학술논문
Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.
Document Type
article
Author
Patil, S; Tamirat, M; Khazhidinov, K; Ardizzoni, E; Atger, M; Austin, A; Baudin, E; Bekhit, M; Bektasov, S; Berikova, E; Bonnet, M; Caboclo, R; Chaudhry, M; Chavan, V; Cloez, S; Coit, J; Coutisson, S; Dakenova, Z; De Jong, B; Delifer, C; Demaisons, S; Do, J; Dos Santos Tozzi, D; Ducher, V; Ferlazzo, G; Gouillou, M; Khan, U; Kunda, M; Lachenal, N; LaHood, A; Lecca, L; Mazmanian, M; McIlleron, H; Moreau, M; Moschioni, M; Nahid, P; Osso, E; Oyewusi, L; Panda, S; Pâquet, A; Thuong Huu, P; Pichon, L; Rich, M; Rupasinghe, P; Salahuddin, N; Sanchez Garavito, E; Seung, K; Velásquez, G; Vallet, M; Varaine, F; Yuya-Septoh, F; Mitnick, C; Guglielmetti, L
Source
Trials. 24(1)
Subject
Language
Abstract
BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. 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 324 participants across 2 arms affords at least 80% power to show the non-inferiority, 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. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.