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

• ClinicalTrials.gov Identifier: NCT01780831
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2013
• Last Update Posted: January 9, 2019
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

This study will evaluate the safety and pharmacokinetics (PKs) of raltegravir (RAL) given to HIV-1-exposed newborn infants at 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 or disease	Intervention/treatment	Phase
HIV Infections	Drug: Raltegravir	Phase 1

Detailed Description:

This study will evaluate the safety and PKs of RAL given to HIV-1-exposed newborn infants at risk of acquiring HIV-1 infection. The study also seeks to determine the appropriate dosing regimen of RAL that can be safely given to infants in the first 6 weeks of life.

The study will enroll 50 mother-infant pairs. Mothers will be followed until discharge from the labor and delivery unit, and infants will be followed for 24 weeks after birth. Infants will be assigned non-randomly to 1 of 2 cohorts. Each cohort will include two groups of infants: a RAL-naïve group including infants born to mothers who did not receive RAL before delivery, and a RAL-exposed group including infants born to mothers who received at least one dose of RAL within 2 to 24 hours before delivery.

A minimum of 12 infants will be enrolled into Cohort 1. All infants in Cohort 1 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.

A minimum of 20 infants will be enrolled into Cohort 2. Within Cohort 2, RAL will be started within 48 hours of birth in the RAL-naïve infants and between 12 and 60 hours of birth in the RAL-exposed infants. Both the RAL-naïve and the RAL-exposed infants in Cohort 2 will receive RAL for 6 weeks, in addition to standard of care ARV for PMTCT. Dosing will be determined based on analyses of data generated from Cohort 1 and from other studies.

Study visits for infants in Cohorts 1 and 2 will occur at study entry through Week 24 and include a medical history, physical exam, blood draw, and, at select study visits, PK samplings.

Note: As of January 2017, enrollment and follow-up to Cohort 1 (RAL-exposed and RAL-naïve groups) and enrollment to Cohort 2 (RAL-naïve group) are complete.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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 Risk of Acquiring HIV-1 Infection
• Study Start Date: July 2013
• Estimated Primary Completion Date: March 31, 2020
• Estimated Study Completion Date: April 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Cohort 1 will enroll HIV-1-exposed full-term infants (aged 48 hours or less). Infants will receive a single dose of RAL within 48 hours of birth and a second dose of RAL on Day 7 to 10 of life.	Drug: Raltegravir; RAL will be given as oral granules for suspension. Dose may be modified after ongoing PK and safety analyses.; Other Name: RAL
Experimental: Cohort 2; Cohort 2 will enroll HIV-1-exposed full-term infants (aged 60 hours or less). RAL-naïve infants will receive RAL daily starting within 48 hours of birth and RAL-exposed infants will receive RAL daily starting between 12 and 60 hours of birth. Both the RAL-naïve and RAL-exposed infants will receive RAL for 6 weeks.	Drug: Raltegravir; RAL will be given as oral granules for suspension. Dose may be modified after ongoing PK and safety analyses.; Other Name: RAL

Outcome Measures

Primary Outcome Measures :

1. Toxicity endpoint: Adverse events (AEs) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ]
2. Toxicity endpoint: death [ Time Frame: Measured from study entry through 6 weeks of life ]
3. Toxicity endpoint: Suspected adverse drug reaction (SADR) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ]
4. 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 ]
5. 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 ]
6. 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. ]
7. 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 ]
8. 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 ]

Secondary Outcome Measures :

1. Toxicity endpoint: AEs of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ]
2. SADR of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ]
3. Death [ Time Frame: Measured from study entry through 24 weeks of age ]

Eligibility Criteria

• Ages Eligible for Study: up to 60 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Maternal Inclusion Criteria:

• Mother is either i) known to be HIV-1 infected 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 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.
• For Cohort 1 and Cohort 2 (RAL-naive): 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 documented drug resistant virus to at least one class of ARV drugs. Note: Mothers may have received prenatal and/or intrapartum ARVs. Note: For Cohort 2 RAL-exposed, there is no requirement that the mother be determined '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 receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant
• For Cohort 1 (up to 6 mothers only) and Cohort 2 RAL-naïve: Mother who received RAL prior to and through delivery

Infant Inclusion Criteria:

• For Cohort 1 and Cohort 2 (RAL-naive): Full-term infants exposed to HIV aged 48 hours or less. Infant may have received up to 48 hours of standard of care ARV prophylaxis before enrollment. For Cohort 2 (RAL-exposed): Full-term infants exposed to HIV aged 60 hours or less. Infant may have received standard of care ARV prophylaxis/treatment 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
• For Cohort 2 RAL-exposed Group: Infants born to a mother who received at least one dose of RAL within 2 to 24 hours of delivery. Note: Based on mother's self-report and confirmed by medical records if available. Note: For Cohort 1 RAL-exposed Group infants were born to mothers receiving RAL as part of their ARV regimen.

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
• For Cohort 2 RAL naïve, and Cohort 1 (RAL-naive and RAL-exposed): Receipt of disallowed medications (phenytoin, phenobarbital, or rifampin)

Contacts and Locations

Locations

United States, California

Usc La Nichd Crs

Los Angeles, California, United States, 90089

United States, District of Columbia

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

Washington, District of Columbia, United States, 20010

United States, Florida

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, United States, 32209

United States, Illinois

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Chicago, Illinois, United States, 60612

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, United States, 60614-3393

United States, Massachusetts

Boston Medical Center Ped. HIV Program NICHD CRS

Boston, Massachusetts, United States, 02118

United States, New York

Bronx-Lebanon Hospital Center NICHD CRS

Bronx, New York, United States, 10457

United States, Tennessee

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, United States, 38105-3678

Brazil

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, Brazil, 20221-903

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, Brazil, 26030

Univ. of Sao Paulo Brazil NICHD CRS

Sao Paulo, Brazil, 14049-900

Puerto Rico

University of Puerto Rico Pediatric HIV/AIDS Research Program CRS

San Juan, Puerto Rico, 00935

South Africa

Umlazi CRS

Durban, KwaZulu-Natal, South Africa, 4001

Fam-Cru Crs

Tygerberg, Western Cape Province, South Africa, 7505

Thailand

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, Thailand, 10700

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Diana F. Clarke, PharmD; Section of Pediatric Infectious Diseases, Boston Medical Center

More Information

Publications:

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01780831 History of Changes
• Other Study ID Numbers: P1110; 11891 ( Registry Identifier: DAIDS ES registry number ); IMPAACT P1110
• First Posted: January 31, 2013
• Last Update Posted: January 9, 2019
• Last Verified: January 2019

Additional relevant MeSH terms:

Infection; Communicable Diseases; Raltegravir Potassium; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action