PA-824-401 Study (BPaLM Study)

A Single-Arm, Multicenter, Open-Label Post-Marketing Clinical Study to Evaluate the Efficacy and Safety of Pretomanid-Containing BPaL Regimen in Patients with Rifampicin-Resistant Pulmonary Tuberculosis

• Study acronym: PA-824-401
• Protocol version: V6.0, 07 Jan 2025
• Primary sponsor: Shenyang Hongqi Pharmaceutical Co., Ltd
• Secondary sponsor: Innovation Alliance on Tuberculosis Diagnosis and Treatment (Beijing)
• Lead study site: Beijing Chest Hospital, Capital Medical Universitys
• Principal Investigator: Gao Mengqiu
• Study phase: Phase IV Post-marketing Confirmatory Trial
• Study type: Interventional, Single-arm, Multicenter, Open-label

• Study Background: Globally, around 400,000 new rifampicin-resistant TB (RR-TB) cases emerge annually, with China ranking high in DR-TB burden and low treatment success rates for MDR-TB. Pretomanid (PA-824), developed by TB Alliance, exerts bactericidal activity against both replicating and non-replicating Mycobacterium tuberculosis. The all-oral BPaL regimen (Bedaquiline + Pretomanid + Linezolid) demonstrated ~90% cure rate for XDR/MDR-TB in the pivotal Nix-TB trial with manageable adverse events. WHO 2025 guidelines designated BPaLM as the preferred regimen for MDR-TB. Pretomanid obtained domestic marketing approval in China in Dec 2024; this post-marketing study aims to generate real-world Chinese clinical data for the regimen.

• Study objectives

• Primary objective: To evaluate the efficacy and safety of the pretomanid-based BPaL regimen among Chinese patients with rifampicin-resistant pulmonary tuberculosis (RR-TB).

• Secondary objectives

1. Characterize long-term safety profile of pretomanid combination therapy.
2. Assess serial sputum culture conversion rates across treatment visits.
3. Quantify favorable treatment response rates at Week 26 (or Week 39 for extended therapy).
4. Describe changes in TB clinical symptoms and chest CT lesions over treatment.

• Inclusion criteria

1. Voluntarily sign written informed consent prior to any study procedures.
2. Age 14–65 years, any gender; body weight >30 kg.
3. Sputum culture positive within 4 weeks of screening, or smear ≥2+ once / ≥1+ twice.
4. Molecular or phenotypic DST confirming rifampicin resistance.
5. Chest CT consistent with pulmonary tuberculosis lesions.
6. Reproductive-age females with negative urine pregnancy test and effective contraception; male participants commit to consistent contraception during study.
7. Prior exposure to bedaquiline/linezolid/delamanid/pretomanid <1 month, or confirmed susceptibility if exposure ≥1 month.

• Exclusion criteria

1. Poor adherence unable to complete full treatment and follow-up schedule.
2. Enrolled in another interventional clinical trial within 3 months pre-screening.
3. Known hypersensitivity to nitroimidazoles, bedaquiline or linezolid.
4. Recent use of strong CYP450 inhibitors/inducers within 30 days pre-dosing.
5. Severe disseminated, extrapulmonary, miliary, CNS, bone or abdominal TB.
6. Advanced chronic lung disease (silicosis, severe fibrosis, uncontrolled COPD/asthma).
7. Clinically significant hepatic/renal impairment (ALT/AST ≥3×ULN, creatinine ≥1.5×ULN), uncontrolled diabetes, active alcohol/drug abuse.
8. Baseline QTcF/QTcB >450ms, history of long QT syndrome, torsades de pointes, heart failure, or concurrent QT-prolonging medications within 30 days pre-dosing.
9. Severe neurological, psychiatric, epileptic, hematologic, autoimmune or malignant disorders, long-term immunosuppressant use.

• Intervention Regimens:
  All patients receive 6–9 months all-oral therapy, followed by 12 months post-treatment follow-up.
  BPaLM Regimen (Fluoroquinolone susceptible / unknown DST)
  Bedaquiline (B): 40mg qd Weeks 1–14; then 20mg thrice weekly
  Pretomanid (Pa): 20mg qd daily throughout treatment
  Linezolid (L): 60mg qd; may reduce to 30mg qd or interrupt for toxicity
  Moxifloxacin (M): 40mg qd daily
  BPaL Regimen (Fluoroquinolone resistant)
  Discontinue moxifloxacin, retain B-Pa-L dosing above.
  Treatment extension rule: If sputum culture remains positive Week 16–26, extend total therapy to 39 weeks; otherwise complete 26-week course.
  Study drug supply: Pretomanid manufactured by Shenyang Hongqi Pharma; other agents sourced commercially.

• Core Endpoint Definitions
  Primary Endpoint
  Proportion of participants with negative sputum culture at Week 26 (or Week 39 for extended treatment), assessed via exact binomial method with 95% CI. Subgroup analysis stratified by RR-TB / MDR-TB phenotype.
  Secondary Endpoints

1. Serial sputum culture conversion proportion at Weeks 2,4,6,8,12,16,20.
2. Favorable treatment response rate at Week 26/39.
3. Frequency and severity of treatment-emergent adverse events (TEAEs).
4. Radiographic improvement of pulmonary lesions and cavities on serial CT scans.

• Treatment Outcome Classification

1. Cure: Complete 6/9-month therapy, sustained negative sputum culture without relapse, no treatment failure.
2. Treatment completed: Full therapy course finished without meeting cure or failure criteria.
3. Treatment success = Cure + Treatment completed.
4. Treatment failure: Persistent positive culture, permanent discontinuation, or ≥2 study drug substitutions.
5. Unfavorable outcomes: Death, loss to follow-up, unevaluable bacteriology.

• Study Assessments Schedule
  Screening Phase (<4 weeks): Demographics, medical history, eligibility confirmation, DST testing, chest CT, CBC, urinalysis, liver/renal function, electrolytes, HbA1c, ECG, visual/color vision exam, peripheral neuropathy assessment, urine pregnancy test (female).
  Treatment Phase (Weeks 2,4,6,8,12,16,20,26; extended to Week39 if needed)
  Sputum smear & liquid culture, repeat CT, full laboratory panel, ECG, ophthalmic screening, neuropathy evaluation, adverse event documentation, medication adherence review. Culture-positive isolates at Week26/39 undergo full phenotypic DST.
  Post-Treatment Follow-Up (Months 3,6,9,12 after therapy end)
  Sputum bacteriology, safety lab tests, clinical symptom and radiographic review.
  Safety Monitoring & Key Toxicity Management
  Common TEAEs of BPaL
  Hepatic enzyme elevation, nausea/vomiting, QT interval prolongation, linezolid-related anemia, peripheral neuropathy, optic neuropathy, myelosuppression.
  Critical Toxicity Intervention Rules

1. Hepatic toxicity: Pause all anti-TB therapy if total bilirubin >2×ULN with transaminitis; ALT/AST >8×ULN; ALT/AST >5×ULN sustained ≥2 weeks.
2. Myelosuppression: Reduce/interrupt/permanently stop linezolid if Hb<80g/L, ANC<0.75×10⁹/L, PLT<50×10⁹/L.
3. Peripheral neuropathy: Taper linezolid to half dose or suspend until symptom resolution.
4. Optic neuropathy: Hold linezolid for visual acuity/color vision impairment; permanent discontinuation if neuropathy confirmed.
5. QT prolongation: Discontinue study drugs if QTcF ≥500ms, new complete heart block or Mobitz type II block.

• SAE Reporting Requirement
  All serious adverse events must be notified to the sponsor within 24 hours of investigator awareness; suspected unexpected serious adverse reactions (SUSARs) submitted to NMPA and all study sites.

• Sample Size & Statistical Methodology
  Target enrollment: 110 participants across 27 national TB designated hospitals in China, 2–5 patients per center.
  Analysis sets defined:

• 1. Enrolled Subject Set (ES): All screened participants (screening descriptive statistics).
  2. Full Analysis Set (FAS): All enrolled subjects (baseline demographics).
  3. Efficacy Analysis Set (EAS): All participants receiving ≥1 dose of study medication (primary efficacy evaluation).
  4. Safety Set (S): All participants receiving ≥1 dose of study medication (all safety analyses).

• Safety analysis: Descriptive tabulation of TEAE frequency, severity, causality, laboratory shifts, ECG QT changes, ophthalmic findings.

• Study Timeline

1. Enrollment window: June 2025 – September 2025
2. Final database lock & study summary: January 2027
3. Individual participant total duration: <4w screening + 26–39w treatment + 12m post-treatment follow-up

• Quality Control & Data Management

1. Uniform training for all site investigators, standardized CRF completion criteria.
2. Source data verification via on-site monitoring; data queries (DRQs) resolved before database lock.
3. Target dropout rate controlled ≤20%.
4. All source documents archived at Beijing Chest Hospital as primary repository.

• Patient Subsidy

1. Pretomanid supply: 4 free boxes for 6-month therapy; 5 free boxes for extended 9-month therapy (remaining boxes purchased by participant).
2. Visit stipend: ¥10 per treatment-period visit; ¥30 per post-treatment follow-up visit; total maximum stipend per participant capped at ¥2000.

• Participating Study Sites (27 Multicenter Hospitals)
  Chengdu Public Health Clinical Center, Anhui Chest Hospital, Changsha Central Hospital, Henan Chest Hospital, Fuzhou Pulmonary Hospital, Changchun Infectious Disease Hospital, Heilongjiang Infectious Disease Hospital, Shaanxi TB Prevention & Treatment Hospital, Jiangxi Chest Hospital, Wuhan Pulmonary Hospital, Shandong Public Health Clinical Center, Nanning No.4 People’s Hospital, Xizang No.3 People’s Hospital, Yichang No.3 People’s Hospital, Inner Mongolia No.4 Hospital, Taiyuan No.4 People’s Hospital, Guangxi Chest Hospital, Harbin Chest Hospital, Hotan Prefectural Infectious Disease Hospital, Hulunbuir No.2 People’s Hospital, plus additional regional TB designated centers.

• Trial Background & Status: 
  This post-marketing Phase IV trial is required for real-world clinical validation of domestic pretomanid in Chinese RR-TB patients, aligned with 2025 WHO updated DR-TB treatment guidelines recommending BPaLM as first-line short-course all-oral regimen. Multi-center patient recruitment launched nationwide in June 2025. Primary efficacy and safety analysis will be performed after the last participant completes 12-month post-treatment follow-up in January 2027.