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
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 230
- 试验地点
- 1
- 主要终点
- Step 2: Unfavorable TB treatment outcome
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Months 至 9 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Arm 3: 14 week duration
N = 40, 8 weeks of odRHZE followed by 6 weeks of odRH
干预措施: Ethambutol (Drug)
Arm 4: 17 week duration
N = 40, 8 weeks of odRHZE followed by 9 weeks of odRH
干预措施: Rifampicin (Drug)
Arm 4: 17 week duration
N = 40, 8 weeks of odRHZE followed by 9 weeks of odRH
干预措施: Isoniazid (Drug)
Arm 5: Control (17 or 24 week duration)
N = 40, 8 week of RHZ(E) followed by 9 weeks (5a - non-severe TB) or 16 weeks (5b - severe TB) of RH
干预措施: Pyrazinamide (Drug)
Step 1: PK - Dosing Schedule B > A
N = 15
- Period 1 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Rifampicin (Drug)
Arm 1: 8 week duration
N = 40, 8 weeks of odRHZE
干预措施: Isoniazid (Drug)
Arm 1: 8 week duration
N = 40, 8 weeks of odRHZE
干预措施: Rifampicin (Drug)
Step 1: PK - Dosing Schedule B > A
N = 15
- Period 1 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Ethambutol (Drug)
Arm 1: 8 week duration
N = 40, 8 weeks of odRHZE
干预措施: Pyrazinamide (Drug)
Arm 3: 14 week duration
N = 40, 8 weeks of odRHZE followed by 6 weeks of odRH
干预措施: Isoniazid (Drug)
Arm 3: 14 week duration
N = 40, 8 weeks of odRHZE followed by 6 weeks of odRH
干预措施: Pyrazinamide (Drug)
Arm 4: 17 week duration
N = 40, 8 weeks of odRHZE followed by 9 weeks of odRH
干预措施: Pyrazinamide (Drug)
Arm 5: Control (17 or 24 week duration)
N = 40, 8 week of RHZ(E) followed by 9 weeks (5a - non-severe TB) or 16 weeks (5b - severe TB) of RH
干预措施: Rifampicin (Drug)
Step 1: PK - Dosing Schedule A > B
N = 15
- Period 1 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Rifampicin (Drug)
Step 1: PK - Dosing Schedule B > A
N = 15
- Period 1 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Pyrazinamide (Drug)
Step 1: PK - Dosing Schedule A > B
N = 15
- Period 1 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Isoniazid (Drug)
Arm 5: Control (17 or 24 week duration)
N = 40, 8 week of RHZ(E) followed by 9 weeks (5a - non-severe TB) or 16 weeks (5b - severe TB) of RH
干预措施: Ethambutol (Drug)
Arm 2: 11 week duration
N = 40, 8 weeks of odRHZE followed by 3 weeks of odRH
干预措施: Isoniazid (Drug)
Arm 3: 14 week duration
N = 40, 8 weeks of odRHZE followed by 6 weeks of odRH
干预措施: Rifampicin (Drug)
Arm 1: 8 week duration
N = 40, 8 weeks of odRHZE
干预措施: Ethambutol (Drug)
Arm 4: 17 week duration
N = 40, 8 weeks of odRHZE followed by 9 weeks of odRH
干预措施: Ethambutol (Drug)
Step 1: PK - Dosing Schedule B > A
N = 15
- Period 1 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Isoniazid (Drug)
Arm 2: 11 week duration
N = 40, 8 weeks of odRHZE followed by 3 weeks of odRH
干预措施: Rifampicin (Drug)
Arm 2: 11 week duration
N = 40, 8 weeks of odRHZE followed by 3 weeks of odRH
干预措施: Pyrazinamide (Drug)
Step 1: PK - Dosing Schedule A > B
N = 15
- Period 1 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Ethambutol (Drug)
Arm 2: 11 week duration
N = 40, 8 weeks of odRHZE followed by 3 weeks of odRH
干预措施: Ethambutol (Drug)
Arm 5: Control (17 or 24 week duration)
N = 40, 8 week of RHZ(E) followed by 9 weeks (5a - non-severe TB) or 16 weeks (5b - severe TB) of RH
干预措施: Isoniazid (Drug)
Step 1: PK - Dosing Schedule A > B
N = 15
- Period 1 - odRIF Dosing Schedule A with HZE, PK sampling after 4 weeks followed by
- Period 2 - odRIF Dosing Schedule B with HZE, PK sampling after 4 weeks
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg)
干预措施: Pyrazinamide (Drug)
结局指标
主要结局
Step 2: Unfavorable TB treatment outcome
时间窗: 48 weeks
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
次要结局
- 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(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(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)(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)(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(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(up to 28 weeks)
- Step 2: Tolerability Measured by discontinuation of at least one drug in Main Trial(up to 24 weeks)
- Step 2: Lung function post-TB treatment(week 48)
- Step 2: Acceptability of optimized-dose rifampicin summarized by participant count(baseline (at dose 1), week 4, week 8)
- Step 2: Acceptability of overall TB treatment regimen summarized by participant count(week 4, week 8)