Shortened Regimen for Drug-susceptible TB in Children
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 860
- 试验地点
- 19
- 主要终点
- TB disease-free survival at 48-weeks
研究概览
简要总结
While drug-susceptible tuberculosis (TB) disease in children currently requires four to six months of treatment, most children may be able to be cured with a shorter treatment of more powerful drugs. Shorter treatment may be easier for children to tolerate and finish as well as ease caregiver strain from managing treatment side effects and supporting children over many months. The primary objective of this study is to evaluate if a 2-month regimen (including isoniazid (H), rifapentine (P), pyrazinamide (Z) and moxifloxacin (M)) is as safe and effective as a 4- to 6-month regimen (isoniazid, rifampicin (R), pyrazinamide, ethambutol (E)) in curing drug-susceptible TB disease in children under 10 years old. The study is also evaluating the safety of the HPZM in children with and without HIV.
详细描述
In previously untreated individuals with presumed drug-susceptible pulmonary and or peripheral lymph node TB treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (2HPZM), all given daily throughout, the proportion of participants who experience absence of cure (unsuccessful outcome) will not be inferior to that observed in participants who are treated with the standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide, with or without ethambutol followed by 8 to 16 weeks of rifampin plus isoniazid depending on disease severity) all given daily throughout.
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
- 0 Days 至 9 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Parent or guardian is willing and able to provide written informed consent for potential participant's study participation; in addition, when applicable per Ethics Committee/Institutional Review Board (EC/IRB) policies and procedures, potential participant is willing and able to provide assent for study participation.
- •At Entry, age of less than 10 years.
- •At Entry, weight 3 kilograms (kg) or greater.
- •At Entry, diagnosed with TB disease, defined as:
- •Pulmonary (including pleural effusion) and/or lymph node (extra-thoracic and/or intra-thoracic) TB with or without bacteriologic confirmation;
- •Clinician has decided to treat with standard first-line drug-susceptible TB regimen.
- •Known HIV status or HIV testing in progress based on meeting testing requirements.
- •Has normal, Grade 1 or 2 test results for all of the following done at or within 14 days of Entry (including the most recent):
- •Alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal;
- •Total bilirubin less than or equal to 2.5 times the upper limit of normal;
- •Potassium level of 3.0 milliequivalent/L or greater;
- •Hemoglobin level of 7.0 g/dL or greater;
- •Platelet count of 100,000/mm3 or greater;
- •Estimated glomerular filtration rate (eGFR; bedside Schwartz formula) 60 mL/min/1.73m2 or higher.
- •For children living with HIV:
- •On antiretroviral therapy (ART) at Entry: Must be on, or able to be switched to a dolutegravir-based regimen at or prior to Entry;
- •Not on ART at Entry: Planned initiation of dolutegravir before or at study Week
- •For participants who have reached menarche or who are engaging in sexual activity (self-reported): negative serum or urine pregnancy test within 7 days of Entry.
- •For participants who are engaging in sexual activity that could lead to pregnancy (self-reported): agrees to practice at least one non-hormonal method of contraception or abstain from heterosexual intercourse during study drug treatment and for 30 days after stopping study medications. Non-hormonal methods include:
- •Male or female condoms
- •Diaphragm or cervical cap (with spermicide, if available)
- •Non-hormonal intrauterine device (IUD) or intrauterine system (IUS)
- •At Entry, intends to remain in the catchment area of the study site for the duration of study follow-up or willingness to be followed up beyond the catchment area if/when applicable, as determined by the site investigator based on participant/parent/guardian report.
排除标准
- •Presumed or documented extra-pulmonary TB involving the central nervous system and/or bones and/or joints, and/or miliary TB, and/or pericardial TB and/or TB of the gastrointestinal (GI) tract and/or renal TB.
- •Premature infant (born less than 37-weeks gestation) who is less than 3 months of age at Entry.
- •Any known contraindication to taking any study drug:
- •Known allergy or intolerance to any of the study drugs or drugs in the same class as the study drugs;
- •Any prohibited medications within three days prior to Entry or planned use within the following 6 months;
- •Unable to take oral medications;
- •Known history of prolonged QT syndrome not caused by electrolyte derangements.
- •Received more than 10 days of treatment directed against TB disease within 6 months preceding initiation of study drugs.
- •M. tuberculosis isolate known or suspected to be resistant to isoniazid, rifampin, pyrazinamide, ethambutol, and/or fluoroquinolones.
- •Known exposure to an infectious adult with drug-resistant TB, including resistance to isoniazid, rifampin, pyrazinamide, ethambutol, and/or fluoroquinolones.
- •Has any other documented or suspected clinically significant medical condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
- •Previously enrolled in this study.
- •Late Exclusions:
- •M. tuberculosis cultured or detected through World Health Organization (WHO) approved molecular assays (e.g., Cepheid Xpert MTB/RIF, Xpert XDR, sequencing or Hain MTB-DR plus assays) from sputum, swallowed sputum, nasopharyngeal aspirates, stool, or lymph node aspirate obtained around the time of study entry is determined to be resistant to isoniazid and/or rifampin and/or pyrazinamide and/or ethambutol and/or fluoroquinolones.
- •Any child with a clinical TB diagnosis who is found to have a definitive alternative diagnosis for their presenting signs and symptoms whose TB treatment is discontinued prior to completion.
研究组 & 干预措施
Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)
8 weeks of daily HPZM
干预措施: Rifapentine (Drug)
Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)
8 weeks of daily HPZM
干预措施: Moxifloxacin (Drug)
Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)
8 weeks of daily HPZM
干预措施: Pyrazinamide (Drug)
Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care
干预措施: Isoniazid (Drug)
Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care
干预措施: Rifampin (Drug)
Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care
干预措施: Pyrazinamide (Drug)
Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)
8 weeks of daily HPZM
干预措施: Isoniazid (Drug)
Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care
干预措施: Ethambutol (Drug)
结局指标
主要结局
TB disease-free survival at 48-weeks
时间窗: Measured from study entry through week 48
Non-inferiority will be assessed by comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the proportion of participants who are classified as having an unsuccessful outcome on the control regimen (HRZ(E)) and the intervention regimen (HPZM) to the predefined non-inferiority margin of 6% at 48 weeks.
Proportion of participants with grade 3 or higher adverse events over 28 weeks
时间窗: Measured from study entry through Week 28
The proportion of participants with a Grade 3 or higher adverse event and the corresponding 95% confidence intervals will be generated. An exact test for equality of proportions will be used to compare safety outcomes between the arms.
次要结局
- Adherence to treatment regimens(Measured from study entry through Week 48)
- TB disease-free survival at 48-weeks(Measured from study entry through Week 48)
- Moxifloxacin Cmin(Measured from study entry through Week 8)
- Parent/guardian and/or participant reported palatability and acceptability of study regimen(Baseline, Week 4, Week 8 (Regimens 1 and 2) and at Weeks 16 and 24 (Regimen 1 only))
- TB disease-free survival at 72-weeks(Measured from study entry through Week 72)
- Moxifloxacin AUC0-24(Measured from study entry through Week 8)
- Adherence as assessed by proportion of participants who have taken at least 90% of their doses(Baseline through Week 8 for HPZM, Week 16 for HRZ(E) with non-severe disease, or Week 24 for HRZ(E) with severe disease)
- Tolerability as assessed by proportion of participants who discontinue treatment(Week 8 (intervention/HPZM) or Week 16 or Week 24 (control/HRZ(E)))
- Rifapentine Area under the curve (AUC0-24)(Measured from study entry through Week 8)
- Rifapentine minimal concentration (Cmin)(Measured from study entry through Week 8)
- Rifapentine peak concentration (Cmax)(Measured from study entry through Week 8)
- Moxifloxacin Cmax(Measured from study entry through Week 8)
- Risk Stratification Algorithm(Measured from study entry through Week 48)
- Cost effectiveness as assessed by the incremental cost-effective ratio (ICER)(Measured from study entry through Week 24)