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.

Thursday 30 November 2023

Patil SB 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 BC Delifer C Demaisons S Do JM Dos Santos Tozzi D Ducher V Ferlazzo G Gouillou M Khan U Kunda M Lachenal N LaHood AN 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 ML Rupasinghe P Salahuddin N Sanchez Garavito E Seung KJ Velásquez GE Vallet M Varaine F Yuya-Septoh FJ Mitnick CD Guglielmetti L

Trials 2023 Nov 30; 24(1); . doi: 10.1186/s13063-023-07701-6. Epub 2023 11 30

Bedaquiline Clofazimine Delamanid Fluroquinolone-resistant Linezolid MDR-TB Multidrug-resistant Non-inferiority Pre-XDR TB RR-TB Rifampicin-resistant Stratified medicine Treatment shortening Tuberculosis

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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