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

Praharshinie Rupasinghe, S. B. Patil, M. Tamirat, K Khazhidinov, Elisa Ardizzoni, M. Atger, A Austin, E. Baudin, M Bekhit, S Bektasov, E. Berikova, M. Bonnet, R Caboclo, M Chaudhry, V Chavan, Sandrine Cloez, J. M. Coit, S Coutisson, Z Dakenova, Bouke de JongC. Delifer, S Demaisons, J. M. Do, D. Dos Santos Tozzi, V Ducher, Gabriella Ferlazzo, M. Gouillou, U Khan, M Kunda, N. Lachenal, A. N. LaHood, L. Lecca, M. Mazmanian, Helen McIlleron, M Moreau, M. Moschioni, Payam Nahid, E Osso, L. Oyewusi, Sayantan Panda, A Pâquet, Huu Thuong Pham, L. Pichon, M. L. Rich, N Salahuddin, E Sanchez Garavito, K. J. Seung, G. E. Velasquez, M Vallet, F. Varaine, FJ Yuya-Septoh, Carole D. Mitnick, L. Guglielmetti

Research output: Contribution to journalA1: Web of Science-articlepeer-review


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.

Original languageEnglish
Article number773
Issue number1
Number of pages14
Publication statusPublished - 2023


  • Antitubercular Agents/adverse effects
  • Clinical Trials, Phase III as Topic
  • Clofazimine/adverse effects
  • Extensively Drug-Resistant Tuberculosis/diagnosis
  • Fluoroquinolones/adverse effects
  • Humans
  • Linezolid/adverse effects
  • Randomized Controlled Trials as Topic
  • Tuberculosis, Multidrug-Resistant/diagnosis


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