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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01780831
First received: January 29, 2013
Last updated: June 30, 2014
Last verified: June 2014
  Purpose

This study will evaluate the safety and pharmacokinetics (PKs) of raltegravir (RAL) given to HIV-1-exposed newborns at high risk of acquiring HIV-1 infection. (Pharmacokinetics are the various interactions between a drug and the body.) This study will also evaluate the appropriate dose of RAL to give to an infant to prevent the infant from getting HIV infection from its mother.


Condition Intervention Phase
HIV Infections
Drug: Raltegravir
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Neonates at High Risk of Acquiring HIV-1 Infection

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Toxicity endpoint: Adverse events (AEs) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  • Toxicity endpoint: death [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  • Toxicity endpoint: Suspected adverse drug reaction (SADR) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  • PK endpoint for Cohort 1: maximum concentration (Cmax) of RAL [ Time Frame: Measured within 48 hours of birth, at Day 3 to 4 of life, and at Day 7 to 10 of life ] [ Designated as safety issue: No ]
  • PK endpoint for Cohort 1: area under the concentration-time curve at the 12-hour dosing internal (AUC12) of RAL [ Time Frame: Measured within 48 hours of birth, at Day 3 to 4 of life, and at Day 7 to 10 of life ] [ Designated as safety issue: No ]
  • PK endpoint for once-daily dosing in Cohort 2: area under the concentration-time curve at the 24-hour dosing internal (AUC24) [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6. ] [ Designated as safety issue: No ]
  • PK endpoint for twice-daily dosing in Cohort 2: AUC12 [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6 ] [ Designated as safety issue: No ]
  • PK endpoint for Cohort 2: geometric mean (GM) trough [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Toxicity endpoint: AEs of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]
  • SADR of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: July 2013
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Cohort 1 will enroll HIV-1-exposed full-term neonates (aged 48 hours or less). Newborns will receive a single dose of RAL within 48 hours of birth in addition to standard of care ARVs for PMTCT, and a second dose of RAL on Day 7 to 10 of life.
Drug: Raltegravir

RAL will be given as 3 mg/kg oral granules for suspension. Dose may be modified after ongoing PK and safety analyses.

RAL-exposed infants enrolled into Cohort 1 will receive an initial dose of 1.5 mg/kg; the second dose will be the same for RAL-exposed and unexposed infants.

Other Name: RAL
Experimental: Cohort 2
Cohort 2 will enroll HIV-1-exposed full-term neonates (aged 48 hours or less). Newborns will receive RAL daily within 48 hours of birth and continued for 6 weeks in addition to standard of care ARVs for PMTCT. After analyses of PK and safety data from Cohort 1 (as well as ongoing analyses), dosing frequency in this cohort may be changed from once to twice daily.
Drug: Raltegravir

RAL will be given as 3 mg/kg oral granules for suspension. Dose may be modified after ongoing PK and safety analyses.

RAL-exposed infants enrolled into Cohort 1 will receive an initial dose of 1.5 mg/kg; the second dose will be the same for RAL-exposed and unexposed infants.

Other Name: RAL

Detailed Description:

Significant progress has been made in the use of antiretroviral (ARV) drugs for the prevention of mother-to-child transmission (PMTCT) of HIV, but new pediatric HIV infections continue. If the diagnosis of HIV infection in a pregnant woman goes unrecognized and ARVs have not been used during pregnancy and labor, ARVs can be used to lower the risk of HIV transmission to the infant. However, it is important to develop new and more effective regimens for post-birth PMTCT.

The integrase inhibitor raltegravir (RAL ) has the potential to play an important role in both the prevention and treatment of HIV in infants at high risk of HIV-1 infection. This study will evaluate the safety and PKs of RAL given to HIV-1-exposed newborns at high risk of acquiring HIV-1 infection. The study also seeks to determine the appropriate dosing regimen of RAL that can be safely given to newborns and infants in the first 6 weeks of life.

The study will enroll 50 mother-infant pairs from the time of delivery through 48 hours of life. Mothers will be followed until discharge from the labor and delivery unit, and infants will be followed for 24 weeks after birth.

Newborns will be assigned non-randomly to 1 of 2 cohorts. A minimum of 12 newborns will be enrolled into Cohort 1. These newborns will receive RAL as oral granules for suspension as a single dose within 48 hours of birth, in addition to standard of care ARV drugs for PMTCT, and a second dose of RAL at 7 to 10 days of life. All newborns in Cohort 1 will undergo a medical history, physical exam, and blood draw at entry and at the Day 3 to 4, Day 7 to 10, Week 2, Week 6, and Week 24 study visits. Cohort 1 newborns will have 3 PK samplings: an intensive PK at the time of the first dose, a random PK at Day 3 to 4, and a limited PK at the time of dose 2.

All data from Cohort 1 will be reviewed and analyzed before any participants are enrolled into Cohort 2. Based on ongoing analyses of PK data and safety information, dosing may be modified.

A minimum of 20 newborns will be enrolled into Cohort 2. These newborns will receive daily RAL starting within 48 hours of birth for 6 weeks, in addition to standard of care ARV for PMTCT. After analyses of PK and safety data from Cohort 1 (as well as ongoing analyses), dosing frequency in this cohort may be changed from once to twice daily, and dosing (amount) may also be changed. All newborns in Cohort 2 will undergo a medical history, physical exam, and blood draw at all study visits. Study visits will occur at entry, Day 3 to 4, Day 14, Day 28, Week 6, Week 8 to 10, and Week 24. Cohort 2 newborns will have four PK samplings: a random PK sample at Day 3 to 4, intensive PK samplings at Day 14 and Day 28, and a random PK sampling at Week 6.

  Eligibility

Ages Eligible for Study:   up to 48 Hours
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Maternal Inclusion Criteria:

  • Mother is either known to be HIV-1 infected prior to labor or identified as HIV-1 infected at the time of labor or in the immediate postpartum period. More information on this criterion can be found in the protocol.
  • Mother 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; mother has known documented multi-class drug resistant virus. Mothers may have received prenatal and/or intrapartum ARVs.
  • 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 receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant
  • Up to 6 mothers only: mother who received RAL prior to and through delivery (Cohort 1 infants only)

Infant Inclusion Criteria:

  • HIV-1 exposed full-term neonates aged 48 hours or less. Infant may have received up to 48 hours of standard of care ARV prophylaxis before enrollment.
  • 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

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01780831

  Show 26 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Diana F. Clarke, PharmD Section of Pediatric Infectious Diseases, Boston Medical Center
  More Information

Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01780831     History of Changes
Other Study ID Numbers: P1110, 11891, IMPAACT P1110
Study First Received: January 29, 2013
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases

ClinicalTrials.gov processed this record on July 10, 2014