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Journal Article > ProtocolFull Text

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

Trials. 25 September 2021; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
Guglielmetti L, Ardizzoni E, Atger M, Baudin E, Berikova E,  et al.
Trials. 25 September 2021; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
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.
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Journal Article > ResearchFull Text

Light-emitting diode fluorescence microscopy for tuberculosis diagnosis: a meta-analysis

Eur Respir J. 2 December 2015; Volume 47 (Issue 3); DOI:10.1183/13993003.00978-2015
Chang EW, Page AL, Bonnet MMB
Eur Respir J. 2 December 2015; Volume 47 (Issue 3); DOI:10.1183/13993003.00978-2015
Light-emitting diode fluorescence microscopy (LED-FM) is recommended by the World Health Organization to replace conventional Ziehl–Neelsen microscopy for pulmonary tuberculosis diagnosis. Uptake of LED-FM has been slow. One reason is its reported loss of specificity compared with Ziehl–Neelsen microscopy. We aimed to determine the diagnostic accuracy of LED-FM for tuberculosis detection and explore potential factors that might affect its performance.A comprehensive search strategy based on pre-specified criteria was employed to identify eligible studies between January 1, 2000 and April 1, 2014 in 11 databases. Standardised study selection, data extraction and quality assessment were conducted. Pooled sensitivity and specificity of LED-FM using culture as the reference standard were estimated through meta-analyses using a bivariate random-effects model. Investigation of heterogeneity was performed by subgroup analyses.We identified 12 unique studies, half of which were from peripheral healthcare facilities. LED-FM achieved a pooled sensitivity of 66.9% (95% CI 60.5–72.7%) and pooled specificity of 96.8% (95% CI 93.1–98.6%). A pooled sensitivity of 53.0% (95% CI 42.8–63.0%) and pooled specificity of 96.1% (95% CI 86.0–99.0%) were obtained by LED-FM among HIV-infected patients. Study methodology factors and differences in the LED-FM procedure or device could also affect the performance.LED-FM specificity is high and should not be a barrier to device introduction, particularly among peripheral healthcare settings where this technology is meant to be used. Sensitivity is reduced in HIV-infected patients.More