Trials (Nov 2023)

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

  • S. B. Patil,
  • M. Tamirat,
  • K. Khazhidinov,
  • E. Ardizzoni,
  • M. Atger,
  • A. Austin,
  • E. Baudin,
  • M. Bekhit,
  • S. Bektasov,
  • E. Berikova,
  • M. Bonnet,
  • R. Caboclo,
  • M. Chaudhry,
  • V. Chavan,
  • S. Cloez,
  • J. Coit,
  • S. Coutisson,
  • Z. Dakenova,
  • B. C. De Jong,
  • C. Delifer,
  • S. Demaisons,
  • J. M. Do,
  • D. Dos Santos Tozzi,
  • V. Ducher,
  • G. Ferlazzo,
  • M. Gouillou,
  • U. Khan,
  • M. Kunda,
  • N. Lachenal,
  • A. N. LaHood,
  • L. Lecca,
  • M. Mazmanian,
  • H. McIlleron,
  • M. Moreau,
  • M. Moschioni,
  • P. Nahid,
  • E. Osso,
  • L. Oyewusi,
  • S. Panda,
  • A. Pâquet,
  • P. Thuong Huu,
  • L. Pichon,
  • M. L. Rich,
  • P. Rupasinghe,
  • N. Salahuddin,
  • E. Sanchez Garavito,
  • K. J. Seung,
  • G. E. Velásquez,
  • M. Vallet,
  • F. Varaine,
  • F. J. Yuya-Septoh,
  • C. D. Mitnick,
  • L. Guglielmetti

DOI
https://doi.org/10.1186/s13063-023-07701-6
Journal volume & issue
Vol. 24, no. 1
pp. 1 – 14

Abstract

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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.

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