Short-Course Regimen With Bedaquiline, Moxifloxacin and Pyrazinamide for Early Bactericidal Activity in Drug-Susceptible Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 45
- 主要终点
- Early Bactericidal Activity CFU 0-14 (EBA CFU₀-₁₄)
研究概览
简要总结
Brief Summary
This study aims to evaluate the early bactericidal activity (EBA), safety, and tolerability of 4-month short-course regimens containing bedaquiline, moxifloxacin, and pyrazinamide in patients with drug-susceptible tuberculosis. This is a prospective, randomized, controlled, multicenter study planned to enroll 45 rifampicin-susceptible tuberculosis patients, who will be randomized in a 1:1:1 ratio to the BZMD group (bedaquiline + pyrazinamide + moxifloxacin + delamanid), BZMH group (bedaquiline + pyrazinamide + moxifloxacin + isoniazid), and standard control group. Subjects in the test groups will receive 17 weeks (4 months) of group-specific treatment regimens, while subjects in the control group will receive 26 weeks (6 months) of standard HRZE regimen treatment.
The primary endpoint is the change from baseline in log₁₀ colony-forming units (CFU) per milliliter of sputum specimen from Day 0 (pre-dose) to Day 14 of treatment (EBA CFU₀-₁₄), used to evaluate the early bactericidal activity of the drugs. Secondary endpoints include EBA CFU and EBA TTP (time to positive culture) at other time intervals, pharmacokinetic characteristics, sustained microbiological clearance rates, relapse rates, and safety indicators. The study will analyze the daily decline in log₁₀ CFU counts and daily increase in TTP using nonlinear mixed-effects models to reflect the bactericidal activity of the study regimens.
This study will help provide more effective and safer short-course treatment options for Chinese patients with drug-susceptible tuberculosis, thereby improving treatment adherence and treatment success rates, and providing scientific evidence for optimizing short-course treatment regimens for drug-susceptible tuberculosis.
详细描述
Study Background and Rationale Tuberculosis remains a significant global health challenge, with China ranking among the top three countries with the highest TB burden globally. Current anti-TB treatments for drug-susceptible tuberculosis face major obstacles, primarily poor adherence to long-term (at least 6 months) and complex treatment regimens. Incomplete TB treatment may lead to increased morbidity and mortality, prolonged infectivity, and development of drug resistance.
Recent international studies have demonstrated promising results for shorter treatment regimens. The SimpliciTB study showed that a 4-month short-course regimen containing bedaquiline, moxifloxacin, and pyrazinamide significantly increased 8-week sputum culture clearance rates compared to the standard 6-month regimen. The TRUNCATE-TB study demonstrated that a 2-month regimen containing bedaquiline, isoniazid, and pyrazinamide was non-inferior to standard 6-month treatment. However, bedaquiline-based 4-month short-course regimens have not yet been validated in early-stage studies in the Chinese population.
Study Methodology Treatment Regimens
BZMD Group (Total treatment: 17 weeks):
Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Delamanid Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Delamanid Bedaquiline: 400 mg once daily for 2 weeks, then 200 mg three times weekly for weeks 3-17 Pyrazinamide: Weight-based dosing (1000-2000 mg daily) - intensive phase only Moxifloxacin: 400 mg once daily throughout treatment Delamanid: 100 mg twice daily (200 mg total daily) throughout treatment
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
盲法说明
Not applicable - open-label study
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years and ≤60 years
- •Male or female
- •Body weight 40-90 kg
- •Capable of producing adequate sputum, with collection of at least 10ml overnight sputum
- •Willing to participate in trial treatment and follow-up, with signed informed consent (legal guardian may sign for patients lacking civil capacity)
- •Positive acid-fast bacilli smear microscopy of respiratory specimens (≥1+ according to WHO criteria) and positive rapid amplification test for Mycobacterium tuberculosis in respiratory specimens
- •Rifampicin-susceptible based on molecular drug susceptibility testing or conventional drug susceptibility testing
- •No anti-TB treatment for more than 3 days received within 6 months before the screening period
- •Subjects whose imaging findings meet the diagnostic criteria for TB, as determined by the investigator
- •Women of childbearing potential who have not undergone surgical sterilization must agree to use appropriate contraceptive methods
排除标准
- •Evidence of concurrent extrapulmonary TB
- •Subjects who have participated in other clinical studies within 8 weeks before the screening period
- •Confirmed resistance of mycobacterium tuberculosis isolates to any of the following: Isoniazid, fluoroquinolones, revealed by molecular drug susceptibility testing
- •Known allergy or intolerance to any study drug
- •Patients who cannot receive oral therapy
- •Abnormal liver function (alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin [TBil] exceeding 2 times the upper limit of normal) or known cirrhosis or known alcoholic hepatitis
- •The hematology indicates white blood cells <3.0×10⁹/L, or hemoglobin <80 g/L, or platelets <80×10⁹/L
- •The estimated glomerular filtration rate (eGFR) is less than 60 mL/min/1.73 m²
- •The blood electrolyte test indicates a baseline serum potassium level less than 3.5 mmol/L
- •Subjects who have used drugs known to prolong the QTcF interval for more than 3 days within 30 days before the screening period (including but not limited to amiodarone, bisoprolol, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, digoxin, dofetilide, domperidone, ertapenem, ibutilide, levomethadone, methadone, pentamidine, quinidine, sotalol, sparfloxacin, thioridazine)
- •Subjects with clinically significant ECG abnormalities as determined by the investigator, including but not limited to: baseline QTcF >450 ms for males or >470 ms for females, presence of second- or third-degree atrioventricular block, QRS duration >120 ms
- •Combined heart failure, coronary artery disease, myocardial infarction, ventricular hypertrophy, clinically significant arrhythmia, poorly controlled hypertension-related cardiovascular disease
- •Patients with known QT prolongation syndrome or a family history thereof
- •Subjects who have used any drug or substance known to be a strong inhibitor of cytochrome P450 enzymes within 30 days before the screening period (including but not limited to ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin, fluvoxamine, warfarin, rivaroxaban, and other novel oral anticoagulants)
- •Subjects with known bleeding disorders or family history of bleeding disorders
- •Subjects with HIV infection
- •Subjects with known optic neuritis, history of alcoholism, gout, epilepsy, mental illness, porphyria, myasthenia gravis, or malignant tumors
- •Patients with type I or type II diabetes, or HbA1c ≥6.5%, or random blood glucose ≥11.1 mmol/L with typical diabetic symptoms
- •Pregnant or lactating patients
研究组 & 干预措施
BZMD Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Delamanid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Delamanid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Delamanid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Bedaquiline (B) (Drug)
BZMD Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Delamanid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Delamanid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Delamanid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Moxifloxacin (Drug)
BZMD Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Delamanid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Delamanid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Delamanid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Pyrazinamide (PZA) (Drug)
BZMD Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Delamanid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Delamanid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Delamanid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Delamanid (D) (Drug)
BZMH Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Isoniazid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Isoniazid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Isoniazid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Bedaquiline (B) (Drug)
BZMH Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Isoniazid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Isoniazid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Isoniazid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Moxifloxacin (Drug)
BZMH Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Isoniazid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Isoniazid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Isoniazid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Pyrazinamide (PZA) (Drug)
BZMH Group (Bedaquiline + Moxifloxacin + Pyrazinamide + Isoniazid)
4-month short-course regimen. Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Isoniazid. Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Isoniazid. Total treatment duration 17 weeks followed by follow-up until week 38.
干预措施: Isoniazid (H) (Drug)
Standard Control Group (HRZE)
Standard 6-month regimen. Intensive phase (8 weeks): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol. Consolidation phase (18 weeks): Rifampicin + Isoniazid. Total treatment duration 26 weeks followed by follow-up until week 38.
干预措施: Pyrazinamide (PZA) (Drug)
Standard Control Group (HRZE)
Standard 6-month regimen. Intensive phase (8 weeks): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol. Consolidation phase (18 weeks): Rifampicin + Isoniazid. Total treatment duration 26 weeks followed by follow-up until week 38.
干预措施: Isoniazid (H) (Drug)
Standard Control Group (HRZE)
Standard 6-month regimen. Intensive phase (8 weeks): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol. Consolidation phase (18 weeks): Rifampicin + Isoniazid. Total treatment duration 26 weeks followed by follow-up until week 38.
干预措施: Rifampicin (R) (Drug)
Standard Control Group (HRZE)
Standard 6-month regimen. Intensive phase (8 weeks): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol. Consolidation phase (18 weeks): Rifampicin + Isoniazid. Total treatment duration 26 weeks followed by follow-up until week 38.
干预措施: Ethambutol (E) (Drug)
结局指标
主要结局
Early Bactericidal Activity CFU 0-14 (EBA CFU₀-₁₄)
时间窗: Day 0 (baseline) to Day 14 of treatment
The change from baseline in log10 colony-forming units (CFU) per milliliter of sputum specimen from baseline (Day 0, pre-dose) to Day 14 of treatment. This measures the early bactericidal activity of the drug regimens over the first 14 days of treatment.
次要结局
- Early Bactericidal Activity CFU 0-2 (EBA CFU₀-₂)(Day 0 to Day 2)
- Early Bactericidal Activity CFU 0-7 (EBA CFU₀-₇)(Day 0 to Day 7)
- Early Bactericidal Activity TTP 0-14 (EBA TTP₀-₁₄)(Day 0 (baseline) to Day 14 of treatment)
- Sustained Microbiological Clearance Rate(Week 17 (end of treatment))
- Safety - Grade 3 or Higher Adverse Events(From enrollment through study completion, up to 52 weeks)
研究者
Wei Sha MD & PhD
Chief Physician and Doctoral Supervisor
Shanghai Pulmonary Hospital, Shanghai, China