First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants

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

Official Title
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A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4004280 in Healthy Participants

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: VH4004280
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participant must be 18 to 55 years of age inclusive. Participants who are overtly healthy. Male or female participants of non-childbearing potential. Capable of giving signed informed consent. Exclusion criteria: 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. Abnormal blood pressure. Symptomatic herpes zoster. Evidence of active or latent tuberculosis (TB). 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. Breast cancer within the past 10 years. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). QT interval corrected for heart rate according to Fridericia's formula (QTcF) greater than (>)450 milliseconds (msec). Past or intended use of over-the-counter or prescription medication including herbal medications. Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study. Exposure to more than 4 new investigational products within 12 months prior to the first dosing day. Current enrollment or past participation in another investigational study. ALT >1.5 times upper limit of normal (ULN), total bilirubin >1.5 times ULN, and/or estimated serum creatinine clearance less than 60 milliliters per minute. History of or current infection with hepatitis B or hepatitis C. Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test, having signs and symptoms, or having contact with known Coronavirus Disease-2019 (COVID-19) positive person/s. Positive HIV antibody test. User of tobacco or nicotine-containing products, regular alcohol consumption and/or regular use of known drugs of abuse. Sensitivity to the study drug, or components thereof.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (SAD): Participants receiving VH4004280<br> | Drug: VH4004280<br>* VH4004280 will be administered.<br>* Other names: GSK4004280;|
| Placebo Comparator: Part 1 (SAD): Participants receiving placebo<br> | Drug: Placebo<br>* Placebo will be administered.<br>|
| Experimental: Part 2 (MAD) Non Drug-Drug Interaction (DDI) cohort: Participants receiving VH4004280<br> | Drug: VH4004280<br>* VH4004280 will be administered.<br>* Other names: GSK4004280;|
| Placebo Comparator: Part 2 (MAD) Non DDI cohort: Participants receiving placebo<br> | Drug: Placebo<br>* Placebo will be administered.<br>|
| Experimental: Part 2 (MAD) DDI cohort: Participants receiving VH4004280 and Midazolam<br> | Drug: VH4004280<br>* VH4004280 will be administered.<br>* Other names: GSK4004280;Drug: Midazolam<br>* Midazolam will be administered<br>|
| Placebo Comparator: Part 2 (MAD) DDI cohort: Participants receiving Placebo and Midazolam<br> | Drug: Placebo<br>* Placebo will be administered.<br>Drug: Midazolam<br>* Midazolam will be administered<br>|
| Experimental: Part 3 (Single dose): Participants receiving VH4004280 (new formulation)<br> | Drug: VH4004280<br>* VH4004280 will be administered.<br>* Other names: GSK4004280;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants with adverse events (AEs) |  | Up to Day 49 | 
| Part 2: Number of participants with AEs |  | Up to Day 63 | 
| Part 3: Number of participants with AEs |  | Up to Day 49 | 
| Part 1: Number of participants with AEs by severity |  | Up to Day 49 | 
| Part 2: Number of participants with AEs by severity |  | Up to Day 63 | 
| Part 3: Number of participants with AEs by severity |  | Up to Day 49 | 
| Part 2: Percentage of participants discontinuing treatment due to AEs |  | Up to Day 14 | 
| Part 1: Absolute values of liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Up to Day 49 | 
| Part 1: Absolute values of liver panel parameters: Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and Aspartate aminotransferase (AST) (International units per Liter) |  | Up to Day 49 | 
| Part 2: Absolute values of liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Up to Day 63 | 
| Part 2: Absolute values of liver panel parameters: ALT, ALP and AST (International units per Liter) |  | Up to Day 63 | 
| Part 3: Absolute values of liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Up to Day 49 | 
| Part 3: Absolute values of liver panel parameters: ALT, ALP and AST (International units per Liter) |  | Up to Day 49 | 
| Part 1: Change from Baseline in liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Baseline and up to Day 49 | 
| Part 1: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter) |  | Baseline and up to Day 49 | 
| Part 2: Change from Baseline in liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Baseline and up to Day 63 | 
| Part 2: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter) |  | Baseline and up to Day 63 | 
| Part 3: Change from Baseline in liver panel parameters: Direct and total bilirubin (Micromoles per liter) |  | Baseline and up to Day 49 | 
| Part 3: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter) |  | Baseline and up to Day 49 | 
| Part 1: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters |  | Up to Day 49 | 
| Part 2: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters |  | Up to Day 63 | 
| Part 3: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters |  | Up to Day 49 | 
| Part 1: Area under the plasma concentration time curve from time zero to infinity (AUC[0-infinity]) following single dose administration of VH4004280 |  | Up to Day 49 | 
| Part 2: Area under the plasma concentration time curve over a dosing interval from time of dosing to the time of the subsequent dose (AUC[0-tau]) following repeat dose administration of VH4004280 |  | Up to Day 63 | 
| Part 1: Maximum observed plasma concentration (Cmax) following single dose administration of VH4004280 |  | Up to Day 49 | 
| Part 1: Time to maximum observed plasma concentration (Tmax) and Apparent terminal half-life (T1/2) following single dose administration of VH4004280 (Hours) |  | Up to Day 49 | 
| Part 2: Cmax following repeat dose administration of VH4004280 |  | Up to Day 63 | 
| Part 2: Tmax and T1/2 following repeat dose administration of VH4004280 (Hours) |  | Up to Day 63 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First-time-in-human, GSK4004280, VH4004280, HIV-1 capsid inhibitor, Single ascending doses, Multiple ascending doses