Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at Risk of Acquiring HIV-1 Infection

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Cohort 2: Daily RAL dosing through 6 weeks of life. Cohort 2, RAL-naive: Daily dosing through 6 weeks of life with initial RAL dosing within 48 hours of birth: 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. Cohort 2, RAL-exposed: Daily dosing through 6 weeks of life with initial RAL dosing between 12-60 hours of birth: 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. Target enrollment was approximately 50 infants and their mothers in order to have a minimum of 12 and 20 PK evaluable infants in Cohorts 1 and 2, respectively. Cohort 1 and Cohort 2 RAL-naive infants (and their mothers) were enrolled under protocol Version 1.0. Cohort 2 RAL-exposed infants (and their mothers) were enrolled under protocol Version 2.0. Infants and their mothers were enrolled within 48 and within 60 hours of delivery under protocol Versions 1.0 and 2.0, respectively. Infants were followed through 24 weeks of life and their mothers were followed until discharge from the labor and delivery unit. Infant PK samples were collected as follows: Cohort 1: Dose #1 (within 48 hours of birth) intensive PK sampling: Within 30 min pre-dose, and 1-2 hours post-dose, 4-8 hours post-dose, 12 (±1) hours post-dose, and 24 (±1) hours post-dose. One random PK sample at 3-4 days of life. Dose #2 (7-10 days of life) limited PK sampling: Within 30 min pre-dose, and 1-2 hours post-dose and 24 (±1) hours post-dose. Cohort 2: Initial dose (within 48 and 12-60 hours of birth for RAL-naive and RAL-exposed infants, respectively) intensive PK sampling: Within 1 hour pre-dose, and 1-2 hours, 6-10 hours, 20-24 hours post-dose. PK sampling for second dose: 3-6 hours post-dose. PK sampling at 6-9 days of life: Within 1 hour pre-dose of initiating 3mg/kg twice daily. Intensive PK sampling at 15-18 days of life: Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose. PK sampling at 28-32 days of life: Within 1 hour pre-dose of initiating 6 mg/kg twice daily. PK sampling at 33-42 days of life done at Week 5-6 visit: Within 1 hour pre-dose, and 3-6 hours post-dose. Protocol defined infant safety evaluations were done at: Cohort 1: Entry, 3-4 days of life, 7-10 days of life, 2 weeks of life, 6 weeks of life and 24 weeks of life. Cohort 2: Entry, 2-4 days of life, 6-9 days of life, 15-18 days of life, 28-32 days of life, 5-6 weeks of life, 8-10 weeks of life and 24 weeks of life. Infant safety data included death, signs/symptoms, diagnoses and laboratory test results. Laboratory test results included results from evaluations specified in the protocol and evaluations done as part of the infant's clinical care which the sites considered relevant. PK evaluable infants were those determined by the protocol pharmacologist to have PK results which provide analyzable data on the primary PK parameters of interest. Infants who were PK unevaluable were replaced for PK analysis but continued with the study safety follow-up visits. Infants were evaluable for safety analysis if they received at least one dose of RAL. The safety analyses were based on data from all safety evaluable infants, regardless of whether they were evaluable for PK analysis. The study initially opened accrual to Cohort 1 RAL-naive group. The PK and safety data from IMPAACT P1110 Cohort 1 RAL-naive group and from IMPAACT P1097 were used to determine the starting dose for the Cohort 1 RAL-exposed group. Opening accrual to the Cohort 2 RAL-naive group was contingent upon infants enrolled in Cohort 1 RAL-naive and RAL-exposed groups successfully meeting safety criteria and providing adequate PK data to determine a regimen to be tested for daily dosing through 6 weeks of life for the Cohort 2 RAL-naive group. The initial dosing regimen for the Cohort 2 RAL-naive group was determined using population PK modeling and simulations incorporating IMPAACT P1110 Cohort 1 data, along with data from the following IMPAACT studies: P1097, P1066 (NCT00485264) (Cohorts IV and V) and P1026s (NCT00042289). Since the PK results of Cohort 1 RAL-naive and exposed groups were similar except in the first 1-2 days of life and P1097 Cohort 1 results suggested that maternal RAL readily crosses the placenta and results to washout RAL exposure in neonates, Cohort 2 RAL-exposed group was determined to receive the same dose of RAL as Cohort 2 RAL-naive group, except the initial dose for RAL-exposed was delayed to within 12 to 60 hours of life.

Official Title
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A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection

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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Maternal Inclusion Criteria: 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 Maternal Exclusion Criteria: 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).
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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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. | Drug: Raltegravir<br>* RAL was given as oral granules for suspension.<br>* Other names: ISENTRESS;|
| Experimental: Cohort 2<br>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. | Drug: Raltegravir<br>* RAL was given as oral granules for suspension.<br>* Other names: ISENTRESS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infants Who Died or Had Grade 3/4 Adverse Event 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. | From first dosing of RAL through 6 weeks of life | 
| AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) | 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) | 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. | 
| Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) | Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth) | 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. | 
| AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively) | 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). | 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. | 
| Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively) | 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. | 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. | 
| RAL AUC12 for Cohort 2 at 15-18 Days of Life | Area Under the Concentration-time Curve at 12-hour interval (AUC12) of RAL for Cohort 2 at 15-18 days of life. | 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 C12 for Cohort 2 at 15-18 Days of Life | RAL concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 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. | From first RAL dose through 24 weeks of life | 
| Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life | Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL. | From first RAL dose through 6 weeks of life | 
| Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life | Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL. | From first RAL dose through 24 weeks of life | 
| Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group | Cohort 1 Dose #1 neonatal RAL elimination was represented by Clearance (CL/F), which is the volume of plasma cleared of the drug per unit time. 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) . | 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. | 
| Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group | Cohort 2 initial dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time. 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) . | 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. | 
| Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group | Cohort 2 15-18 days of life dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time at 15-18 days of life when RAL dosing would have been 3 mg/kg twice daily. 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) . | 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 Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype | Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin. | 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 Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype | Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin. | 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 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype | Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin. | 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 | Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin. | 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. |