Clinical trial NCT01828073: Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants
Official title: Raltegravir Pharmacokinetics and Safety in Neonates
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2013-04-10
Enrollment: 40
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants were enrolled in two cohorts.

Cohort 1 enrolled Mother-Infant (M-I) pairs prior to delivery. Infants expected to be full term (i.e. ≥2000 grams at birth) 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, and their mothers, were enrolled to Cohort 1.

Cohort 2 enrolled M-I pairs prior to delivery or within 48 hours after delivery. Infants expected to be LBW (i.e. ≤2500 grams at birth) 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, and their mothers, were enrolled to Cohort 2.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: PK Parameter: Neonatal RAL Elimination Half-life (T1/2)
timeFrame: 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.
measure: Ratio of Cord Blood to Maternal Blood RAL Concentrations
timeFrame: Maternal blood samples were scheduled to be collected within 1 hour after delivery and cord blood sample were collected immediately after cord was clamped
measure: Number of Infants Who Met Composite Safety Endpoint (Grade 3/4 Adverse Event, Adverse Birth Outcome, Death)
timeFrame: Assessed at entry through Week 20 for Cohort 1 infants and through Week 6 for Cohort 2 infants.
measure: Infant Total Bilirubin
timeFrame: 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.
measure: Infant Direct Bilirubin
timeFrame: 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.
measure: Number of Infants Who Received Treatment to Reduce Bilirubin or for Jaundice
timeFrame: Assessed from entry through around week 1 after birth
Secondary outcomes:
measure: Neonatal RAL Elimination (T1/2) by UGT1A1 Genotype Group (Normal VS Mutation)
timeFrame: 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.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: Usc La Nichd Crs
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD CRS
state: California
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS
state: Washington
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao NICHD CRS
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC)
city: Chiang Mai
country: Thailand
facility: Chiangrai Prachanukroh Hospital NICHD CRS
Study officials:
affiliation: Boston Medical Center
name: Diana F. Clarke, PharmD
role: STUDY_CHAIR
References:
citation: Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA, Gottesdiener KM, Wagner JA. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther. 2008 Feb;83(2):293-9. doi: 10.1038/sj.clpt.6100281. Epub 2007 Aug 22.
citation: Wenning LA, Petry AS, Kost JT, Jin B, Breidinger SA, DeLepeleire I, Carlini EJ, Young S, Rushmore T, Wagner F, Lunde NM, Bieberdorf F, Greenberg H, Stone JA, Wagner JA, Iwamoto M. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin Pharmacol Ther. 2009 Jun;85(6):623-7. doi: 10.1038/clpt.2009.12. Epub 2009 Mar 11.