A Study of the Safety, Tolerability, and Pharmacokinetics of Dolutegravir in Neonates Exposed to HIV-1

NCT05406583 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: IMPAACT 202338637
• Study Type: interventional
• Target: 96
• Locations: 3 countries
• Sites: 15

Brief Summary

The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of dolutegravir (DTG) in infants born to mothers living with HIV-1. The primary goal of the study was to propose a dose of DTG that is safe and meets PK targets when administered to infants through the first four weeks of life in addition to the infant's standard HIV-1 ARV prophylaxis. The study was expected to enroll a minimum of 36 and up to 108 mother-infant (M-I) pairs from Brazil, South Africa, Thailand, and the United States. Infants were followed through 16 weeks of life. Mothers did not receive study drug and were off study after completion of the Entry visit. A total of 48 M-I pairs were enrolled in the study.

Conditions

HIV

Keywords

Antiretroviral; Dolutegravir; Newborn; Infant; HIV/AIDS; Perinatal; Pharmacokinetics; Prophylaxis; Prevention; Safety

Outcome Measures

Primary Outcomes (10)

• Proportion of Infants Classified as Study Drug-related Safety Failures Through 2 Weeks After DTG-Discontinuation.

  An infant is classified as a "study drug-related" safety failure for the primary safety study objective if any of the following occurred after the initial study drug dosing through two weeks after permanent discontinuation of the study drug (i.e., two weeks after off treatment date): * Grade 3 or 4 Adverse Event (AE) assessed as related to study drug, or * Death (Grade 5 AE) assessed as related to the study drug, or * Life-threatening AE assessed as related to study drug, or * AE assessed as related to study drug that leads to premature permanent discontinuation of the study drug.

  Initial study drug dosing through 2 weeks after off treatment date (after treatment discontinuation), up to 5 weeks for Cohort 1 and up to 8 weeks for Cohort 2

• Proportion of Infants Classified as Safety Failures Through 2 Weeks After DTG-Discontinuation.

  An infant is classified as a safety failure for the primary safety study objective if any of the following occurred after the initial study drug dosing through two weeks after permanent discontinuation of the study drug (i.e., two weeks after off treatment date): * Grade 3 or 4 AE, or * Death (Grade 5 AE)

  Initial study drug dosing through 2 weeks after off treatment date (after treatment discontinuation), up to 5 weeks for Cohort 1 and up to 8 weeks for Cohort 2

• Proportion of Infants Who Are Not Able to Tolerate the Study Drug.

  An infant is considered not able to tolerate the study drug if the infant experiences problems taking the study drug or experiences any AE assessed as related to study drug that leads to premature permanent discontinuation of the study drug.

  Initial study drug dosing through study drug discontinuation, up to 3 weeks for Cohort 1 and up to 8 weeks for Cohort 2

• DTG Ctrough for Cohort 1

  Cohort 1 Trough concentration (Ctrough) based on intensive PK sampling for DTG. Ctrough is defined as the concentration at the last measurable time point or at the end of dosing interval.

  Entry visit intensive PK sampling (0-5 days of life): pre-dose, and 1-2, 4-8, 11-13, 22-26 and 48-72 hours post-dose; 7 Days (+3 days) Post Initial Dose intensive PK sampling: pre-dose, and 1-2, 22-26 hours post-dose

• DTG AUC0-48 for Cohort 1 at Entry Visit

  Cohort 1 area under the concentration-time curve at 48-hour interval (AUC0-48) based on intensive PK sampling for DTG at Entry visit.

  Entry visit intensive PK sampling (0-5 days of life): pre-dose, and 1-2, 4-8, 11-13, 22-26 and 48-72 hours post-dose

• DTG AUC0-24 for Cohort 1 at 7 Days (+3 Days) Post Initial Dose Visit

  Cohort 1 area under the concentration-time curve at 24-hour interval (AUC0-24) based on intensive PK sampling for DTG at 7 Days (+3 days) Post Initial Dose Visit.

  7 days (+3 days) post initial dose intensive PK sampling: pre-dose, and 1-2, 22-26 hours post-dose

• DTG Ctrough for Cohort 2 at 7 Days (+3 Days) Post Initial Dose Visit

  Cohort 2 Trough concentration (Ctrough) based on intensive PK sampling for DTG. For the five participants with PK sampling performed at the last dose of Q48h dosing (first dose of Q24h dosing, and a 48-hour sample was not collected), Ctrough was estimated using the terminal slope of preceding points. Based on the protocol-defined visit windows, the 7 days post initial dose visit may occur between 7 and 15 days of life. At this visit, participants may be receiving either Q48h or Q24h dosing, depending on the timing of their first dose day and the day for the 7 days post initial dose visit.

  7 days (+3 days) post initial dose PK sampling: pre-dose, and 1-2, 6-10, 22-26 hours post-dose, and prior to the next dose (for infants continuing to receive DTG every 48 hours)

• DTG Ctrough for Cohort 2 at Week 4

  Cohort 2 Trough concentration (Ctrough) based on intensive PK sampling for DTG

  Week 4 intensive PK sampling (22-33 days of life): pre-dose, and 1-2, 6-10, 22-26 hours post-dose

• DTG AUC(0-tau) for Cohort 2 at 7 Days (+3 Days) Post Initial Dose Visit

  Cohort 2 area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-tau) based on intensive PK sampling for DTG at 7 Days (+3 days) Post Initial Dose Visit. Based on the protocol-defined visit windows, the 7 days post initial dose visit may occur between 7 and 15 days of life. At this visit, participants may be receiving either Q48h or Q24h dosing, depending on the timing of their first dose day and the day for the 7 days post initial dose visit.

  7 days (+3 days) post initial dose PK sampling: pre-dose, and 1-2, 6-10, 22-26 hours post-dose, and prior to the next dose (for infants continuing to receive DTG every 48 hours)

• DTG AUC(0-tau) for Cohort 2 at Week 4 Visit

  Cohort 2 area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-tau) based on intensive PK sampling for DTG at Week 4 visit

  Week 4 intensive PK sampling (22-33 days of life): pre-dose, and 1-2, 6-10, 22-26 hours post-dose

Secondary Outcomes (2)

• Proportion of Infants Classified as Study Drug-related Safety Failures Through 16 Weeks.

  Initial study drug dosing through Week 16

• Proportion of Infants Classified as Safety Failures Through 16 Weeks.

  Initial study drug dosing through Week 16

Study Arms (10)

Infant Cohort 1 Stratum 1A

EXPERIMENTAL

Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) who received two single doses of DTG 0.5 mg/kg liquid suspensions

Drug: Dolutegravir 0.5 mg/kg liquid suspension (starts at 0-5 days of life)

Infant Cohort 1 Stratum 1B

EXPERIMENTAL

Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery) who received two single doses of DTG 0.5 mg/kg liquid suspensions

Drug: Dolutegravir 0.5 mg/kg liquid suspension (starts at 2-5 days of life)

Infant Cohort 1 Stratum 1C

EXPERIMENTAL

Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) who received two single doses of DTG 5 mg dispersible tablet

Drug: Dolutegravir 5 mg Dispersible Tablets (single doses)

Infant Cohort 2 Stratum 2A

EXPERIMENTAL

Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) who received chronic dosing of DTG 5 mg dispersible tablet

Drug: Dolutegravir 5 mg Dispersible Tablets (chronic dose)

Infant Cohort 2 Stratum 2B

EXPERIMENTAL

Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery) who received chronic dosing of DTG 5 mg dispersible tablet

Drug: Dolutegravir 5 mg Dispersible Tablets (chronic dose)

Maternal Cohort 1 Stratum 1A

NO INTERVENTION

Mothers of infants in Cohort 1 Stratum 1A with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery)

Maternal Cohort 1 Stratum 1B

NO INTERVENTION

Mothers of infants in Cohort 1 Stratum 1B with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery)

Maternal Cohort 1 Stratum 1C

NO INTERVENTION

Mothers of infants in Cohort 1 Stratum 1C with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery)

Maternal Cohort 2 Stratum 2A

NO INTERVENTION

Mothers of infants in Cohort 2 Stratum 2A with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery)

Maternal Cohort 2 Stratum 2B

NO INTERVENTION

Mothers of infants in Cohort 2 Stratum 2B with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery)

Interventions

Dolutegravir 0.5 mg/kg liquid suspension (starts at 0-5 days of life) DRUG

DTG 0.5 mg/kg liquid suspension administered orally once at Entry visit (0-5 days of life) and again at 7 Days Post Initial Dose visit (+3 days). Mothers do not receive any drug

Also known as: DTG

Infant Cohort 1 Stratum 1A

Dolutegravir 5 mg Dispersible Tablets (single doses) DRUG

DTG 5 mg dispersible tablets administered orally once at Entry visit (0-5 days of life) and again at 7 Days Post Initial Dose visit (+3 days) Mothers do not receive any drug

Also known as: DTG

Infant Cohort 1 Stratum 1C

Dolutegravir 5 mg Dispersible Tablets (chronic dose) DRUG

DTG 5 mg dispersible tablets administered orally every 48 hours from the Entry visit (0-5 days of life) through Day 13 (week 2) of life; then every 24 hours from Day 14 of life through the Week 4 or Week 6 visit based on the duration of local standard ARV prophylaxis at each site Mothers do not receive any drug

Also known as: DTG

Infant Cohort 2 Stratum 2A; Infant Cohort 2 Stratum 2B

Dolutegravir 0.5 mg/kg liquid suspension (starts at 2-5 days of life) DRUG

DTG 0.5 mg/kg liquid suspension administered orally once at Entry visit (2-5 days of life) and again at 7 Days Post Initial Dose visit (+3 days).

Also known as: DTG

Infant Cohort 1 Stratum 1B

Eligibility Criteria

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

You may qualify if:

• Mother is of legal age or circumstance to provide independent informed consent and is willing and able to provide written informed consent for her and permission for her infant's participation in this study.
• Mother has confirmed HIV-1 infection based on positive test results from two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 protocol requirements. Test results may be obtained from medical records or from testing performed during the study screening period:
• For results obtained from medical records, adequate source documentation, including the date of specimen collection, date of testing or date of test result, name of test/assay performed, and test result, must be available in study records prior to study entry. Requirements related to laboratory operations (e.g., CLIA, GCLP, or VQA) and related to regulatory authority (e.g., FDA) approvals do not apply to results obtained from medical records.
• If adequate source documentation is not available, Sample #1 and/or Sample #2 should be collected during the study screening period and tested in the site's designated testing laboratory. If both samples are tested using antibody tests, at least one of the samples must be tested in a laboratory that operates according to CLIA or equivalent (for US sites) or GCLP (for non-US sites) guidelines and participates in an appropriate external quality assurance program. If nucleic acid testing is used, at least one test must be performed in the site's CLIA-certified or equivalent (for US sites) or VQA-certified (for non-US sites) laboratory.
• All study-specific samples tested to determine HIV-1 status must be whole blood, serum, or plasma. HIV testing methods and algorithms must be approved for each site by the IMPAACT Laboratory Center (for NIAID-funded sites) or Westat (for NICHD-funded sites). All test methods should be FDA-approved, if available.
• At entry, infant meets DTG exposure requirements, based on mother's report and confirmed by medical records if available, as follows:
• For Cohort 1, Strata 1A and 1C, and Cohort 2, Stratum 2A: Infant born to a mother who did not receive DTG during the two weeks immediately prior to delivery.
• For Cohort 1, Stratum 1B, and Cohort 2, Stratum 2B: Infant born to a mother who received at least one dose of DTG less than or equal to 72 hours prior to delivery.
• Infant was singleton with a gestational age at birth of at least 37 weeks.
• At birth, infant's weight was as follows:
• For Cohort 1, Strata 1A,1B, 1C, and Cohort 2, Strata 2A and 2B: At least 2 kg
• At screening, infant has the following laboratory test results, based on severity grading specified in the protocol section 7.3.3:
• ALT (normal)
• AST (normal or Grade 1)
• Total bilirubin (normal or Grade 1)

You may not qualify if:

• Known maternal-fetal blood group incompatibility as evidenced by the presence of an unexpected clinically significant maternal red blood cell antibody that is known to cause hemolytic disease of the fetus and newborn.
• Infant or breastfeeding mother is receiving any disallowed medicationlisted in protocol Section 5.8.1.
• At entry, infant with a documented positive HIV nucleic acid test result.
• Infants with prior exchange transfusion or with elevated bilirubin that would require exchange transfusion.
• Mother or infant has any condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• ViiV Healthcare: collaborator
• National Institute of Mental Health (NIMH): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (15)

USC - Maternal Child Adolescent/Adult Center

Los Angeles, California, 90033-1075, United States

Location

David Geffen School of Medicine at UCLA NICHD CRS

Los Angeles, California, 90095-1752, United States

Location

University of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

Emory University School of Medicine NICHD CRS

Atlanta, Georgia, 30322, United States

Location

Rush University, Cook County Hospital Chicago NICHD CRS

Chicago, Illinois, 60612, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105-3678, United States

Location

Baylor College of Medicine/ Texas Children's Hospital NICHD CRS

Houston, Texas, 77030, United States

Location

Soweto

Johannesburg, Gauteng, 1864, South Africa

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Umlazi

Durban, KwaZulu-Natal, 4013, South Africa

Location

FAMCRU

Cape Town, 7500, South Africa

Location

Siriraj Hospital, Mahidol University NICHD CRS

Bangkok, 10700, Thailand

Location

Chiang Mai University HIV Treatment

Chiang Mai, 50200, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Rai, 57000, Thailand

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

dolutegravir

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Diana Clarke, Pharm.D.

  Boston Medical Center/ Section of Pediatric Infectious Diseases

  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: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2022
• First Posted: June 6, 2022
• Study Start: October 5, 2022
• Primary Completion: March 12, 2025
• Study Completion: May 22, 2025
• Last Updated: May 22, 2026
• Results First Posted: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network. * For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network. * By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

Locations

ZA (4); US (8); TH (3)