Journal Article

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

2022

Overview

With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20–24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis. In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19–85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20–24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were “cured” and “treatment completed” were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than −10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994. Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI –9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group. 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis. Korea Disease Control and Prevention Agency, South Korea

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Antibiotics / Antitubercular Agents - therapeutic use / Cavitation / Clinical outcomes / Clinical trials / Diabetes / Diabetes mellitus / Disease control / Drug resistance / Drug Therapy, Combination / Drug withdrawal / Drugs / Female / Fluoroquinolones - therapeutic use / Guidelines / Health services / Humans / Laboratories / Levofloxacin / Levofloxacin - therapeutic use / Linezolid / Linezolid - therapeutic use / Male / Multidrug resistance / Multidrug resistant organisms / Nitroimidazoles / Oxazoles / Peripheral neuropathy / Pyrazinamide / Pyrazinamide - therapeutic use / Randomization / Rifampin / Safety / Success / Treatment Outcome / Tuberculosis / Tuberculosis, Multidrug-Resistant - drug therapy