Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial

Guglielmetti L. Ardizzoni E. Atger M. Baudin E. Berikova E. Bonnet M. Chang E. Cloez S. Coit J.M. Cox V. de Jong B.C. Delifer C. Do J.M. Tozzi D.D.S. Ducher V. Ferlazzo G. Gouillou M. Khan A. Khan U. Lachenal N. LaHood A.N. Lecca L. Mazmanian M. McIlleron H. Moschioni M. O’Brien K. Okunbor O. Oyewusi L. Panda S. Patil S.B. Phillips P.P.J. Pichon L. Rupasinghe P. Rich M.L. Saluhuddin N. Seung K.J. Tamirat M. Trippa L. Cellamare M. Velásquez G.E. Wasserman S. Zimetbaum P.J. Varaine F. Mitnick C.D.
December 2021 BioMed Central Ltd

Trials
2021 #22 Issue 1

Background: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. Methods: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. 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 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, 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: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. Trial registration: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Bayesian adaptive randomization , Bedaquiline , Clofazimine , Delamanid , Fluoroquinolone , Linezolid , MDR-TB , Non-inferiority , Pyrazinamide , Rifampicin-resistant tuberculosis , Rifampin-resistant tuberculosis , Treatment shortening

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Médecins Sans Frontières, Paris, France
Sorbonne Université, INSERM, U1135, Centre d’Immunologie Et Des Maladies Infectieuses, Paris, France
Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié-Salpêtrière, Centre National De Référence Des Mycobactéries Et De La Résistance Des Mycobactéries Aux Antituberculeux, Paris, France
Institute of Tropical Medicine, Antwerp, Belgium
Epicentre, Paris, France
Partners In Health, Astana, Kazakhstan
National Scientific Center of Phthisiopulmonology, Almaty, Kazakhstan
Institut de Recherche pour le Développement/INSERM U1175/UMI233/ Université de Montpellier, Montpellier, France
Médecins Sans Frontières, Toronto, ON, Canada
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
Centre for Infectious Disease Epidemiology and Research, School of Public Health and Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Southern Africa Medical Unit, Médecins Sans Frontières, Cape Town, South Africa
Interactive Research and Development, Karachi, Pakistan
Socios En Salud-Sucursal Peru, Lima, Peru
Assistance Publique Hôpitaux de Paris, Unité de Recherche Clinique, Hôpital Pitié-Salpêtrière, Paris, France
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Abiomed, Inc., Danvers, MA, United States
Social & Scientific Systems-DLH, Silver Spring, MD, United States
Partners In Health, Maseru, Lesotho
Epidemiology and Communicable Diseases Division, Indian Council of Medical Research, Pune, India
Indian Council of Medical Research – National AIDS Research Institute, Pune, India
University of San Francisco Center for Tuberculosis, San Francisco, CA, United States
Partners In Health, Boston, MA, United States
Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, United States
Department of Infectious Diseases, Indus Hospital, Karachi, Pakistan
Dana-Farber Cancer Institute, Boston, MA, United States
Harvard T.H. Chan School of Public Health, Boston, MA, United States
Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, United States
Wellcome Centre for Infectious Diseases Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
Harvard Medical School, Boston, MA, United States
Beth Israel Deaconess Medical Center, Boston, MA, United States

Médecins Sans Frontières
Sorbonne Université
Assistance Publique Hôpitaux de Paris
Institute of Tropical Medicine
Epicentre
Partners In Health
National Scientific Center of Phthisiopulmonology
Institut de Recherche pour le Développement/INSERM U1175/UMI233/ Université de Montpellier
Médecins Sans Frontières
Department of Global Health and Social Medicine
Centre for Infectious Disease Epidemiology and Research
Southern Africa Medical Unit
Interactive Research and Development
Socios En Salud-Sucursal Peru
Assistance Publique Hôpitaux de Paris
Division of Clinical Pharmacology
Wellcome Centre for Infectious Diseases Research in Africa
Abiomed
Social & Scientific Systems-DLH
Partners In Health
Epidemiology and Communicable Diseases Division
Indian Council of Medical Research – National AIDS Research Institute
University of San Francisco Center for Tuberculosis
Partners In Health
Division of Global Health Equity
Department of Infectious Diseases
Dana-Farber Cancer Institute
Harvard T.H. Chan School of Public Health
Division of Infectious Diseases
Wellcome Centre for Infectious Diseases Research in Africa
Division of Infectious Diseases and HIV Medicine
Harvard Medical School
Beth Israel Deaconess Medical Center

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