A Phase 2, Partially-blinded, Randomised Trial Assessing the Safety and Efficacy of TBAJ-876 or Bedaquiline, in Combination With Pretomanid and Linezolid in Adult Participants With Newly Diagnosed, Drug-sensitive, Smear-positive Pulmonary Tuberculosis

NC-009

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

2023-10-24

2025-02-01

2026-06-01

Recruiting

Early phase I

300

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.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'interventionModelDescription': '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:', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'QUADRUPLE', 'maskingDescription': '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', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 300, 'type': 'ESTIMATED'}}

2024-03-07