An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study)

Esmail, Aliasgar; Oelofse, Suzette; Lombard, Carl; Perumal, Rubeshan; Mbuthini, Linda; Mahomed, Akhter Goolam; Variava, Ebrahim; Black, John; Oluboyo, Patrick; Gwentshu, Nelile; Ngam, Eric; Ackerman, Tertius; Marais, Linde; Mottay, Lynelle; Meier, Stuart; Pooran, Anil; Tomasicchio, Michele; Riele, Julian Te; Derendinger, Brigitta; Ndjeka, Norbert; Maartens, Gary; Warren, Robin M.; Martinson, Neil; Dheda, Keertan

doi:10.1164/rccm.202107-1779oc

Cited by 58 publications

(49 citation statements)

References 16 publications

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“…This was reported by fourteen studies with 21,515 participants [25,27,29,32,35,37,38,40,41,43,44,46,48,52], and ve of which were RCTs. The meta-analysis found no signi cant difference between the intervention groups and control groups (Figure S4).…”

Section: The Rate Of Complete At End Of the Treatmentmentioning

confidence: 86%

“…Seven studies with 575 participants were included [24,25,29,36,38,41,44] and compared the rate of culture conversion in participants taking different regimens at 8 weeks, three of which were RCTs (Figure S2). The RCTs showed no signi cant difference in culture conversion rates between those who initiated BDQ-containing regimen (RR = 1.48, 95%Cl: 0.79 to 2.77).…”

Section: The Rate Of Sputum Culture Conversion At 8 Weeksmentioning

confidence: 99%

“…The pooled RRs remained consistent across the meta-analysis of studies, that the results were robust except for three studies. Esmail 2022 [29], Wu 2020 [35] and Ling 2021 [30] showed inconsistency in the sensitivity analysis.…”

Section: Sensitivity Analysismentioning

confidence: 99%

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The efficacy and safety of bedaquiline in the treatment of pulmonary tuberculosis patients: a systematic review and meta-analysis

Tong

Chen

et al. 2022

Preprint

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Background The World Health Organization (WHO) recommends bedaquiline (BDQ) as a Group A drug for the treatment of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). This systematic review and meta-analysis aimed to evaluate the efficacy and safety of BDQ-containing regimens for the treatment of pulmonary TB patients. Methods MEDLINE (PubMed), EBSCO, the Cochrane Central Register of Controlled Trials and CNKI (China National Knowledge Infrastructure) were searched to identify eligible trials until September 8, 2022, for randomized controlled trials (RCTs) and non-randomized studies (NRSs) where BDQ was administered to patients with TB. Outcomes of interest were: (1) efficacy, including the rate of sputum culture conversion at 8 weeks, 24 weeks, and follow-up, and the rate of complete, cure, death, failure, and lost to follow-up at end of the treatment. (2) safety, which includes the incidence of cardiotoxicity, hepatotoxicity, and grade 3–5 adverse events during the treatment. Results A total of 29 articles (N = 23,358) fulfilled the eligibility criteria and were included in the meta-analysis. Compared with the BDQ-unexposed patients, The BDQ-containing regimen improved the rate of sputum conversion in RCTs (24 weeks: RR = 1.27, 95%Cl:1.10 to 1.46, follow-up: RR = 1.33, 95%Cl:1.06 to 1.66) and increased cure rate (RR = 1.60, 95%Cl: 1.13 to 2.26), and it also decreased the failure rate by 0.56 (95%Cl: 0.56 to 0.88). In NRSs, BDQ-containing regimen improved the sputum culture conversion rate (follow-up: RR = 1.53, 95%Cl: 1.07 to 2.20) and the rate of cure (RR = 1.86,95%Cl:1.23 to 2.83), reduced the rate of all-cause death (RR = 0.68, M-H random-effects 95%Cl: 0.48 to 0.97) and failure (RR = 0.57, 95%Cl:0.46 to 0.71). In terms of safety, BDQ-containing regimen administration increased the incidence of cardiotoxicity (RR = 4.54, M-H random-effects 95%Cl: 1.74–11.87) and grade 3–5 adverse events (RR = 1.42, M-H random-effects 95%Cl: 1.17–1.73) in RCTs; NRSs showed cardiotoxicity was associated with BDQ-containing regimen (RR = 6.00, M-H random-effects 95%Cl: 1.32–27.19). In the other outcomes, there was no significant difference between the intervention and control groups. Conclusions RCTs and NRSs data support the efficacy of BDQ for pulmonary TB, but cardiotoxicity and serious adverse events of BDQ were frequent. Overall, there is a lack of comparative data on efficacy and safety. Due to the serious risk of bias and discrepancy, further confirmation is needed.

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Section: The Rate Of Complete At End Of the Treatmentmentioning

confidence: 86%

Section: The Rate Of Sputum Culture Conversion At 8 Weeksmentioning

confidence: 99%

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The efficacy and safety of bedaquiline in the treatment of pulmonary tuberculosis patients: a systematic review and meta-analysis

Tong

Chen

et al. 2022

Preprint

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“…The NExT trial reduced the linezolid dose to 600 mg daily, and ZeNix studied that dose plus two regimens in which linezolid was given for only the first 2months at either 1,200 or 600 mg per day, and TB-PRACTECAL gave linezolid at 600 mg for 4 months followed by 2 months at 300mg daily. 2,4,5 All of these dose reductions decreased toxicity substantially. Although the protocoldefined favorable outcome proportion with the NExT regimen was only 51%, this was largely attributable to the discontinuation of linezolid; overall positive outcomes at 24 months were 75%.…”

Section: Providing Accessmentioning

confidence: 99%

“…Subsequent to the Nix-TB trial regimen, three new regimens were reported recently and those are the NExT trial by Esmail et al, 4 the ZeNix trial as discussed above, 3 and the TB-PRACTECAL trial, although the latter two are reported in abstract form only. 3,5 These trials are built on the 6-month "NiX-TB" regimen, 2 an all-oral 6-month treatment regimen with bedaquiline, pretomanid, and high-dose linezolid, that achieved a 90% cure rate in a cohort of patients with an advanced spectrum of drug-resistant TB.…”

Section: Providing Accessmentioning

confidence: 99%

To End Tuberculosis, India must Embrace Innovation: Lessons from the ZeNix Trial Results

Behera¹

2022

The Indian Journal of Chest Diseases and Allied Sciences

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Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

Metcalfe,

Economou,

Naufal

et al. 2024

JAMA Netw Open

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ImportanceRifampin-resistant tuberculosis treatment regimens require electrocardiographic (ECG) monitoring due to the use of multiple QTc-prolonging agents. Formal 12-lead ECG devices represent a significant burden in resource-constrained clinics worldwide and a potential barrier to treatment scale-up in some settings.ObjectiveTo evaluate the diagnostic accuracy of a handheld 6-lead ECG device within resource-constrained clinics.Design, Setting, and ParticipantsThis diagnostic study was performed within a multicenter, pragmatic (broad eligibility criteria with no exclusions for randomized participants), phase 3 rifampin-resistant tuberculosis treatment trial (BEAT Tuberculosis [Building Evidence for Advancing New Treatment for Tuberculosis]) in South Africa. A total of 192 consecutive trial participants were assessed, and 191 were recruited for this substudy between January 21, 2021, and March 27, 2023. A low proportion (3 of 432 [0.7%]) of all screened trial participants were excluded due to a QTc interval greater than 450 milliseconds. Triplicate reference standard 12-lead ECG results were human calibrated with readers blinded to 6-lead ECG results.Main Outcomes and MeasuresDiagnostic accuracy, repeatability, and feasibility of a 6-lead ECG device.ResultsA total of 191 participants (median age, 36 years [IQR, 28-45 years]; 81 female participants [42.4%]; 91 participants [47.6%] living with HIV) with a median of 4 clinic visits (IQR, 3-4 visits) contributed 2070 and 2015 12-lead and 6-lead ECG assessments, respectively. Across 170 participants attending 489 total clinic visits where valid triplicate QTc measurements were available for both devices, the mean 12-lead QTc measurement was 418 milliseconds (range, 321-519 milliseconds), and the mean 6-lead QTc measurement was 422 milliseconds (range, 288-574 milliseconds; proportion of variation explained, R2 = 0.4; P &lt; .001). At a QTc interval threshold of 500 milliseconds, the 6-lead ECG device had a negative predictive value of 99.8% (95% CI, 98.8%-99.9%) and a positive predictive value of 16.7% (95% CI, 0.4%-64.1%). The normal expected range of within-individual variability of the 6-lead ECG device was high (±50.2 milliseconds [coefficient of variation, 6.0%]) relative to the 12-lead ECG device (±22.0 milliseconds [coefficient of variation, 2.7%]). The mean (SD) increase in the 12-lead QTc measurement during treatment was 10.1 (25.8) milliseconds, with 0.8% of clinic visits (4 of 489) having a QTc interval of 500 milliseconds or more.Conclusions and RelevanceThis study suggests that simplified, handheld 6-lead ECG devices are effective triage tests that could reduce the need to perform 12-lead ECG monitoring in resource-constrained settings.

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An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study)

Cited by 58 publications

References 16 publications

The efficacy and safety of bedaquiline in the treatment of pulmonary tuberculosis patients: a systematic review and meta-analysis

The efficacy and safety of bedaquiline in the treatment of pulmonary tuberculosis patients: a systematic review and meta-analysis

To End Tuberculosis, India must Embrace Innovation: Lessons from the ZeNix Trial Results

Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

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