title: Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: study protocol for a prospective, multicenter, randomized, open-label, phase II trial.
abstract: Linezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We started a trial to test whether the use of linezolid instead of ethambutol could increase the rate of sputum culture conversion as of 8 weeks of treatment in patients with drug-susceptible tuberculosis.
  
  
  
  This is a phase II, multicenter, randomized study with three arms. We are enrolling patients with pulmonary tuberculosis without rifampicin resistance screened by the Xpert MTB/RIF® assay. The standard treatment arm uses isoniazid (6 months), rifampicin (6 months), pyrazinamide (2 months), and ethambutol (2 months). Experimental arm 1 uses linezolid (600 mg/day) for 4 weeks instead of ethambutol. Experimental arm 2 uses linezolid (600 mg/day) for 2 weeks instead of ethambutol. The primary outcome is the sputum culture conversion rate on liquid media after 2 months of treatment. Secondary outcomes include the sputum culture conversion rate on solid media after 2 months of treatment, time to sputum culture conversion on liquid and solid media, cure rate, and treatment success rate. The frequencies of total adverse events (AEs) and serious AEs will be described and documented. Based on an α = 0.05 level of significance, a power of 85%, a 15% difference in the culture conversion rate after 2 months between the control arm and experimental arm 1 (75% vs. 90%), a 10% default (loss to follow-up) rate, and a 10% culture failure, the required number per arm was calculated to be 143 (429 in total).
  
  
  
  This trial will reveal the effectiveness and safety of 2 or 4 weeks of use of linezolid instead of ethambutol for patients with drug-susceptible pulmonary tuberculosis. If a new regimen including linezolid shows a higher culture conversion rate by week 8, and is safe, it could be tested as a 4-month antituberculosis treatment regimen in the future.
  
  
  
  ClincalTrials.gov, NCT01994460 . Registered on 13 November 2013.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Deog Kyeom
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Jung-Kyu
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ho Il
authors.initials: HI
authors.lastname: Yoon
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea.
authors.forename: Ina
authors.initials: I
authors.lastname: Jeong
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Heo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Park
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Park
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Choi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea.
authors.forename: Joon-Sung
authors.initials: JS
authors.lastname: Joh
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Young-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Yeon Joo
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Se Joong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Hwang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Hyeonjeong
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea.
authors.forename: Jongeun
authors.initials: J
authors.lastname: Ki
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Hyungsook
authors.initials: H
authors.lastname: Choi
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Han
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Heejung
authors.initials: H
authors.lastname: Ahn
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Seokyung
authors.initials: S
authors.lastname: Hahn
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. yimjj@snu.ac.kr.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. yimjj@snu.ac.kr.
authors.forename: Jae-Joon
authors.initials: JJ
authors.lastname: Yim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002985:Clinical Protocols; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D000069349:Linezolid / Q000008:administration & dosage* / Q000009:adverse effects; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D056910:Republic of Korea; D012107:Research Design; D013183:Sputum / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D000069349:Linezolid
keywords: Ethambutol; Linezolid; Multicenter; Randomized trial; Tuberculosis