Pharmacokinetics and Safety of DolutegravIr in Neonate

NCT05590325 | Unknown Phase 1

• 1 other identifier: 2019-36-SUN-MDR
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hiv

Keywords

HIV exposed; Neonates

Outcome Measures

Primary Outcomes (12)

• 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 Outcomes (2)

• Acceptability to caregivers and neonates of using DTG-DT will be measured by means of a questionnaire

  first 28 days of life

• Qualitative acceptability data from mothers and health workers

  first 28 days of life

Study Arms (1)

single arm, two-stage

EXPERIMENTAL

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

Interventions

Dolutegravir DRUG

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.

single arm, two-stage

Eligibility Criteria

• Age: 1 Day - 14 Days
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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 1A: Infant \<14 days of life Cohort 1B: Infant ≤3 days of life
• 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 2: Infant \<7 days of life

You may not qualify if:

• 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

Sponsors & Collaborators

• Desmond Tutu TB Centre: lead
• Chiang Mai University: collaborator
• UNITAID: collaborator
• University of Stellenbosch: collaborator

Study Sites (1)

Tygerberg Hospital

Cape Town, Western Cape, 7505, South Africa

RECRUITING

Related Publications (2)

• Bekker A, Salvadori N, Rabie H, du Toit S, Than-In-At K, Groenewald M, Barnabas S, Ganger L, Luangcharoenkul T, Pingkarawat S, Capparelli EV, Owen A, Cressey R, Fry S, Le Roux G, Tawon Y, Kaewmalee J, Phitak T, Lallemant M, Cotton MF, Cressey TR. Safety and pharmacokinetics of dolutegravir dispersible tablets and oral films in term neonates exposed to HIV in South Africa (PETITE-DTG study): an open-label, randomised, phase 1/2 trial. Lancet HIV. 2025 Nov;12(11):e753-e762. doi: 10.1016/S2352-3018(25)00239-5. Epub 2025 Oct 8.

  PMID: 41075812 DERIVED

• Cressey TR, Salvadori N, Rabie H, du Toit S, Than-In-At K, Groenewald M, Capparelli E, Owen A, Cressey R, Lallemant M, Cotton MF, Bekker A. Single Doses of Pediatric Dolutegravir Dispersible Tablets in Neonates Support Multidosing: PETITE-Dolutegravir Study. J Acquir Immune Defic Syndr. 2025 Jun 1;99(2):195-201. doi: 10.1097/QAI.0000000000003652.

  PMID: 39972540 DERIVED

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

Study Officials

• Adrie Bekker, Prof

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adrie Bekker, Prof

CONTACT

+27 (0)219389198; adrie@sun.ac.za

Tina Sachs, MSc

CONTACT

+27 (0)620474701; tsachs@sun.ca.za

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I/II, open-label, single arm, two-stage pharmacokinetic and safety study

Study Record Dates

• First Submitted: September 6, 2022
• First Posted: October 21, 2022
• Study Start: September 12, 2022
• Primary Completion: June 30, 2024
• Study Completion: December 31, 2024
• Last Updated: December 18, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)