학술논문
Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial
Document Type
article
Author
Guglielmetti, L; Ardizzoni, E; Atger, M; Baudin, E; Berikova, E; Bonnet, M; Chang, E; Cloez, S; Coit, JM; Cox, V; de Jong, BC; Delifer, C; Do, JM; Tozzi, D Dos Santos; Ducher, V; Ferlazzo, G; Gouillou, M; Khan, A; Khan, U; Lachenal, N; LaHood, AN; Lecca, L; Mazmanian, M; McIlleron, H; Moschioni, M; O’Brien, K; Okunbor, O; Oyewusi, L; Panda, S; Patil, SB; Phillips, PPJ; Pichon, L; Rupasinghe, P; Rich, ML; Saluhuddin, N; Seung, KJ; Tamirat, M; Trippa, L; Cellamare, M; Velásquez, GE; Wasserman, S; Zimetbaum, PJ; Varaine, F; Mitnick, CD
Source
Trials. 22(1)
Subject
Language
Abstract
BackgroundTreatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.MethodsendTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.DiscussionThe lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.Trial registrationClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.