Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis

Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis

A Phase 2, Partially-blinded, Randomised Trial Assessing the Safety and Efficacy of TBAJ876 or Bedaquiline, in Combination With Pretomanid and Linezolid in Adult Participants With Newly Diagnosed, Drug-sensitive, Smear-positive Pulmonary Tuberculosis

The goal of this clinical trial is to evaluate 3 dose levels of TBAJ876 for 8 weeks in combination with pretomanid and linezolid, compared to 8 weeks of Isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE), in adult participants with newly diagnosed, smear-positive, pulmonary drug sensitive tuberculosis (DS-TB). The main questions the trial aims to answer are: What is the optimal dose of TBAJ876 to continue further in development. What is the bactericidal activity of bedaquiline with pretomanid and linezolid (B-Pa-L) compared to 2HRZE and TBAJ876-Pa-L over 8 weeks What is the efficacy and safety of the 26-week B-Pa-L regimen compared with the SOC (2HRZE/4HR) in participants with DS-TB. Participants will be seen regularly during treatment (up to 26 weeks) and follow-up (52 weeks post treatment) for safety and efficacy assessments, including but not limited to: Safety labs, ECGs, vital signs, physical exams, PK sampling, neuropathy assessments and adverse event monitoring Sputum collection

Participants will be treated up to 26 weeks with either: TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight). TBAJ876 and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the TBAJ876 or bedaquiline arms will receive open-label pretomanid and linezolid. Participants randomised to the 2HRZE/4HR arm will receive open-label HRZE. After receiving 8 weeks of treatment, participants randomised to the TBAJ876-Pa-L treatment arms will receive open-label HR for at least 7 weeks. Treatment completion will be allowed at Week 15 in participants randomised to the TBAJ876-Pa-L arms, if the below criteria are met: Week 8 or EOT Make-up Period 1 sputum MGIT culture is negative, and The participant has no TB-related symptoms by Week 15. Participants with symptoms that have a more likely alternative explanation are eligible to complete treatment at Week 15. If the MGIT result is MTB positive and/or there are still TB symptom(s), participants will continue to receive HR (in the 3 TBAJ876 arms) and will complete 18 weeks of treatment with HR, for a total of 26 weeks of treatment. After receiving 8 weeks of trial treatment, all participants randomised to the HRZE arm will receive open-label HR for 18 weeks, for a total of 26 weeks of treatment. After receiving 8 weeks of treatment, a participants randomised to the B-Pa-L arm will receive open-label bedaquiline 100 mg (a reduction from the 200 mg daily dose in the first 8 weeks), pretomanid 200 mg, and linezolid 600 mg daily for 18 weeks, for a total of 26 weeks of trial treatment.

Participants who meet all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1:1:1:1 ratio using an interactive response technology that stratifies based on country and severity of disease (AFB 3+ and/or bilateral cavitation) to 1 of the 5 treatment arms:

TBAJ-876 and the first 8 weeks of bedaquiline will be blinded. Participants randomized to TBAJ-876 or bedaquiline arms will received active TBAJ-876 (and placebo TBAJ876 to blind the dose) and placebo bedaquiline or placebo TBAJ-876 and active bedaquiline

Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks

Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight).

Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) plus ethambutol (E) fixed dose combination tablets dosed by weight

Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.

Inclusion Criteria: Signed informed consent DS-TB as defined as 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 Of non-childbearing potential OR using effective birth control methods Body weight ≥ 35 kg Exclusion Criteria: Karnofsky score < 60 at screening Any evidence of extrapulmonary TB Cardiovascular or QT prolongation risk factors Pregnant or breast-feeding Any of the following lab toxicities: Platelets <100,000/mm³ Creatinine >1.3 x ULN Haemoglobin <9.5 g/dL or <95 g/L Absolute neutrophil count <800/mm³ Serum potassium less than the lower limit of normal for the laboratory. ALT and/or AST ≥2.5 x ULN Total bilirubin ≥1.6 x ULN Direct bilirubin >1 x ULN Haemoglobin A1c ≥8.0% Total lipase ≥1.5 x ULN Total amylase ≥1.5 x ULN CPK >3 x ULN (if >3 x ULN, enquire about the participant's recent strenuous activity and consider repeating the test within the screening window) TSH >1 x ULN Positive results at screening for HBsAg, HAV IgM, or hepatitis C antibodies For participants living with HIV only: CD4+ count<200 cells/μL. WHO Clinical Stage 4 HIV disease Participant does not agree to use DTG/TFV/3TC during trial if ARV therapy is indicated, and randomised to the TBAJ876 or the B-Pa-L regimen If initiation of ARV therapy is indicate, participants who are known to be intolerant, non-responsive to DTG/TFV/3TC or have DTG/TFV/3TC as a contraindication.