Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants

Study Overview
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Brief Summary
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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).

Detailed Description
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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. Cohort 1 mother-infant pairs were enrolled prior to delivery. The women were followed-up until discharge from the labor/delivery unit. Infants were followed from birth through 20 weeks after birth. If infant was eligible for PK sampling (see Eligibility section), blood samples were collected at 1-5, 8-14, 18-24, and 30-36 hours after birth. Protocol defined infant safety evaluations were at birth, and at 8-14 hours, 30-36 hours, 1 week and 20 weeks after birth. Cohort 2 mother-infant pairs were enrolled prior to delivery or within 48 hours after delivery. The women were followed-up until discharge from the labor/delivery unit. Infants were followed from birth/entry through 6 weeks after birth. If infant was eligible for PK sampling, blood samples were collected at 1-6, 12-24, 36-48, 72-84, and 108-132 hours and 7-14 days after birth. Protocol defined infant safety evaluations were at entry/birth, and at 36-48 hours, 72-84 hours, 1 week and 6 weeks after birth. For both cohorts, all infants regardless of whether they were eligible for PK sampling were included in the safety analyses. Infant safety data included adverse birth outcomes, signs/symptoms, diagnoses and chemistry/hematology test results. Protocol required chemistry tests were AST, ALT, serum creatinine, total bilirubin and direct bilirubin. Protocol required hematology tests were CBC with differential and platelet count. Also included in the safety data were additional laboratory events done outside of the study but considered by the site as relevant information. For both cohorts, maternal blood and cord blood for RAL concentration testing were collected at delivery when specimen collection was possible. The optional genotypic testing (i.e. testing was done only if the mother consented) was limited to infants who were eligible for PK sampling. Information obtained about the effect of UGT1A1 polymorphisms on the PK of RAL was thought to provide a better understanding of the effect of genetics on the metabolism of RAL in neonates.

Official Title
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Raltegravir Pharmacokinetics and Safety in Neonates

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Raltegravir


Participation Criteria
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Eligibility Criteria
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Participant study inclusions and exclusion criteria are listed below. Cohort 1 M-I pairs were enrolled prior to delivery so that only maternal study inclusion and exclusion criteria were assessed at enrollment. Cohort 1: Maternal Study Inclusion Criteria Documentation of HIV-1 infection. Viable singleton pregnancy with gestational age of at least 35 weeks based on clinical or other obstetrical measurements with normal fetal anatomy Currently receiving RAL 400 mg twice daily for at least 2 weeks prior to enrollment in combination with other ARV agents for clinical care Plan to continue taking RAL in combination with other ARV agents through labor prior to 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 1: Maternal Study Exclusion Criteria - Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to enrollment Cohort 1 Infants were enrolled prior to delivery so there were no infant study inclusion/exclusion criteria. However, only infants who met the following criteria were eligible for PK blood sampling. Infants ineligible for PK sampling remained in the study and were followed-up for safety. Cohort 1: Infant PK Sampling Inclusion Criteria Infant born to women who received at least 2 weeks of RAL prior to delivery and continue to receive RAL during labor prior to delivery in addition to their other ARV drugs Infant birth weight of at least 2 kg Infant at least 37 weeks gestation at delivery Infant not receiving disallowed medications (phenobarbital, phenytoin, rifampin). If these medications are required for the infant's care, the infant will be ineligible for further PK sampling. PK samples will be obtained up to the time of the introduction of the disallowed medication. Cohort 1: Infant PK Sampling Exclusion Criteria - 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 Cohort 2 enrolled M-I pairs at two time points: prior to delivery and within 48 hours after delivery. For M-I pairs enrolled prior to delivery, the maternal study eligibility criteria were assessed at enrollment. There were no infant study eligibility criteria. However, only infants who met the PK sampling eligibility criteria had PK blood sampling. Infants ineligible for PK sampling remained in the study and were followed-up for safety. For M-I pairs enrolled within 48 hours delivery, the maternal and infant study eligibility criteria were assessed at enrollment. A M-I pair was enrolled only if both the mother and the infant were eligible for the study. For multiple births, only infants who met the study eligibility criteria were enrolled. Cohort 2: Maternal Study Inclusion Criteria: 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 Exclusion Criteria: 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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1: Full term infants exposed in utero to maternal RAL<br>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. | Drug: Raltegravir<br>* No study-specific drugs were given to women or infants during this study. Women received RAL for clinical indications outside of the study.<br>* Other names: RAL;|
| Cohort 2: LBW infants exposed in utero to maternal RAL<br>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. | Drug: Raltegravir<br>* No study-specific drugs were given to women or infants during this study. Women received RAL for clinical indications outside of the study.<br>* Other names: RAL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: Neonatal RAL Elimination Half-life (T1/2) | 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 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. | 
| Ratio of Cord Blood to Maternal Blood RAL Concentrations | Ratio of the neonatal cord blood RAL concentration to the mother's plasma RAL concentration at birth | Maternal blood samples were scheduled to be collected within 1 hour after delivery and cord blood sample were collected immediately after cord was clamped | 
| Number of Infants Who Met Composite Safety Endpoint (Grade 3/4 Adverse Event, Adverse Birth Outcome, Death) | 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. | Assessed at entry through Week 20 for Cohort 1 infants and through Week 6 for Cohort 2 infants. | 
| Infant Total Bilirubin | Total bilirubin measured from infant blood specimens. | 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. | 
| Infant Direct Bilirubin | Direct bilirubin measured from infant blood specimens. | 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. | 
| Number of Infants Who Received Treatment to Reduce Bilirubin or for Jaundice | Assessment if infant received exchange transfusion, Phototherapy, or other treatment to reduce bilirubin or for jaundice | Assessed from entry through around week 1 after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal RAL Elimination (T1/2) by UGT1A1 Genotype Group (Normal VS Mutation) | Neonatal RAL elimination was the time required for neonatal plasma concentration to decrease by one-half. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians(i.e. genotyping was optional) . The goal of the genotypic analysis is to determine if certain polymorphisms, particularly those with the UGT1A1*28/*28 genotype have slower RAL elimination than those with the UGT1A1*1/*1 genotype. | 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. |