Clinical trial NCT05069688: Dolutegravir Pharmacokinetics Among HIV/TB Coinfected Children Receiving Standard and High-dose Rifampicin
Official title: Mind the Gaps: Pharmacokinetic Research to Advance Pediatric HIV/TB Cotreatment and TB Prevention
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Pediatric HIV Infection
Tuberculosis Infection
Keywords: pharmacokinetic
dolutegravir
rifampicin
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: APIN Public Health Initiatives
name: University of Cape Town
First posted: 2021-10-06
Enrollment: 20
Sex: ALL
Minimum age (years): 4
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective single-arm, open-label, pharmacokinetic and safety study
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Dolutegravir AUC during standard-dose rifampicin
timeFrame: week 20
measure: Dolutegravir AUC during high-dose rifampicin
timeFrame: week 22
Secondary outcomes:
measure: Rifampicin maximum concentration (Cmax) during standard-dose rifampicin
timeFrame: week 20
measure: Rifampicin Cmax during high-dose rifampicin
timeFrame: week 22
measure: Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events
timeFrame: Week 48
Other outcomes:
Locations:
city: Ibadan
country: Nigeria
facility: University College Hospital/ University of Ibadan
state: Oyo State
Study officials:
affiliation: Brigham and Women's Hospital
name: Holly Rawizza, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: