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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05406583

Collaborator

ViiV Healthcare (Industry), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Institute of Mental Health (NIMH) (NIH)

Enrollment

Locations

Arms

Anticipated Duration (Months)

2.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will test an anti-HIV drug (ARV) for newborn babies. The study will include a minimum of 36 and up to 108 mothers living with HIV and their newborn babies from Brazil, South Africa, Thailand, and the United States. Infants will be in the study for approximately 16 weeks (four months) after they are born. Mothers will not receive study drug and will exit the study after the Entry visit.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Dolutegravir 0.5 mg/kg oral suspension Drug: Dolutegravir 5 mg Dispersible Tablets	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Feb 28, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Cohort 1 will be opened first to accrual, with Strata 1A and 1B being opened concurrently, to evaluate the PK and safety of two single DTG liquid suspension doses for the relevant stratum. Stratum 1C will only be opened to accrual if PK and safety data from Strata 1A and 1B infants support administration of DTG 5 mg DT across all neonates, or only in neonates with a minimum birth weight. Stratum 1A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) Stratum 1B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery) Stratum 1C (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery).	Drug: Dolutegravir 0.5 mg/kg oral suspension DTG 0.5 mg/kg liquid suspension administered orally Other Names: DTG Drug: Dolutegravir 5 mg Dispersible Tablets DTG 5 mg DT administered orally
Experimental: Cohort 2 Cohort 2, Strata 2A and 2B, will be opened to accrual when the DTG dose and formulation to be administered for each stratum are established based on the PK and safety data from all Cohort 1 strata (Strata 1A and 1B, and 1C if applicable) and available data from other studies. Stratum 2A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) Stratum 2B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery)	Drug: Dolutegravir 0.5 mg/kg oral suspension DTG 0.5 mg/kg liquid suspension administered orally Other Names: DTG Drug: Dolutegravir 5 mg Dispersible Tablets DTG 5 mg DT administered orally

Arm

Intervention/Treatment

Experimental: Cohort 1

Cohort 1 will be opened first to accrual, with Strata 1A and 1B being opened concurrently, to evaluate the PK and safety of two single DTG liquid suspension doses for the relevant stratum. Stratum 1C will only be opened to accrual if PK and safety data from Strata 1A and 1B infants support administration of DTG 5 mg DT across all neonates, or only in neonates with a minimum birth weight. Stratum 1A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) Stratum 1B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery) Stratum 1C (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery).

Drug: Dolutegravir 0.5 mg/kg oral suspension

DTG 0.5 mg/kg liquid suspension administered orally

Other Names:

DTG

Drug: Dolutegravir 5 mg Dispersible Tablets

DTG 5 mg DT administered orally

Experimental: Cohort 2

Cohort 2, Strata 2A and 2B, will be opened to accrual when the DTG dose and formulation to be administered for each stratum are established based on the PK and safety data from all Cohort 1 strata (Strata 1A and 1B, and 1C if applicable) and available data from other studies. Stratum 2A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) Stratum 2B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery)

Drug: Dolutegravir 0.5 mg/kg oral suspension

DTG 0.5 mg/kg liquid suspension administered orally

Other Names:

DTG

Drug: Dolutegravir 5 mg Dispersible Tablets

DTG 5 mg DT administered orally

Outcome Measures

Primary Outcome Measures

Proportion of infants classified as "study drug-related" safety failures. [Initial study drug dosing through 2 weeks after off treatment date]
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 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.
Proportion of infants classified as safety failures. [Initial study drug dosing through 2 weeks after off treatment date]
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)
Proportion of infants who are not able to tolerate the study drug. [Initial study drug dosing through study drug discontinuation]
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.
C(last) for DTG [28 months]
Area under the curve (AUC) for DTG [28 months]
C(trough) for DTG [28 months]
AUC(0-tau) for DTG [28 months]

Secondary Outcome Measures

Proportion of infants classified as "study drug-related" safety failures. [Initial study drug dosing through Week 16]
An infant is classified as a "study drug-related" safety failure for the secondary study safety objective if any of the following occurred after the initial study drug dosing through Week 16: Grade 3 or 4 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.
Proportion of infants classified as safety failures. [Initial study drug dosing through Week 16]
An infant is classified as a safety failure for the secondary study safety objective if any of the following occurred after the initial study drug dosing through Week 16: Grade 3 or 4 AE, or Death (Grade 5 AE)

Other Outcome Measures

Association of UGT1A1 gene sequence variants with DTG CL/F [28 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 and 1B, and Cohort 2, Strata 2A and 2B: At least 2 kg
For Cohort 1, Stratum 1C:

At least 2 kg
At least 3 kg
At screening, infant has the following laboratory test results

ALT (normal)
AST (normal or Grade 1)
Total bilirubin (normal or Grade 1)
Hemoglobin (normal, Grade 1, or Grade 2)
White blood cells (normal, Grade 1, or Grade 2)
Platelets (normal, Grade 1, or Grade 2)
Creatinine (normal, Grade 1, or Grade 2)

At entry, infant is less than or equal to five days of life.
At entry, infant has initiated standard of care ARV prophylaxis (i.e., received at least one dose of ARV regimen prior to entry).
At entry, infant is generally healthy as determined by the site investigator based on review of all available medical history information and physical examination findings.

Exclusion Criteria:

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 medication.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California NICHD CRS	Los Angeles	California	United States	90033-1075
2	David Geffen School of Medicine at UCLA NICHD CRS	Los Angeles	California	United States	90095-1752
3	University of Colorado Denver NICHD CRS	Aurora	Colorado	United States	80045
4	Emory University School of Medicine NICHD CRS	Atlanta	Georgia	United States	30322
5	Rush University, Cook County Hospital NICHD CRS	Chicago	Illinois	United States	60612
6	Bronx-Lebanon Hospital Center NICHD CRS	Bronx	New York	United States	10457
7	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105-3678
8	Baylor College of Medicine/ Texas Children's Hospital NICHD CRS	Houston	Texas	United States	77030
9	University of Sao Paulo Brazil NICHD CRS	Ribeirão Preto	São Paulo	Brazil	14048-900
10	University of Puerto Rico Pediatric HIV/AIDS Research CRS	San Juan		Puerto Rico	00935
11	Soweto	Johannesburg	Gauteng	South Africa	1864
12	Wits RHI Shandukani Research Centre	Johannesburg	Gauteng	South Africa	2001
13	Umlazi	Durban	Kwa Zulu Natal	South Africa	4013
14	FAMCRU	Cape Town		South Africa	7500
15	Siriraj Hospital, Mahidol University NICHD CRS	Bangkok		Thailand	10700
16	Chiang Mai University HIV Treatment	Chiang Mai		Thailand	50200
17	Chiangrai Prachanukroh Hospital NICHD CRS	Chiang Rai		Thailand	57000

Sponsors and Collaborators

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