A Phase 1 Double-Blind (Sponsor-unblinded), Placebo-Controlled Randomized, Single Ascending Dose and Multiple Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Parenterally Administered VH4524184 in Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 372
- 试验地点
- 3
- 主要终点
- Percentage of participants reporting adverse events (AEs) and related AEs
研究概览
简要总结
The purpose of this study is to identify 1 or more doses of parenterally administered VH4524184 that are safe, well tolerated and yield a PK drug exposure profile necessary to deliver a long-acting antiretroviral therapy for the treatment of HIV-1 infection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
- •Type of Participant and Characteristics
- •Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- •Participants who are negative for SARS-CoV-2, performed on admission/readmission to the Phase 1 unit, using an approved molecular test (PCR).
- •Participants who are able to understand and comply with protocol requirements and timetables, instructions, and protocol-stated restrictions.
- •Body weight ≥50.0 kg (110 lbs) for men and ≥45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 32.0 kg/m^2 (inclusive) for all cohorts except B
- •For Cohort B19, body mass index within the range >32.0 to 37.0 kg/m^2 (inclusive).
- •Sex and Contraceptive/Barrier Requirements
- •Male or female
- •Male Participants: No restrictions for male participants
- •Participants of female sex assigned at birth:
- •A participant of childbearing potential (POCBP) (female sex assigned at birth) is eligible to participate as long as the participant is not pregnant, breastfeeding and utilizes a highly effective method of contraception.
- •A participant of non-childbearing potential (PONCBP) is eligible to participate if all other eligibility criteria are met.
- •Informed Consent
- •Capable of providing signed informed consent.
排除标准
- •Medical Conditions
- •History or presence of clinical condition or disorder that could be capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study drug, interfering with the interpretation of data or would make the participant unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits.
- •Clinically significant abnormal blood pressure as determined by the investigator.
- •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.
- •Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome.
- •Underlying skin disease or disorder that would interfere with the administration of study product and/or assessment of injection site reactions.
- •Clinically significant history of drug hypersensitivity, delayed-type hypersensitivity or severe hypersensitivity reactions, as well as history of /sensitivity to any of the study interventions including hyaluronidases.
- •Current or anticipated need for chronic anti-coagulation except for the use of low dose acetylsalicylic acid (≤325 mg) or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.
- •History of seizure.
- •Any known or suspected pre-existing psychiatric condition, including depression, anxiety and insomnia/sleep disturbances, at the discretion of the investigator.
- •Any positive (abnormal) response confirmed by the investigator or clinician (or qualified designee) administered C-SSRS at screening.
- •Insufficient muscle mass (gluteus medius or thigh) to support IM dose administration in the opinion of the investigator.
- •Presence of tattoos, implants or skin piercings that may interfere with the administration of study product and/or assessment of ISRs, if they occur.
- •History of or on-going high-risk behaviors that may put the participant at increased risk for HIV acquisition in the opinion of the investigator. This includes participants in HIV discordant relationships, or men who report current or prior unprotected anal sex with other men and those reporting prior or current injecting drug use.
- •Prior/Concomitant Therapy
- •Past or intended use of over-the-counter or prescription medication 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.
- •Receipt of any live vaccine(s) or vaccines against SARS-CoV-2 within 28 days prior to screening or 14 days before or after scheduled SC or IM dosing.
- •Prior/Concurrent Clinical Study Experience
- •Exposure to more than 4 new investigational products (including long-acting investigational products) within 12 months prior to the first dosing day.
- •Current enrollment or past participation in another investigational study in which an investigational intervention was administered within the last 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product before signing of consent (OR screening) any other clinical study.
- •Participation in the study would result in loss of blood in excess of 500 mL over a 56-day period.
- •Current enrollment or past participation in this clinical study, with the exception of participants who previously completed the Oral Lead In (OLI) but for operational or logistic reasons did not progress to CRU admission and receipt of injectable suspension for injection (SFI) or powder for suspension for injection (PFS) study medication or placebo, or prior participation in study
- •Diagnostic Assessments
- •eGFR <60 mL/min or serum creatinine >1.1 x ULN.
- •Hemoglobin <12.5 g/dL for men and <11 g/dL for women
- •ALT or AST > upper limit of normal (ULN).
- •Total bilirubin >1.5xULN.
- •Any significant arrhythmia or ECG finding.
- •Exclusion criteria for Screening ECG - a single repeat is allowed for eligibility determination.
- •Presence of HBsAg and/or anti-HBc at Screening or within 3 months prior to first dose of study intervention.
- •Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
- •Positive pre-study drug/alcohol screen.
- •Positive HIV antibody test.
- •Other Exclusions
- •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.
- •Regular use of known drugs of abuse.
- •Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening and at admission.
- •Sensitivity to the study drug, or components thereof, or other drug or other allergy that, in the opinion of the investigator or Sponsor Medical Monitor, contraindicates participation in the study.
研究组 & 干预措施
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: Placebo Formulation B SC (Drug)
Formulation A SC Group
Participants receive a Formulation A starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: rHuPH20 (Drug)
Formulation B SC Group
Participants receive a Formulation B starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: Oral VH4524184 (Drug)
Formulation B SC Group
Participants receive a Formulation B starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: VH4524184 Formulation B SC (Drug)
Formulation A SC Group
Participants receive a Formulation A starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: Oral VH4524184 (Drug)
Formulation A SC Group
Participants receive a Formulation A starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: VH4524184 Formulation A SC (Drug)
Formulation A SC Group
Participants receive a Formulation A starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: Placebo Formulation A SC (Drug)
Formulation B SC Group
Participants receive a Formulation B starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: Placebo Formulation B SC (Drug)
Formulation A IM Group
Participants receive a Formulation A starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: Oral VH4524184 (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: VH4524184 Formulation A IM (Drug)
Formulation A IM Group
Participants receive a Formulation A starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: VH4524184 Formulation A IM (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: Placebo Formulation A IM (Drug)
Formulation B SC Group
Participants receive a Formulation B starting dose of VH4524184 LAI subcutaneously (SC).
干预措施: rHuPH20 (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: VH4524184 Formulation B IM (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: Placebo Formulation B IM (Drug)
Formulation B IM Group
Participants receive a Formulation B starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: VH4524184 Formulation B IM (Drug)
Formulation B IM Group
Participants receive a Formulation B starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: Placebo Formulation B IM (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: Oral VH4524184 (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: VH4524184 Formulation A SC (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: Placebo Formulation A SC (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: VH4524184 Formulation B SC (Drug)
Multiple doses Group
VH4524184 LAI formulations administered SC or IM as single doses that achieve adequate PK exposure targets, may be evaluated for safety and tolerability as multiple doses.
干预措施: rHuPH20 (Drug)
Formulation A IM Group
Participants receive a Formulation A starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: Placebo Formulation A IM (Drug)
Formulation B IM Group
Participants receive a Formulation B starting dose of VH4524184 LAI intramuscularly (IM).
干预措施: Oral VH4524184 (Drug)
结局指标
主要结局
Percentage of participants reporting adverse events (AEs) and related AEs
时间窗: From first study dose administration (Day 1) up to study end (Week 52 post last dose)
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. Related AE = AE assessed by the investigator as related to the study drug.
Percentage of participants with AEs by severity
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Severity of AEs will be assessed using Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS). DAIDS grading scale is used to grade the toxicity associated with injection site reactions (ISR) including injection site pain (or tenderness), erythema (or redness), induration (or swelling), and pruritis. The toxicity level is graded from Grade 1 (lowest toxicity) to 4 (highest toxicity). Higher grade indicates higher toxicity.
Percentage of participants discontinuing the treatment due to AEs
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Change from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase parameters
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
The liver panel laboratory parameters are assessed after the administration of long-acting injectable (LAI) VH4524184.
Change from baseline in total bilirubin parameters
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
The liver panel laboratory parameters are assessed after the administration of LAI VH4524184.
Maximum toxicity grade increase from baseline in total bilirubin
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Change from baseline in international normalized ratio (INR) parameters
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
The liver panel laboratory parameters are assessed after the administration of LAI VH4524184.
Maximum toxicity grade increase from baseline in ALT, AST and alkaline phosphatase
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Maximum toxicity grade increase from baseline in INR
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Duration of injection site reaction AEs
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinity time (AUC[0-inf]) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Maximum observed plasma drug concentration (Cmax) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Cmax of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Percentage of participants reporting injection site reaction (ISR) AEs
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Assessed ISRs are pain, tenderness, infections, erythema, swelling, induration, or nodules (granulomas or cysts). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, and Grade 4 = potentially life threatening.
Area under the plasma drug concentration-time curve from zero (pre-dose) to the end of the dosing interval at steady state (AUC[0-t]) of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Time to maximum observed plasma drug concentration (Tmax) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Tmax of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Apparent terminal half-life (t1/2) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
t1/2 of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to study end (Week 52 post last dose)
Percentage of participants reporting adverse events (AEs) and related AEs
时间窗: From first study dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
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. Related AE = AE assessed by the investigator as related to the study drug.
Percentage of participants with AEs by severity
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Severity of AEs will be assessed using Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS). DAIDS grading scale is used to grade the toxicity associated with injection site reactions (ISR) including injection site pain (or tenderness), erythema (or redness), induration (or swelling), and pruritus. The toxicity level is graded from Grade 1 (lowest toxicity) to 4 (highest toxicity). Higher grade indicates higher toxicity.
Percentage of participants discontinuing the treatment due to AEs
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Change from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase parameters
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
The liver panel laboratory parameters are assessed after the administration of long-acting injectable (LAI) VH4524184.
Change from baseline in total bilirubin parameters
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
The liver panel laboratory parameters are assessed after the administration of LAI VH4524184.
Change from baseline in international normalized ratio (INR) parameters
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
The liver panel laboratory parameters are assessed after the administration of LAI VH4524184.
Maximum toxicity grade increase from baseline in ALT, AST and alkaline phosphatase
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Maximum toxicity grade increase from baseline in total bilirubin
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Maximum toxicity grade increase from baseline in INR
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Percentage of participants reporting injection site reaction (ISR) AEs
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, and Grade 4 = potentially life threatening.
Duration of injection site reaction AEs
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinity time (AUC[0-inf]) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Area under the plasma drug concentration-time curve from zero (pre-dose) to the end of the dosing interval at steady state (AUC[0-t]) of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Maximum observed plasma drug concentration (Cmax) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Cmax of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Time to maximum observed plasma drug concentration (Tmax) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Tmax of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
Apparent terminal half-life (t1/2) of LAI VH4524184 following single dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
t1/2 of LAI VH4524184 following multiple dose administration
时间窗: From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants
次要结局
- Percentage of participants with treatment emergent Grade 3 or Grade 4 laboratory abnormalities(From first dose administration of VH4524184 (Day 1) up to study end (Week 52 post last dose))
- Percentage of participants with treatment emergent Grade 3 or Grade 4 laboratory abnormalities(From first dose administration (Day 1) up to Week 52 post last dose, and Week 80 post last dose for a sub-group of participants)