This study aims to assess quabodepistat-based treatment regimens for RR/MDR-TB. The study will enroll adults and adolescents with rifampicin-resistant or multidrug-resistant pulmonary TB. The main goal is to see if a new drug called quabodepistat, when combined with other TB drugs, can shorten treatment duration to 4 months and be as effective and safer than current WHO endorsed treatment regimen given for 6-months. The study will compare different drug combinations in two groups of patients: those whose TB is sensitive to fluoroquinolones and those whose TB is resistant to fluoroquinolones. Participants will be randomly assigned to receive either the new treatment or the standard treatment. The study will last for 16 months for each participant and will measure how well the treatments work and how safe they are.
Age ≥14 years
Body weight ≥30.0 kg
Able to provide written informed consent (if under 18, requires both participant assent and parent/guardian consent)
Documented pulmonary TB: Mtb confirmed by Xpert MTB/RIF Ultra (semi-quantitative result of 'low', 'medium', or 'high')
Known/suspected resistance to BDQ, PMD, LZD, or QBS
Prior treatment with BDQ, PMD, LZD, DLM, QBS, or DprE1 inhibitors for ≥1 month within past 3 months
Severe extrapulmonary TB
Abnormal laboratory values: ALT/AST >2.5×ULN, Total bilirubin >1.5×ULN, eGFR <60 mL/min/1.73m², Hemoglobin <8 g/dL, Platelets <100,000 cells/mm³, WBC <2.0×10⁹/L, ANC <1000 cells/μL, and HbA1c >9.0%
Parallel
BPaQM
DrugBedaquiline 400 mg once daily for 2 weeks then 100 mg once daily for 15 weeks + Pretomanid 200 mg QD for 17 weeks + Quabodepistat 30 mg once daily for 17 weeks + Moxifloxacin 400 mg once daily for 17 weeks
BPaLM
DrugBedaquiline 400 mg once daily for 2 weeks then 200 mg thrice a week for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Linezolid 600 mg once daily for 26 weeks + Moxifloxacin 400 mg once daily for 26 weeks
BPaQ
DrugBedaquiline 400 mg once daily for 2 weeks then 100 mg once daily for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Quabodepistat 30 mg once daily for 26 weeks
BPaL
DrugBedaquiline 400 mg once daily for 2 weeks then 200 mg thrice a week for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Linezolid 600 mg once daily for 26 weeks
Proportion of participants with unfavorable outcome.
Unfavorable outcome is defined as a participant experiencing at least one of the following: death, treatment failure, change in regimen, or sputum culture with growth of Mycobacterium tuberculosis at certain timepoints as follows: Failure to achieve SCC at the end of the treatment period that results in a change in anti-mycobacterial therapy or Relapse during the follow-up period (i.e., the period from end of treatment to Month 12 post-randomization.
Incidence of Grade ≥3 Treatment-Emergent Adverse Events, Serious Adverse Events, or Adverse Events Leading to Dose Reduction or Discontinuation (Safety and Tolerability).
A participant experiencing at least one of the following: Grade 3 toxicity or higher treatment-emergent adverse events (TEAEs), serious TEAEs, or TEAEs leading to dose reduction or discontinuation.
Time to first occurrence of any event meeting the unfavorable outcome definition.
Time to the first occurrence of any event listed under the primary efficacy endpoint.
Time to sputum culture conversion.
Time from randomization to the first of two consecutive negative sputum cultures taken at least 1 week apart.
Proportion of participants with sputum culture conversion.
Proportion of participants achieving sputum culture conversion, defined as two consecutive negative cultures taken at least 1 week apart.
Proportion of participants with microbiological relapse.
Proportion of microbiological relapse.
To evaluate health-related quality of life measures in the experimental and SoC arms.
Changes from baseline in SF-36v2 Physical and Mental Component Summary scores, SF-6D utility score, SGRQ Total score and subscores (Symptoms, Activity, and Impacts), CAAT total score and subscores (symptom burden items and daily impacts items), and descriptive summaries of PRO-CTCAE adverse event frequency, severity, and interference over time.
To estimate the difference in the proportion of unfavorable outcomes between the investigational and SoC arms at specified timepoints.
Proportion of participants with unfavorable outcome at specified timepoints beyond the primary endpoint assessment at 12 months post-randomization to evaluate durability of treatment effect.
To estimate the difference in the proportion of microbiological relapse between the investigational and SoC arms at specified timepoints.
Proportion of participants with microbiological relapse at specified timepoints beyond the primary endpoint assessment at 12 months post-randomization to evaluate durability of treatment effect.
To evaluate the development of resistance and cross-resistance to anti-TB drugs in all treatment arms.
Proportion of participants developing drug resistance during the trial and proportion of participants developing cross-resistance between bedaquiline and quabodepistat during the trial, as determined by phenotypic drug susceptibility testing and genotyping.
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