A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis

Phase 3RecruitingNCT07209761

Otsuka Pharmaceutical Development & Commercialization, Inc.532 enrolled

Overview

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.

This is a Phase 3, randomized, open-label, multicenter trial evaluating quabodepistat-containing regimens for rifampicin-resistant/multidrug-resistant (RR/MDR) pulmonary tuberculosis (TB). The study aims to enroll 532 participants aged 14 years and older. The study has two main cohorts: Fluoroquinolone-sensitive RR/MDR-TB (432 participants): * Experimental arm: BPaQM (bedaquiline, pretomanid, quabodepistat, moxifloxacin) for 4 months * Control arm: BPaLM (bedaquiline, pretomanid, linezolid, moxifloxacin) for 6 months Fluoroquinolone-resistant RR/MDR-TB (100 participants): * Experimental arm: BPaQ (bedaquiline, pretomanid, quabodepistat) for 6 months * Control arm: BPaL (bedaquiline, pretomanid, linezolid) for 6 months The primary efficacy endpoint is an unfavorable outcome by 12 months post-randomization. Secondary endpoints include time to unfavorable outcome, time to sputum culture conversion, and safety/tolerability assessments. Participants will be followed for 16 months post-randomization. The study will be conducted at approximately 40 sites in up to 12 countries. An independent Data Monitoring Committee and Endpoint Adjudication Committee will be used in the study. The trial aims to evaluate if quabodepistat-containing regimens can shorten treatment duration to 4 months for fluoroquinolone-sensitive RR/MDR-TB and provide a safer alternative to linezolid-containing regimens for both fluoroquinolone-sensitive and fluoroquinolone-resistant RR/MDR-TB.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Interventions

BPaQMDRUG

Bedaquiline 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

BPaLMDRUG

Bedaquiline 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

BPaQDRUG

Bedaquiline 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

BPaLDRUG

Bedaquiline 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

Eligibility

Sex: ALLMin age: 14 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥14 years 2. Body weight ≥30.0 kg 3. Able to provide written informed consent (if under 18, requires both participant assent and parent/guardian consent) 4. Documented pulmonary TB: Mtb confirmed by Xpert MTB/RIF Ultra (semi-quantitative result of 'low', 'medium', or 'high') 5. Rifampicin resistance confirmed by Xpert MTB/RIF Ultra test 6. Chest radiograph consistent with active TB disease 7. Able to provide sputum sample 8. Participants of childbearing potential must use 2 different approved birth control methods during treatment and for 12 weeks after last dose 9. Willing to have HIV test (unless previous positive result confirmed) 10. For HIV-positive participants: On stable antiretroviral regimen (dolutegravir, lamivudine/emtricitabine, tenofovir) for ≥3 months, Viral load \<200 copies/mL, and CD4 count \>100 cells/mL Exclusion Criteria: 1. Known/suspected resistance to BDQ, PMD, LZD, or QBS 2. Prior treatment with BDQ, PMD, LZD, DLM, QBS, or DprE1 inhibitors for ≥1 month within past 3 months 3. Severe extrapulmonary TB 4. 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% 5. Pre-existing peripheral neuropathy (≥Grade 1), optic neuritis, or visual impairment 6. Co-enrollment in other therapeutic trials 7. QTcF \>450 msec (males) or \>470 msec (females) 8. Clinically significant cardiovascular disorders 9. Bleeding disorders 10. Conditions interfering with X-ray or sputum assessment 11. Drug allergies/hypersensitivity to study medications 12. Pregnancy or breastfeeding 13. Positive drug screen (case-by-case assessment for some substances) 14. Serious mental disorders 15. Karnofsky score \<60 16. BMI \<16.0 kg/m² 17. Significant comorbidities (metabolic, renal, gastrointestinal, neurological, psychiatric, endocrine, liver) 18. Pulmonary conditions other than TB (silicosis, fibrosis) 19. Active SARS-CoV-2 infection 20. Use of prohibited medications 21. Blood/plasma donation within 30 days 22. Current use of herbal remedies or traditional medicines

Locations (33)

Capital Medical University - Beijing Chest Hospital

Beijing, Beijing Municipality, China

NOT_YET_RECRUITING

The Third People's Hospital of Shenzhen

Shenzhen, Guangdong, China

NOT_YET_RECRUITING

Wuhan Institute of Tuberculosis Control (Wuhan Pulmonary Hospital)

Wuhan, Hubei, China

NOT_YET_RECRUITING

The Second Hospital of Nanjing

Nanjing, Jiangsu, China

Outcomes

Primary Outcomes

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.

Time frame: From randomization to Month 12

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 frame: From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)

Secondary Outcomes

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 frame: From randomization to Month 12

Time to sputum culture conversion.

Time from randomization to the first of two consecutive negative sputum cultures taken at least 1 week apart.

Time frame: From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)

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.

Time frame: At Week 8 and at end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)

Proportion of participants with microbiological relapse.

Proportion of microbiological relapse.

Time frame: From end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) to Month 12 post-randomization

Proportion of participants with adverse events of special interest (AESIs).

AESIs include QTc interval prolongation, hepatotoxicity, peripheral neuropathy, optic neuritis, and hematological toxicity.

Time frame: From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)

Proportion of participants with treatment-emergent adverse events (TEAEs).

Proportion of participants with TEAEs, Grade 3 or higher TEAEs, and serious TEAEs.

Time frame: From randomization through Week 68

Proportion of time during treatment spent without adverse events.

Measure of difference in AE-free time during treatment between experimental and standard of care arms.

Time frame: From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)

Proportion of participants who are lost to follow-up.

Measure of participant retention throughout the study period.

Time frame: From randomization through Week 68

Proportion of participants with TB-related death.

Mortality specifically related to tuberculosis.

Time frame: From randomization through Week 68

Plasma concentrations of each analyte at scheduled visits.

Plasma concentrations of trial drugs in experimental arms.

Time frame: From randomization through Week 17 (BPaQM and BPaQ only)

A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis

Overview

Conditions

Interventions

Eligibility

Locations (33)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts