9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea

Mok, Jeongha; Lee, Myungsun; Kim, Deog Kyeom; Kim, Ju Sang; Jhun, Byung Woo; Jo, Kyung-Wook; Jeon, Doosoo; Lee, Taehoon; Lee, Ji Yeon; Park, Jae Seuk; Lee, Seung Heon; Kang, Young Ae; Lee, Jung‐Kyu; Kwak, Nakwon; Ahn, Joong Hyun; Shim, Tae Sun; Kim, Song Yee; Kim, Seungmo; Kim, Kyungjong; Seok, Kwang-Hyuk; Yoon, Soyeong; Kim, Young Ran; Kim, Jisu; Yim, Dahae; Hahn, Seokyung; Cho, Sang Nae; Yim, Jae-Joon

doi:10.1016/s0140-6736(22)01883-9

Cited by 27 publications

(23 citation statements)

References 25 publications

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“…The sample size ranged between 20 and 688 participants. Six studies were randomized clinical trials [22] , [24] , [25] , [26] , [28] , [29] , one non-randomized clinical trial [23] , and three were cohort studies [27] , [30] , [31] . ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Relapse after treatment with standardized all-oral short regimens for rifampicin-resistant tuberculosis (RR-TB): A systematic review and meta-analysis

Reza Yosofi,

Mesic,

Decroo

2024

Journal of Clinical Tuberculosis and Other Mycobacterial Diseas

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Section: Resultsmentioning

confidence: 99%

Relapse after treatment with standardized all-oral short regimens for rifampicin-resistant tuberculosis (RR-TB): A systematic review and meta-analysis

Reza Yosofi,

Mesic,

Decroo

2024

Journal of Clinical Tuberculosis and Other Mycobacterial Diseas

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“…Notably, NExT intervention arm participants were 2.2 times more likely to experience favorable outcomes at 24 months than participants receiving the 9-month WHO-approved injectable-based regimen [51% (25/49) versus 22.7% (10/44); RR 2.2 (1.2–4.1); p = 0.006]. Surprisingly, results of the recent Korean MDR-END study [ 26 , 27 ] demonstrated that a new all-oral 9-month regimen consisting of DLM, LZD, LFX, and PZA was non-inferior to the conventional 20- to 24-month regimen in participants with FQ-sensitive MDR-TB, thus paving the way for investigations of additional SCR regimens incorporating DLM or combinations of BDQ with DLM. Additionally, a cost-effectiveness sub-study of PROSPECT is currently underway to generate cost data for BDQ-containing SCRs and SCRs without BDQ that will enable cost comparisons to be made between the two regimens.…”

Section: Discussionmentioning

confidence: 97%

A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT

Gao,

et al. 2024

Trials

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Introduction The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. Methods This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18–65 years) in China. The trial design mainly mirrors that of the “Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB” (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority. Discussion PROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16. Trial registration ClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.

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“…Moreover, the control group performance, 80.7% favorable outcome, was better than that reported in other recent studies. 3,4,[24][25][26] That non-inferiority could be established against this improved standard-and ruled out for 9DCLLfxZ at 78.8% favorable outcomes-provides confidence in the efficacy of the new regimens. High retention of participantsincluding in the control group-and completeness of study data indicate high-quality implementation.…”

Section: Discussionmentioning

confidence: 99%

Nine-month, all-oral regimens for rifampin-resistant tuberculosis

Guglielmetti,

Khan,

Velasquez

et al. 2024

Preprint

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Background After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options. Methods endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points. Results Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, -0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, -5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control. Conclusions The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care. ClinicalTrials.gov:NCT02754765

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9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea

Cited by 27 publications

References 25 publications

Relapse after treatment with standardized all-oral short regimens for rifampicin-resistant tuberculosis (RR-TB): A systematic review and meta-analysis

Relapse after treatment with standardized all-oral short regimens for rifampicin-resistant tuberculosis (RR-TB): A systematic review and meta-analysis

A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT

Nine-month, all-oral regimens for rifampin-resistant tuberculosis

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