Open Label, Single Arm, Two-stage Trial to Evaluate the Single and Multi-dose Pharmacokinetics and Safety of the Paediatric Dolutegravir (10 mg, Scored) Dispersible Tablet in HIV-exposed Neonates
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- In Cohort 1, PK analysis will be performed to calculate the following parameter: AUC0-24
研究概览
简要总结
A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled.
详细描述
A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled.
Enrolment will be in two stages:
- Stage 1 will assess a single 5 mg dose of the DTG-DT in two sequential cohorts: Cohort 1A (n=8) and Cohort 1B (n=8).
- Stage 2 will assess multiple 5 mg doses of the DTG-DT and DTG-ODF in two parallel cohorts: Cohort 2A (n=20) and Cohort 2B (n=20).
Per national guidelines, all infants receive a birth HIV nucleic acid test (NAT). HIV NAT test results for the infant may or may not be available (HIV pending) at the time of study entry. HIV NAT results are typically available within 72 hours of the blood sample being taken and are checked and acted upon by the hospital HIV PMTCT service, as part of standard of care. If an HIV NAT result comes back positive whilst the neonate is on study, the neonate will not receive any further DTG doses, revert to standard of care antiretroviral therapy (ART), and be followed for safety for the duration of the study.
Primary Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 1 Day 至 14 Days（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Stage 1: Inclusion Criteria
- •HIV-exposed neonate (pending HIV status) born to a woman within HIV on DTG-based ART
- •Birth weight of ≥2000 g and on standard of care ARV prophylaxis
- •Cohort Specific Inclusion Criteria in Stage 1 must be met at Study Entry:
- •Cohort 1A: Infant <14 days of life Cohort 1B: Infant ≤3 days of life
- •Stage 2: Inclusion Criteria
- •Low risk* HIV-exposed neonate (pending HIV status) born to a virologically suppressed woman on DTG-based ART
- •*Neonate born to a woman with a documented plasma HIV-1 RNA result <50 copies/mL in the 4 weeks prior to delivery or between delivery and infant study entry
- •Birth weight of ≥2000 g and on standard of care ARV prophylaxis
- •Cohort Specific Inclusion Criteria in Stage 2 must be met at Study Entry:
- •Cohort 2: Infant <7 days of life
排除标准
- •• Less than 37 weeks gestational age at birth
- •Known blood group incompatibilities which can result in hemolytic disease of the newborn (e.g., Rh-negative mother, presence of antibodies on neonatal red blood cells, etc.)
- •Total bilirubin values approaching an exchange transfusion as defined by local guidelines (Section 18.2)
- •Haemoglobin value of <13.0 g/dL
- •Platelet count of less than 50,000 cells/mm3)
- •Decreased total white blood cell count (Grade 3 and above)
- •Creatinine value more than 1.3 the upper limit of normal (ULN) for gestational age and postnatal age (Grade 2 and above)
- •AST or ALT of more than 2.5 the ULN (Grade 2 and above)
- •Any other current Grade ≥3 event on the DAIDS toxicity table
- •Severe congenital abnormalities or critically ill neonates at discretion of the examining clinician
- •Receiving medicine(s) that can impact DTG pharmacokinetics (Section 8.7)
- •Participation in another clinical trial
- •HIV-infected neonates
研究组 & 干预措施
single arm, two-stage
Participants will be enrolled in two stages:
- Stage 1 will assess a single dose of the DTG-DT in two sequential cohorts: Cohort 1A (n=8) and Cohort 1B (n=8).
- Stage 2 will assess multiple-doses of the DTG-DT and the DTG-ODF in a single cohort: Cohort 2A (n=20) DTG-DT and Cohort 2B (n=20) DTG-ODF
干预措施: Dolutegravir (Drug)
结局指标
主要结局
In Cohort 1, PK analysis will be performed to calculate the following parameter: AUC0-24
时间窗: first 28 days of life
AUC0-all will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together.
In Cohort 1, PK analysis will be performed to calculate the following parameter: AUC0-infinity
时间窗: first 28 days of life
AUC0-infinity will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together.
In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: Tmax
时间窗: first 28 days of life
Population means and variances of Tmax for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability.
In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: Cmax
时间窗: first 28 days of life
Population means and variances of Cmax for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability.
In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: CTau
时间窗: first 28 days of life
Population means and variances of CTau for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. Changes in DTG trough concentrations in neonates following multi-doses of DTG-DT and DTG-ODF during the first 28 days of life will be estimated using the final model.
In Cohort 1, PK analysis will be performed to calculate the following parameter: Cmax
时间窗: first 28 days of life
Cmax will be taken directly from the observed concentration-time data.
In Cohort 1, PK analysis will be performed to calculate the following parameter: Ratio AUC0-24 / AUC0-infinity
时间窗: first 28 days of life
Ratio AUC0-24 / AUC0-infinity will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together.concentration-time data.
Reporting adverse events of Grade 3 or higher; treatment-related adverse events of Grade 3 or higher; any adverse events neonates following administration of DTG dispersible tablet
时间窗: first 28 days of life
Using the DAIDS toxicity table and protocol specific safety criteria
In Cohort 1, PK analysis will be performed to calculate the following parameter: Clast,
时间窗: first 28 days of life
Clast will be taken directly from the observed concentration-time data.
In Cohort 1, PK analysis will be performed to calculate the following parameter: Tmax
时间窗: first 28 days of life
Tmax will be taken directly from the observed concentration-time data.
In Cohort 1, PK analysis will be performed to calculate the following parameter: C24
时间窗: first 28 days of life
C24 will be taken directly from the observed concentration-time data.
In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: AUC0-tau
时间窗: first 28 days of life
Population means and variances of AUC0-tau for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. Changes in DTG drug exposures in neonates following multi-doses of DTG-DT and DTG-ODF during the first 28 days of life will be estimated using the final model.
次要结局
- Qualitative acceptability data from mothers and health workers(first 28 days of life)
- Acceptability to caregivers and neonates of using DTG-DT will be measured by means of a questionnaire(first 28 days of life)