Raltegravir Pharmacokinetics and Safety in Neonates
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 19
- 主要终点
- PK Parameter: Neonatal RAL Elimination Half-life (T1/2)
研究概览
简要总结
The purpose of this study was to determine the washout pharmacokinetics (PK) and safety of in utero/intrapartum exposure to maternal raltegravir (RAL) in infants born to pregnant women with HIV infection who received RAL 400 mg twice daily. The study also provided data for the development of an infant RAL starting dosing regimen for IMPAACT P1110 (NCT01780831).
详细描述
Study participants were enrolled in two cohorts.
- Cohort 1 enrolled mother-infant pairs in which the infant was expected to be ≥2000 grams at birth (i.e. full term) at time of enrollment and the mother was living with HIV and received RAL 400 mg twice daily for at least 2 weeks prior to delivery and continued to receive antiretroviral (ARV) drugs during labor.
- Cohort 2 enrolled mother-infant pairs in which the infant was expected to be ≤2500 grams at birth [i.e. low birth weight (LBW)] at time of enrollment and the mother was living with HIV and received at least one dose of RAL 400 mg within 2 to 24 hours prior to delivery.
Cohorts 1 and 2 provided pharmacokinetics and safety data of in utero and intrapartum exposure to maternal RAL in full-term and LBW infants, respectively. Also, the study data were pooled with data from IMPAACT P1066 (NCT00485264) (Cohorts IV and V) and P1026s (NCT00042289) to determine the starting RAL dosing regimen for full-term and LBW infants in IMPAACT P1110 (NCT01780831).
The study initially opened accrual to Cohort 1 under protocol Version 1.0. Upon completion of accrual and follow-up of Cohort 1, the protocol was amended and accrual to and follow-up of Cohort 2 was under protocol Version 2.0.
No study-specific treatment was given to the participants during this study. The women (mothers) received RAL for clinical indications outside of the study. Infants received standard of care ARV therapy for prophylaxis of perinatal transmission of HIV as prescribed by their primary care physicians.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •M-I pairs enrolled prior to delivery
- •Documentation of HIV-1 infection.
- •Viable singleton or multiple birth pregnancy based on clinical or other obstetrical measurements with infant birth weight anticipated to be less than or equal to 2,500 grams
- •RAL is currently used as part of maternal ARV regimen and planned to continue through labor and delivery
- •Willing and intends to deliver at the study-affiliated clinic or hospital
- •Willing and able to sign informed consent for participation of herself and her infant. Participant must be of an age to provide legal informed consent as defined by the country in which she resides. If not, informed consent must be signed by a legal guardian.
- •Cohort 2: Maternal Study
排除标准
- •M-I pairs enrolled prior to delivery
- •Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to enrollment or intent to be on any of the disallowed medications prior to delivery.
- •Cohort 2: Infant PK Blood Sampling Eligibility Criteria: M-I pairs enrolled prior to delivery
- •Infants were enrolled prior to delivery so there were no infant study eligibility criteria. Only infants who met the following criteria were eligible for PK blood sampling:
- •Infant born to woman who received at least one dose of RAL within 2 to 24 hours prior to delivery. Dose administered to mother must have been at least 2 hours prior to delivery to allow time for adequate absorption and distribution.
- •Infant birth weight less than or equal to 2,500 grams
- •Infant not receiving disallowed medications (phenobarbital, phenytoin, rifampin) as described in the protocol. If these medications are required for the infant's care, the infant will be ineligible for further PK sampling. PK data will be obtained up to the time of the introduction of the disallowed medication.
- •Infant less than or equal to 48 hours of age
- •Infant does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician
- •Cohort 2: Maternal Study Inclusion Criteria: M-I pairs enrolled after delivery
- •Documentation of HIV-1 infection.
- •Received at least one dose of RAL within 2 to 24 hours prior to delivery
- •Willing and able to sign informed consent for participation of herself and her infant. Participant must be of an age to provide legal informed consent as defined by the country in which she resides. If not, informed consent must be signed by a legal guardian.
- •Cohort 2: Maternal Study Exclusion Criteria: M-I pairs enrolled after delivery
- •Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to delivery
- •Cohort 2: Infant Study Inclusion Criteria: M-I pairs enrolled after delivery
- •Infant birth weight less than or equal to 2,500 grams
- •Infant less than or equal to 48 hours of age
- •Cohort 2: Infant Study Exclusion Criteria: M-I pairs enrolled after delivery
- •Received disallowed medications (phenobarbital, phenytoin, rifampin)
- •Infant has a severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician
研究组 & 干预措施
Cohort 1: Full term infants exposed in utero to maternal RAL
Infants, who were expected to be ≥2000 grams at birth (i.e. full-term) at time of enrollment, born to women with HIV-1 infection who received RAL 400 mg twice daily for at least two weeks prior to delivery and continued to receive ARVs during labor. The group also includes the mothers of these infants.
干预措施: Raltegravir (Drug)
Cohort 2: LBW infants exposed in utero to maternal RAL
Infants, who were expected to be ≤2500 grams at birth (i.e. LBW) at time of enrollment, born to women with HIV-1 infection who received at least one dose of RAL 400 mg within 2 to 24 hours prior to delivery. The group also includes the mothers of these infants.
干预措施: Raltegravir (Drug)
结局指标
主要结局
PK Parameter: Neonatal RAL Elimination Half-life (T1/2)
时间窗: Infant blood specimens were collected at 1-5, 8-14, 18-24, and 30-36 hours after birth for Cohort 1; and at 1-6, 12-24, 36-48, 72-84, and 108-132 hours after birth, and on day 7-14 for Cohort 2.
Time required for neonatal plasma concentration to decrease by one-half. T1/2 was estimated using the terminal 3 concentration-time points for each infant when available.
Infant Total Bilirubin
时间窗: Measured at 8-14 hours (Visit 1), 30-36 hours (Visit 2) and 1-2 weeks (Visit 3) after birth for Cohort 1; and at 36-48 hours (Visit 1), 72-84 hours (Visit 2) and 1 week (Visit 3)after birth for Cohort 2.
Total bilirubin measured from infant blood specimens.
Number of Infants Who Received Treatment to Reduce Bilirubin or for Jaundice
时间窗: Assessed from entry through around week 1 after birth
Assessment if infant received exchange transfusion, Phototherapy, or other treatment to reduce bilirubin or for jaundice
Ratio of Cord Blood to Maternal Blood RAL Concentrations
时间窗: Maternal blood samples were scheduled to be collected within 1 hour after delivery and cord blood sample were collected immediately after cord was clamped
Ratio of the neonatal cord blood RAL concentration to the mother's plasma RAL concentration at birth
Number of Infants Who Met Composite Safety Endpoint (Grade 3/4 Adverse Event, Adverse Birth Outcome, Death)
时间窗: Assessed at entry through Week 20 for Cohort 1 infants and through Week 6 for Cohort 2 infants.
An infant was said to have met the composite safety endpoint if any of the following was observed: * adverse events (AEs) of Grade 3 or 4 as defined in DAIDS AE Grading Table * adverse birth outcomes including stillbirth and low birth weight (LBW), or * death. Stillbirth could only be observed on infants enrolled prior to delivery. Cohort 2 enrolled LBW infants and prematurity and growth restriction which were highly linked to LBW were considered as baseline events and not AEs or adverse birth outcome for Cohort 2 infants.
Infant Direct Bilirubin
时间窗: Measured at 8-14 hours (Visit 1), 30-36 hours (Visit 2) and 1-2 weeks (Visit 3) after birth for Cohort 1; and at 36-48 hours (Visit 1), 72-84 hours (Visit 2) and 1 week (Visit 3)after birth for Cohort 2.
Direct bilirubin measured from infant blood specimens.
次要结局
- Neonatal RAL Elimination (T1/2) by UGT1A1 Genotype Group (Normal VS Mutation)(Genotype was assessed close to birth and if this is not possible at 1-2 wks after birth. PK samples were collected at 1-5, 8-14, 18-24 and 30-36 hrs after birth for Cohort 1; 1-6, 12-24, 36-48, 72-84 and 108-132 hrs after birth, and day 7-14 for Cohort 2.)