A Phase 3 Trial Assessing Safety and Efficacy of B-Pa-L in Participants With DR-TB

Up to 200 male and female participants aged 14 and over with confirmed sputum positive for M.tb. in culture pulmonary XDR-TB, or with pulmonary MDR-TB with a documented intolerability or non-response to the best treatment available for 6 months or more will be enrolled.

All participants will have up to a maximum of 9 days for screening, receive 6 months of treatment, and have followup visits performed 1 and 2 months after treatment completion and every 3 months after study treatment completion for 24 months. If a participant is culture positive or revert to being culture positive between Month 4 and Month 6 visits and their clinical condition suggests they may have ongoing TB infection, they may have treatment extended to 9 months (with 24 months of Follow Up) or be withdrawn from the study.

Participants who withdraw after <14 days of IMP should attend an Early Withdrawal visit. Participants who withdraw after >15 days of IMP should return for an Early Withdrawal visit and follow-up visits at 3, 6 and 24 months after their last dose of IMP to check for survival, SAEs and resolution of TB symptoms.

Key Inclusion Criteria

• Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
• Body weight of ≥35 kg (in light clothing and no shoes).
• Male or female, aged 14 years or above.
• Subjects with one of the following pulmonary TB conditions (WHO definitions prior to 2021):

a. Extensively Drug Resistant Tuberculosis (XDR-TB) with

i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening;

ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening;

b. Multi-Drug Resistant Tuberculosis (MDR-TB) documented by culture positive results (for M.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen;

c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to:

i. PAS, ethionamide, aminoglycosides or fluoroquinolones;

ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion.

• Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator.

Key Exclusion Criteria

• Karnofsky score < 50 within 30 days prior to entry.
• Body Mass index (BMI) < 17 kg/m²
• History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
• HIV infected Subjects having a CD4+ count ≤ 50 cells/μL
• Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. Subjects who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion.
• Significant cardiac arrhythmia requiring medication.
• Subjects with the following at Screening:

• QTcF interval on ECG >500 msec.
• History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
• Clinically significant ventricular arrhythmias;
• Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec.
• Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
• A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator.
• Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.
• Subjects with the following toxicities at Screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

a. serum potassium less than the lower limit of normal for the laboratory; b. Hemoglobin level grade 2 or greater (< 8.0 g/dL); c. Platelets grade 2 or greater(<75,000/mm3); d. Absolute neutrophil count (ANC) < 1000/ mm3; e. Aspartate aminotransferase (AST) > 3 x ULN g. Total bilirubin > or = to 2xULN h. Direct bilirubin > ULN i. Serum creatinine level greater than 2 times upper limit of normal j. Albumin <32 g/L