An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-month Treatment of Bedaquiline Plus Pretomanid Plus Moxifloxacin Plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in Adult Participants With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants With Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB)
Overview
- Phase
- Phase 2
- Intervention
- Pretomanid
- Conditions
- Tuberculosis, Pulmonary
- Sponsor
- Global Alliance for TB Drug Development
- Enrollment
- 455
- Locations
- 26
- Primary Endpoint
- Number of Participants With Culture Negative Status by 8 Weeks
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)
Detailed Description
Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants. All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from the start of therapy. Participants with Drug Sensitive TB (DS-TB): Participants with DS-TB will be randomized to one of two treatment arms. These participants will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for co-infection with human immunodeficiency virus (HIV) and cavitation. Participants with Drug Resistant TB (DR-TB): Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease \[IUATLD\]/WHO scale (Appendix 1) on smear microscopy) at the trial laboratory.
- •Participants with one of the following pulmonary TB conditions:
- •DS-TB treatment arm participants should be:
- •sensitive to rifampicin and isoniazid by rapid sputum based test AND
- •either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB.
- •DR-TB treatment arm participants should be Resistant to rifampicin and/or isoniazid.
- •Of non-childbearing potential or willing to practice effective methods of birth control
- •Body weight (in light clothing and no shoes) ≥ 30 kg.
- •Completed informed consent form
Exclusion Criteria
- •Karnofsky score \<60%
- •Any risk factor for QT prolongation
- •Any planned contraindicated medicines
- •Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests).
- •Any of the following lab toxicities/abnormalities:
- •CD4+ count \< 100 cells/µL (HIV infected participants)
- •platelets \<75,000/mm³
- •creatinine \>1.5 times upper limit of normal (ULN)
- •eGFR ≤ 60 mL/min
- •haemoglobin \<8.0 g/dL
Arms & Interventions
Drug Sensitive BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months
Intervention: Pretomanid
Drug Sensitive BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months
Intervention: Bedaquiline
Drug Sensitive BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months
Intervention: Moxifloxacin
Drug Sensitive BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months
Intervention: Pyrazinamide
Drug Sensitive Standard Treatment
isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26
Intervention: HRZE
Drug Sensitive Standard Treatment
isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26
Intervention: HR
Drug Resistant BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Intervention: Pretomanid
Drug Resistant BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Intervention: Bedaquiline
Drug Resistant BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Intervention: Moxifloxacin
Drug Resistant BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Intervention: Pyrazinamide
Outcomes
Primary Outcomes
Number of Participants With Culture Negative Status by 8 Weeks
Time Frame: Days 0-56 (8 weeks)
Culture negative status is achieved when a participant produces at least two negative culture results at different visits (at least 7 days apart) without an intervening positive culture result for M.tb.
Secondary Outcomes
- Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months)(52 weeks after start of therapy)
- Time to Culture Negative Status(During treatment (17 or 26 weeks))