Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients

Study Overview
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Brief Summary
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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
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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).

Official Title
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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)

Conditions
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Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Tuberculosis, MDR, Tuberculosis, Drug-Resistant Tuberculosis

Intervention / Treatment
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* Drug: Pretomanid
* Drug: Bedaquiline
* Drug: Moxifloxacin
* Drug: Pyrazinamide
* Drug: HRZE
* Drug: HR


Participation Criteria
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Eligibility Criteria
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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 serum potassium less than the lower limit of normal for the laboratory. GGT: greater than 3 x ULN AST: ≥3.0 x ULN to be excluded; ALT: ≥3.0 x ULN to be excluded ALP: ≥3.0 x ULN to be excluded Total bilirubin: >1.5 x ULN to be excluded; Direct bilirubin: greater than 1x ULN to be excluded

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug Sensitive BPaMZ<br>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 | Drug: Pretomanid<br>* 200 mg tablets<br>* Other names: Pa;Drug: Bedaquiline<br>* 100 mg tablets<br>* Other names: TMC207;Drug: Moxifloxacin<br>* 400 mg tablets<br>* Other names: M;Drug: Pyrazinamide<br>* 500 mg tablets<br>* Other names: Z;|
| Active Comparator: Drug Sensitive Standard Treatment<br>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 | Drug: HRZE<br>* isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets<br>* Other names: ethambutol;Drug: HR<br>* isoniazid 75 mg plus rifampicin 150 mg combination tablets<br>* Other names: rifampicin;|
| Experimental: Drug Resistant BPaMZ<br>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) | Drug: Pretomanid<br>* 200 mg tablets<br>* Other names: Pa;Drug: Bedaquiline<br>* 100 mg tablets<br>* Other names: TMC207;Drug: Moxifloxacin<br>* 400 mg tablets<br>* Other names: M;Drug: Pyrazinamide<br>* 500 mg tablets<br>* Other names: Z;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Culture Negative Status by 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. | Days 0-56 (8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Unfavorable status: Participants not classified as having achieved or maintained culture negative status when last seen Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture Participants who had a positive culture not followed by at least two negative cultures when last seen Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide Participants definitely or possibly dying from TB related cause during the follow-up phase Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy Participants lost to follow up or withdrawn from the study before end of treatment | 52 weeks after start of therapy | 
| Time to Culture Negative Status | Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity | During treatment (17 or 26 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tuberculosis, drug-resistant tuberculosis, TB, DR-TB, pretomanid, PA-824, bedaquiline, TMC207, moxifloxacin, pyrazinamide, HRZE, TB Alliance, NC-008, drug-sensitive tuberculosis, DS-TB