Pharmacokinetics and Safety of DolutegravIr in Neonate

Study Overview
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Brief Summary
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A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled.

Detailed Description
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A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled. Enrolment will be in two stages: Stage 1 will assess a single 5 mg dose of the DTG-DT in two sequential cohorts: Cohort 1A (n=8) and Cohort 1B (n=8). Stage 2 will assess multiple 5 mg doses of the DTG-DT and DTG-ODF in two parallel cohorts: Cohort 2A (n=20) and Cohort 2B (n=20). Per national guidelines, all infants receive a birth HIV nucleic acid test (NAT). HIV NAT test results for the infant may or may not be available (HIV pending) at the time of study entry. HIV NAT results are typically available within 72 hours of the blood sample being taken and are checked and acted upon by the hospital HIV PMTCT service, as part of standard of care. If an HIV NAT result comes back positive whilst the neonate is on study, the neonate will not receive any further DTG doses, revert to standard of care antiretroviral therapy (ART), and be followed for safety for the duration of the study. Primary Objectives: To evaluate the pharmacokinetics of dolutegravir (DTG) during the first 28 days of life in HIV-exposed term neonates (born to a mother with HIV) following administration of DTG dispersible tablet (DTG-DT) and DTG oral dispersible film (DTG-ODF) To determine the safety of DTG during the first 28 days of life in HIV-exposed term neonates following administration of DTG-DT and DTG-ODF Secondary Objectives: • To quantitatively and qualitatively assess the acceptability of DTG-DT and DTG-ODF for the neonate, the caregiver and health workers Primary endpoints: DTG plasma pharmacokinetics parameters: area under the concentration time curve (AUC); maximum plasma concentration (Cmax), apparent clearance (CL/F), and trough concentration (Ctrough) Occurrence of the following events: adverse events of Grade 3 or higher; treatment-related adverse events of Grade 3 or higher; any adverse events Secondary endpoints: • Acceptability to caregivers and neonates of using DTG-DT will be measured by means of a questionnaire

Official Title
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Open Label, Single Arm, Two-stage Trial to Evaluate the Single and Multi-dose Pharmacokinetics and Safety of the Paediatric Dolutegravir (10 mg, Scored) Dispersible Tablet in HIV-exposed Neonates

Conditions
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Hiv

Intervention / Treatment
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* Drug: Dolutegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage 1: Inclusion Criteria HIV-exposed neonate (pending HIV status) born to a woman within HIV on DTG-based ART Birth weight of ≥2000 g and on standard of care ARV prophylaxis Cohort Specific Inclusion Criteria in Stage 1 must be met at Study Entry: Cohort 1A: Infant <14 days of life Cohort 1B: Infant ≤3 days of life Stage 2: Inclusion Criteria Low risk* HIV-exposed neonate (pending HIV status) born to a virologically suppressed woman on DTG-based ART *Neonate born to a woman with a documented plasma HIV-1 RNA result <50 copies/mL in the 4 weeks prior to delivery or between delivery and infant study entry Birth weight of ≥2000 g and on standard of care ARV prophylaxis Cohort Specific Inclusion Criteria in Stage 2 must be met at Study Entry: Cohort 2: Infant <7 days of life Exclusion Criteria: • Less than 37 weeks gestational age at birth Known blood group incompatibilities which can result in hemolytic disease of the newborn (e.g., Rh-negative mother, presence of antibodies on neonatal red blood cells, etc.) Total bilirubin values approaching an exchange transfusion as defined by local guidelines (Section 18.2) Haemoglobin value of <13.0 g/dL Platelet count of less than 50,000 cells/mm3) Decreased total white blood cell count (Grade 3 and above) Creatinine value more than 1.3 the upper limit of normal (ULN) for gestational age and postnatal age (Grade 2 and above) AST or ALT of more than 2.5 the ULN (Grade 2 and above) Any other current Grade ≥3 event on the DAIDS toxicity table Severe congenital abnormalities or critically ill neonates at discretion of the examining clinician Receiving medicine(s) that can impact DTG pharmacokinetics (Section 8.7) Participation in another clinical trial HIV-infected neonates

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 14 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I/II, open-label, single arm, two-stage pharmacokinetic and safety study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm, two-stage<br>Participants will be enrolled in two stages: Stage 1 will assess a single dose of the DTG-DT in two sequential cohorts: Cohort 1A (n=8) and Cohort 1B (n=8). Stage 2 will assess multiple-doses of the DTG-DT and the DTG-ODF in a single cohort: Cohort 2A (n=20) DTG-DT and Cohort 2B (n=20) DTG-ODF | Drug: Dolutegravir<br>* Single dose of the DTG-DT in two sequential cohorts and multiple-doses of the DTG-DT or DTG-ODF in a two cohorts. Qualitative Acceptability will be collected from mothers and health workers in structured discussion guides.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In Cohort 1, PK analysis will be performed to calculate the following parameter: Cmax | Cmax will be taken directly from the observed concentration-time data. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: Clast, | Clast will be taken directly from the observed concentration-time data. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: Tmax | Tmax will be taken directly from the observed concentration-time data. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: C24 | C24 will be taken directly from the observed concentration-time data. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: AUC0-24 | AUC0-all will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: AUC0-infinity | AUC0-infinity will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together. | first 28 days of life | 
| In Cohort 1, PK analysis will be performed to calculate the following parameter: Ratio AUC0-24 / AUC0-infinity | Ratio AUC0-24 / AUC0-infinity will be determined using the linear-up log-down trapezoidal method. Total body clearance for extravascular administration will be calculated using Dose/ AUC0-infinity. Median (range), means (standard deviations), and geometric means with 95%CI for each PK parameter will be calculated separately for Cohorts 1A and 1B, as well as for Cohort 1A/1B together.concentration-time data. | first 28 days of life | 
| Reporting adverse events of Grade 3 or higher; treatment-related adverse events of Grade 3 or higher; any adverse events neonates following administration of DTG dispersible tablet | Using the DAIDS toxicity table and protocol specific safety criteria | first 28 days of life | 
| In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: Cmax | Population means and variances of Cmax for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. | first 28 days of life | 
| In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: AUC0-tau | Population means and variances of AUC0-tau for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. Changes in DTG drug exposures in neonates following multi-doses of DTG-DT and DTG-ODF during the first 28 days of life will be estimated using the final model. | first 28 days of life | 
| In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: CTau | Population means and variances of CTau for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. Changes in DTG trough concentrations in neonates following multi-doses of DTG-DT and DTG-ODF during the first 28 days of life will be estimated using the final model. | first 28 days of life | 
| In Cohorts 2A and 2B, both non-compartmental and population PK analyses will be performed using the following parameter: Tmax | Population means and variances of Tmax for DTG will be estimated using nonlinear mixed-effects regression models. Subject covariates will be assessed to explain sources of inter-subject PK variability. | first 28 days of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability to caregivers and neonates of using DTG-DT will be measured by means of a questionnaire | key characteristics: Palatability, Swallowability, the device used to administer the dose, The complexity for the caregiver to prepare the dose correctly, Required dose, Need for a vehicle, Dosing frequency and duration of treatment, Selected administration devices, Primary container closure system, Actual mode of administration that reflects understanding of user instructions and feasibility of following them, Acceptability will be recorded by focusing on: Attitude of the child when presented with the formulation: facial expression, crying or smiling, reaction to drug intake, fighting drug intake, spitting out the suspension, Swallowability, i.e., ability to take the full dose, The way the caregiver prepares the dose | first 28 days of life | 
| Qualitative acceptability data from mothers and health workers | Data will be collected using a semi-structured discussion guide | first 28 days of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV exposed, Neonates