Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at Risk of Acquiring HIV-1 Infection
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ClinicalTrials.gov Identifier: NCT01780831 |
Recruitment Status :
Completed
First Posted : January 31, 2013
Results First Posted : July 17, 2020
Last Update Posted : November 5, 2021
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Condition or disease | Intervention/treatment | Phase |
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HIV Infections | Drug: Raltegravir | Phase 1 |

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 |
Actual Study Start Date : | January 28, 2014 |
Actual Primary Completion Date : | December 14, 2017 |
Actual Study Completion Date : | April 20, 2018 |
Arm | Intervention/treatment |
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Experimental: Cohort 1
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:
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Drug: Raltegravir
RAL was given as oral granules for suspension.
Other Name: ISENTRESS |
Experimental: Cohort 2
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
RAL was given as oral granules for suspension.
Other Name: ISENTRESS |
- Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life [ Time Frame: From first dosing of RAL 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.
- AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [ Time Frame: 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. ]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)
- Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [ Time Frame: 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. ]Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth)
- AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively) [ Time Frame: 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. ]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).
- Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively) [ Time Frame: 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. ]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.
- RAL AUC12 for Cohort 2 at 15-18 Days of Life [ Time Frame: 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. ]Area Under the Concentration-time Curve at 12-hour interval (AUC12) of RAL for Cohort 2 at 15-18 days of life.
- RAL C12 for Cohort 2 at 15-18 Days of Life [ Time Frame: 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 concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life.
- Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life [ Time Frame: From first RAL dose through 24 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.
- Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life [ Time Frame: From first RAL dose through 6 weeks of life ]
Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table.
Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL.
- Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life [ Time Frame: From first RAL dose through 24 weeks of life ]
Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table.
Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL.
- Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group [ Time Frame: 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 1 Dose #1 neonatal RAL elimination was represented by Clearance (CL/F), which is the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional) .
- Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group [ Time Frame: 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. ]Cohort 2 initial dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional) .
- Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group [ Time Frame: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2 hours post-dose, 4-6, 8-12 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry. ]Cohort 2 15-18 days of life dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time at 15-18 days of life when RAL dosing would have been 3 mg/kg twice daily. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians(i.e. genotyping was optional) .
- Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype [ Time Frame: Specimens for bilirubin testing were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at entry. ]Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
- Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype [ Time Frame: Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry. ]Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
- Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype [ Time Frame: Specimens for bilirubin test were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at study entry. ]Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
- Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype [ Time Frame: Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry. ]Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.

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Ages Eligible for Study: | Child, Adult, Older Adult |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Maternal Inclusion Criteria:
- 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.
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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
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 will be receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant
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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
Infant Inclusion Criteria:
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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
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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.
- Cohort 2 RAL-exposed: Infants born to a mother who received at least one dose of RAL within 2 to 24 hours prior to delivery.
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).

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01780831
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 | |
Cape Town, South Africa, 7505 | |
Thailand | |
Siriraj Hospital ,Mahidol University NICHD CRS | |
Bangkok, Bangkoknoi, Thailand, 10700 |
Study Chair: | Diana F. Clarke, PharmD | Section of Pediatric Infectious Diseases, Boston Medical Center |
Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Publications:
Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
ClinicalTrials.gov Identifier: | NCT01780831 |
Other Study ID Numbers: |
P1110 11891 ( Registry Identifier: DAIDS ES ) IMPAACT P1110 |
First Posted: | January 31, 2013 Key Record Dates |
Results First Posted: | July 17, 2020 |
Last Update Posted: | November 5, 2021 |
Last Verified: | July 2020 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Infections Communicable Diseases Disease Attributes Pathologic Processes 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 |