Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial
L. Guglielmetti,
E. Ardizzoni,
M. Atger,
E. Baudin,
E. Berikova,
M. Bonnet,
E. Chang,
S. Cloez,
J. M. Coit,
V. Cox,
B. C. de Jong,
C. Delifer,
J. M. Do,
D. Dos Santos Tozzi,
V. Ducher,
G. Ferlazzo,
M. Gouillou,
A. Khan,
U. Khan,
N. Lachenal,
A. N. LaHood,
L. Lecca,
M. Mazmanian,
H. McIlleron,
M. Moschioni,
K. O’Brien,
O. Okunbor,
L. Oyewusi,
S. Panda,
S. B. Patil,
P. P. J. Phillips,
L. Pichon,
P. Rupasinghe,
M. L. Rich,
N. Saluhuddin,
K. J. Seung,
M. Tamirat,
L. Trippa,
M. Cellamare,
G. E. Velásquez,
S. Wasserman,
P. J. Zimetbaum,
F. Varaine,
C. D. Mitnick
Affiliations
L. Guglielmetti
Médecins Sans Frontières
E. Ardizzoni
Institute of Tropical Medicine
M. Atger
Médecins Sans Frontières
E. Baudin
Epicentre
E. Berikova
Partners In Health
M. Bonnet
Médecins Sans Frontières
E. Chang
Médecins Sans Frontières
S. Cloez
Médecins Sans Frontières
J. M. Coit
Department of Global Health and Social Medicine, Harvard Medical School
V. Cox
Centre for Infectious Disease Epidemiology and Research, School of Public Health and Medicine, Faculty of Health Sciences, University of Cape Town
B. C. de Jong
Institute of Tropical Medicine
C. Delifer
Médecins Sans Frontières
J. M. Do
Department of Global Health and Social Medicine, Harvard Medical School
D. Dos Santos Tozzi
Epicentre
V. Ducher
Médecins Sans Frontières
G. Ferlazzo
Southern Africa Medical Unit, Médecins Sans Frontières
M. Gouillou
Epicentre
A. Khan
Interactive Research and Development
U. Khan
Interactive Research and Development
N. Lachenal
Médecins Sans Frontières
A. N. LaHood
Department of Global Health and Social Medicine, Harvard Medical School
L. Lecca
Department of Global Health and Social Medicine, Harvard Medical School
M. Mazmanian
Médecins Sans Frontières
H. McIlleron
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town
M. Moschioni
Médecins Sans Frontières
K. O’Brien
Abiomed, Inc.
O. Okunbor
Social & Scientific Systems-DLH
L. Oyewusi
Partners In Health
S. Panda
Epidemiology and Communicable Diseases Division, Indian Council of Medical Research
S. B. Patil
Indian Council of Medical Research – National AIDS Research Institute
P. P. J. Phillips
University of San Francisco Center for Tuberculosis
L. Pichon
Médecins Sans Frontières
P. Rupasinghe
Institute of Tropical Medicine
M. L. Rich
Department of Global Health and Social Medicine, Harvard Medical School
N. Saluhuddin
Department of Infectious Diseases, Indus Hospital
K. J. Seung
Department of Global Health and Social Medicine, Harvard Medical School
M. Tamirat
Partners In Health
L. Trippa
Dana-Farber Cancer Institute
M. Cellamare
Dana-Farber Cancer Institute
G. E. Velásquez
Department of Global Health and Social Medicine, Harvard Medical School
S. Wasserman
Wellcome Centre for Infectious Diseases Research in Africa, Department of Medicine, University of Cape Town
P. J. Zimetbaum
Harvard Medical School
F. Varaine
Médecins Sans Frontières
C. D. Mitnick
Department of Global Health and Social Medicine, Harvard Medical School
Abstract 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.
