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.
December 2023BioMed Central Ltd
Trials
2023#24Issue 1
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.
Bedaquiline , Clofazimine , Delamanid , Fluroquinolone-resistant , Linezolid , MDR-TB , Multidrug-resistant , Non-inferiority , Pre-XDR TB , Rifampicin-resistant , RR-TB , Stratified medicine , Treatment shortening , Tuberculosis
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Indian Council of Medical Research (ICMR) – National AIDS Research Institute, Pune, India
Partners In Health, Maseru, Lesotho
Partners In Health, Astana, Kazakhstan
Institute of Tropical Medicine (ITM), Antwerp, Belgium
Medical Department, Médecins Sans Frontières, 14-34 Avenue Jean Jaurès, Paris, 75019, France
UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States
Epicentre, Paris, France
National TB Center, Almaty, Kazakhstan
National Scientific Center of Phthisiopulmonology, Almaty, Kazakhstan
Université de Montpellier, IRD, INSERM, TransVIHMI, Montpellier, France
Médecins Sans Frontières, Mumbai, India
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
Médecins Sans Frontières, Geneva, Switzerland
City Center of Phthisiopulmonology, Astana, Kazakhstan
Incyte, Morges, Switzerland
Interactive Research and Development (IRD) Global, Singapore, Singapore
Socios En Salud-Sucursal Peru, Lima, Peru
Assistance Publique Hôpitaux de Paris (APHP), Unité de Recherche Clinique, Hôpital Pitié-Salpêtrière, Paris, France
Santé Arménie French-Armenian Research Center, Yerevan, Armenia
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Medicines Patent Pool, Geneva, Switzerland
Indian Council of Medical Research Headquarters, New Delhi, India
Indian Journal of Medical Research, New Delhi, India
Hanoi Lung Hospital, Hanoi, Viet Nam
Partners In Health, Boston, MA, United States
Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, United States
Indus Hospital & Health Network, Karachi, Pakistan
Hospital Nacional Sergio E. Bernales, Lima, Peru
Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, United States
Brigham and Women’s Hospital, Boston, MA, United States
Sorbonne Université, INSERM, U1135, Centre d’Immunologie Et Des Maladies Infectieuses, Paris, France
Assistance Publique Hôpitaux de Paris (APHP), Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié Salpêtrière, Centre National De Référence Des Mycobactéries Et De La Résistance Des Mycobactéries Aux Antituberculeux, Paris, France
Indian Council of Medical Research (ICMR) – National AIDS Research Institute
Partners In Health
Partners In Health
Institute of Tropical Medicine (ITM)
Medical Department
UCSF Center for Tuberculosis
Epicentre
National TB Center
National Scientific Center of Phthisiopulmonology
Université de Montpellier
Médecins Sans Frontières
Department of Global Health and Social Medicine
Médecins Sans Frontières
City Center of Phthisiopulmonology
Incyte
Interactive Research and Development (IRD) Global
Socios En Salud-Sucursal Peru
Assistance Publique Hôpitaux de Paris (APHP)
Santé Arménie French-Armenian Research Center
Division of Clinical Pharmacology
Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa)
Medicines Patent Pool
Indian Council of Medical Research Headquarters
Indian Journal of Medical Research
Hanoi Lung Hospital
Partners In Health
Division of Global Health Equity
Indus Hospital & Health Network
Hospital Nacional Sergio E. Bernales
Division of HIV
Brigham and Women’s Hospital
Sorbonne Université
Assistance Publique Hôpitaux de Paris (APHP)
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