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PROSPECT Study

Date: 2026-07-24 Author:

Study full title: A Randomized, Controlled, Pragmatic Phase IV Trial to Evaluate the Efficacy and Safety of an All-Oral Short-Course Regimen Containing Bedaquiline in Chinese Patients with Multidrug-Resistant Pulmonary Tuberculosis

  • Study acronym: PROSPECT
  • Approval Date: December 8, 2021
  • Primary sponsor: Innovation Alliance on Tuberculosis Diagnosis and Treatment (IATB, Beijing)
  • Co-sponsor: Janssen Research & Development, LLC, Xian Janssen Pharmaceutical Ltd
  • Study phase: Phase 4 Post-marketing Confirmatory Clinical Trial
  • Study type: Interventional, Pragmatic, Multicenter, Open-label, Parallel-group Randomized Controlled Trial

  • Study objectives

  • Primary objective: to compare the efficacy of all-oral short-course regimen (SCR) containing bedaquiline versus bedaquiline-free all-oral SCR at Week 40 (end of treatment) among Chinese adult multidrug-resistant tuberculosis (MDR-TB) patients, with the proportion of participants achieving favorable outcome as the primary endpoint.

  • Secondary objectives

  1. Evaluate the proportion of participants achieving favorable outcome at Week 88 (48 weeks after completion of treatment).
  2. Assess the treatment success rate defined by WHO 2014 criteria at Week 40.
  3. Compare modified favorable outcomes (defined by the last 2 consecutive negative sputum cultures) between two groups at Week 40 and Week 88.
  4. Evaluate the overall safety profiles of two regimens, including all-cause mortality, proportion of participants with Grade ≥3 treatment-emergent adverse events (TEAEs), and overall incidence of TEAEs.
  5. Compare the incidence of tuberculosis relapse and exogenous reinfection during the 48-week post-treatment follow-up period.
  6. Assess the rate of acquired resistance to bedaquiline and other backbone anti-tuberculosis drugs in both treatment arms.

  • Inclusion criteria

  1. Voluntarily sign written informed consent before any study-related procedures are performed.
  2. Positive sputum culture for Mycobacterium tuberculosis at screening.
  3. Rifampicin resistance confirmed by GeneXpert, accompanied by katG mutation detected via molecular drug susceptibility testing (DST), confirming co-resistance to isoniazid (MDR-TB confirmation).
  4. Chest CT imaging consistent with pulmonary tuberculosis lesions.
  5. Aged 18 to 65 years old, male or female subjects.
  6. Normal serum potassium, magnesium and corrected calcium levels at screening.
  7. Willing to accept HIV serology testing at screening.
  8. Reside within the service area of the study site and able to complete the full treatment and follow-up schedule.
  9. Females with childbearing potential must adopt dual contraceptive measures;
  10. Males without vasectomy must consistently use condoms during sexual intercourse.
  11. Agree to maintain effective contraception throughout the 40-week treatment period:

Exclusion criteria

 
  1. Clinically significant Grade 3 or 4 laboratory abnormalities at screening:
  2. Molecular or phenotypic DST confirms fluoroquinolone resistance, inhA-mediated low-level isoniazid resistance, or baseline resistance to any backbone anti-TB drug in the study regimen (bedaquiline excluded).
  3. Prior treatment with bedaquiline at any time point before screening.
  4. Received any second-line anti-TB drug included in the study regimen for a cumulative duration of ≥4 weeks prior to enrollment.
  5. Confirmed pregnancy, planned pregnancy or breastfeeding status.
  6. Unable or unwilling to comply with scheduled treatment and follow-up visits.
  7. QTcF interval ≥450 ms on screening ECG.
  8. ALT/AST >3× upper limit of normal (ULN), or total bilirubin >2×ULN;
  9. Creatinine clearance <30 mL/min;
  10. Hemoglobin ≤7.0 g/dL; platelet count <50 ×10⁹/L.
  11. Personal or family medical history of long QT syndrome, torsades de pointes, heart failure, sinus bradycardia (<50 bpm), symptomatic arrhythmia or unexplained cardiogenic syncope.
  12. Severe uncontrolled cardiovascular, hepatic, renal, hematological, malignant or systemic disorders; uncontrolled diabetes mellitus; severe mental disorders judged to interfere with study compliance.
  13. HIV seropositive subjects.
  14. Infection with non-tuberculous mycobacteria.
  15. Isolated extrapulmonary tuberculosis, or disseminated/miliary/CNS/bone/joint tuberculosis.
  16. Confirmed hypersensitivity or intolerance to any component of the study treatment regimens.
  17. Concurrent participation in another interventional clinical trial of investigational medicinal products.
  18. Critically ill subjects deemed unable to complete the full study course by investigators.

  • Intervention Arms (Subjects are randomly assigned at a 1:1 ratio, stratified by study site and lung cavity severity (no cavity / single cavity <2 cm / bilateral cavities ≥2 cm).

  • Arm 1: Bedaquiline-containing experimental all-oral short-course regimen
    Bedaquiline (BDQ, 100 mg oral tablet):
    Weeks 1–2: 400 mg once daily with meals;
    Weeks 3–24: 200 mg three times weekly (at least 48 hours between two doses);
    If sputum culture remains positive at Week 16, BDQ administration will be extended to full 40 weeks.
    Fixed backbone drugs administered for full 40 weeks: Levofloxacin (LFX, weight-adjusted daily dose), Cycloserine (CS, weight-adjusted daily dose), Clofazimine (CFZ 100 mg daily).
    Linezolid (LZD 600 mg daily): administered for a minimum of 24 weeks.

  • Arm 2: Bedaquiline-free control all-oral short-course regimen
    No bedaquiline included in the regimen; all below drugs administered as scheduled:
    Full 40 weeks: Levofloxacin (LFX), Cycloserine (CS), Clofazimine (CFZ), Pyrazinamide (PZA, weight-adjusted daily dose).
    Linezolid (LZD 600 mg daily): administered for a minimum of 24 weeks.
    Prothionamide (PTO, weight-adjusted daily dose): administered only for the first 16 weeks of treatment.

  • Core Endpoint Definitions
    Primary Endpoint: Favorable Outcome (Week 40, End of Treatment)
    Subjects without any unfavorable classification, with 3 consecutive negative sputum cultures collected at separate visits; the last sputum sample must be collected no earlier than 8 weeks prior to Week 40.
    Unfavorable outcome includes any of the following events: premature permanent discontinuation of study treatment, administration of ≥2 off-protocol anti-TB drugs, treatment duration exceeding permitted limit, all-cause death, loss to follow-up, confirmed tuberculosis relapse or exogenous reinfection. Single non-group A drug replacement (excluding delamanid) is not classified as unfavorable outcome.
    Secondary Endpoint: Modified Favorable Outcome
    Subjects without unfavorable classification, with the last 2 consecutive negative sputum cultures collected at separate visits; the last sputum sample collected no earlier than 8 weeks prior to assessment timepoint, consistent with STAGE 2 trial definition.
    Treatment Success (WHO 2014 Definition): subjects complete the full assigned treatment course, or present ≥3 negative sputum cultures collected at separate timepoints after the initial 6-month intensive phase.

  • Sample Size & Statistical Methodology: total randomized subjects: 212 (106 per arm); 95 evaluable subjects per arm for primary efficacy analysis.

  • Trial design: Non-inferiority trial, one-sided α = 0.025, pre-specified non-inferiority margin = 15%.
  • Statistical assumptions under null hypothesis: Favorable outcome rate of control arm = 85%; favorable outcome rate of BDQ arm =70%; statistical power =80%; anticipated 10% loss from evaluable population.
  • Primary analysis: Cochran-Mantel-Haenszel stratified analysis (stratified by study site and lung cavity). Non-inferiority is concluded if the upper bound of the 95% confidence interval for between-group risk difference is less than 15%.
  • No pre-planned interim analysis; no independent Data Monitoring Committee (DMC) established.
  • Analytic sets defined: Intent-to-Treat (ITT), Safety Set, Modified ITT (mITT), Efficacy Analysis Set.

  • Full Study Timeline per Subject

  1. Screening phase: Maximum 8 weeks (eligibility screening, molecular/phenotypic DST, baseline safety tests).
  2. Active treatment phase: Fixed 40 weeks of assigned oral anti-TB regimen.
  3. Post-treatment follow-up phase: 48 consecutive weeks after Week 40 end-of-treatment.
  4. Total individual study duration (excluding screening): 88 weeks.

  • Study Assessments
    Efficacy Assessments: serial sputum smear and MGIT 960 liquid culture collected at all scheduled visits (W2, W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W52, W64, W76, W88). Phenotypic DST and mycobacterial strain genotyping are performed for all culture-positive isolates to distinguish endogenous relapse and exogenous reinfection.
    Safety Assessments: 

  1. Serial physical examination, vital signs, visual acuity test, urinalysis, complete blood count, serum biochemistry panel, TSH test (only for subjects receiving prothionamide).
  2. Serial ECG recordings at baseline and all treatment visits; extended ECG monitoring for subjects with prolonged QTcF or BDQ extended to 40 weeks.
  3. Hepatitis B and C serology only performed at screening.
  4. Continuous adverse event (AE) capture from ICF signature to final Week 88 follow-up; all serious adverse events (SAEs) reported to sponsor within 24 hours after investigator identification.

  • Randomization & Blinding

  • Randomization tool: Interactive Web Response System (IWRS), permuted block design, allocation ratio 1:1, stratified by study site and lung cavity severity.
  • Blinding status: Open-label trial; no blind implemented for investigators, site staff or subjects.

  • Trial Background & Status: PROSPECT is a post-marketing commitment study required by NMPA CDE for bedaquiline marketing approval in China, jointly conducted by IATB and Xian Janssen Pharmaceutical Ltd. Protocol Amendment 2 received full regulatory and ethical approval on December 8, 2021. Multi-center enrollment was launched across national IATB tuberculosis network hospitals. Primary analysis will be conducted after the last subject completes Week 88 post-treatment follow-up.