MOXIFLOXACIN for Multidrug-resistant pulmonary tuberculosis|Rifampicin-resistant tuberculosis

Inclusion criteria

• {"criterion_text":"- 1) Is 18 years old or more\n- 2) Is affected by bacteriologically- or molecularly-confirmed tuberculosis, due to strains of M. tuberculosis resistant to rifampicin (with or without resistance to isoniazid) according to a rapid molecular test\n- 3) Is willing and able to give informed consent to be enrolled in the research project (signed or witnessed consent if the patient is illiterate)\n- 4) Is willing to use effective contraception: women with childbearing potential must agree to use effective contraception, unless their partner has had a vasectomy, for the duration of study treatment and up to 6 months after the end of study treatment; men who have not had a vasectomy must agree to use effective contraception for the duration of study treatment and up to 3 months after the end of study treatment;\n- 5) Is affiliated to a social security system (as beneficiary) or has state medical aid (AME) or has an ongoing demand for AME or has an ongoing demand for an emergency medical care (dispositif de soins d'urgence, as applicable for tuberculosis)"}

Exclusion criteria

• {"criterion_text":"- 1) Is unable to take oral drugs\n- 2) Has known allergies, hypersensitivity or intolerance or any other medical condition and contra indications to any drug of the regimen\n- 3) Unwilling to comply to study procedures, at the clinician appreciation\n- 4) Has proven or likely resistance to bedaquiline, clofazimine, linezolid, pretomanid or moxifloxacine, or has had exposure (for 30 days or more) in past five years to bedaquiline, clofazimine, delamanid, linezolid, or pretomanid\n- 5) Is taking or needs to take contraindicated medications in association with investigational medicinal products\n- 6) Has ≥500 msec QTcF interval on any ECG taken at screening or baseline visits, or has any cardiac risk factor for severe arrhythmia\n- 7) Has severe extrapulmonary TB, including meningo-encephalitis, brain abscess, osteo-arthritis, osteomyelitis\n- 8) Is concurrently participating in another trial of any medicinal product\n- 9) Is already on a MDR/RR-TB treatment regimen since 4 weeks or more, and has no need to change the treatment regimen (i.e. adverse events, treatment failure)\n- 10) Has significant and uncorrectable lab abnormalities at baseline: haemoglobin ≤7.9 g/dL, platelet count <75 000/mm3; absolute neutrophil count <1 000/ mm3; potassium <3.0 mEq/L; serum creatinine >3 x upper level of normality (ULN); alanine aminotransferase (ALT) ≥3 x ULN\n- 11) Has peripheral neuropathy of grade 3 or 4 (CTCAE scale)\n- 12) Has any other condition (social or medical) which, in the opinion of the site investigator, would make the study participant unsafe\n- 13) Is known to be pregnant or is unwilling or unable to stop breastfeeding an infant"}

Primary endpoints

• {"endpoint_text":"- For BPaLM interventional arm: proportion of study participants achieving sustained treatment success at 18 months after study treatment start, according to 2021 WHO definitions, in the absence of permanent addition of any TB drug to the regimen or >4 consecutive weeks treatment interruption or >4 weeks treatment prolongation. For the historical cohort: proportion of patients achieving treatment success (2021 WHO definitions).","definition_or_measurement_approach":"Measured at 18 months after study treatment start using 2021 WHO definitions; for BPaLM arm requires absence of permanent addition of any TB drug to the regimen or >4 consecutive weeks treatment interruption or >4 weeks treatment prolongation; comparator is historical cohort treatment success per 2021 WHO definitions."}

Other endpoints

• {"endpoint_text":"- 1) Evaluate early markers of BPaLM effectiveness (endpoints: a) proportion of participants with a negative sputum culture at two months after study treatment start, and b) time to sputum culture conversion [2021 WHO definitions]);\n- 2) Determine if BPaLM has non-inferior effectiveness at 6 and 12 months after treatment start compared to the historical cohort at the end of treatment (endpoint: for BPaLM arm, treatment success at 6 months, and sustained treatment success at 12 months, without addition of any TB drug or >4 consecutive weeks treatment interruption or >4 weeks treatment prolongation; for historical cohort: treatment success [all according to 2021 WHO definitions])\n- 3) Compare the rate of post-treatment relapse in the BPaLM arm and in the historical cohort (endpoint: for BPaLM arm, proportion of participants with TB relapse at 12 and 18 months after study treatment start. For historical cohort: proportion of patients with TB relapse according to latest available post-treatment follow-up data)\n- 4) Identify factors associated with effectiveness of BPaLM at 18 months after study treatment start (endpoint: factors associated with effectiveness, as per the primary endpoint definition)\n- 5) Assess the safety of BPaLM at 12 and 18 months after study treatment start (endpoint: proportion of participants with any serious adverse event [US FDA definition] or any Grade 3 or higher adverse event [CTCAE Severity Scale v 5.0])\n- 6) Perform blood therapeutic drug monitoring (TDM) (kinetic curves, total and free drug concentrations) and minimal inhibitory concentration (MIC) measurement on participant strains for each drug in the regimen, and assess the correlation with effectiveness/safety of BPaLM (endpoint: multivariate models adjusting for MICs, strain lineage and patient factors to identify TDM measures associated, for each drug, with effectiveness, safety, and drug resistance acquisition)\n- 7) Compare the rate of acquisition of drug resistance of BPaLM arm at 12 and 18 months after study treatment start to the historical cohort at the end of treatment (endpoint: acquired drug resistance, compared to baseline, to any drug in the study regimen)\n- 8) Assess diagnostic delay and accuracy of genotypic DST for the identification of patients who are eligible for BPaLM, compared to phenotypic DST (endpoint: diagnostic delay and accuracy)\n- 9) Assess treatment adherence to the BPaLM regimen (endpoint: proportion of doses taken out of total expected doses)\n- 10) Measure the health-related quality of life of BPaLM-treated participants before, during and after the treatment (endpoint: Saint George's Respiratory questionnaire)\n- 11) Measure the satisfaction of study participants and health care workers at 12 months after study treatment start (endpoint: Likert scales)\n- 12) Assess the overall costs of BPaLM and compare it with those of the historical cohort (endpoint: economic evaluation)\n- 13) Randomize participants to one of two bedaquiline dosing strategies to describe and compare between the two groups: a) bedaquiline blood TDM results, b) effectiveness and c) safety (endpoint: bedaquiline population pharmacokinetics, safety and effectiveness endpoints as defined above)","definition_or_measurement_approach":"Secondary/exploratory endpoints include sputum culture conversion at 2 months and time to culture conversion (WHO 2021 definitions); treatment success at 6 and 12 months per WHO 2021 definitions; relapse at 12 and 18 months; safety by SAE and CTCAE v5.0 Grade ≥3; TDM and MIC correlated via multivariate models; acquired drug resistance compared to baseline; diagnostic delay and accuracy of genotypic vs phenotypic DST; adherence measured as proportion of doses taken; QoL measured by Saint George's Respiratory questionnaire; satisfaction by Likert scales; economic evaluation for costs; bedaquiline dosing strategies compared by population PK, safety and effectiveness measures."}

Methods

• Patients diagnosed at the study sites with rifampicin-resistant tuberculosis during the recruitment period will be evaluated for study inclusion.

France

Earliest CTIS Part Ii Submission Date

24-06-2025

Latest Decision Or Authorization Date

31-07-2025

Processing Time Days

37

Number Of Sites

13

Number Of Participants

50

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France