Study Rationale and Background:
Tuberculosis (TB) remains a significant global health threat, with Rifampicin-Resistant TB (RR-TB) posing a particularly severe challenge due to prolonged treatment durations, high toxicity, and suboptimal success rates. While the standard of care in China has historically involved 18-20 month regimens, the World Health Organization (WHO) has recently endorsed shorter, all-oral regimens. The BLMZ regimen, composed of Bedaquiline (B), Linezolid (L), Moxifloxacin (M), and Pyrazinamide (Z), demonstrated high efficacy (89% favorable outcome) in the global endTB trial. However, prospective data on its application and performance in the Chinese population are lacking. This study aims to bridge this evidence gap by prospectively evaluating the efficacy, safety, and feasibility of the 9-month BLMZ regimen in a Chinese RR-TB cohort, thereby informing national policy and clinical practice.
Study Design:
This is a prospective, multicenter, single-arm, open-label, interventional study. The study employs a Bayesian statistical framework with a pre-specified success threshold to evaluate the primary efficacy endpoint. Historical data from the endTB study (BLMZ arm) will be incorporated using a power prior model to augment the statistical analysis, allowing for more robust inference with the planned sample size.
Intervention:
Participants will receive the all-oral BLMZ regimen for a total of 9 months. The regimen consists of:
* Bedaquiline (BDQ): 400 mg once daily for 2 weeks, followed by 200 mg three times per week for the remainder of the 9-month treatment.
* Linezolid (LZD): 600 mg once daily for the first 4 months, followed by a dose reduction to 300 mg once daily (or intermittent dosing) for the remaining 5 months, with provisions for earlier adjustment in case of intolerance.
* Moxifloxacin (MFX): 400 mg once daily. In cases of MFX unavailability, intolerance, or resistance, it may be substituted with Levofloxacin (LFX) at a weight-based dose (750 mg for 35-49.9 kg, 1000 mg for ≥50 kg).
* Pyrazinamide (PZA): Administered at a weight-based dose (750 mg for 30-34.9 kg, 1000 mg for 35-49.9 kg, 1500 mg for ≥50 kg) once daily.
Drug doses are adjusted according to pre-specified weight bands. Treatment may be extended to a maximum of 11 months under specific conditions (e.g., positive culture at Month 2, unclosed cavity at Month 9).
Study Population and Follow-up:
The study will enroll approximately 120 participants aged ≥12 years with bacteriologically confirmed pulmonary RR-TB who are susceptible to fluoroquinolones. Participants may be either treatment-naïve or previously treated for drug-susceptible TB.
The study duration for each participant is 24 months, comprising:
Screening Period: Up to 4 weeks. Treatment Period: 9 months (extendable to 11 months), with monthly on-site visits for clinical, bacteriological (sputum smear and culture), and safety assessments (including hematology, biochemistry, electrolytes, visual acuity, peripheral neuropathy screening, and 12-lead ECG). Chest CT scans are performed at baseline, Month 5, and Month 8.
Post-Treatment Follow-up Period: 15 months, with quarterly visits until Month 24. Follow-up focuses on long-term efficacy and safety, primarily through sputum culture for relapse detection.
Key Technical and Operational Considerations:
1. Outcome Definitions: Favorable and unfavorable outcomes at 9, 18, and 24 months are rigorously defined based on a composite of bacteriological results, treatment modifications, and clinical status, aligning with contemporary TB trial standards.
2. Safety Monitoring: A comprehensive safety management plan is in place. Special attention is given to Adverse Events of Special Interest (AESI), including hepatotoxicity, QT interval prolongation, optic neuropathy, and peripheral neuropathy, with predefined grading and reporting procedures.
3. Concomitant Medication Restrictions: The protocol explicitly prohibits the use of strong CYP3A4 inducers/inhibitors, monoamine oxidase inhibitors, drugs known to cause significant QT prolongation or bone marrow suppression, to minimize drug-drug interactions and overlapping toxicities.
4. Management of Non-Adherence and Interruptions: The protocol allows for temporary treatment interruptions and defines criteria for permanent discontinuation. Strategies to promote adherence are implemented, and the impact of interruptions on the overall treatment duration is clearly specified.
5. Statistical Analysis Plan: The primary analysis will be conducted on the modified Intent-to-Treat (mITT) population. The Bayesian decision rule for success is defined as a posterior probability \>0.95 that the true favorable outcome rate at 18 months is ≥85%. A simulation study was conducted to determine the optimal sample size (n=120) and the power prior weight (ω=0.35) to control Type I error and ensure adequate statistical power.
6. Quality Assurance: The study will be conducted under the principles of Good Clinical Practice (GCP). Data quality will be ensured through centralized monitoring, risk-based source data verification, and regular site training and oversight.
