Re-evaluating the Duration in Children of TB Treatment

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

Inclusion criteria

• 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

Exclusion criteria

• 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)