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

NCT01780831 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: P111011891IMPAACT P1110
• Study Type: interventional
• Target: 52
• Locations: 5 countries
• Sites: 15

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (10)

• 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

• 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

• 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

• 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.

• 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.

Study Arms (2)

Cohort 1

EXPERIMENTAL

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

Cohort 2

EXPERIMENTAL

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

Interventions

Raltegravir DRUG

RAL was given as oral granules for suspension.

Also known as: ISENTRESS

Cohort 1; Cohort 2

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

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

Study Sites (15)

Usc La Nichd Crs

Los Angeles, California, 90089, United States

Location

Children's National Med. Ctr. Washington DC NICHD CRS

Washington D.C., District of Columbia, 20010, United States

Location

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, 32209, United States

Location

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Chicago, Illinois, 60612, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, 60614-3393, 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

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105-3678, United States

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

University of Puerto Rico Pediatric HIV/AIDS Research Program CRS

San Juan, PR, 00935, Puerto Rico

Location

Umlazi CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Fam-Cru Crs

Cape Town, 7505, South Africa

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Related Publications (1)

• Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Ceriotto M, Machado D, Bethel J, Morgado MG, Dickover R, Camarca M, Mirochnick M, Siberry G, Grinsztejn B, Moreira RI, Bastos FI, Xu J, Moye J, Mofenson LM; NICHD HPTN 040/PACTG 1043 Protocol Team. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012 Jun 21;366(25):2368-79. doi: 10.1056/NEJMoa1108275.

  PMID: 22716975 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

  Section of Pediatric Infectious Diseases, Boston Medical Center

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2013
• First Posted: January 31, 2013
• Study Start: January 28, 2014
• Primary Completion: December 14, 2017
• Study Completion: April 20, 2018
• Last Updated: November 5, 2021
• Results First Posted: July 17, 2020

Record last verified: 2020-07

Locations

BR (3); ZA (2); TH (1); PR (1); US (8)