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

Study Overview
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Brief Summary
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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.

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

Conditions
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HIV

Intervention / Treatment
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* Drug: Dolutegravir 0.5 mg/kg oral suspension
* Drug: Dolutegravir 5 mg Dispersible Tablets


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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<br>* DTG 0.5 mg/kg liquid suspension administered orally<br>* Other names: DTG;Drug: Dolutegravir 5 mg Dispersible Tablets<br>* DTG 5 mg DT administered orally<br>|
| Experimental: Cohort 2<br>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<br>* DTG 0.5 mg/kg liquid suspension administered orally<br>* Other names: DTG;Drug: Dolutegravir 5 mg Dispersible Tablets<br>* DTG 5 mg DT administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of infants classified as study drug-related safety failures. | 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. | Initial study drug dosing through 2 weeks after off treatment date | 
| Proportion of infants classified as safety failures. | 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 | 
| 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 | 
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of infants classified as study drug-related safety failures. | 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. | Initial study drug dosing through Week 16 | 
| Proportion of infants classified as safety failures. | 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) | Initial study drug dosing through Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiretroviral, Dolutegravir, Newborn, Infant, HIV/AIDS, Perinatal, Pharmacokinetics, Prophylaxis, Prevention, Safety