First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4011499 in Healthy Participants

A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4011499 in Healthy Participants

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: VH4011499; Drug: Placebo; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • GSK Investigational Site
  • Texas
    • Austin, Texas, United States, 78744
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants who are overtly healthy.
• Participants must have two consecutive Severe Acute Respiratory Syndrome Coronavirus 2 (SARs-CoV-2) Polymerase chain reaction (PCR) negative results prior to dosing.
• Participants must have body weight > 50 kilograms (kg) and body mass index (BMI) within the range 19-32 kilograms per meter square (kg/m^2).
• Male or female participants (either of non-childbearing potential or of child-bearing potential and using acceptable contraception).
• 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.
• 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 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.
• Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study.
• Exposure to more than 4 investigational products within 12 months prior to dosing.
• Current enrollment or recent 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 within 14 days.
• Positive HIV antibody test.
• Use 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 midazolam, excipients contained therein, benzodiazepines, or drug or other allergy that, contraindicates participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part 1 Single Ascending Dose (SAD): Placebo Powder-in-a-bottle (PiB); Healthy participants were given a single dose of placebo on Day 1 and were followed up until Day 28.	Drug: Placebo; Placebo will be administered.
Placebo Comparator: Part 1 (SAD): VH4011499 25 mg PiB; Healthy participants were given a single dose of 25 mg VH4011499 on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 1 (SAD): VH4011499 125 mg PiB; Healthy participants were given a single dose of 125 mg VH4011499 on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 1 (SAD): VH4011499 200 mg PiB; Healthy participants were given a single dose of 200 mg VH4011499 on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 1 (SAD): VH4011499 625 mg PiB; Healthy participants were given a single dose of 625 mg VH4011499 on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 1 (SAD): VH4011499 1875 mg PiB; Healthy participants were given a single dose of 1875 mg VH4011499 on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Placebo Comparator: Part 2 Multiple Ascending Dose (MAD): Placebo PiB; Healthy participants were given a dose of placebo once daily for a 14-day period and were followed up until Day 42.	Drug: Placebo; Placebo will be administered.
Experimental: Part 2 (MAD): VH4011499 200 mg PiB; 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.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 2 (MAD): VH4011499 300 mg + Midazolam (MDZ) PiB; 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.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499; Drug: Midazolam; Midazolam will be administered
Experimental: Part 2 (MAD): VH4011499 400 mg PiB; 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.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499
Experimental: Part 3 (Single dose): VH4011499 200 mg tablet; Healthy participants were given a dose of VH4011499 200 mg tablet on Day 1 and were followed up until Day 28.	Drug: VH4011499; VH4011499 will be administered.; Other Names: GSK4011499

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention.	Up to Day 28
Part 2: Number of Participants With AEs	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention.	Up to Day 42
Part 3: Number of Participants With AEs	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention.	Up to Day 28
Part 1: Number of Participants With AEs by Severity	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention. The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AE was used for all AE severity grading, where Grade 1=Mild symptoms causing no or minimal interference with usual social & functional activities with intervention not indicated, 2=Moderate symptoms causing greater than minimal interference with usual social & functional activities with intervention indicated, 3=Severe symptoms causing inability to perform usual social & functional activities with intervention or hospitalization indicated, 4=Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability or death, 5=Death.	Up to Day 28
Part 2: Number of Participants With AEs by Severity	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention. The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AE was used for all AE severity grading, where Grade 1=Mild symptoms causing no or minimal interference with usual social & functional activities with intervention not indicated, 2=Moderate symptoms causing greater than minimal interference with usual social & functional activities with intervention indicated, 3=Severe symptoms causing inability to perform usual social & functional activities with intervention or hospitalization indicated, 4=Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability or death, 5=Death.	Up to Day 42
Part 3: Number of Participants With AEs by Severity	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a study intervention whether or not considered related to the study intervention. The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AE was used for all AE severity grading, where Grade 1=Mild symptoms causing no or minimal interference with usual social & functional activities with intervention not indicated, 2=Moderate symptoms causing greater than minimal interference with usual social & functional activities with intervention indicated, 3=Severe symptoms causing inability to perform usual social & functional activities with intervention or hospitalization indicated, 4=Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability or death, 5=Death.	Up to Day 28
Part 2: Number of Participants Discontinuing Treatment Due to AEs	Number of participants who discontinued treatment due to AEs are presented.	Up to Day 42
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.	Up to Day 28
Part 1: Absolute Values of Liver Panel Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST)	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST.	Up to Day 28
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.	Up to Day 42
Part 2: Absolute Values of Liver Panel Parameters: ALT, ALP and AST	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST	Up to Day 42
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.	Up to Day 28
Part 3: Absolute Values of Liver Panel Parameters: ALT, ALP and AST	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST	Up to Day 28
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.	From Baseline (Day 1) and up to Day 28
Part 1: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.	From Baseline (Day 1) and up to Day 28
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value. Standard Deviation (SD)=0.0000 is defined as following: if all participants analyzed for a specific parameter at a specific time point have the same value, then SD is equal with 0.0000.	From Baseline (Day 1) and up to Day 42
Part 2: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value. SD=0.00 is defined as following: if all participants analyzed for a specific parameter at a specific time point have the same value, then SD is equal with 0.00.	From Baseline (Day 1) and up to Day 42
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.	From Baseline (Day 1) and up to Day 28
Part 3: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST. Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.	From Baseline (Day 1) and up to Day 28
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of the liver panel parameters: ALT, ALP, AST, total bilirubin and direct bilirubin. The number of participants with any grade increase (from grade 1 [mild] to grade 4 [potentially life-threatening]) have been presented.	Up to Day 28
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of the liver panel parameters: ALT, ALP, AST, total bilirubin and direct bilirubin. The number of participants with any grade increase (from grade 1 [mild] to grade 4 [potentially life-threatening]) have been presented.	Up to Day 42
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters	Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of the liver panel parameters: ALT, ALP, AST, total bilirubin and direct bilirubin. The number of participants with any grade increase (from grade 1 [mild] to grade 4 [potentially life-threatening]) have been presented.	Up to Day 28
Part 1: Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to Infinity (0-inf) Following Single Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for pharmacokinetic (PK) analysis to determine AUC(0-inf). For AUC, a linear trapezoidal method was employed for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Geometric Coefficient of Variation was expressed in percentages.	At Day 1
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (0-t) Following Repeat Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine AUC(0-t). For AUC, a linear trapezoidal method was employed for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations.	At Days 1 and 14 for Part 2 (MAD): VH4011499 200 mg PiB and Part 2 (MAD): VH4011499 400 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4011499 300 mg + Midazolam PiB group
Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of VH4011499.	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.	At Day 1
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) Following Single Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.	At Day 1
Part 1: Apparent Terminal Half-life (T1/2) Following Single Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.	At Day 1
Part 2: Cmax Following Repeat Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.	At Days 1 and 14 for Part 2 (MAD): VH4011499 200 mg PiB and Part 2 (MAD): VH4011499 400 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4011499 300 mg + Midazolam PiB group
Part 2: Tmax Following Repeat Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.	At Days 1 and 14 for Part 2 (MAD): VH4011499 200 mg PiB and Part 2 (MAD): VH4011499 400 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4011499 300 mg + Midazolam PiB group
Part 2: T1/2 Following Repeat Dose Administration of VH4011499	Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.	At Day 14 for Part 2 (MAD): VH4011499 200 mg PiB and Part 2 (MAD): VH4011499 400 mg PiB groups, and at Day 15 for Part 2 (MAD): VH4011499 300 mg + Midazolam PiB group

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Investigators: Study Director: GSK Clinical Trials, ViiV Healthcare

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2022
• Primary Completion (Actual): April 24, 2023
• Study Completion (Actual): April 24, 2023

Study Registration Dates

• First Submitted: May 23, 2022
• First Submitted That Met QC Criteria: May 23, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Actual): April 1, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: GSK4011499; VH4011499; First-time-in-human; HIV-1 capsid inhibitor; Single ascending doses; Multiple ascending doses; Drug-drug Interaction
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; HIV Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anesthetics; Central Nervous System Depressants; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 218490

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.viiv-studyregister.com/documents/About_ViiV_Patient_Level_Data_Sharing_Final_25Sep2023.pdf
• IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No