All-Oral Short-Course BDL Regimen for MDR/RR-Pulmonary Tuberculosis Study Protocol (V2.0)

Basic Trial Information

1. Study Background

2. Core Study Objectives

1. Short-term efficacy: Evaluate sputum conversion and clinical cure outcomes of BDL regimen within the 26-week intensive treatment phase
2. Long-term efficacy: Assess TB relapse rate and sustained cure status during 1-year post-treatment follow-up
3. Safety profile: Monitor incidence, severity and management of treatment-emergent adverse events (TEAEs) related to BDL triple therapy
4. Cost-effectiveness: Conduct economic analysis to compare medical expenditure of short-course BDL versus standard long-term MDR-TB regimens

3. Trial Type

1. Intervention: Receive 26-week all-oral BDL triple therapy (extend to maximum 39 weeks if persistent sputum positivity between Week 16–26)
2. Intensive-phase monitoring: Serial laboratory, imaging, ECG and symptom assessments throughout treatment; short-term efficacy & safety analysis upon Week 26 completion
3. Post-treatment follow-up: 12-month regular follow-up every 3 months; long-term efficacy and cost-benefit analysis after full follow-up

4. Eligibility Criteria

Inclusion Criteria

1. Voluntary participation with signed informed consent
2. Microbiologically confirmed MDR/RR pulmonary TB (culture or molecular testing within 2 months)
3. Age ≥ 18 years old
4. Prior exposure to BDQ/DLM/LZD ≤4 weeks or no prior use
5. Positive mycobacterial sputum culture within 1 month, without effective second-line anti-TB treatment recently
6. Baseline ECG QTcF <450 ms; no severe cardiac dysfunction or respiratory failure
7. Able to complete scheduled medication, examinations and follow-up per trial requirements

Exclusion Criteria

1. Grade 3/4 peripheral neuropathy, or mild neuropathy with high progression risk
2. Liver dysfunction: ALT/AST ≥3×ULN or total/direct bilirubin ≥2×ULN
3. Pregnant, lactating or childbearing women without effective contraception
4. Participation in other investigational new drug trials within 3 months
5. Congenital long QT syndrome, symptomatic arrhythmia, uncontrolled severe hypertension, heart failure or untreated hypothyroidism
6. Severe electrolyte disturbance (hypokalemia, hypomagnesemia, hypocalcemia)
7. Known hypersensitivity to BDQ, DLM, LZD or excipients
8. BMI <17 kg/m²
9. Karnofsky score <50 or predicted survival <6 months
10. Planned pulmonary surgical intervention during treatment

5. Intervention Regimen: BDL Triple All-Oral Therapy

• Core drugs: Bedaquiline (B), Delamanid (D), Linezolid (L)
• Standard treatment duration: 26 weeks (6–9 months short-course core period)
• Extended treatment rule: If sputum smear/culture remains positive or reconverts positive during Week 16–26, extend BDL therapy to maximum 39 weeks or discontinue trial treatment
• Drug supply: Free domestic bedaquiline for full course, delamanid for initial 13 weeks, full-course linezolid provided by the study

6. Scheduled Monitoring Assessments

6.1 Efficacy Monitoring (Sputum, Imaging & Clinical Symptoms)

1. Sputum smear & liquid/Roche culture: Baseline, Week 1/2/4/6/8, then every 4 weeks until Week 26
2. Mycobacterial DST: Baseline; repeat DST at Week 26 if culture remains positive
3. Chest CT: Baseline (within 1 month pre-treatment), every 12 weeks during treatment, additional CT at treatment discontinuation
4. TB symptoms & body weight: Consistent schedule with sputum testing visits

6.2 Safety Monitoring (Lab & Cardiac/Otolaryngologic/Ophthalmologic Tests)

1. ECG: Baseline, weekly from Week 1–16, Week 20 & 26; immediate unscheduled ECG if QTcF ≥450 ms
   • Safety management: QTcF 450–499 ms: weekly ECG recheck; QTcF ≥500 ms (confirmed by repeat ECG): expert panel decides temporary/permanent drug withdrawal; resume therapy once QTcF <450 ms
2. Blood routine, urine routine, liver/kidney function, serum electrolytes (K/Mg/Ca): Baseline, weekly Week 1–16, Week 20 & 26
3. Hearing & visual acuity screening: Baseline, every 4 weeks until Week 26
4. HIV screening at baseline; repeat testing for high-risk subjects during trial
5. Pregnancy test for women of childbearing age at baseline and suspected pregnancy visits

6.3 Post-Treatment Follow-Up (12 months after Week 26)

• Frequency: Every 3 months
• Assessments: TB clinical symptoms, sputum culture, chest CT to monitor relapse and long-term cure

7. Sample Size Calculation

8. Risks, Benefits & Patient Obligations

Potential Risks

1. Drug-related adverse events: QTc prolongation, gastrointestinal discomfort, liver injury, headache, peripheral neuropathy; rare severe reactions including anaphylactic shock and organ failure
2. Phlebotomy-related local pain, bruising or swelling
3. Risk of treatment failure or TB relapse due to inherent difficulty of MDR-TB therapy

Patient Benefits

1. Free supply of core study anti-TB drugs
2. Standardized full-cycle efficacy and safety monitoring with free trial-related examinations
3. Shorter all-oral regimen without injectable agents, potentially higher cure rates and shorter infectious window
4. Long-term follow-up to timely detect and manage relapse

Mandatory Patient Responsibilities

1. Strictly adhere to fixed dosing schedule and all scheduled hospital visits
2. No self-adjustment of anti-TB drugs or initiation of new unapproved therapy without investigator consent
3. Report all adverse symptoms and concurrent medications promptly
4. Complete final safety/efficacy evaluation even upon early trial withdrawal
5. Prohibit enrollment in other interventional clinical trials during participation

9. Informed Consent & Ethics

1. Full written informed consent obtained before any trial procedures; participants retain unconditional right to withdraw at any time without penalty to routine medical care
2. All personal clinical data strictly confidential; individual identifiers removed from published study results; only ethics committees and national clinical trial auditors may access raw data
3. Protocol and consent document approved by the Ethics Committee of Beijing Chest Hospital, Capital Medical University; participants may file ethical appeals for rights violations during trial execution
4. Two identical signed consent copies retained by the patient and study investigator respectively

10. Trial Endpoints Definition

Primary Efficacy Endpoint

Secondary Endpoints

1. Long-term favorable outcome at 12-month post-treatment follow-up (no relapse, sustained culture negativity)
2. Cumulative incidence of Grade ≥3 adverse events throughout treatment and follow-up
3. Cost-effectiveness incremental analysis of BDL short-course versus conventional long-term MDR-TB regimens
4. Current status: following up on going, expected to be completed in 2027