Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial
Authors: Guglielmetti L. , Ardizzoni E. , Atger M. , Baudin E. , Berikova E. , Bonnet M. , Chang E. , Cloez S. , Coit J. M. , Cox V. , de Jong B. C. , Delifer C. , Do J. M. , Tozzi D. Dos Santos , Ducher V. , Ferlazzo G. , Gouillou M. , Khan A. , Khan U. , Lachenal N. , LaHood A. N. , Lecca L. , Mazmanian M. , McIlleron H. , Moschioni M. , O’Brien K. , Okunbor O. , Oyewusi L. , Panda S. , Patil S. B. , Phillips P. P. J. , Pichon L. , Rupasinghe P. , Rich M. L. , Saluhuddin N. , Seung K. J. , Tamirat M. , Trippa L. , Cellamare M. , Velásquez G. E. , Wasserman S. , Zimetbaum P. J. , Varaine F. , Mitnick C. D. 
Published: September 2021

Abstract
Background
Treatment 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.

Methods
endTB 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.

Discussion
The 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 registration
ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.