Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial
Notice bibliographique
Résumé
Background Pre-extensively drug-resistant (pre-XDR) tuberculosis (ie, multidrug-resistant or rifampicin-resistant with additional resistance to any fluoroquinolone) is difficult to treat. endTB-Q aimed to evaluate the efficacy and safety of bedaquiline, delamanid, linezolid, and clofazimine (BDLC) compared with the standard of care for patients with pre-XDR tuberculosis. Methods This open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial was conducted in ten hospitals in India, Kazakhstan, Lesotho, Pakistan, Peru, and Viet Nam. Participants aged 15 years or older who had pulmonary tuberculosis with resistance to rifampicin and fluoroquinolones were included. Participants were randomly assigned (2:1) to the BDLC group (all-oral bedaquiline 400 mg once per day for 2 weeks followed by 200 mg three times per week, delamanid 100 mg twice per day, linezolid 600 mg once per day for 16 weeks and then either 300 mg once per day or 600 mg three times per week, and clofazimine 100 mg once per day) or the control group (individualised WHO-recommended longer standard of care). Randomisation was stratified by country and baseline disease extent. BDLC was administered for 39 weeks (9-month regimen) for extensive disease and 24 weeks (6-month regimen) for limited disease and extended to 9 months for those with a positive culture at 8 weeks or later or a missing 8-week culture result. Site staff and participants were not masked, whereas investigators and laboratory staff were masked to treatment assignment. The primary endpoint was favourable outcome (two consecutive, negative cultures including one between weeks 65 and 73; or favourable bacteriological, radiological, and clinical evolution) at week 73 after randomisation in the modified intention-to-treat (mITT) and per-protocol populations. We report the risk differences adjusted for stratification variables, with a non-inferiority margin of –12%. This trial is registered with ClinicalTrials.gov, NCT03896685. Findings Between April 4, 2020, and March 28, 2023, 1030 individuals were screened and 324 (31%) were randomly assigned (219 to the BDLC group and 105 to the control group). 114 (46%) participants were female and 133 (54%) were male. Median age was 30·5 years (IQR 21·6–43·0). 157 (64%) participants had extensive disease at baseline. In the BDLC group, 47 (29%) of 163 were assigned to receive the 6-month regimen and 116 (71%) the 9-month regimen. The core regimen of BDLC plus one or more other drugs was used for 76 (91%) of 84 participants in the control group. At week 73, favourable outcome was reached by 141 (87%) participants in the BDLC group versus 75 (89%) in the control group in the mITT population (adjusted risk difference 0·2% [95% CI –9·1 to 9·5]; p non-inferiority =0·0051) and by 138 (88%) of 157 versus 71 (93%) of 76 in the per-protocol population (adjusted risk difference –3·5% [–12·8 to 5·9]; p non-inferiority =0·037). Overall non-inferiority was not shown. 145 (68%) of 213 participants in the BDLC group and 77 (73%) of 105 in the control group had at least one grade 3 or higher adverse event, with eight (4%) and two (2%) all-cause deaths by week 73, respectively. Interpretation The shortened BDLC strategy was not non-inferior to the control. Accumulating evidence suggests that this patient population might require longer, reinforced regimens. Funding Unitaid, Médecins Sans Frontières, Partners In Health, Interactive Research and Development, Ramón Areces Foundation, the Jung Foundation for Science and Research, Research Foundation-Flanders. Translations For the Hindi, Marathi, Spanish, Vietnamese, Russian, Urdu and French translations of the abstract see Supplementary Materials section.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,007 | 0,007 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,003 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».