Pulmonary Tuberculosis
Conditions
Keywords
Pulmonary Tuberculosis, Quabodepistat, Bedaquiline, Pretomanid, Linezolid, Moxifloxacin, Fluoroquinolone-sensitive TB, Fluoroquinolone-resistant TB, Drug-resistant TB, Shortened TB treatment
Brief summary
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.
Detailed description
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.
Interventions
DRUGBPaQM
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
DRUGBPaLM
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
DRUGBPaQ
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
DRUGBPaL
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
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study with blinded endpoint adjudication of the primary efficacy outcome. Certain sponsor team members will be blinded to treatment assignments to minimize potential bias as much as possible
Intervention model description
The study has two parallel cohorts based on fluoroquinolone sensitivity status, each with an experimental arm and a control arm.
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with unfavorable outcome. | From randomization to Month 12 | 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). | From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first occurrence of any event meeting the unfavorable outcome definition. | From randomization to Month 12 | Time to the first occurrence of any event listed under the primary efficacy endpoint. |
| Time to sputum culture conversion. | From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) | 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. | At Week 8 and at end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) | 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. | From end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) to Month 12 post-randomization | Proportion of microbiological relapse. |
| Proportion of participants with adverse events of special interest (AESIs). | From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) | AESIs include QTc interval prolongation, hepatotoxicity, peripheral neuropathy, optic neuritis, and hematological toxicity. |
| Proportion of participants with treatment-emergent adverse events (TEAEs). | From randomization through Week 68 | Proportion of participants with TEAEs, Grade 3 or higher TEAEs, and serious TEAEs. |
| Proportion of time during treatment spent without adverse events. | From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) | Measure of difference in AE-free time during treatment between experimental and standard of care arms. |
| Proportion of participants who are lost to follow-up. | From randomization through Week 68 | Measure of participant retention throughout the study period. |
| Proportion of participants with TB-related death. | From randomization through Week 68 | Mortality specifically related to tuberculosis. |
| Plasma concentrations of each analyte at scheduled visits. | From randomization through Week 17 (BPaQM and BPaQ only) | Plasma concentrations of trial drugs in experimental arms. |
Countries
China, Georgia, Japan, Moldova, Peru, Philippines, South Africa, South Korea
Contacts
CONTACTOtsuka Call Center
STUDY_DIRECTORSimbarashe G Takuva, MD, MSc.
Study Sponsor
Outcome results
None listed