# 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.

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.

Inclusion Criteria:

1. Age ≥18 years and ≤60 years
2. Male or female
3. Body weight 40-90 kg
4. Capable of producing adequate sputum, with collection of at least 10ml overnight sputum
5. Willing to participate in trial treatment and follow-up, with signed informed consent (legal guardian may sign for patients lacking civil capacity)
6. 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
7. Rifampicin-susceptible based on molecular drug susceptibility testing or conventional drug susceptibility testing
8. No anti-TB treatment for more than 3 days received within 6 months before the screening period
9. Subjects whose imaging findings meet the diagnostic criteria for TB, as determined by the investigator
10. Women of childbearing potential who have not undergone surgical sterilization must agree to use appropriate contraceptive methods

Exclusion Criteria:

1. Evidence of concurrent extrapulmonary TB
2. Subjects who have participated in other clinical studies within 8 weeks before the screening period
3. Confirmed resistance of mycobacterium tuberculosis isolates to any of the following: Isoniazid, fluoroquinolones, revealed by molecular drug susceptibility testing
4. Known allergy or intolerance to any study drug
5. Patients who cannot receive oral therapy
6. 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
7. The hematology indicates white blood cells <3.0×10⁹/L, or hemoglobin <80 g/L, or platelets <80×10⁹/L
8. The estimated glomerular filtration rate (eGFR) is less than 60 mL/min/1.73 m²
9. The blood electrolyte test indicates a baseline serum potassium level less than 3.5 mmol/L
10. 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)
11. 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
12. Combined heart failure, coronary artery disease, myocardial infarction, ventricular hypertrophy, clinically significant arrhythmia, poorly controlled hypertension-related cardiovascular disease
13. Patients with known QT prolongation syndrome or a family history thereof
14. 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)
15. Subjects with known bleeding disorders or family history of bleeding disorders
16. Subjects with HIV infection
17. Subjects with known optic neuritis, history of alcoholism, gout, epilepsy, mental illness, porphyria, myasthenia gravis, or malignant tumors
18. Patients with type I or type II diabetes, or HbA1c ≥6.5%, or random blood glucose ≥11.1 mmol/L with typical diabetic symptoms
19. Pregnant or lactating patients

De-identified individual participant data (IPD) underlying the results reported in this study will be shared, including:

1. Efficacy data: Early bactericidal activity measurements (CFU counts, time to positive culture), sustained microbiological clearance rates, and relapse rates
2. Safety data: Adverse events, serious adverse events, laboratory values, and vital signs
3. Pharmacokinetic data: Drug concentration measurements and calculated PK parameters for participants who consented to PK sampling
4. Demographic and baseline characteristics: Age, sex, body weight, baseline disease characteristics, and medical history
5. Treatment data: Drug dosing, treatment duration, adherence, and treatment modifications Data will be shared after de-identification and removal of all direct and indirect identifiers. The study protocol, statistical analysis plan, informed consent form, and clinical study report will also be made available.

Not applicable - open-label study