Re-evaluating the Duration in Children of TB Treatment

Официальное название

Multi-arm, Open-label, Duration-randomized, Phase IIc Study of the Efficacy, Safety, Tolerability, and Pharmacokinetics of Optimized Rifampicin in Combination With Isoniazid, Pyrazinamide, and Ethambutol for the Treatment of Children With Drug-susceptible Tuberculosis

Обзор

Current tuberculosis (TB) treatment is effective (works well), but it takes a long time to cure TB. This study will evaluate if TB treatment with a higher dose of rifampicin, one of the TB medicines, and shorter TB treatment duration is as effective and safe as the standard, TB treatment (with the usual rifampicin dose and usual duration). This study hopes to find a better shorter treatment that works as well as the current treatment (standard of care). This could benefit children worldwide who are getting TB treatment. Children 3 months to less than 10 years of age who have drug-susceptible TB (can be successfully treated with standard TB medicines) are eligible for this study.

Подробное описание

This is a multi-arm open-label phase IIc trial with duration randomization, with a lead-in pharmacokinetics (PK) study. Children 3 months to less than 10 years of age with routinely diagnosed clinical or confirmed drug-susceptible TB will be screened and if eligible randomly assigned 1:1:1:1:1 to one of five arms (durations of TB treatment and control arm). Randomization will be stratified by age (3 months to less than 5 years of age vs 5 to less than 10 years of age).

A total of 200 participants will be enrolled in the main trial (Step 2), with 40 per study arm, with an additional 30 participants enrolled in a Lead-in PK study (Step 1).

Step 1 - Lead-in PK study participants will be on treatment for 8 weeks, complete their trial participation in up to 9 weeks, and will not contribute to the main trial endpoints.

Step 2 - Main trial participants will be on study for 48 weeks.

Primary Objective:

In children with drug-susceptible tuberculosis, with and without HIV:

• To characterize the relationship between treatment duration of the experimental regimen and the proportion of participants with unfavorable treatment outcome at 48 weeks after randomization (i.e., the duration-response curve)

Secondary Objectives:

The secondary objectives of the Lead-In PK study are to

* Characterize the safety and tolerability of two optimized doses of rifampicin with standard doses of isoniazid, pyrazinamide and ethambutol * Characterize the pharmacokinetics of two optimized doses of rifampicin * Characterize the acceptability of two optimized doses of rifampicin

The secondary objectives of the Main Study are to:

* Characterize the safety and tolerability of optimized-dose rifampicin with standard doses of isoniazid, pyrazinamide and ethambutol * Characterize the pharmacokinetics of optimized-dose rifampicin * Characterize lung health post-TB treatment at week 48 among children able to complete lung-health assessments * Characterize the acceptability of optimized-dose rifampicin

Вмешательства

• Препарат Rifampicin
  odR for main trial determined from Lead-in PK study 75 mg tablet, and 150 or 300 mg capsule, dosed by weight and age
• Препарат Isoniazid
  50 mg tablet, dosed by weight and age
• Препарат Pyrazinamide
  150 mg tablet, dosed by weight and age
• Препарат Ethambutol
  100 mg tablet, dosed by weight and age
• Препарат Rifampicin
  standard of care and only the 75 mg tablet will be used

Первичные конечные точки

• Step 2: Unfavorable TB treatment outcome [Срок оценки: 48 weeks]

Вторичные конечные точки (10)

• Step 1: Safety measured by occurrence of Grade 3 to 5 Adverse Events after the first dose of study treatment by period in Lead-in PK study [Срок оценки: data collected from individual participants for 2 regimens of 4 weeks each, up to 8 weeks total]
• Step 1: Tolerability Measured by discontinuation of at least one drug in Lead-in PK study [Срок оценки: data collected from individual participants for 2 regimens of 4 weeks each, up to 8 weeks total]
• Step 1: Pharmacokinetics of optimized-dose rifampicin: (AUC0-24) [Срок оценки: data collected at week 4 (and week 8) visit lead-in PK study; pre-dose (0 hour), 1, 2, 4, 8 and 24 hour post dose]
• Step 1: Pharmacokinetics of optimized-dose rifampicin: (Cmax) [Срок оценки: data collected at week 4 (and week 8) visit lead-in PK study; pre-dose (0 hour), 1, 2, 4, 8 and 24 hour post dose]
• Step 1: Acceptability of optimized-dose rifampicin summarized by participant count [Срок оценки: baseline (at dose 1), week 4, week 8]
• Step 2: Safety Measured by Occurrence of at least one new or worsened Grade 3-5 adverse event after the first dose of study treatment in Main Trial [Срок оценки: up to 28 weeks]
• Step 2: Tolerability Measured by discontinuation of at least one drug in Main Trial [Срок оценки: up to 24 weeks]
• Step 2: Lung function post-TB treatment [Срок оценки: week 48]
• Step 2: Acceptability of optimized-dose rifampicin summarized by participant count [Срок оценки: baseline (at dose 1), week 4, week 8]
• Step 2: Acceptability of overall TB treatment regimen summarized by participant count [Срок оценки: week 4, week 8]

Критерии участия

Критерии включения

• 3 months to less than 10 years of age
• Body weight greater than or equal to 3 kilograms (kg) and less than 45 kg at study entry
• Confirmed or clinically diagnosed intrathoracic (pulmonary) and/or some forms of extrathoracic (extrapulmonary) drug-susceptible TB:

• Confirmed intrathoracic (pulmonary) TB, based on chest radiograph and/or symptoms consistent with TB, and/or some forms of extrathoracic TB, with all of the following as determined by the site investigator:

• Microbiological confirmation of M. tuberculosis from any clinical specimen by either culture or molecular methods
• At least rifampicin-susceptibility demonstrated by genotypic (molecular) or phenotypic methods
• Documented clinical decision to treat for drug-susceptible TB
• Clinically diagnosed intrathoracic (pulmonary) TB, based on chest radiograph and/or symptoms consistent with TB, and/or some forms of extrathoracic TB, with all of the following as determined by the site investigator:

• Documented clinical decision to treat for drug-susceptible TB
• HIV positive or negative
• For participants living with HIV, they must be on a dolutegravir-based antiretroviral therapy regimen at the time of study entry

Критерии исключения

• Received routine treatment for TB disease for greater than 5 days at the time of enrollment
• Exposure to a case of intrathoracic TB in the 12 months prior to enrollment with known or suspected resistance to any of the drugs in the treatment regimens OR confirmed resistance on molecular or phenotypic drug-susceptibility testing to any drugs in the treatment regimens
• Has greater than or equal to grade 3 results of any of the following during screening: creatinine, serum ALT, AST, total bilirubin
• Has hemoglobin less than 7.5 g/dL during screening
• Has TB meningitis, osteoarticular TB, or miliary TB as determined by the site investigator
• Severe renal, pulmonary, cardiac, gastrointestinal, neurologic or any other condition that in the judgement of the investigator would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives
• Use of any prohibited drug within 3 days of enrollment
• Severe acute malnutrition defined as weight-for-height/length z-score or BMI-for-age z-score less than -3
• Hypersensitivity to any of the study drugs (rifampicin, isoniazid, pyrazinamide or ethambutol)
• For Main Trial (Step 2) participants, previously enrolled in the Lead-in PK Study (Step 1)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Перу · 1 центр

• Socios en Salud Sucursal Peru — Lima

Идентификаторы

NCT: NCT07656012 · 2026-0205 · Protocol Version 2/10/26 · SMPH | Pediatrics - GPAM · 1U01AI192041-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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