- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06281834
Dolutegravir Pharmacokinetics During Weekly Rifapentine/Isoniazid for TB Prevention
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: Holly Rawizza, MD, MPH
- Phone Number: 617-432-4686
- Email: hrawizza@bwh.harvard.edu
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
Accepts Healthy Volunteers
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Dolutegravir PK during weekly rifapentine/isoniazid for TB prevention
This is a single arm study: all patients are started on standard HIV treatment, with LTBI/TB prevention treatment varying according to age cohorts.
Children 2-11 years receive standard weekly rifapentine/isoniazid (3HP) for TB prevention; those <2 years received a single-dose of extrapolated weekly RPT/INH, followed by standard INH prophylaxis.
|
Children 2-11 years received standard HIV treatment and 3HP (RPT/INH weekly for 12 weeks) for TB prevention.
Children <2 years receive standard HIV treatment, a single-dose of extrapolated weekly RPT/INH, followed by standard INH prophylaxis.
Safety and pharmacokinetics will be evaluated.
All children in this study are living with HIV and thus dolutegravir is a standard part of treatment; in this study we will collect blood samples to measure dolutegravir levels during combination treatment with rifapentine/isoniazid treatment for TB prevention
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Dolutegravir AUC during weekly rifapentine/isoniazid
Time Frame: Weeks 4 and 6
|
Dolutegravir area under the concentration time curve (AUC) will be compared to therapeutic ranges established in the adult and pediatric literature.
Intensive PK sampling will occur at week 6 for dolutegravir and rifapentine PK.
Week 4 sparse PK sampling will provide dolutegravir exposures without rifapentine.
|
Weeks 4 and 6
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rifapentine AUC
Time Frame: weeks 6 and 7
|
Rifapentine AUC will be compared against adult targets.
Week 7 sparse PK will provide weekly Cmin estimate.
|
weeks 6 and 7
|
Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events
Time Frame: Week 48
|
Laboratory and clinical toxicities are monitored at 8-9 time points throughout the study and the proportion of children experiencing severe adverse events will be determined.
|
Week 48
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Holly Rawizza, MD, MPH, Brigham and Women's Hospital
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Latent Infection
- Tuberculosis
- Latent Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Anti-Bacterial Agents
- Leprostatic Agents
- HIV Integrase Inhibitors
- Integrase Inhibitors
- Antitubercular Agents
- Antibiotics, Antitubercular
- Rifapentine
- Dolutegravir
Other Study ID Numbers
- 2024P000306
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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