Re-evaluating the Duration in Children of TB Treatment

Phase 2Not Yet RecruitingNCT07656012

University of Wisconsin, Madison230 enrolled

Overview

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.

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

Study Type

Interventions

RifampicinDRUG

odR for main trial determined from Lead-in PK study 75 mg tablet, and 150 or 300 mg capsule, dosed by weight and age

IsoniazidDRUG

50 mg tablet, dosed by weight and age

PyrazinamideDRUG

150 mg tablet, dosed by weight and age

EthambutolDRUG

100 mg tablet, dosed by weight and age

RifampicinDRUG

standard of care and only the 75 mg tablet will be used

Eligibility

Sex: ALLMin age: 3 MonthsMax age: 9 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Step 2: Unfavorable TB treatment outcome

A participant has unfavorable treatment outcomes if they fail to meet either of the following criteria: * No treatment extension or re-treatment for TB at any time up through 48 weeks after randomization. * TB recurrence-free cure or Probable TB recurrence-free cure

Time frame: 48 weeks

Secondary Outcomes

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

Occurrence of at least one new or worsened Grade 3-5 Adverse Event (AE) after the first dose of study treatment by period.

Time frame: 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

Permanent discontinuation of at least one drug in the study regimen during each treatment period due to an AE of any grade that is either safety- or tolerability-related, death due to toxicity (probably/possibly/certainly) related to one or more of the study drugs, or participant/parent/guardian request.

Time frame: 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)

Area under the concentration time curve over 24 hours (AUC0-24)

Time frame: 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)

Maximum concentration (Cmax)

Time frame: 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

Participant and/or parent/guardian responses to rifampicin acceptability question of "Overall, how did you/your child feel about taking this medicine?", scored on a likert scale from 1-5 with higher scores being more acceptable. Summarized by number of responses per score.

Time frame: 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

Occurrence of at least one new or worsened Grade 3-5 adverse event after the first dose of study treatment and during the 28 weeks following randomization, where 28 weeks is 4 weeks beyond the longest scheduled treatment duration of 24 weeks.

Time frame: up to 28 weeks

Step 2: Tolerability Measured by discontinuation of at least one drug in Main Trial

Permanent discontinuation of at least one drug in the study regimen prior to the end of the assigned treatment period due to an AE of any grade that is either safety- or tolerability-related, death due to toxicity (probably/possibly/certainly) related to one or more of the study drugs, or participant/parent/guardian request.

Time frame: up to 24 weeks

Step 2: Lung function post-TB treatment

The outcome of interest is abnormal lung function classified as having at least one of the following physiological findings based on results of spirometry and oscillometry (FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity): * Obstructive lung disease: defined as FEV1, or FEV1/FVC of \<-1.64 z-score (z-score\<-1.64 = lower limit of normal, LLN) with normal FVC * Restrictive lung disease: defined as FVC \<-1.64 z-score with normal FEV1 * Mixed lung disease: defined as FEV1/FVC \<LLN; * Isolated small airway dysfunction: defined as oscillometry Area of reactance (AX) \>1.64 z-score and/or oscillometry peripheral airway resistance (R5-20) \>1.64 z-score with normal FEV1 on spirometry

Time frame: week 48

Step 2: Acceptability of optimized-dose rifampicin summarized by participant count

Time frame: baseline (at dose 1), week 4, week 8

Step 2: Acceptability of overall TB treatment regimen summarized by participant count

Participant and/or parent/guardian responses to overall TB treatment regimen acceptability question of "In the last 4 weeks, how did you/your child feel about taking this TB treatment regimen, considering all of the TB medicines in the regimen together?", scored on a likert scale from 1-5 with higher scores being more acceptable. Summarized by number of responses per score.

Time frame: week 4, week 8