A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4011499 in Healthy Participants
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 73
- 试验地点
- 1
- 主要终点
- Part 1: Number of Participants With Adverse Events (AEs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
This is a double-blind (sponsor unblinded) study.
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: VH4011499 (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: Midazolam (Drug)
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.
干预措施: VH4011499 (Drug)
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.
干预措施: VH4011499 (Drug)
结局指标
主要结局
Part 1: Number of Participants With Adverse Events (AEs)
时间窗: Up to Day 28
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.
Part 2: Number of Participants With AEs
时间窗: Up to Day 42
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.
Part 3: Number of Participants With AEs
时间窗: Up to Day 28
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.
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
时间窗: 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
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 1: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of VH4011499.
时间窗: At Day 1
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) Following Single Dose Administration of VH4011499
时间窗: At Day 1
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.
Part 1: Apparent Terminal Half-life (T1/2) Following Single Dose Administration of VH4011499
时间窗: At Day 1
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.
Part 2: Cmax Following Repeat Dose Administration of VH4011499
时间窗: 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
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Cmax.
Part 2: Tmax Following Repeat Dose Administration of VH4011499
时间窗: 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
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine Tmax.
Part 2: T1/2 Following Repeat Dose Administration of VH4011499
时间窗: 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
Blood samples were collected as assessed by protocol, at specific time points for PK analysis to determine T1/2.
Part 1: Number of Participants With AEs by Severity
时间窗: Up to Day 28
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 2: Number of Participants With AEs by Severity
时间窗: Up to Day 42
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 3: Number of Participants With AEs by Severity
时间窗: Up to Day 28
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 2: Number of Participants Discontinuing Treatment Due to AEs
时间窗: Up to Day 42
Number of participants who discontinued treatment due to AEs are presented.
Part 1: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: Up to Day 28
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.
Part 1: Absolute Values of Liver Panel Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST)
时间窗: Up to Day 28
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST.
Part 2: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: Up to Day 42
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.
Part 2: Absolute Values of Liver Panel Parameters: ALT, ALP and AST
时间窗: Up to Day 42
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST
Part 3: Absolute Values of Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: Up to Day 28
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of bilirubin.
Part 3: Absolute Values of Liver Panel Parameters: ALT, ALP and AST
时间窗: Up to Day 28
Blood samples were collected as assessed by protocol, at specific time points for laboratory analysis of ALT, ALP and AST
Part 1: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: From Baseline (Day 1) and up to Day 28
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.
Part 1: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST
时间窗: From Baseline (Day 1) and up to Day 28
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.
Part 2: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: From Baseline (Day 1) and up to Day 42
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.
Part 2: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST
时间窗: From Baseline (Day 1) and up to Day 42
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.
Part 3: Change From Baseline in Liver Panel Parameters: Direct Bilirubin, Total Bilirubin
时间窗: From Baseline (Day 1) and up to Day 28
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.
Part 3: Change From Baseline in Liver Panel Parameters: ALT, ALP and AST
时间窗: From Baseline (Day 1) and up to Day 28
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.
Part 1: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
时间窗: Up to Day 28
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: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
时间窗: Up to Day 42
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 3: Number of Participants With Maximum Toxicity Grade Increase From Baseline for Liver Panel Parameters
时间窗: Up to Day 28
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 (AUC) From Time Zero to Infinity (0-inf) Following Single Dose Administration of VH4011499
时间窗: 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.
次要结局
未报告次要终点