A Study of Daily Rifapentine Combined With Isoniazid (1HP) for Tuberculosis Prevention in Children Less Than 13 Years of Age With and Without HIV

Official title

Phase I/II Dose Finding, Safety and Tolerability Study of Daily Rifapentine Combined With Isoniazid (1HP) for Tuberculosis Prevention in Children Less Than 13 Years of Age With and Without HIV

Overview

This study aims to find the proposed dose of Rifapentine (RPT) taken once daily with Isoniazid (INH) for 28 days to prevent tuberculosis (TB). The study will take place at multiple locations and children under 13 years old will be divided into two groups: one group will include children without HIV, and the other group will include children with HIV who are on antiretroviral treatment. Up to 144 children will participate, and participants in each group will be followed for 24 weeks.

Interventions

• Drug Rifapentine
  Dispersible Tablet administered orally
• Drug Isoniazid
  Dispersible Tablet administered orally
• Drug Dolutegravir
  Tablets and Tablets for oral suspension administered orally

Primary outcome measures

• Plasma concentration of Rifapentine (RPT) at specified time points among children with and without HIV [Time frame: Through Day 28]
• Area Under the Curve (AUC)(0-inf) of RPT [Time frame: Through Day 28]
• Maximum serum concentration (C(max)) of RPT [Time frame: Through Day 28]
• Half-life (t1/2) of RPT [Time frame: Through Day 28]
• Apparent oral clearance (CL/F) of RPT [Time frame: Through Day 28]
• Apparent oral volume of distribution (V/F) of RPT [Time frame: Through Day 28]
• Absorption rate (ka) of RPT [Time frame: Through Day 28]
• Trough serum concentration (C(trough)) of DTG (Cohort 2 only) [Time frame: At study entry, Day 28 and Day 42]
• CL/F of DTG (Cohort 2 only) [Time frame: At study entry, Day 28 and Day 42]
• Proportion of participants experiencing Adverse Events (AEs) [Time frame: Through Day 28]

Secondary outcome measures (12)

• Relative effects of significant covariates on RPT PK [Time frame: Through Day 28]
• Proportion of participants experiencing AEs [Time frame: Through Day 168]
• Proportion of participants experiencing Grade 3 or higher AEs [Time frame: Through Day 168]
• Proportion of participants experiencing Grade 2 or higher AEs assessed as related to 1HP [Time frame: Through Day 168]
• Proportion of participants experiencing SAEs assessed as related to 1HP [Time frame: Through Day 168]
• Participant and/or parent/guardian reported palatability and acceptability of 1HP regimen [Time frame: At Day 1, Day 14, and Day 28]
• Number of occurrences of permanent discontinuation of 1HP regimen due to participant refusal to take 1HP or participant's parent/guardian decision to prematurely discontinue 1HP regimen [Time frame: Through Day 168]
• Participant adherence to the 1HP regimen [Time frame: Through Day 28]
• Proportion of participants experiencing Grade 2 or higher AEs assessed as related to DTG (Cohort 2 only) [Time frame: Through Day 42]
• Proportion of participants experiencing SAEs assessed as related to DTG (Cohort 2 only) [Time frame: Through Day 42]
• Proportion of participants experiencing AEs assessed as related to DTG that led to permanent discontinuation of the regimen (Cohort 2 only) [Time frame: Through Day 42]
• Number of participants with HIV-1 RNA less than 200 copies/mL (Cohort 2 only) [Time frame: At Day 42]

Eligibility criteria

Inclusion criteria

• A parent or legal guardian must be willing and able to give written permission for the child to participate in the study. If required by local policies, the child must also be willing and able to give written assent to participate. All sites must follow local policies and procedures.
• Age requirements at entry:

• Cohort 1: Children under 13 years old.
• Cohort 2: Children aged 12 weeks to under 13 years old.
• For Cohort 1 participants under 28 days old: The child must have been born at or after 37 weeks of pregnancy, as determined by the site investigator using parent/guardian report or medical records.
• Weight requirements at entry:

• Cohort 1: 3 kg to under 45 kg.
• Cohort 2: 6 kg to under 45 kg.
• HIV status:

• Cohort 1: Must be living without HIV.
• Cohort 2: Must be living with HIV.
• At risk of TB disease, defined as meeting at least one of the following:

• Having close contact with someone with infectious pulmonary TB within the past six months.
• A positive tuberculin skin test (TST) or, for those over two years old, a positive interferon gamma release assay (IGRA) if TST is not available.
• For Cohort 2 only: Living in a high TB burden area (≥ 60 TB cases per 100,000 people per year).
• Normal or mild (grade 1 or 2) test results for the following at screening (within 21 days before entry):

• ALT (liver enzyme)
• Estimated glomerular filtration rate (kidney function)
• Absolute neutrophil count (white blood cells)
• Hemoglobin (red blood cells)
• For Cohort 2 participants:

• Must have been on antiretroviral therapy (ART) for at least 12 weeks before entry.
• Must have been on a specific ART regimen (once-daily DTG and two NRTIs) for at least 14 days before entry.
• Must have used the same formulation of DTG (tablet or dispersible tablet) for at least three days before entry.
• Must agree to continue the same formulation of DTG for the study duration.
• Must have an HIV-1 RNA level below 200 copies/mL at screening.
• Must intend to stay in the same area for the study duration.
• Must have access to at least one meal per day during the 28-day treatment period.

Exclusion criteria

• The child has active TB, confirmed by medical records, parent/guardian report, or tests during screening, indicated by:

• Currently being treated for active TB.
• Symptoms like poor growth, poor weight gain, weight loss, cough for at least 11 days, or fever for at least eight days.
• X-ray or CT scan showing TB.
• Positive TB test results (e.g., culture, Xpert MTB/RIF Ultra, Truenat M.tb, other nucleic acid tests, urine tests).
• The child has been exposed to an adult with drug-resistant TB (resistant to Rifampicin or Isoniazid) within the past six months.
• The child has taken the following medications:

• Daily Isoniazid in the 28 days before entry.
• Any prohibited medications listed in the study within three days before entry.
• The child has any of the following conditions:

• Acute or chronic hepatitis.
• Allergy to Isoniazid or rifamycins.
• Porphyria.
• Severe peripheral neuropathy.
• The child has severe acute malnutrition (weight-for-height/length less than -3 z-scores of WHO standards). Note: Children who are stunted (height-for-age more than two standard deviations below WHO standards) are eligible.
• For Cohort 2: The child has an active AIDS-defining opportunistic infection.
• The child has started menstruation.
• The child has taken NVP, EFV, lopinavir/ritonavir, and/or raltegravir within 14 days before entry.
• The child has received long-term immunosuppressive therapy (more than eight days) within 30 days before entry. Note: Short courses of steroids (seven days or less) may be allowed with approval.
• The child is a result of a multiple birth (e.g., twins, triplets).
• The child has any other significant medical condition that would make participation unsafe, complicate data interpretation, or interfere with study objectives, as determined by the site investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Prevention

Study locations

Zimbabwe · 3 centers

• Harare Family Care (Site ID: 31890) — Belgravia
• Seke North (Site ID: 30306) — Belgravia
• St Mary's (Site ID: 30303) — Chitungwiza

Botswana · 2 centers

• Gaborone (Site ID: 12701) — Gaborone
• Molepolole (Site ID: 12702) — Gaborone

Thailand · 2 centers

• Siriraj Hospital, Mahidol University (Site ID: 5115) — Bangkok
• Chiangrai Prachanukroh Hospital (Site ID: 5116) — Chiang Rai

Uganda · 2 centers

• Baylor-Uganda (Site ID: 31798) — Kampala
• MU-JHU Care Limited (Site ID: 5126) — Kampala

Haiti · 1 center

• Les Centres GHESKIO (Site ID: 30022) — Port-au-Prince

Kenya · 1 center

• Kenya Medical Research Institute, Walter Reed Project Clinical Research Center (Site ID: 5 — Kericho

Identifiers

NCT: NCT07124559 · IMPAACT 2024 · 38747

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗