Lancet. 2022;400(10362):1522-1530.
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.
제1저자 목정하, 이명선 · 교신저자 임재준
소속 (19)
- Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Pusan National University Hospital, Busan, South Korea; Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, South Korea.
- Division of Clinical Research, International Tuberculosis Research Centre, Seoul, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Centre, Seoul, South Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Incheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, South Korea; Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Centre, Seoul, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dankook University Hospital, Cheonan, South Korea.
- Department of Pulmonology, Korea University Ansan Hospital, Ansan, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Centre, Seoul, South Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
- Department of Laboratory Medicine, The Korean Institute of Tuberculosis, Cheongju, South Korea.
- Department of R&D, The Korean Institute of Tuberculosis, Cheongju, South Korea; DNA Analysis Division, Seoul Institute, National Forensic Service, Seoul, South Korea.
- Medical Research Collaborating Centre, Seoul National University Hospital, Seoul, South Korea.
- Department of Human Systems Medicine, Seoul National University College of Medicine, Seoul, South Korea; Medical Research Collaborating Centre, Seoul National University Hospital, Seoul, South Korea.
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Electronic address: yimjj@snu.ac.kr.
Abstract
BACKGROUND 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.
METHODS 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.
FINDINGS 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.
INTERPRETATION 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis.
FUNDING Korea Disease Control and Prevention Agency, South Korea.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Comment · 정정
Conflict of interest statement
Declaration of interests We declare no competing interests.
그 밖의 정보
- 출판 형태
- Randomized Controlled Trial, Multicenter Study, Clinical Trial, Phase III, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Equivalence Trial
- 저널
- Lancet (London, England) · eISSN 1474-547X
- MeSH
- Male · Female · Humans · Pyrazinamide* / therapeutic use · Linezolid / therapeutic use · Levofloxacin / therapeutic use · Fluoroquinolones / therapeutic use · Drug Therapy, Combination · Tuberculosis, Multidrug-Resistant* / drug therapy · Antitubercular Agents / therapeutic use · Treatment Outcome · Nitroimidazoles · Oxazoles
- Substances
- Pyrazinamide · Linezolid · Levofloxacin · Fluoroquinolones · Antitubercular Agents · OPC-67683 · Nitroimidazoles · Oxazoles
- 데이터
- ClinicalTrials.gov: NCT02619994