A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 15
- 主要终点
- AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)
研究概览
简要总结
The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of raltegravir (RAL) when given to HIV-1-exposed, normal birth weight newborn infants at risk of acquiring HIV-1 infection. (PK is the study of the time course of absorption, distribution, metabolism, and excretion of drugs in the body.) The primary goal of this study was to determine a dose of RAL that was safe and met the PK targets for infants when administered during the first 6 weeks of life in addition to standard of care antiretroviral (ARV) agents for prevention of perinatal transmission.
详细描述
This is a Phase I multi-center, open label, non-comparative study to evaluate the safety and PK of RAL administered to HIV-1-exposed full-term (≥37 weeks of gestation) infants when administered during the first 6 weeks of life in addition to the infants' standard HIV-1 ARV prophylaxis.
IMPAACT P1097 (NCT01828073) demonstrated that RAL crossed the placenta from mother to fetus after maternal dosing during pregnancy and RAL was slowly eliminated by the newborn after birth. Therefore, for P1110, within each cohort, infants were stratified into the "RAL-naive" or "RAL-exposed" groups depending on infants' in utero exposure to maternal RAL. The study stratification with respect to in utero RAL exposure allowed for adjustment of the initial RAL dosing (i.e. timing and/or dose size).
Study participants were enrolled in two sequential cohorts with the following actual dosing of RAL in addition to their local standard of care ARV agents for prevention of perinatal transmission. PK and safety data from Cohort 1 (two single doses) provided information for the starting dosing for Cohort 2 (daily dosing through 6 weeks of life).
Cohort 1: Two single RAL doses: first dose within 48 hours of birth and second dose at 7-10 days of life.
- Cohort 1, RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life. (P1110 V1.0 Clarification Memorandum #3, dated January 15, 2015, adjusted the first dose from 3 mg/kg to 2 mg/kg based on available PK data.)
- Cohort 1, RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Mother is living with HIV and either i) known to have HIV diagnosis prior to labor (testing obtained and designated per local SOC in the medical record and either on or recently started CART prior to delivery) or ii) identified as having HIV diagnosis at the time of labor or in the immediate postpartum period. More information on this criterion can be found in the protocol.
- •Risk of mothers transmitting HIV to their infants:
- •Cohort 1 and Cohort 2 (RAL-naive): Mother living with HIV is at "high risk" of transmitting HIV to infant as evidenced by any of the following: Mother has not received any ARV therapy during the current pregnancy prior to the onset of labor and delivery; HIV RNA level greater than 1000 copies/mL within 4 weeks (28 days) prior to delivery; receipt of ARV for less than 4 weeks (28 days) before delivery; on ARVs for 4 weeks or longer but has not taken any ARV for more than 7 days prior to delivery; or mother has documented drug resistant virus to at least one class of ARV drugs.
- •Cohort 2 RAL-exposed: there was no requirement that the mother living with HIV is at "high-risk" of transmitting HIV to her infant.
- •Maternal written informed consent for study participation
排除标准
- •Known maternal-fetal blood group incompatibility as evidenced by the presence of an unexpected clinically significant maternal red cell antibody that is known to be capable of causing hemolytic disease of the fetus/newborn
- •Mother will be receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant
- •For Cohort 1 and Cohort 2 RAL-naive groups:
- •Cohort 1 RAL-naive: Mother who received RAL prior to and through delivery unless last RAL dosing during prenatal period was >7 days prior to delivery
- •Cohort 2 RAL-naive: Mother who received RAL prior to and through delivery
- •Infant Inclusion Criteria:
- •Age at enrollment (Note: The full-term infants were HIV-exposed and may have received standard of care ARV prophylaxis/treatment before enrollment):
- •Cohort 1 and Cohort 2 RAL-naive: Aged 48 hours or less.
- •Cohort 2 RAL-exposed: Aged 60 hours or less.
- •Infant gestational age at birth at least 37 weeks
- •No known 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
- •Birth weight at least 2 kg
- •Able to take oral medications
- •Parent or legal guardian able and willing to provide signed informed consent
- •For Cohort 1 and Cohort 2 RAL-exposed groups:
- •Cohort 1 RAL-exposed: Infants born to mothers who received RAL during pregnancy with last dose taken within 7 days before delivery.
- •Cohort 2 RAL-exposed: Infants born to a mother who received at least one dose of RAL within 2 to 24 hours prior to delivery.
- •Infant Exclusion Criteria:
- •Infant with bilirubin exceeding the American Academy of Pediatrics guidelines for phototherapy, using the infant's gestational age and risk factors as described in the protocol.
- •Clinical evidence of renal disease such as edema, ascites, or encephalopathy.
- •Receipt of disallowed medications (phenytoin, phenobarbital, or rifampin).
研究组 & 干预措施
Cohort 1
HIV-1-exposed full-term infants. Infants received two single doses of RAL: first dose within 48 hours of birth and second dose at 7-10 days of life:
- RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.
- RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.
干预措施: Raltegravir (Drug)
Cohort 2
HIV-1-exposed full-term infants. Daily RAL through 6 weeks of life with first dosing within 48 hours of birth and between 12-60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively.
Daily RAL through 6 weeks of life: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
干预措施: Raltegravir (Drug)
结局指标
主要结局
AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)
时间窗: Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.
Area Under the Concentration-time Curve at the 24-hour interval (AUC24) for Cohort 2 initial RAL dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively).
AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
时间窗: Cohort 1 RAL dose #1 (within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.
Area Under the Concentration-time Curve at 24-hour interval (AUC24) based on intensive PK sampling around Cohort 1 RAL dose #1 (within 48 hours of birth)
Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively)
时间窗: Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed groups, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.
Last concentration of the drug (Clast) at 24 hour interval post dosing for the Cohort 2 initial RAL dose (within 48 and at 12-60 hours of birth for RAL-naive and RAL-exposed, respectively). This is the plasma RAL concentration from a sample collected at or close to 24 hours post dose.
Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life
时间窗: From first dosing of RAL through 6 weeks of life
Number of infants who died or had adverse events (AEs) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs.
Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
时间窗: Cohort 1 dose #1(within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.
Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth)
RAL AUC12 for Cohort 2 at 15-18 Days of Life
时间窗: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.
Area Under the Concentration-time Curve at 12-hour interval (AUC12) of RAL for Cohort 2 at 15-18 days of life.
RAL C12 for Cohort 2 at 15-18 Days of Life
时间窗: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.
RAL concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life.
次要结局
- Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life(From first RAL dose through 24 weeks of life)
- Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group(Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2 hours post-dose, 4-6, 8-12 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.)
- Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life(From first RAL dose through 24 weeks of life)
- Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype(Specimens for bilirubin testing were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at entry.)
- Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life(From first RAL dose through 6 weeks of life)
- Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group(Cohort 1 Dose #1 Intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12, 24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.)
- Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype(Specimens for bilirubin test were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at study entry.)
- Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype(Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry.)
- Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype(Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry.)
- Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group(Intensive PK sampling for Cohort 2 initial dose: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.)