MDR-TB, Tuberculosis Multi Drug Resistant Active, Antibiotic Resistance, Mycobacterium Tuberculosis
Conditions
Keywords
MDR-TB, BPaLM, Tuberculosis Multi Drug Resistant
Brief summary
The FAST-MDR trial is an externally-controlled, multicentre trial with one prospective arm, evaluating the non-inferiority of the effectiveness of BPaLM in the interventional arm versus the effectiveness of the long, conventional regimen in a French historical cohort of MDR-TB patients (2006-2022). In light of recent WHO recommendations suggesting using BPaLM as a first choice for routine MDR-TB treatment and of the expected benefits of BPaLM over the standard treatment, there will be no internal comparator arm in the study.
Detailed description
This study will be conducted in all adult patients diagnosed at the study sites with rifampicin-resistant tuberculosis. The study will assess a treatment strategy, with the regimen being adapted to the result of rapid molecular testing and phenotypic DST for fluoroquinolone resistance. Study participants will perform a rapid molecular test for fluoroquinolone resistance at screening/baseline visit: if the result is susceptible, they will receive BPaLM; if the result is resistant, they will receive a regimen with clofazimine instead of moxifloxacin (BPaLC); if the result is inconclusive, they will receive BPaLM plus clofazimine (BPaLMC). In this latter case, the regimen will be adapted according to result of phenotypic DST for fluoroquinolones: in case of susceptibility, clofazimine will be dropped (BPaLM); in case of resistance, moxifloxacin will be dropped (BPaLC).
Interventions
Bedaquiline will be given as 400 mg once daily for 2 weeks and then 200 mg thrice weekly for the remaining 22 weeks
Sponsors
Assistance Publique - Hôpitaux de Paris
Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Study participants will be treated with a six-month treatment based on the combination of bedaquiline, linezolid, moxifloxacin and pretomanid (BPaLM), with the possible addition of clofazimine. All these drugs are routinely used for MDR-TB treatment, recommended by the WHO and other international guidelines, and approved by US FDA and EU EMA. The drugs will be given as follows: * Bedaquiline: 400 mg once daily for 2 weeks, then 200 mg thrice weekly; or 200 mg once daily for 8 weeks, then 100 mg once daily (dosing determined by randomization) * Clofazimine: 200 mg once daily for two weeks, then 100 mg once daily * Linezolid: 600 mg once daily * Moxifloxacin: 400 mg once daily * Pretomanid: 200 mg once daily
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is 18 years old or more 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 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) 4. Patients seen in consultation or hospitalized in one of the centers involved for rifampicin-resistant TB, with screening results available and compatible within 14 days following consent signature; 5. 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; * The following contraception methods are considered effective, according to local regulation (CTFG recommendations, March 2024): 1. Combined hormonal contraception (oestrogen + progestin) 2. Progestin-only hormonal contraception 3. Intrauterine device (IUD) 4. Intrauterine hormone-releasing system (IUS) 5. Bilateral tubal occlusion 6. Vasectomised partner * A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 6. Is affiliated to a social security system (as beneficiary) or has state medical aid (AME) or has an ongoing demand for AMEor has an ongoing demand for an emergency medical care (dispositif de soins d'urgence, as applicable for tuberculosis)
Exclusion criteria
: 1. Is unable to take oral drugs 2. Has known allergies, hypersensitivity or intolerance or any other medical condition and contra indications to any drug of the regimen 3. Unwilling to comply to study procedures, at the clinician appreciation 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 5. Is taking or needs to take contraindicated medications in association with investigational medicinal products 6. Has ≥500 msec QTcF interval on any ECG taken at screening or baseline visits, or has any cardiac risk factor for severe arrhythmia 7. Has severe extrapulmonary TB, including meningo-encephalitis, brain abscess, osteo-arthritis, osteomyelitis 8. Is concurrently participating in another trial of any medicinal product 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) 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 11. Has peripheral neuropathy of grade 3 or 4 (CTCAE scale) 12. Has any other condition (social or medical) which, in the opinion of the site investigator, would make the study participant unsafe 13. Is known to be pregnant or is unwilling or unable to stop breastfeeding an infant 14. Individuals permanently legally incompetent adults, under judicial or administrative protection and vulnerable persons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness of BPaLM compared to conventional MDR-TB regimens | Day 0 to Month 18 | 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. For the historical cohort: proportion of patients achieving treatment success (2021 WHO definitions) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early markers of BPaLM effectiveness (proportion of participants) | Day 0 to Day 60 | Proportion of participants with a negative sputum culture at two months after study treatment start |
| Early markers of BPaLM effectiveness (time to sputum culture conversion) | Day 0 to month 18 | Time to sputum culture conversion (defined as time between treatment start and the first of two consecutive negative sputum cultures, from specimens taken at least 7 days apart, as per WHO definitions) |
| BPaLM non-inferior effectiveness | Start to month 6 | For BPaLM arm, treatment success at 6 months, without addition of any TB drug or \>4 consecutive weeks treatment interruption; For historical cohort: treatment success \[all according to 2021 WHO definitions\] |
| Rate of post-treatment relapse | Start to month 12 | For BPaLM arm, proportion of participants with TB relapse at 12 months after study treatment start. For historical cohort: proportion of patients with TB relapse according to latest available post-treatment follow-up data |
| Factors associated with effectiveness of BPaLM at 18 month (interventional group only) | Start to month 18 | Factors associated with effectiveness of BPaLM at 18 months after study treatment start defined as patient characteristics, extension of TB disease, previous TB treatment, resistance profile and lineage of the TB strain, treatment adherence, and adverse events. |
| Safety of BPaLM regimen | Start to month 18 | Proportion of participants with any serious adverse event \[US FDA definition\] or any Grade 3 or higher adverse event \[CTCAE Severity Scale v 5.0\] |
| Pharmacology effectiveness (pharmacokinetic analyses) | Start to month 6 | Defined as population pharmacokinetic analyses for each drug |
| Pharmacology effectiveness (evolution of MICs according to strain lineage) | Start to month 6 | Defined as 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 |
| Pharmacology effectiveness (evolution of MICs according to patient characteristics) | Start to month 6 | Defined as multivariate models adjusting for patient characteristics and extension of TB disease |
| Rate of acquisition of drug resistance at 12 months (experimental group only) | Start to month 12 | Defined as the proportion of participants who acquired drug resistance to any of the study regimen drugs. |
| Rate of acquisition of drug resistance at 18 months (each groups) | Start to month 18 | Defined as the proportion of participants who acquired drug resistance to any of the study regimen drugs. |
| Microbiology eligibility - diagnostic delay (interventional group only) | Start to Month 1 | Defined as time between screening and microbiological eligibilty assessment |
| Microbiology eligibility - diagnostic accuracy (interventional group only) | Start to Month 1 | Defined as diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of different genotypic tests |
| Treatment adherence (interventional group only) | Start to month 6 | Proportion of doses taken out of total expected doses |
| Health-related quality of life at treatment start (interventional group only) | Start to month 1 | Measured by Saint George's Respiratory questionnaire at treatment start |
| Health-related quality of life at 6 months (interventional group only) | Start to month 6 | Measured by Saint George's Respiratory questionnaire at 6 months |
| Health-related quality of life at 12 months (interventional group only) | Start to month 12 | Measured by Saint George's Respiratory questionnaire at 12 months |
| Satisfaction of study participants | Start to month 12 | Measured by Likert scales at 12 months after study treatment start. |
| Satisfaction of health care workers | Start to month 12 | Measured by Likert scales at 12 months after study treatment start. |
| Health economy | Start to month 18 | Incremental cost per additional treatment success, calculated as: difference in costs (between groups)/ difference in treatment success (between groups). |
Countries
France
Contacts
CONTACTLorenzo GUGLIELMETTI, MD
Outcome results
None listed