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.

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.

• Authors: 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
• Journal: Trials (Trials) Vol. 24 Issue 1 Pg. 773 (Nov 30 2023) ISSN: 1745-6215 [Electronic] England
• PMID: 38037119 (Publication Type: Clinical Trial Protocol, Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• OPC-67683
• Fluoroquinolones
• Clofazimine
• Linezolid
• Antitubercular Agents

Topics

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