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
Authors: Patil S. B. , 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. C. , Delifer C. , Demaisons S. , Do J. M. , Dos Santos Tozzi D. , Ducher V. , Ferlazzo G. , Gouillou M. , Khan U. , Kunda M. , Lachenal N. , LaHood A. N. , 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. L. , Rupasinghe P. , Salahuddin N. , Sanchez Garavito E. , Seung K. J. , Velásquez G. E. , Vallet M. , Varaine F. , Yuya-Septoh F. J. , Mitnick C. D. , Guglielmetti L. 
Published: November 2023

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.