Short-Course Regimen With Bedaquiline, Moxifloxacin and Pyrazinamide for Early Bactericidal Activity in Drug-Susceptible Tuberculosis

Обзор

\# 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.

Подробное описание

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

BZMH Group (Total treatment: 17 weeks):

Intensive phase (8 weeks): Bedaquiline + Pyrazinamide + Moxifloxacin + Isoniazid Consolidation phase (9 weeks): Bedaquiline + Moxifloxacin + Isoniazid Bedaquiline: Same dosing as BZMD group Pyrazinamide: Weight-based dosing - intensive phase only Moxifloxacin: 400 mg once daily throughout treatment Isoniazid: 300 mg once daily throughout treatment

Standard Control Group (Total treatment: 26 weeks):

Intensive phase (8 weeks): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol Consolidation phase (18 weeks): Rifampicin + Isoniazid

Early Bactericidal Activity Assessment The study employs a rigorous EBA assessment protocol with overnight sputum collections. Subjects must provide at least 10 mL of overnight sputum during each collection cycle. Two pre-treatment overnight sputum specimens are collected on consecutive days before treatment initiation to establish baseline CFU counts. Daily overnight sputum collections continue for the first 14 days of treatment to monitor bactericidal activity.

Pharmacokinetic Substudy A subset of subjects (10-15 per test group) will participate in intensive PK sampling on Day 14, involving 11 blood draws over 24 hours to evaluate steady-state pharmacokinetic characteristics and potential drug-drug interactions between study medications.

Follow-up and Retreatment Criteria All subjects are followed until week 38 post-treatment initiation. For test group subjects who fail to achieve sustained microbiological clearance at end of treatment (week 17) or experience recurrence during follow-up, a standard 6-month HRZE regimen will be re-initiated.

Quality Control Measures

The study implements comprehensive quality assurance including:

* Standardized personnel training for all sites * Consecutive case enrollment to ensure representativeness * Dual physician verification of patient information * Regular monitoring visits by the lead site * Laboratory quality control with proficiency testing * Blinded sputum smear rechecking

Statistical Considerations Bactericidal activity will be analyzed using nonlinear mixed-effects models to estimate daily log₁₀ CFU reduction and TTP increases. The study design allows for replacement of subjects who cannot provide adequate sputum specimens to ensure statistical precision. Pharmacokinetic parameters will be compared between test groups using nonparametric methods.

Clinical Significance This study addresses a critical need in tuberculosis treatment by evaluating whether bedaquiline-based short-course regimens can reduce treatment duration from 6 months to 4 months while maintaining efficacy. Successful results could lead to improved treatment adherence, reduced healthcare costs, and decreased risk of drug resistance development. The study specifically focuses on the Chinese population, addressing potential pharmacokinetic and genetic variations that may influence treatment outcomes.

The early bactericidal activity endpoint provides rapid assessment of regimen efficacy, allowing for early identification of promising combinations before larger, longer-term studies. This approach accelerates the development of improved tuberculosis treatment regimens while maintaining rigorous safety monitoring.

Вмешательства

• Препарат Bedaquiline (B)
  Bedaquiline tablets administered orally. Dosing: 400 mg once daily for the first 2 weeks, then 200 mg three times per week for weeks 3-17. Used in both experimental arms (BZMD and BZMH groups) as part of the 4-month short-course regimen for drug-susceptible tuberculosis treatment.
• Препарат Moxifloxacin
  Moxifloxacin 400 mg tablets administered orally once daily before or after meals throughout the entire treatment period (17 weeks). Used in both experimental arms (BZMD and BZMH groups) as part of the 4-month short-course regimen for drug-susceptible tuberculosis treatment.
• Препарат Pyrazinamide (PZA)
  Pyrazinamide tablets administered orally once daily in the morning during intensive phase (8 weeks). Dosing by weight: 1000 mg for 40.0-49.9 kg, 1500 mg for 50.0-70.9 kg, 2000 mg for ≥75.0 kg. Used in both experimental arms (BZMD and BZMH groups) and control group as part of tuberculosis treatment regimen.
• Препарат Delamanid (D)
  Delamanid tablets administered orally at 100 mg twice daily (total daily dose 200 mg) throughout the entire treatment period (17 weeks). Used only in the BZMD experimental arm as part of the 4-month short-course regimen for drug-susceptible tuberculosis treatment.
• Препарат Isoniazid (H)
  Isoniazid tablets administered orally at 300 mg once daily in the morning throughout the entire treatment period. Used in the BZMH experimental arm (17 weeks) and in the standard control group (26 weeks) as part of tuberculosis treatment regimens.
• Препарат Rifampicin (R)
  Rifampicin tablets administered orally once daily in the morning throughout the entire treatment period (26 weeks). Dosing by weight: 450 mg for 40.0-49.9 kg, 600 mg for 50.0-70.9 kg and ≥75.0 kg. Used only in the standard control group as part of the 6-month standard tuberculosis treatment regimen.
• Препарат Ethambutol (E)
  Ethambutol tablets administered orally during the intensive phase (8 weeks). Dosing by weight: 750 mg for 40.0-49.9 kg, 1000 mg for 50.0-70.9 kg and ≥75.0 kg. Used only in the standard control group as part of the 6-month standard tuberculosis treatment regimen.

Первичные конечные точки

• Early Bactericidal Activity CFU 0-14 (EBA CFU₀-₁₄) [Срок оценки: Day 0 (baseline) to Day 14 of treatment]

Вторичные конечные точки (5)

• Early Bactericidal Activity CFU 0-2 (EBA CFU₀-₂) [Срок оценки: Day 0 to Day 2]
• Early Bactericidal Activity CFU 0-7 (EBA CFU₀-₇) [Срок оценки: Day 0 to Day 7]
• Early Bactericidal Activity TTP 0-14 (EBA TTP₀-₁₄) [Срок оценки: Day 0 (baseline) to Day 14 of treatment]
• Sustained Microbiological Clearance Rate [Срок оценки: Week 17 (end of treatment)]
• Safety - Grade 3 or Higher Adverse Events [Срок оценки: From enrollment through study completion, up to 52 weeks]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, Lu Q, Kusmiati T, Balanag VM, Lee SL, Ruslami R, Pokharkar Y, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM; TRUNCATE-TB Trial Team. Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Fe PMID 36808186
• Cevik M, Thompson LC, Upton C, Rolla VC, Malahleha M, Mmbaga B, Ngubane N, Abu Bakar Z, Rassool M, Variava E, Dawson R, Staples S, Lalloo U, Louw C, Conradie F, Eristavi M, Samoilova A, Skornyakov SN, Ntinginya NE, Haraka F, Praygod G, Mayanja-Kizza H, Caoili J, Balanag V, Dalcolmo MP, McHugh T, Hunt R, Solanki P, Bateson A, Crook AM, Fabiane S, Timm J, Sun E, Spigelman M, Sloan DJ, Gillespie SH; PMID 38768617
• Tasneen R, Garcia A, Converse PJ, Zimmerman MD, Dartois V, Kurbatova E, Vernon AA, Carr W, Stout JE, Dooley KE, Nuermberger EL. Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0239821. doi: 10.1128/aac.02398-21. Epub 2022 Mar 22. PMID 35315690

Идентификаторы

NCT: NCT07129629 · Beams Study

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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