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

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)

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)

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).

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