A Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Dolutegravir in Neonates Exposed to HIV-1
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 96
- 试验地点
- 30
- 主要终点
- Proportion of infants who are not able to tolerate the study drug.
研究概览
简要总结
The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of dolutegravir (DTG) in infants born to mothers living with HIV-1. The primary goal of the study was to propose a dose of DTG that is safe and meets PK targets when administered to infants through the first four weeks of life in addition to the infant's standard HIV-1 ARV prophylaxis. The study was expected to enroll a minimum of 36 and up to 108 mother-infant (M-I) pairs from Brazil, South Africa, Thailand, and the United States. Infants were followed through 16 weeks of life. Mothers did not receive study drug and were off study after completion of the Entry visit. A total of 48 M-I pairs were enrolled in the study.
详细描述
This was a Phase I, multi-centered, open-label, non-comparative dose-finding study to evaluate the safety, tolerability, and PK of DTG when added to standard ARV prophylaxis in singleton full-term (≥ 37 weeks gestation at birth) infants born to mothers living with HIV-1, and to propose an appropriate DTG dosing regimen during the first four weeks of life for infants born to mothers living with HIV-1.
The infant and mother were enrolled as a pair, with the mother taken off study after completing the Entry visit and the infant followed through the Week 16 visit (Days 112-140 of life).
Infants were enrolled in two sequential dosing cohorts: Cohort 1 (two single DTG doses) and Cohort 2 (chronic DTG dosing through a Week 4 or 6 visit per local standard of care for ARV prophylaxis). Cohort 1 was intended to generate the PK and safety data that would inform DTG dose selection for Cohort 2.
At study entry in both cohorts, the participants were stratified based on the infant's in utero exposure to maternal DTG using the criteria below:
- DTG-naïve: Infant born to a mother who did not receive DTG during the two weeks immediately prior to delivery.
- DTG-exposed: Infant born to a mother who received at least one dose of DTG less than or equal to 72 hours prior to delivery.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Mother is of legal age or circumstance to provide independent informed consent and is willing and able to provide written informed consent for her and permission for her infant's participation in this study.
- •Mother has confirmed HIV-1 infection based on positive test results from two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 protocol requirements. Test results may be obtained from medical records or from testing performed during the study screening period:
- •For results obtained from medical records, adequate source documentation, including the date of specimen collection, date of testing or date of test result, name of test/assay performed, and test result, must be available in study records prior to study entry. Requirements related to laboratory operations (e.g., CLIA, GCLP, or VQA) and related to regulatory authority (e.g., FDA) approvals do not apply to results obtained from medical records.
- •If adequate source documentation is not available, Sample #1 and/or Sample #2 should be collected during the study screening period and tested in the site's designated testing laboratory. If both samples are tested using antibody tests, at least one of the samples must be tested in a laboratory that operates according to CLIA or equivalent (for US sites) or GCLP (for non-US sites) guidelines and participates in an appropriate external quality assurance program. If nucleic acid testing is used, at least one test must be performed in the site's CLIA-certified or equivalent (for US sites) or VQA-certified (for non-US sites) laboratory.
- •All study-specific samples tested to determine HIV-1 status must be whole blood, serum, or plasma. HIV testing methods and algorithms must be approved for each site by the IMPAACT Laboratory Center (for NIAID-funded sites) or Westat (for NICHD-funded sites). All test methods should be FDA-approved, if available.
- •At entry, infant meets DTG exposure requirements, based on mother's report and confirmed by medical records if available, as follows:
- •For Cohort 1, Strata 1A and 1C, and Cohort 2, Stratum 2A: Infant born to a mother who did not receive DTG during the two weeks immediately prior to delivery.
- •For Cohort 1, Stratum 1B, and Cohort 2, Stratum 2B: Infant born to a mother who received at least one dose of DTG less than or equal to 72 hours prior to delivery.
- •Infant was singleton with a gestational age at birth of at least 37 weeks.
- •At birth, infant's weight was as follows:
- •For Cohort 1, Strata 1A,1B, 1C, and Cohort 2, Strata 2A and 2B: At least 2 kg
- •At screening, infant has the following laboratory test results, based on severity grading specified in the protocol section 7.3.3:
- •ALT (normal)
- •AST (normal or Grade 1)
- •Total bilirubin (normal or Grade 1)
- •Hemoglobin (normal, Grade 1, or Grade 2)
- •White blood cells (normal, Grade 1, or Grade 2)
- •Platelets (normal, Grade 1, or Grade 2)
- •Creatinine (normal, Grade 1, or Grade 2)
- •At entry, infant is less than or equal to five days of life.
- •At entry, infant has initiated standard of care ARV prophylaxis (i.e., received at least one dose of ARV regimen prior to entry).
- •At entry, infant is generally healthy as determined by the site investigator based on review of all available medical history information and physical examination findings.
排除标准
- •Known maternal-fetal blood group incompatibility as evidenced by the presence of an unexpected clinically significant maternal red blood cell antibody that is known to cause hemolytic disease of the fetus and newborn.
- •Infant or breastfeeding mother is receiving any disallowed medicationlisted in protocol Section 5.8.
- •At entry, infant with a documented positive HIV nucleic acid test result.
- •Infants with prior exchange transfusion or with elevated bilirubin that would require exchange transfusion.
- •Mother or infant has any condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
结局指标
主要结局
Proportion of infants who are not able to tolerate the study drug.
时间窗: Initial study drug dosing through study drug discontinuation
An infant is considered not able to tolerate the study drug if the infant experiences problems taking the study drug or experiences any AE assessed as related to study drug that leads to premature permanent discontinuation of the study drug.
Area under the curve (AUC) for DTG
时间窗: 28 months
Proportion of infants classified as "study drug-related" safety failures.
时间窗: Initial study drug dosing through 2 weeks after off treatment date
An infant is classified as a "study drug-related" safety failure for the primary safety study objective if any of the following occurred after the initial study drug dosing through two weeks after permanent discontinuation of the study drug (i.e., two weeks after off treatment date): * Grade 3 or 4 AE assessed as related to study drug, or * Death (Grade 5 AE) assessed as related to the study drug, or * Life-threatening AE assessed as related to study drug, or * AE assessed as related to study drug that leads to premature permanent discontinuation of the study drug.
C(last) for DTG
时间窗: 28 months
C(trough) for DTG
时间窗: 28 months
AUC(0-tau) for DTG
时间窗: 28 months
Proportion of infants classified as safety failures.
时间窗: Initial study drug dosing through 2 weeks after off treatment date
An infant is classified as a safety failure for the primary safety study objective if any of the following occurred after the initial study drug dosing through two weeks after permanent discontinuation of the study drug (i.e., two weeks after off treatment date): * Grade 3 or 4 AE, or * Death (Grade 5 AE)
次要结局
- Proportion of infants classified as safety failures.(Initial study drug dosing through Week 16)
- Proportion of infants classified as "study drug-related" safety failures.(Initial study drug dosing through Week 16)