Dolutegravir Pharmacokinetics Among HIV/TB Coinfected Children Receiving Standard and High-dose Rifampicin

Tuberculosis Infection Clinical Trial

Official title:

Mind the Gaps: Pharmacokinetic Research to Advance Pediatric HIV/TB Cotreatment and TB Prevention

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05069688
• Other study ID #: 2021P002401
• Status: Recruiting
• Phase: Phase 1
• Start date: July 7, 2023
• Est. completion date: March 31, 2025

Study information

• Verified date: July 2023
• Source: Brigham and Women's Hospital
• Contact: Holly Rawizza, MD, MPH
• Phone: 617-432-4686
• Email: hrawizza[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics of newer HIV/TB cotreatment strategies in children. Current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined in children. This study aims to evaluate the safety and pharmacokinetics of dolutegravir twice daily among HIV/TB coinfected children receiving standard-dose and high-dose rifampicin.

Description:

This study is a prospective, single-arm, open-label, intensive and sparse pharmacokinetic (PK) and safety study to evaluate steady-state dolutegravir (DTG) concentrations among 20 HIV/TB coinfected children 4 weeks to <6 years of age requiring concurrent TB treatment. Ten patients will be recruited into each of two age cohorts: 4 weeks to <2 years and ≥2 years to <6 years.

Children will be recruited from two large pediatric HIV clinics in Nigeria. Children in this study will receive HIV/TB cotreatment that is considered standard of care consisting of DTG twice daily during rifampicin (RIF)-containing TB treatment. For this portion of the study, the primary intervention is additional blood sampling for drug concentration determination and biomarker assessment. Additionally, during a two week period (study weeks 20-21), the RIF dose will be increased from standard-dose to high-dose RIF, during which two-way PK and toxicity monitoring will occur. Clinical and laboratory monitoring for toxicity during HIV/TB cotreatment is consistent with routine care.

PK sampling for drug concentration determination will occur at three time points during the 48-week study. Specifically, PK sampling will occur at week-20 to evaluate DTG twice daily during standard-dose RIF, week-22 to evaluate DTG twice daily during high-dose RIF, and at week-30 to evaluate DTG once daily after TB treatment is complete.

Additionally, the endogenous biomarker of CYP3A4 activity, 4-beta-hydroxycholesterol to cholesterol ratio, will be evaluated to advance understanding of underlying mechanisms of drug action. Blood sampling to quantify this biomarker will occur at either 4 (among ART-experienced children) or 5 (ART-naive) time points during the 48-week study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Weeks to 5 Years

Eligibility

Inclusion Criteria:

• ART-naïve or ART-experienced HIV-infected children between 4 weeks and <6 years of age

• Active TB diagnosis

• Weight of at least 3 kilograms

• Consent of the parent or legal guardian

Exclusion Criteria:

• Baseline labs with evidence of =grade 3 abnormalities: ALT, total bilirubin, absolute neutrophil count (ANC), platelets, or creatinine

• Suspected TB meningitis or presenting with acute respiratory distress or decompensation

• Receipt of a medication that has drug-drug interactions with dolutegravir or rifampicin

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Latent Tuberculosis
• Pediatric HIV Infection
• Tuberculosis
• Tuberculosis Infection

Intervention

Drug:
• rifampicin
Patients will receive standard TB and HIV treatment, however, for two weeks (study weeks 20-21) the dose of rifampicin will be increased from standard-dose to high-dose to assess pharmacokinetics and safety

Locations

Country	Name	City	State
Nigeria	University College Hospital/ University of Ibadan	Ibadan	Oyo State

Sponsors (3)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	APIN Public Health Initiatives, University of Cape Town

Country where clinical trial is conducted

Nigeria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dolutegravir AUC during standard-dose rifampicin	Dolutegravir area under the concentration time curve (AUC) will be compared to therapeutic ranges established in the adult and pediatric literature	week 20
Primary	Dolutegravir AUC during high-dose rifampicin	Dolutegravir AUC will be compared against therapeutic ranges established in the literature and during standard-dose rifampicin	week 22
Secondary	Rifampicin maximum concentration (Cmax) during standard-dose rifampicin	Rifampicin Cmax will be determined during standard rifampicin	week 20
Secondary	Rifampicin Cmax during high-dose rifampicin	Rifampicin Cmax will be determined during high-dose rifampicin and compared to that observed during standard-dose rifampicin	week 22
Secondary	Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events	Laboratory and clinical toxicities are monitored at 8 time points throughout the study and the proportion of children experiencing severe adverse events will be determined	Week 48