Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants

NCT01828073 | Completed Results

• 3 other identifiers: P109711790IMPAACT P1097
• Study Type: observational
• Target: 40
• Locations: 5 countries
• Sites: 19

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).

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (1)

• 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.

Study Arms (2)

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.

Drug: Raltegravir

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.

Drug: Raltegravir

Interventions

Raltegravir DRUG

No study-specific drugs were given to women or infants during this study. Women received RAL for clinical indications outside of the study.

Also known as: RAL

Cohort 1: Full term infants exposed in utero to maternal RAL; Cohort 2: LBW infants exposed in utero to maternal RAL

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may not qualify if:

• 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.
• \- Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to enrollment
• 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.
• \- 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (19)

University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program

La Jolla, California, 92093-0672, United States

Location

Miller Children's Hosp. Long Beach CA NICHD CRS

Long Beach, California, 90806, United States

Location

Usc La Nichd Crs

Los Angeles, California, 90089, United States

Location

David Geffen School of Medicine at UCLA NICHD CRS

Los Angeles, California, 90095-1752, United States

Location

Univ. of California San Francisco NICHD CRS

San Francisco, California, 94143, United States

Location

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, 32209, United States

Location

Johns Hopkins Univ. Baltimore NICHD CRS

Baltimore, Maryland, 21287, United States

Location

Boston Medical Center Ped. HIV Program NICHD CRS

Boston, Massachusetts, 02118, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

Jacobi Med. Ctr. Bronx NICHD CRS

The Bronx, New York, 10461, United States

Location

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105-3678, United States

Location

Seattle Children's Research Institute CRS

Seattle, Washington, 98101, United States

Location

Hospital Nossa Senhora da Conceicao NICHD CRS

Porto Alegre, Rio Grande do Sul, 91350-200, Brazil

Location

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, 20221-903, Brazil

Location

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, 26030, Brazil

Location

Univ. of Sao Paulo Brazil NICHD CRS

São Paulo, 14049-900, Brazil

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, Tanzania

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, 50100, Thailand

Location

Related Publications (2)

• 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.

  PMID: 17713476 BACKGROUND

• 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.

  PMID: 19279563 BACKGROUND

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, dated December 2004, Clarification August 2009

MeSH Terms

Conditions

HIV Infections

Interventions

Raltegravir Potassium

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Diana F. Clarke, PharmD

  Boston Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2013
• First Posted: April 10, 2013
• Study Start: May 19, 2011
• Primary Completion: April 23, 2018
• Study Completion: April 23, 2018
• Last Updated: November 8, 2021
• Results First Posted: May 15, 2019

Record last verified: 2020-02

Locations

BR (4); US (12); ZA (1); TA (1); TH (1)