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
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
Affiliations
S. B. Patil
Indian Council of Medical Research (ICMR) – National AIDS Research Institute
M. Tamirat
Partners In Health
K. Khazhidinov
Partners In Health
E. Ardizzoni
Institute of Tropical Medicine (ITM)
M. Atger
Medical Department, Médecins Sans Frontières
A. Austin
UCSF Center for Tuberculosis, University of California,
E. Baudin
Epicentre
M. Bekhit
Medical Department, Médecins Sans Frontières
S. Bektasov
National TB Center
E. Berikova
Partners In Health
M. Bonnet
Université de Montpellier, IRD, INSERM
R. Caboclo
Medical Department, Médecins Sans Frontières
M. Chaudhry
Medical Department, Médecins Sans Frontières
V. Chavan
Médecins Sans Frontières
S. Cloez
Medical Department, Médecins Sans Frontières
J. Coit
Department of Global Health and Social Medicine, Harvard Medical School
S. Coutisson
Médecins Sans Frontières
Z. Dakenova
City Center of Phthisiopulmonology
B. C. De Jong
Institute of Tropical Medicine (ITM)
C. Delifer
Medical Department, Médecins Sans Frontières
S. Demaisons
Medical Department, Médecins Sans Frontières
J. M. Do
Department of Global Health and Social Medicine, Harvard Medical School
D. Dos Santos Tozzi
Incyte
V. Ducher
Medical Department, Médecins Sans Frontières
G. Ferlazzo
Médecins Sans Frontières
M. Gouillou
Epicentre
U. Khan
Interactive Research and Development (IRD) Global
M. Kunda
Partners In Health
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
Medical Department, Médecins Sans Frontières
H. McIlleron
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town
M. Moreau
Medical Department, Médecins Sans Frontières
M. Moschioni
Medicines Patent Pool
P. Nahid
UCSF Center for Tuberculosis, University of California,
E. Osso
Department of Global Health and Social Medicine, Harvard Medical School
L. Oyewusi
Partners In Health
S. Panda
Indian Council of Medical Research Headquarters
A. Pâquet
Medical Department, Médecins Sans Frontières
P. Thuong Huu
Hanoi Lung Hospital
L. Pichon
Medical Department, Médecins Sans Frontières
M. L. Rich
Partners In Health
P. Rupasinghe
Institute of Tropical Medicine (ITM)
N. Salahuddin
Indus Hospital & Health Network
E. Sanchez Garavito
Hospital Nacional Sergio E. Bernales
K. J. Seung
Partners In Health
G. E. Velásquez
UCSF Center for Tuberculosis, University of California,
M. Vallet
Medical Department, Médecins Sans Frontières
F. Varaine
Medical Department, Médecins Sans Frontières
F. J. Yuya-Septoh
Epicentre
C. D. Mitnick
Department of Global Health and Social Medicine, Harvard Medical School
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.
