Clinical trial NCT06281834: Dolutegravir Pharmacokinetics During Weekly Rifapentine/Isoniazid for TB Prevention
Official title: Dolutegravir Pharmacokinetics During Weekly Rifapentine/Isoniazid for TB Prevention
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Pediatric HIV Infection
Latent Tuberculosis
Keywords: Pediatric HIV
rifapentine
TB prevention
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: APIN Public Health Initiatives
name: University of Cape Town
First posted: 2024-02-28
Enrollment: 25
Sex: ALL
Minimum age (years): 4
Maximum age (years): 11
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 living with HIV, yet insufficient data are available on the pharmacokinetics of newer TB prevention strategies in children. Short-course TB prevention/latent TB infection (LTBI) treatment regimens increase completion rates but have not been adequately studied among children living with HIV. Our prospective, open-label PK study will examine and extend use of weekly rifapentine and isoniazid (3HP) among children receiving dolutegravir. This will address gaps in knowledge by examining two-way PK of short-course LTBI treatment in a vulnerable pediatric population.

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) and rifapentine (RPT) concentrations among 25 ART-naïve or experienced children living with HIV who screen negative for TB in two age categories. Study design differs by age cohort since RPT dosing is well-established for children ≥2 years of age but not for children \<2 years. Children 2-11 years receive standard weekly rifapentine/isoniazid (3HP) dosing for a 12-week course, a World Health Organization (WHO)-recommended LTBI treatment option. For young children \<2 years of age, intensive PK will be evaluated after a single-dose of extrapolated weekly rifapentine/isoniazid (RPT/INH), followed by standard WHO-recommended LTBI prophylaxis (isoniazid daily).

Children will be recruited from two large pediatric HIV clinics in Nigeria. Children 2-11 years will receive HIV treatment that is considered standard of care consisting of weight-based DTG once daily along with two non-nucleoside reverse transcriptase inhibitors (NRTIs), plus 3HP at standard doses for LTBI treatment. Children \<2 years of age also receive standard DTG-based ART as well as standard isoniazid (INH) prophylaxis for LTBI, however, they will additionally receive a single dose of weekly RPT/INH for study purposes. The primary study intervention is, therefore, additional blood sampling for drug concentration determination (both DTG and RPT) and biomarker assessment. Clinical and laboratory monitoring for toxicity occur throughout the 48 week study period.

PK sampling for drug concentration determination will occur at three time points during the 48-week study. Specifically, intensive PK sampling will occur at study week 6, while sparse PK sampling will occur at weeks 4 and 7. 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:

* (1) ART-naïve or ART-experienced HIV-infected children 4 weeks to \<12 years of age;
* (2) no evidence of active TB based on an appropriate clinical evaluation;
* (3) negative TB diagnostic test if performed (other than tuberculin skin testing);
* (4) weight of at least 4 kilograms; and
* (5) consent of the parent or legal guardian and assent of the child (if ≥7 years of age).

Exclusion Criteria:

* (1) Baseline labs with evidence of ≥grade 3 abnormalities: alanine aminotransferase (ALT), total bilirubin, absolute neutrophil count (ANC), platelets, creatinine;
* (2) presenting with acute respiratory distress or decompensation, or any clinical syndrome which could suggest undiagnosed TB or other opportunistic infection; or
* (3) receipt of a medication that has drug-drug interactions with DTG or RPT.

Primary outcomes:
measure: Dolutegravir AUC during weekly rifapentine/isoniazid
timeFrame: Weeks 4 and 6
Secondary outcomes:
measure: Rifapentine AUC
timeFrame: weeks 6 and 7
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
state: Oyo
Study officials:
affiliation: Brigham and Women's Hospital
name: Holly Rawizza, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: