A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4004280 in Healthy Participants
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- ViiV Healthcare
- Enrollment
- 73
- Locations
- 1
- Primary Endpoint
- Part 3: Number of Participants With Any AEs and by Severity
Study Overview
Brief Summary
This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4004280 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD), Part 2 will investigate multiple ascending doses and drug-drug interaction (MAD/MAD DDI) Part 3 will investigate single dose relative bioavailability (RBA) of a new formulation of VH4004280.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Masking Description
This is a double-blind (sponsor unblinded) study.
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Part 1 Single Ascending Dose (SAD): Placebo Powder-in-bottle (PiB)
Healthy participants were given a single oral dose of placebo on Day 1 and were followed up to approximately Day 49.
Intervention: Placebo (Drug)
Part 1 (SAD): VH4004280 10 mg PiB
Healthy participants were given a single oral dose of 10 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Part 1 (SAD): VH4004280 50 mg PiB
Healthy participants were given a single oral dose of 50 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Part 1 (SAD): VH4004280 150 mg PiB
Healthy participants were given a single oral dose of 150 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Part 1 (SAD): VH4004280 450 mg PiB
Healthy participants were given a single oral dose of 450 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Part 1 (SAD): VH4004280 900 mg PiB
Healthy participants were given a single oral dose of 900 mg VH4004280 PiB on Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Part 2 Multiple Ascending Dose (MAD): Placebo PiB
Healthy participants were given a dose of placebo once daily (QD) for a 14-day period and were followed up to approximately Day 63.
Intervention: Placebo (Drug)
Part 2 (MAD): VH4004280 100 mg PiB
Healthy participants were given a dose of 100 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.
Intervention: VH4004280 (Drug)
Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB
Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.
Intervention: VH4004280 (Drug)
Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB
Healthy participants were given a dose of 250 mg VH4004280 PiB QD for a 14-day period, and a single dose of Midazolam on days 1, 2, and 15, and were followed up to approximately Day 63.
Intervention: Midazolam (Drug)
Part 2 (MAD): VH4004280 350 mg PiB
Healthy participants were given a dose of 350 mg VH4004280 PiB QD for a 14-day period and were followed up to approximately Day 63.
Intervention: VH4004280 (Drug)
Part 3 (Single dose): VH4004280 450 mg tablet
Healthy participants were given a single oral dose of VH4004280 450 mg tablet at Day 1 and were followed up to approximately Day 49.
Intervention: VH4004280 (Drug)
Outcomes
Primary Outcomes
Part 3: Number of Participants With Any AEs and by Severity
Time Frame: Up to Day 49
The 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.
Part 2: Number of Participants Discontinuing Treatment Due to AEs
Time Frame: Up to Day 63
Number of participants who discontinued treatment due to AEs are presented.
Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity
Time Frame: Up to Day 49
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.
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin
Time Frame: Up to Day 49
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. 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.
Part 2: Absolute Values of Liver Panel Parameters: ALP, ALT and AST
Time Frame: Up to Day 63
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.
Part 1: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST
Time Frame: From Baseline (Day 1) and up to Day 49
Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.
Part 2: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST
Time Frame: From Baseline (Day 1) and up to Day 63
Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.
Part 2: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
Time Frame: Up to Day 63
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.
Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of VH4004280
Time Frame: At Day 1
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.
Part 1: Apparent Terminal Half-life (T1/2) Following Single Dose Administration of VH4004280
Time Frame: Day 1 to Day 49
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
Time Frame: From Baseline (Day 1) and up to Day 49
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.
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
Time Frame: From Baseline (Day 1) and up to Day 63
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.
Part 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
Time Frame: Up to Day 49
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.
Part 2: Cmax Following Repeat Dose Administration of VH4004280
Time Frame: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.
Part 2: Number of Participants With Any AEs and by Severity
Time Frame: Up to Day 63
The 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.
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin and Total Bilirubin
Time Frame: Up to Day 63
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin. Standard Deviation (SD)=0.00000 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 0.00000.
Part 3: Absolute Values of Liver Panel Parameters: ALP, ALT and AST
Time Frame: Up to Day 49
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
Time Frame: Up to Day 49
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.
Part 1: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC[0-infinity]) Following Single Dose Administration of VH4004280
Time Frame: At Day 1
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.
Part 2: AUC Over a Dosing Interval From Time of Dosing to the Time of the Subsequent Dose (AUC[0-t]) Following Repeat Dose Administration of VH4004280
Time Frame: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group
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.
Part 2: T1/2 Following Repeat Dose Administration of VH4004280
Time Frame: Day 14 to Day 63 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and Day 15 to Day 63 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.
Part 1: Absolute Values of Liver Panel Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
Time Frame: Up to Day 49
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALP, ALT and AST.
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
Time Frame: Up to Day 49
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
Time Frame: From Baseline (Day 1) and up to Day 49
Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.
Part 3: Change From Baseline in Liver Panel Parameters: ALP, ALT and AST
Time Frame: From Baseline (Day 1) and up to Day 49
Change from baseline was calculated by subtracting the baseline value from the post-dose visit value.
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) Following Single Dose Administration of VH4004280
Time Frame: At Day 1
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.
Part 2: Tmax Following Repeat Dose Administration of VH4004280
Time Frame: At Days 1 and 14 for Part 2 (MAD): VH4004280 100 mg PiB and Part 2 (MAD): VH4004280 350 mg PiB groups, and at Days 2 and 15 for Part 2 (MAD): VH4004280 250 mg + Midazolam (MDZ) PiB group
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.
Secondary Outcomes
No secondary outcomes reported