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

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. · Trials (2023) · DOI: 10.1186/s13063-023-07701-6

Resumen

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.