
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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 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 
 
7.4.1. 
PK Stopping Criteria for SAD and MAD 
 
Assuming that safety stopping criteria have not been met (See Section 7.4.2)  and the top 
CCI


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dose in MAD has not already been achieved (See Section 4.3.6), dose escalation in Part 2 
(MAD) will be stopped in the event that safety or PK stopping criteria are not met, but 
the Bayesian predicted probability is >50% that any participant's Cmax or AUC0-24 on the 
day of the last dose in the subsequent dose will exceed the MAD PK stopping criteria. At 
the time of any dose escalation decision, the most current NOAEL parameters for 
VH4011499 (which are based on emerging non-clinical toxicity data and defined in the 
SDEC charter) will be used and will not be exceeded. 
 
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. 
 
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 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 VH4011499. 
• Two participants (within the same dosing group) experience a ≥Grade 3 AE of the 
same type that the Investigator considers reasonably attributable to VH4011499 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 VH4011499. 
• 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 VH4011499. Excluded from this are asymptomatic changes in lipid 
panel or creatine kinase changes with an alternative aetiology. 


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• 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 VH4011499) 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: 
Regulatory, Ethical, and Study Oversight Considerations (Section 10). 


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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. 
Efficacy and/or Immunogenicity Assessments 
 
Not applicable. 
 
8.2. 
Safety Assessments 
 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
 
8.2.1. 
Physical Examinations 
 
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded. 
A 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 
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8.2.2. 
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 
SoA, Section 1.3)). 
 
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. 
 
8.2.3. 
Electrocardiograms 
 
8.2.3.1. 
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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8.2.4. 
Clinical Safety Laboratory Tests 
 
See Appendix 2: Clinical Laboratory Tests for the list of clinical laboratory tests to be 
performed and the SoA (Section 1.3) for the timing and frequency. 
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 21 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). 
 
 
8.2.5. 
Pregnancy Testing 
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
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Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at weekly intervals during study intervention period. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure and correspond with the time frame for female 
participant contraception in Section 5.1, Inclusion Criteria 
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
Pregnancy testing will be performed on all female participants at screening for eligibility 
but will not be required throughout the conduct of the study for female participants 
considered WONCBP since, to be eligible, they must be of non-childbearing potential. 
 
 
8.3. 
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. 
 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
 
All SAEs will be collected from the signing of the ICF until the 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: AEs and SAEs: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. The 
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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. 
 
8.3.2. 
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. 
 
8.3.3. 
Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in Section 
10.3. 
 
8.3.4. 
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. 
o Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
 
 


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8.3.5. 
Pregnancy 
 
In Parts 1 and 3, female participants who become pregnant after administration of the 
study intervention may continue the study at the discretion of the investigator.  
In Part 2, female participants who become pregnant after the first study intervention dose 
must not receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
Details of all pregnancies in female participants will be collected after the start of study 
drug and until 58 days after the last dose of study drug.  
Details of all pregnancies in female partners of male participants will be collected after 
the start of study drug and until 118 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 
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 participant or pregnant partner will be followed to determine the outcome 
of the pregnancy. Information on the status of the mother and child 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 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants 
pregnant female partner, he or she may learn of an SAE through spontaneous reporting. 
 
8.3.6. 
Adverse Events of Special Interest 
 
Adverse events of special interest are not evaluated in this study. 
 
8.4. 
Pharmacokinetics 
Blood Sample Collection 
 
Whole blood PK and metabolite samples will be collected for measurement of plasma 
concentrations of VH4011499 (1 mL) and to assess for VH4011499-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). 
 
One whole blood sample of sufficient volume (typically 3 mL whole blood but will be 


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typically 5 mL or 6mL at 12 and 24 h post-dose timepoints, where applicable) will be 
processed into two aliquots of plasma: one to measure concentrations of VH4011499 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. 
 
In Part 2, whole blood PK samples will also be collected for the measurement of plasma 
concentrations of midazolam and 1-hydroxymidazolam (2mL) at the timepoints specified 
in the SoA (Section 1.3). 
 
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 VH4011499-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 
VH4011499- related material. 
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. 
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shipping procedures are provided in the SRM. The metabolite analyses will be conducted 
and reported separate from the main study report. 
 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
 
8.6. 
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 (2mL) 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. 
 
8.7. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
 
8.8. 
Medical Resource Utilization and Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
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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 
VH4011499 in healthy participants following single (Parts 1 and 3) and multiple (Part 2) 
doses and describe the plasma pharmacokinetic characteristics of VH4011499 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. 
 
VH499 PK 
All participants in the Safety analysis set who have taken at least 
one full dose with at least one non-missing 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 VH4011499 and 
collectively from all dosing groups for placebo, unless otherwise specified. 
 


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For all endpoints, except for ECG, the baseline value will be the latest pre-dose 
assessment with a non-missing value, including those from unscheduled visits. 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. 
 
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 Endpoint(s)/Estimands(s) Analysis 
 
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 VH4011499 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 Part 1 and Part 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. 


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Primary Endpoints 
Statistical Analysis Methods 
Liver panel laboratory 
parameters 
In each part, data for liver panel parameters will be summarised by 
dosing group for VH4011499 and collectively for placebo and by 
visit. Summary statistics (e.g. mean, median, std) for absolute 
values and for change from baseline will be presented. Summaries 
of maximum grade increase relative to Baseline will also be 
presented. 
 
Liver panel laboratory parameters will be summarised separately 
for each part of the study 
 
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 VH499 Pharmacokinetic 
analysis set. 
 
Plasma VH4011499 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): Cmax, tmax, t1/2 AUC(0-inf) 
• 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 
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Plasma VH4011499 concentrations will be presented in graphical and/or tabular form and 
will be summarized descriptively by dose. Plasma VH4011499 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. 
Study treatment discontinuation: 
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. VH4011499 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 Analysis 
 
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 group 1 and optional dosing group 3 or 4, and Day 15 for dosing group 
2 (and optional dosing group 3, if needed)) to first dose (i.e. Day 1 for dosing group 1 and 
optional dosing group 3 or 4, and Day 2 for dosing group 2 (and optional dosing group 3, 
if needed)) 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 log-transformed PK parameters (for VH4011499 tablet and for VH4011499 
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. 
 
 
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9.3.6. 
Safety and PK dose escalation analyses 
 
Refer to Section 10.1.5 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 document. 
 
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 VH4011499 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. 
 
 
Where     is log-PK of the   -th participant,  is the log-dose administered to the   -th 
participant. 
 and     are population intercept and slope, respectively, and    is the random 
error of the   -th participant. 
 
For the prediction of the second dose in Part 1 and Part 2, 
 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, 
 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. 
 
9.3.6.2. 
Bayesian model Operating Characteristics (OC) – SAD part 
 
In this part, we explore the operating characteristics of the Bayesian dose escalation 
model for a 
, in an optional 
expansion dosing group (see Table 10 and Table 15). We are interested to calculate the 
probability to escalate the dose to a
 
given that all previous possible doses (i.e. 25, 125, 600 and 1200 mg) have been 
administered successfully (see Table 15). This will occur when the posterior predictive 
probability that the Cmax for any participant to exceed the 
 
is less than a threshold (i.e. 40%, 50%, 60%), given the data from 
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all previous doses. Additionally, we are interested in calculating the predicted maximum 
Cmax among the 6 participants who will receive the 
 
 
 
Assuming θ1 = log(0.03) or log(1.82), θ2 = 1 (dose proportionality) and various between 
participant Cmax variability values (geoCV = 30%, 40%, 50% and 60%) we simulated 
data for 10,000 virtual trials using Whitehead’s model for each combination of θ1, θ2, and 
geoCV. log(Cmax) data were simulated from the distribution 
 
log(Cmax)ij ~ N(θ1 + θ2dj, σ2), 
where θ1 = log(0.03) or log(1.82), θ2 = 1, dj is the j-th log-dose administered to the i-th 
participant and σ2 is the between participant variance of log(Cmax) calculated from the 
assumed geoCV. 
 
The values of θ1 are based on the predicted human Cmax using preclinical data, based on 
two set of simulations that used different assumptions; one assumed a low bioavailability 
and the other high bioavailability. For each combination of θ1, θ2, and geoCV, each 
virtual trial contains simulated Cmax values for 4 dosing groups (i.e. 25, 125, 600 and 
1200 mg) of 6 participants each, for the prediction of the 2000 mg dose. 
 
For each combination of θ1, θ2, and geoCV, for each simulated virtual trial, we fitted an 
MCMC procedure for log(Cmax) response using Whitehead’s model with the following 
non-informative priors on the model parameters 
 
θ1 ~ Ν(0, 1/0.01) 
 
θ2 ~ Ν(1, 1/0.01) 
 
1/σ2 ~ Gamma(0.01, 0.01) 
For each virtual trial, we calculated the Bayesian probability of an individual exceeding 
the Cmax threshold in the following way: 
 
We had 20,000 iterations in the MCMC procedure. In each iteration, we obtained the 
estimated parameters 
, 
, and 
 (the estimated variance of    ). Based on the 
estimation, a random sample of 20,000 values for each of the 6 participants was drawn 
from the distribution 
 . This sample represents the predicted 
log(Cmax) for each participant with a possible highest dose of 2000 mg. The proportion of 
iterations with the simulated Cmax for any participant exceeding the 
 
 is the Bayesian probability of any participant exceeding the 
. 
For each virtual trial, the Bayesian probability of any participant to exceed the NOAEL 
Cmax with the highest dose is compared against different thresholds (i.e. 40%, 50% or 
60%). Among the 10,000 simulated trials, the percentage of trials with Bayesian 
probability below the threshold (i.e. 40%, 50% or 60%) stands for the percentage of trials 
in which we would escalate 
 (Table 17), given that all previous 
possible doses (e.g., 25, 125, 600 and 1200 mg; see Table 15) have been administered. 
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Additionally, we calculated the predicted maximum Cmax among the 6 participants 
planned to receive the 
, by averaging the maximum Cmax of the 6 
participants across all MCMC iterations and virtual trials (Table 17). 
 
Table 17 shows the predicted maximum Cmax concentration among 6 participants planned 
to receive a 
 (in an optional expansion dosing group) for 
various assumptions of θ1 and geoCV, given that all previous possible doses have been 
administered successfully. It also shows the probability to escalate to 
 
 using various thresholds (for decision making) for the probability of any 
participant to exceed the 
 
 given that all previous doses have been administered successfully (e.g. in each 
simulated trial the estimated Bayesian probability of any participant to exceed the Cmax 
NOAEL is compared against a threshold of 40% or 50% or 60%, and if it’s higher then 
decision is not to 
). For example, assuming θ1=log(1.82) and 
low between participant Cmax variability (i.e. geoCV=30%) the probability to escalate to a 
, given that all previous doses have been administered 
successfully, is 4% using a 40% threshold (conservative approach) for the probability of 
any participant to exceed the 
 
 increases to 18% using a 60% (liberal approach) threshold. 
 
Table 17 
 
 
θ1 
 
 
geoCV 
log(0.03) 
30% 
log(0.03) 
40% 
log(0.03) 
50% 
log(0.03) 
60% 
log(1.82) 
30% 
log(1.82) 
40% 
log(1.82) 
50% 
log(1.82) 
60% 
 
 
Based on Table 16 assuming θ1 = log(0.03) the predicted maximum Cmax among the 6 
participants on 
 is much below the 
 
 and all simulated trials had 
Bayesian probability of any 
 
below the thresholds of 40%, 50% and 60%, regardless of the assumed geoCV. So, if θ1 = 
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log(0.03) as expected from simulations using preclinical data based on an assumption of 
low bioavailability, and all other assumptions hold (e.g. dose proportionality, i.e. θ1 = 1 
etc.) it will be possible to escalate the
, if needed, assuming all previous 
possible doses in SAD (e.g. 25, 125, 600 and 1200 mg; see Table 15) have been 
administered. 
If θ1 = log(1.82), as expected from simulations using preclinical data based on an 
assumption of high bioavailability, and all other assumptions hold (e.g. dose 
proportionality, i.e. θ1 = 1 etc.) the probability to escalate 
, assuming 
all previous possible doses in SAD (e.g. 25, 125, 600 and 1200 mg; see Table 15) have 
been administered is low (i.e. <20%), regardless of the assumed between participant Cmax 
variability (i.e. the assumed geoCV) and probability threshold. 
 
9.3.6.3. 
Bayesian model Operating Characteristics (OC) – MAD part 
In this section, we explore the operating characteristics of escalating to various top doses 
(for example, 500 mg, 500 mg) in the MAD part of the study given a starting dose of 200 
mg. 
Under different assumptions of between participant variability (%CVb = 20%, 40%) for 
Cmax and AUC0-24, PK data (in the log scale) were simulated for 10,000 virtual trials 
from a normal distribution with 
 
. The means are based on predictions from a population 
PK model for the last dosing day in the first dosing group (for a dose of 200mg) in MAD, 
based on observed PK data from the first 3 dosing groups in the SAD part. 
Each simulated trial contains Cmax and AUC0-24 values (in the log scale) for 6 subjects 
on treatment for a starting dose of 100 mg. Dose proportional jumps from 200 mg to 
either 500 mg or 700 mg were assumed. The same priors as in Section 9.3.6.2 were used 
in the Bayesian analysis for each PK parameter. No correlation between PK parameters 
was assumed. We assumed 8 participants in the top dose. We estimated (i) the proportion 
of virtual trials in which the Bayesian predictive probability (using simulated data from 
the starting dose of 200 mg) for at least one participant to have a Cmax or AUC0-24 
above their respective NOAEL threshold (see Section 7.4.1) in the top dose is <50%, (ii) 
the predicted mean Cmax and AUC0-24 exposures across all participants in the top dose, 
and (iii) the predicted maximum Cmax and AUC0-24 across all participants in the top 
dose (see Table 18). 
 
 
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Table 18 
Predicted mean and maximum Cmax and AUC0-24 across all participants in the top dose and probability of 
escalating to the reference top dose for various assumptions of data variability and top doses  
Top 
Dose 
(mg) 
Cmax 
Variability 
(%CVb) 
AUC0-24 
Variability 
(%CVb) 
Predicted mean 
Cmax (95% 
CrI1) (ng/mL) 
Predicted mean 
AUC0-24 (95% 
CrI) (ng/mL) 
Predicted 
max Cmax 
(ng/mL) 
Predicted max 
AUC0-24 
(ng/mL) 
Probability 
to escalate 
to top 
dose2 
500 
20% 
20% 
40% 
40% 
20% 
40% 
700 
20% 
20% 
40% 
40% 
20% 
40% 
1CrI = Credibility interval  
2This was estimated as the proportion of virtual trials with Bayesian Predicted Probability <50% 
 
These results indicate that there is a high probability of escalating close to a top dose of 500 mg, or even to 700 mg if data variability is 
not large, if the assumptions of the simulation hold.  
 
 
 
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9.4. 
Interim Analysis 
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 VH4011499 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 


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study 213052; GSK Document Number 2019N422949_01) for AUC(0-∞), the expected 
precision of the estimated ratio of midazolam AUC(0-∞) for midazolam + VH4011499 
vs. midazolam will be as follows: 
 
 
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 VH4011499 PK 
parameters from the PiB administration across the first 3 dosing groups in SAD in this 
study were 26% and 30% 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-Inf)) 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 19 
below shows the expected precision of the estimated ratio of AUC(0-∞) of midazolam for 
midazolam +VH4011499 vs. midazolam. 


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Table 19 
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) 
 
The precision of the estimated ratio (i.e. 90% CI width) of midazolam AUC(0-∞) 
midazolam +VH4011499 vs. midazolam increases only by ~14% when increasing the 
sample size from 8 to 10 participants in the VH4011499 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 20 below shows the expected 90% CI of the 
ratio of geometric means for various assumed estimated ratios, as an example. 
 
Table 20 
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 VH4011499 
tablet and VH4011499 PiB increases only by ~13% when increasing the sample size from 6 to 10 
active participants in the VH4011499 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/or 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 
 
 


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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. 
 
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. 
 
In case of unexpected pregnancy, participant must be informed that personal information 
such as date of birth and sex of the baby will be collected as part of safety follow-up. 
Consent for the baby may be obtained from the participant and/or their partner as per 
local regulations.  
 
If partners of male participants become pregnant during the study, consent will need to be 
obtained or notification given as per local regulation to the partner before collecting their 
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. 
 
Participants who are rescreened are required to sign a new ICF. 
 
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samples and other information to carry out this study; understand the results of this study; 
learn more about VH4011499 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. 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. 
Committees Structure (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 
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 to 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. 
 


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10.1.6. 
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 
subjects, 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 
 
10.1.7. 
Data Quality Assurance 
 
All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Guidance on completion of CRFs will be provided in eCRF completion guidelines. 
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. 


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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. 
 
10.1.8. 
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. 
 
10.1.9. 
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. 
 


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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. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. The investigator may initiate study-site 
closure at any time, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination. 
 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
 
For study termination: 
 
• Discontinuation of further study intervention development For site termination:Failure 
of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment 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 subject and should assure appropriate participant therapy and/or 
follow-up 
 
10.1.10. 
Publication Policy 
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 21 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 21 
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) 


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Laboratory 
Assessments 
Parameters 
Alanine aminotransferase (ALT or SGPT)  
Total Bile Acid (TBA) 
Laboratory 
Assessments 
Parameters 
Lipid Panel 
(fasting) 
Triglycerides Total cholesterol 
Low-density lipoprotein (LDL) cholesterol 
High-density lipoprotein (HDL) cholesterol 
Routine Urinalysis 
Specific gravity 
Dipstick (pH, glucose, protein, blood, ketones, bilirubin, nitrite, 
leukocyte esterase) 
Microscopic examination (if blood or protein is abnormal) 
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 4th generation test, hepatitis B surface antigen 
[HBsAg], and hepatitis C virus antibody). 
NOTES : 
1. 
Details of liver chemistry stopping criteria and required actions and follow-
up assessments after liver stopping or monitoring event are given in 
Section 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 
V H / GSK in an expedited manner (excluding studies of hepatic 
impairment or cirrhosis). Laboratory analytes to be tested will include the 
routine liver panel and additional analytes [such as lactate dehydrogenase 
(LDH), gamma-glutamyl transferase (GGT), glutamate dehydrogenase 
(GLDH) and serum albumin]. 
2. 
Recommend repeat testing if 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. 
3. 
Estimated serum creatinine clearance (using Chronic Kidney Disease 
Epidemiology Collaboration equation) at screening for eligibility 
determination. 
4. 
If alkaline phosphatase is elevated, consider fractionating. 


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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
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. 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
•
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
•
New condition detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
 
 
 
 
 


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• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant.  
   
 
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. 
•
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. 
 
 
 
 
 
 


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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. 
• 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. 
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. 


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10.3.3. 
Recording and Follow-Up of AE and SAE 
 
 
 
 
•
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. 
•
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. 
 
 
 
 
•
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. 
 


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•
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment 
to determine the relationship. 
•
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 
•
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
•
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality 
 
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to 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 
 


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10.3.4. 
Reporting of SAE to VH/GSK 
 
•
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. 
  
 
 
 
•
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. 
•
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. 
 
  
 
 
 
 
 
 
•
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. 
 
  
 
 
 
 
 
 


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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) or a woman of childbearing potential (WOCBP) 
and is using a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, during the study intervention period and for at least 58 
days after the last dose of study intervention.  
 
 
10.4.1. 
Woman of Nonchildbearing Potential (WONCBP) 
 
Women in the following categories are considered WONCBP: 
 
1. 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. 
 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
>40 IU/L or mIU/mLis required. 
• Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
 
 


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10.4.2. 
Woman of Childbearing Potential (WOCBP) 
 
Women in the following categories are considered WOCBP (fertile): 
 
• Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) 
irrespective of the occurrence of menarche or following menarche. 
• From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below) 
 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth. 
 
10.4.3. 
Contraception Guidance 
 
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 partner (if of child-bearing potential) to use a 
highly effective method of contraception as 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. 
 
FOR FEMALE PARTNERS OF MALE PARTICPANTS CONSIDERED 
WOCBP, 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. 


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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. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 
 
Female participants considered WOCBP must agree to use contraception as detailed below: 
 
• Agree to use an additional highly effective contraceptive method (with a failure 
rate of <1% per year), with low user dependency, during the study intervention period 
and for at least 58 days (e.g., 28- day post dose follow-up period plus 30 days (a 
menstrual cycle) after the last dose of study intervention. Highly effective, low user-
dependency (with a failure rate of <1% per year) are limited to intrauterine 
devices/systems or bilateral tubal occlusion ≥3 months prior to screening. 
 
Note: Documented evidence of contraception procedures (IUD/IUS/occlusion) below are 
required. Documentation can come from the site personnel’s review of the participant’s 
medical records. 
 
 


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FOR FEMALE PARTICIPANTS CONSIDERED WOCBP, 
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. 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 
 
 


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10.5. 
Appendix 5: Liver Safety: 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 
• 
Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• 
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 
• 
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 
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: 
o In participants when serology 
raises the possibility of 
autoimmune hepatitis (AIH) 
o In participants when 
suspected DILI progresses or 
fails to resolve on withdrawal 
of study drug 
o In participants with acute or 
chronic atypical presentation. 
• 
If liver biopsy is conducted, then complete 
liver biopsy form 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation testing is unavailable, record the absence/presence of detectable urinary 
bilirubin on dipstick, which is indicative of direct bilirubin elevations suggesting liver 
injury. 
2. 
All events of ALT  3xULN and total bilirubin  2xULN (>35% direct bilirubin) or ALT  
3xULN and INR>1.5, which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); the INR 
threshold value stated will not apply to participants receiving anticoagulants 


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3. 
Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, heterophile antibody or monospot testing) and hepatitis E IgM antibody 
4. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study 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 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 
 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ARV 
Antiretroviral therapy 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration-Time Curve 
AUC(0-t) 
Area Under the Plasma Concentration Time Curve from Time 
Zero to the Last Quantifiable Time Point 
AUC(0-24) 
Area under the plasma concentration vs time curve from time = 0 
hours to time = 24 hours 
AUC(0-tlast) 
Area under the plasma concentration vs time curve from time = 0 
hours to the time of last quantifiable concentration 
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 
BMI 
Body mass index 
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 
CPSR 
Clinical pharmacology study report 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
Cτ 
Concentration at the end of the dosing interval at steady state 
CV 
Coefficient of Variation 
CVb 
Between participant coefficient of variation 
CVw 
Within-subject variability 
CYP 
Cytochrome P450 
DBL 
Database lock 
DDI 
Drug-Drug Interaction 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EMEA 
European Medicines Agency 
ER 
Extended Release 
F 
Bioavailability 
CCI


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FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FTIH 
First-time-in-human 
FU 
Follow-up 
g 
gram 
g/L 
Gram Per Litre 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
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 
IND 
Investigational New Drug 
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 
LDH 
Lactate Dehydrogenase 
MAD 
Multiple Ascending Dose 
MCH 
Mean Corpuscular Haemoglobin 
MCV 
Mean Corpuscular Volume 
MDZ 
Midazolam 
mg 
Milligram 
min 
Minute 
mL 
Millilitre 
mmHg 
millimetre of Mercury 


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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 
QD 
Once-daily 
QTc 
Corrected QT Interval 
QTcF 
QT Interval Corrected for Heart Rate According to Fridericia’s 
Formula 
QTLs 
Quality tolerance limits 
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 
SAE 
Serious adverse events 
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 
SOA 
Schedule of Activities 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2 
Apparent Terminal Elimination Phase Half-Life 
tlast 
Time of Last Quantifiable Plasma Concentration 
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 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of Non-Childbearing Potential 
 
 
Trademark Information 
Trademarks not owned by the ViiV 
Healthcare and GSK of companies 
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, clinical 
investigators 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 


118 
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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 the 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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Clinical Study Protocol template V17 dated 24-Jan-2022 
 
1.9. Appendix 9: Protocol Amendment History 
 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the table of contents (TOC).  


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Clinical Study Protocol template V17 dated 24-Jan-2022 
 
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-026329, VH4011499 
Investigator's Brochure, Version 00, April 2022. 
 
GlaxoSmithKline Document Number TMF-14580566, Modeling and 
Simulation Analysis Report to predict the Pharmacokinetics of VH4011499 
for FTIH Study, March 2022. 
 
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, Sims J, Brinson C, et al. Lenacapavir as part of a combination 
regimen in treatment-naïve people with HIV: week 54 results 
(CALIBRATE), CROI 2022, 12-16 February, Virtual, Oral Presentation, 
Accessed via https://www.askgileadmedical.com 2 March 2022. 
 
Oguagu, O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in 
people with multidrug-resistant HIV-1: week 52 results (CAPELLA), 
CROI 2022, 12-16 February, Virtual, Poster 1047, Accessed via 
https://www.askgileadmedical.com 2 March 2022.  
 
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 
 
UNAIDS [Internet] Global AIDS Epidemiological Estimates Update 2021 
CCI


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Clinical Study Protocol template V17 dated 24-Jan-2022 
 
[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. 
 
ViiV Healthcare Protocol for Study 217058, First-Time-in-Human (FTIH) 
Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of 
VH4004280 in Healthy Participants, Accessed via 
https://clinicaltrials.gov/ct2/show/NCT05163522 13 March 2022. 
 
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):47-6 
 
 
 


Signature Page for  218490 TMF-14909676 v2.0
Signature Page for TMF-14909676 v2.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 14-Nov-2022 13:52:39 GMT+0000
PPD

SAP_001.pdf: 
 


 
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Information Type: Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title:  
A Randomized, Double-Blinded (Sponsor Unblinded), 
Placebo-Controlled Study to Evaluate the Safety, Tolerability 
and Pharmacokinetics of Orally Administered VH4011499 in 
Healthy Participants. 
Study Number: 
218490 
Compound Number: GSK4011499 (also known as VH4011499) 
Abbreviated Title: 
VH4011499 First-Time-in-Human Study 
 
 
Sponsor Name: ViiV Healthcare UK Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
IND 
159876 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2022 the ViiV Healthcare group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
1.2. 
Objectives, Estimands and Endpoints ........................................................... 6 
1.2.1. 
Estimand........................................................................................ 8 
1.3. 
Study Design .............................................................................................. 14 
2. 
STATISTICAL HYPOTHESES ............................................................................... 15 
2.1. 
Multiplicity Adjustment ................................................................................ 16 
3. 
ANALYSIS SETS ................................................................................................... 16 
4. 
STATISTICAL ANALYSES ..................................................................................... 17 
4.1. 
General Considerations .............................................................................. 17 
4.1.1. 
General Methodology .................................................................. 17 
4.1.2. 
Baseline Definition ....................................................................... 18 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 19 
4.2.1. 
Definition of endpoint(s)/estimands .............................................. 19 
4.2.2. 
Main analytical approach of safety analyses ................................ 20 
4.2.3. 
Main analytical approach of primary PK (VH4011499) 
analyses ...................................................................................... 22 
4.3. 
Safety Analyses .......................................................................................... 24 
4.3.1. 
Safety endpoint(s) ........................................................................ 24 
4.3.2. 
Other Safety Analyses ................................................................. 27 
4.5. 
Other Analyses ........................................................................................... 32 
4.5.1. 
Subgroup analyses ...................................................................... 32 
4.5.2. 
Other Pharmacokinetic Analyses ................................................. 32 
4.6. 
Interim Analyses ......................................................................................... 35 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 36 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 36 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 36 
6.1.1. 
Participant Disposition ................................................................. 36 
6.1.2. 
Protocol Deviations ...................................................................... 37 
6.1.3. 
Demographic and Baseline Characteristics .................................. 37 
6.1.4. 
Prior and Concomitant Medications ............................................. 37 
6.1.5. 
Subject Disposition & Study Treatment Discontinuation: .............. 37 
6.1.6. 
Protocol Deviations: ..................................................................... 38 
6.1.7. 
Additional COVID-19 Assessments: ............................................. 38 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 38 
6.2.1. 
Abbreviations ............................................................................... 38 
6.2.2. 
Trademarks ................................................................................. 39 
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7. 
REFERENCES ....................................................................................................... 40 
 


 
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LIST OF TABLES 
PAGE 
Table 1 
Estimands ................................................................................................ 8 
Table 2 
Analysis sets .......................................................................................... 16 
Table 3 
Definition of primary PK parameters ....................................................... 23 
 


 
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VERSION HISTORY 
SAP 
Version 
Approval Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
1 
24  May 2022 
 
Version 1 
(13th April 
2022) 
Not 
Applicable 
Original 
version 
2 
06 Dec 2022 
Amendment 01  
(14 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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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analysis to be included in the Clinical 
Study Report (CSR) for the Study 218490. Details of 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 01 (Dated: 14 NOV 2022). 
1.2. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and 
tolerability of single (Parts 
1 and 3) and multiple 
(Part 2) doses of 
VH4011499 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 
pharmacokinetic (PK) 
characteristics of 
VH4011499 in healthy 
participants following 
single (Part 1) and 
multiple (Part 2) doses. 
• Area under the plasma-concentration time curve (AUC): 
AUC0-inf for single dose and AUC(0-t) 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 
VH4011499 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 
CCI


 
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1.2.1. 
Estimand 
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 (Parts 1 and 
3) and multiple (Part 2) doses of 
VH4011499 in healthy 
participants. 
• Incidence of AEs overall 
and by severity grade 
• Incidence of AEs leading to 
discontinuation of study 
treatment1 
▪ Absolute values and change 
from Baseline in liver panel 
laboratory parameters  
▪ 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  
▪ 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. 
▪ 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 
IE Strategy: 
o Discontinuation of study 
treatment: 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).  
o All available AE, liver 
panel data will be used. No 
imputation will be done for 
missing data. 
o For parts 1 and 3 no 
relevant intercurrent events 
are anticipated. 
 
Rationale: 


 
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Objective 
Estimand 
Variable/ Endpoint 
Population & Summary 
Measure 
Intercurrent event (IE) 
strategy & rationale 
participants with worst-
case post-baseline changes 
from baseline with respect 
to normal range for any 
non-gradable lab 
parameters 
This attempts to estimate safety 
effects likely to be attributable 
to VH4011499 irrespective of 
whether the participant 
completed the treatment 
 
Primary objective 2: 
To describe the plasma 
pharmacokinetic (PK) 
characteristics of VH4011499 
(PiB) in healthy participants 
following single (Part 1) and 
multiple (Part 2) doses. 
o Part 1:  
▪ 
VH4011499 PK 
Concentrations,  
▪ 
VH4011499PK parameters: 
AUC(0-24), AUC(0-tlast), AUC(0-
∞), Cmax, C24, Tmax, T1/2, Clast, 
Tlast and %AUCex  
o Part 2:  
▪ 
VH4011499 PK 
Concentrations, 
▪ 
VH40114990 PK 
parameters: 
− 
First Dose (Day 1 or 2): 
Cmax, , tmax and any 
VH499 Pharmacokinetic 
analysis set 
• 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. 
 
• Part 2: 
PK Concentrations & 
parameters: Summary 
IE Strategy: 
Discontinuation of VH4011499 
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 VH4011499 
may bias the evaluation of 


 
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Objective 
Estimand 
Variable/ Endpoint 
Population & Summary 
Measure 
Intercurrent event (IE) 
strategy & rationale 
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 
 
statistics (e.g. geometric 
mean, median, mean, std, 
%CV, min, max etc.) by 
visit (only for 
concentrations) and dosing 
group. 
 
Pharmacokinetic behavior of 
VH4011499 (PiB). 
Safety objective: 
To further assess the safety and 
tolerability of single (Part 1) and 
multiple (Part 2) doses of 
VH4011499in healthy 
participants. 
• Absolute values and change 
from Baseline in vital signs 
and ECG parameters 
▪ Absolute values and change 
from Baseline and 
maximum grade increase 
post-Baseline relative to 
Baseline for gradable lab 
hematology, coagulation and 
remaining chemistry 
parameters, or worst-case 
postbaseline changes from 
baseline with respect to 
normal range for non-
Safety analysis set 
• Summaries (e.g., mean, 
median, std etc.) of 
absolute values and 
change from Baseline 
values by visit and 
treatment arm2 
▪ 
Summaries (e.g. mean, 
median, std etc.) of 
absolute values and 
change from Baseline by 
visit and treatment arm, 
and number and 
percentage of participants 
with maximum grade 
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. 
For parts 1 and 3 no relevant 
intercurrent events are 
anticipated.  
 


 
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Objective 
Estimand 
Variable/ Endpoint 
Population & Summary 
Measure 
Intercurrent event (IE) 
strategy & rationale 
gradable lab parameters 
including urianalysis 
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 
Rationale: 
Interest lies to estimate safety 
effects likely to be attributable 
to VH4011499 irrespective of 
whether the participant 
completed the treatment. 
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Objective 
Estimand 
Variable/ Endpoint 
Population & Summary 
Measure 
Intercurrent event (IE) 
strategy & rationale 
CCI


 
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Objective 
Estimand 
Variable/ Endpoint 
Population & Summary 
Measure 
Intercurrent event (IE) 
strategy & rationale 
1In part 1 study treatment is VH4011499 or placebo, in part 2 is VH4011499 with or without midazolam or placebo and in part 3 is VH4011499 
2Data summaries will be presented for each dosing group for VH4011499 and collectively from all dosing groups for placebo, within each part of the study 
CCI


 
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1.3. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• Phase 1, First in Human study in healthy participants 
• Randomized, Placebo-Controlled (Parts 1 and 2), dose-escalation 
study 
• Double- Blinded (Sponsor Unblinded) 
• Participants in Part 1 (SAD), and Part 2 (MAD) and Part 3 will 
have a screening visit within 30 days prior to their first dose 
• Duration of study participants (from Screening Visit to the final 
post-dosing Follow-up Visit) will be approximately 8 weeks for 
participants in both Part 1 (SAD) and Part 3 and approximately 
10 weeks for participants in part 2 (MAD)  
• Participants within each dosing group in Part 1 (SAD) will 
receive a single dose of VH4011499 (PiB) or placebo on Day 1, 
participants within each dosing group in Part 2 (MAD) will 
receive one dose daily of VH4011499 (PiB) or placebo for 14 
days (Days 1-14) and participants in Part 3 will receive a single 
dose of VH4011499 (tablet) 
• Follow up period will be approximately 28-days following final 
dose in both Part 1(SAD) and 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 6 ascending separate dosing 
groups. Within each dosing group, 8 participants will be randomized, to 
receive a single dose of blinded VH4011499 (PiB) or blinded placebo 
(in a 6:2, active:placebo ratio) administered orally, in up to 6 ascending 
repeat-dose groups of 8 healthy adults per group. At the start of each 
SAD dosing group, 2 of the total number of participants will serve as 


 
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Overview of Study Design and Key Features 
sentinel participants, with one receiving blinded VH4011499 (PiB) and 
the other receiving blinded placebo. Dose escalation decisions, including 
the determination of subsequent doses to be administered in Part 1, will 
be determined by the SDEC but will be constrained by any emerging 
safety or tolerability concerns and to a maximum 5x the predicted 
exposure increase between consecutive dosing groups. The proposed 
dosing schedule is designed to investigate single doses of VH4011499 
(PiB) in Part 1 and then, at a suitable cross-over point, begin repeated 
once-daily dosing of VH4011499 (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 VH4011499 (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 VH4011499 (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 VH4011499 (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 VH4011499 (PiB) or PBO to investigate 
the potential of VH4011499 to inhibit OATP1B1/1B3. 
Part 3 (Tablet PK): It will be conducted in 1 dosing group. Participants 
will receive a single dose of VH4011499 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 and 28 for follow up procedures. 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 
10.1.5 Safety and Dose Escalation Committee). 
2. 
STATISTICAL HYPOTHESES  
No formal statistical hypotheses are to be tested. Study objective will be evaluated 
through descriptive summaries. 


 
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2.1. 
Multiplicity Adjustment 
No adjustment for multiplicity will be made. 
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 sign the ICF and are 
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 1 
full or partial dose of study treatment (i.e. 
VH4011499 or midazolam or placebo).  
• 
For VH4011499 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 
VH499 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety analysis set 
who had at least one dose of VH4011499 
tablet or have ingested at least one full dose 
 of VH4011499 PiB and who 
had at least one non-missing VH4011499 PK 
assessment. (Nonquantifiable [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-
• 
PK 
CCI
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Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
quantifiable [NQ] values will be considered as 
non-missing values). 
• 
Data will be reported according to the actual 
study intervention. 
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 the 
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 continuous and categorical variables will be summarized 
using the following descriptive statistics: 
• Continuous data: n (number of subjects used for the 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).  For all other data see the OPS for details. Lab values 
from any laboratory (i.e. central or local) will be included in data summaries. 
Within each part of the study, data will be summarised by dosing group for VH4011499 
and collectively from all dosing groups for placebo, unless otherwise specified.  


 
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 Only selected listings 
required by regulatory agencies will be created in static fashion. See OPS for more 
details.  
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 VH4011499 
or midazolam administration. If time is not collected, day 1 assessments are assumed to 
be taken prior to first dose (of either VH4011499 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. 
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4.2. 
Primary Endpoint(s) Analyses 
Primary Endpoints 
Statistical Analysis Methods 
Adverse Events (AEs) The number and proportion of participants reporting AEs will be 
tabulated by dosing group for VH4011499 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 relationship to study 
product.  
For part 2, AEs leading to study treatment (i.e., VH4011499 or 
midazolam or placebo) withdrawal will also be summarized by 
dosing group for VH4011499 and collectively for placebo. In 
Parts 1and 3, discontinuation of study treatment can’t occur as 
participants receive only 1 dose of study treatment. 
The analysis will be repeated for each part of the study. 
Liver panel laboratory 
parameters 
Data for liver panel parameters will be summarised by dosing 
group for VH4011499 and collectively for placebo and by visit. 
Summary statistics (e.g., mean, median, std) for absolute values 
and for change from baseline will be presented. 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 also be presented. 
 
The analyses will be repeated for each part of the study. 
PK for VH4011499 
PiB 
Summary statistics (e.g., geometric mean, median, %CV etc.) will 
be provided for the VH4011499 Pharmacokinetic concentrations 
and parameters per dosing group for VH4011499 in each part of 
the study. The analyses will be repeated for each part of the study. 
 
 
4.2.1. 
Definition of endpoint(s)/estimands 
• Adverse events: 
o Number and percentages 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 percentages 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: 


 
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o Part 1 (single dose): 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 Section 1.2.1 Estimand. 
4.2.2. 
Main analytical approach of safety analyses 
All primary safety analyses (i.e., AEs and liver panel lab parameters 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 
(VH4011499 or Midazolam or Placebo) and post study intervention (e.g. after 
participants stopped VH4011499 or/and midazolam) will be summarized collectively. 
The following categories and subcategories of AEs will be summarized for each dosing 
group of VH4011499 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 (VH4011499 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 
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• 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 VH4011499 + midazolam, or VH4011499 only or under receiving no 
treatment after the completion of VH4011499 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 VH4011499 or midazolam, as recorded in eCRF (there will be no 
distinction between AEs related to VH4011499 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. 
All planned AE displays are provided in the OPS document. 
4.2.2.2. 
Liver panel laboratory analysis 
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 
summarized by dosing group of VH4011499 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 
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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. 
4.2.3. 
Main analytical approach of primary PK (VH4011499) analyses 
Pharmacokinetic parameters for VH4011499 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 VH4011499 administration in part 2 of the study, only serum 
VH4011499 concentration data up to the time of discontinuation of VH4011499 will be 
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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-) + Clast /λz 
Part 2 
AUC(0-) 
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 
rateconstant 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 
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 VH499 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 VH 4011499 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 subject level figures but will not be included in summaries. The PK sampling 
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displayed. 
 
All derived VH4011499 PK parameters will be summarized 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 
 of study 
treatment or miss a dose, any PK concentrations and PK parameters inferred until the 
next dose 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 
semilogarithmic scales. 
• Separate graphs of the mean and median concentration data over time, on linear 
and semi-logarithmic scales by dosing-group. 
• 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 summarized by 
treatment (i.e. for each dosing group for VH4011499 
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 summarized by 
treatment (i.e. for each dosing group for VH4011499 
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. 
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Hematology, coagulation, 
urianalysis 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 
summarized by treatment (i.e. for each dosing group for 
VH4011499 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 postbaseline 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 Section 1.2 
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. 
 
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 postbaseline 
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 
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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 msec to <=480 msec, increase >480 msec 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. 
 
Hematology, coagulation, urinanalysis 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 Liver panel laboratory 
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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 Liver panel laboratory analysis 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 Liver panel laboratory analysis 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 
 
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 VH4011499 or Placebo will be summarised for part 2. Number of 
days of exposure will be calculated based on the formula: 
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For MAD/DDI dosing groups in part 2, treatment start and stop dates refer to 
VH4011499 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 analysis is planned. 
 
4.5.2. 
Other Pharmacokinetic Analyses 
All other pharmacokinetic analyses will be performed on the VH499 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 Section1.2.1. 
• If a participant does not take the full dose 
 of VH4011499 or miss a 
dose, any PK concentrations and PK parameters inferred until the next dose from 
the partial or missed dose may be excluded from the statistical analyses, as 
appropriate.  
4.5.2.1. 
Dose Proportionality Assessment in SAD 
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. 
Endpoint/ Variables 
• For SAD part: AUC(0-∞) (AUC0-t may be used if required), Cmax 
• For MAD part: 
• 
First dose (Day 1 or 2): Cmax, AUC0-24 
• 
Last dose (Day 14 or 15): Cmax, AUC(0-24), AUC(0-t) 
Model Specification 
• Dose proportionality of VH4011499 PK parameters will be assessed using the 
following power model: 
𝑦 = 𝛼 ∗ 𝑑𝑜𝑠𝑒𝛽 
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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. 
Mode Results Presentations 
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 and C) 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. 
 
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: 
 


 
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The analysis will be based on the available AUC(0-τ) and Cmax 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 C), 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 VH4011499 
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 VH4011499 
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. 
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, Section4.5.2.2, Section4.5.2.3, 
distributional assumptions underlying the model used for analysis will be examined by 


 
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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 the PK threshold(s) (as 
specified in the protocol) on Day 14 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 + 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. 


 
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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 VH4011499 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 
protocol. 
 
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 1and 3 study treatment 
discontinuation is not possible as participants receive only 1 dose of study treatment. 
 


 
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The number and percentage of participants who withdrew from the study due to an AE 
will be summarized 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 
summarized. 
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 of important protocol deviations. 
 
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. 
Prior and Concomitant Medications 
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 
CCI
CCI


 
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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 
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. 
 
 
6.2. 
Appendix 2 Data Derivations Rule 
This section will be part of OPS document and will be described there. 
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 
CCI
CCI


 
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SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
VH 
ViiV Healthcare group of companies 
6.2.2. 
Trademarks 
Trademarks of the ViiV Healthcare 
 
Trademarks not owned by ViiV 
Healthcare 
None 
 
WinNonlin 
CCI


 
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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. 
 


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