Pharmacokinetics and Safety of DolutegravIr in Neonate (PETITE-DTG)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hiv
• Intervention / Treatment: Drug: Dolutegravir

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Adrie Bekker, Prof; Phone Number: +27 (0)219389198; Email: adrie@sun.ac.za
• Study Contact Backup: Name: Tina Sachs, MSc; Phone Number: +27 (0)620474701; Email: tsachs@sun.ca.za

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7505
      • Recruiting
      • Tygerberg Hospital
      • Contact: Adrie Beker, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 2 weeks (Child)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: single arm, two-stage; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Desmond Tutu TB Centre
• Collaborators: University of Stellenbosch; UNITAID; Chiang Mai University
• Investigators: Principal Investigator: Adrie Bekker, Prof, University of Stellenbosch

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: September 6, 2022
• First Submitted That Met QC Criteria: October 18, 2022
• First Posted (Actual): October 21, 2022

Study Record Updates

• Last Update Posted (Estimated): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Neonates; HIV exposed
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: 2019-36-SUN-MDR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No