A Phase 2 Randomized, Open-label Trial to Evaluate the Early Bactericidal Activity, Safety, Tolerability, and Dose-Response of Oral Alpibectir in Combination With Ethionamide, and With Ethionamide, Rifampicin, Pyrazinamide, and Ethambutol in Adults With Newly Diagnosed, Drug-Susceptible Pulmonary Tuberculosis
A multi-centre, randomized, open-label clinical trial. All treatments will be administered orally (PO) on days 1-14. 15 participants will be recruited into each treatment arm in two sequential cohorts. Each cohort will have participants enrolled onto the experimental regimen(s) or the standard of care (SOC; HRZE) control arm. • Cohort 1 aims to generate safety data for a higher dose of alpibectir plus ethionamide 125 mg and 250 mg (arm 1: A45E125 and arm2: A45E250). Once 5 participants have enrolled into arms 1 and 2 each, and completed 14 days of treatment, an interim safety review will be conducted to determine whether the study can advance to cohort 2. • Cohort 2 will investigate safety of alpibectir and ethionamide (A45E250) in combination with rifampicin, pyrazinamide and ethambutol (A45E250RZE). Participants on HRZE will serve as control for the EBA quantitative mycobacteriology in each cohort, and additionally as a safety benchmark for the A45E250RZE arm. The study is not statistically powered to make between arm comparisons of activity or safety. The treatment will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.
• Provide written, informed consent prior to all trial-related procedures and willing to adhere to all required study procedures and restrictions for the duration of the trial.
• Male or female, aged between 18 and 65 years, inclusive.
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Newly diagnosed and untreated for this episode of pulmonary TB.
• Rifampicin- and isoniazid susceptible pulmonary TB as determined by molecular testing (GeneXpert XDR or Genotype MTBDRplus for INH).
• A chest X-ray taken during the screening period or up to 2 weeks before screening which, in the opinion of the investigator, is consistent with TB.
• GeneXpert positive with a quantitative readout of medium or high.
• Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
• Be of non-childbearing potential or of childbearing potential using effective methods of birth control, as defined in section 5.2 and in Appendix 1.
• Female Participants
⁃ For WOCBP who are not already receiving contraception per Appendix 1 requirements, agree to receive injectable or other contraceptive methods (per Appendix 1), to be given during screening, and at least 1 day prior to first dose of IMP.
⁃ Male Participants
⁃ Agree to ALL of the following during the study intervention period and for at least 90 days, after the last dose of study intervention:
∙ Refrain from donating fresh unwashed semen
‣ Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.