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

Ji Yeon Lee, Deog Kyeom Kim, Jung Kyu Lee, Ho Il Yoon, Ina Jeong, Eun Young Heo, Young Sik Park, Jaeho Lee, Sung Soo Park, Sang-Min Lee, Chang Hoon Lee, Jinwoo Lee, Sun Mi Choi, Jong Sun Park, Joon Sung Joh, Young Jae Cho, Yeon Joo Lee, Se Joong Kim, Young Ran Hwang, Hyeonjeong KimJongeun Ki, Hyungsook Choi, Jiyeon Han, Heejung Ahn, Seokyung Hahn, Jae-Joon Yim

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Abstract

Background: 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. Methods/design: 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). Discussion: 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. Trial registration: ClincalTrials.gov, NCT01994460. Registered on 13 November 2013.

Original languageEnglish
Article number68
JournalTrials
Volume18
Issue number1
DOIs
StatePublished - 13 Feb 2017

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Linezolid
Ethambutol
Pulmonary Tuberculosis
Sputum
Rifampin
Therapeutics
Extensively Drug-Resistant Tuberculosis
Oxazolidinones
Pyrazinamide
Multidrug-Resistant Tuberculosis
Isoniazid
Pharmaceutical Preparations
Multicenter Studies
Tuberculosis

Keywords

  • Ethambutol
  • Linezolid
  • Multicenter
  • Randomized trial
  • Tuberculosis

Cite this

@article{5dae32713dc94b1ebfdb3fac64621742,
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 = "Background: 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. Methods/design: 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{\circledR} 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). Discussion: 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. Trial registration: ClincalTrials.gov, NCT01994460. Registered on 13 November 2013.",
keywords = "Ethambutol, Linezolid, Multicenter, Randomized trial, Tuberculosis",
author = "Lee, {Ji Yeon} and Kim, {Deog Kyeom} and Lee, {Jung Kyu} and Yoon, {Ho Il} and Ina Jeong and Heo, {Eun Young} and Park, {Young Sik} and Jaeho Lee and Park, {Sung Soo} and Sang-Min Lee and Lee, {Chang Hoon} and Jinwoo Lee and Choi, {Sun Mi} and Park, {Jong Sun} and Joh, {Joon Sung} and Cho, {Young Jae} and Lee, {Yeon Joo} and Kim, {Se Joong} and Hwang, {Young Ran} and Hyeonjeong Kim and Jongeun Ki and Hyungsook Choi and Jiyeon Han and Heejung Ahn and Seokyung Hahn and Jae-Joon Yim",
year = "2017",
month = "2",
day = "13",
doi = "10.1186/s13063-017-1811-0",
language = "English",
volume = "18",
journal = "Trials",
issn = "1745-6215",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis

T2 - Study protocol for a prospective, multicenter, randomized, open-label, phase II trial

AU - Lee, Ji Yeon

AU - Kim, Deog Kyeom

AU - Lee, Jung Kyu

AU - Yoon, Ho Il

AU - Jeong, Ina

AU - Heo, Eun Young

AU - Park, Young Sik

AU - Lee, Jaeho

AU - Park, Sung Soo

AU - Lee, Sang-Min

AU - Lee, Chang Hoon

AU - Lee, Jinwoo

AU - Choi, Sun Mi

AU - Park, Jong Sun

AU - Joh, Joon Sung

AU - Cho, Young Jae

AU - Lee, Yeon Joo

AU - Kim, Se Joong

AU - Hwang, Young Ran

AU - Kim, Hyeonjeong

AU - Ki, Jongeun

AU - Choi, Hyungsook

AU - Han, Jiyeon

AU - Ahn, Heejung

AU - Hahn, Seokyung

AU - Yim, Jae-Joon

PY - 2017/2/13

Y1 - 2017/2/13

N2 - Background: 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. Methods/design: 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). Discussion: 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. Trial registration: ClincalTrials.gov, NCT01994460. Registered on 13 November 2013.

AB - Background: 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. Methods/design: 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). Discussion: 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. Trial registration: ClincalTrials.gov, NCT01994460. Registered on 13 November 2013.

KW - Ethambutol

KW - Linezolid

KW - Multicenter

KW - Randomized trial

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=85013016903&partnerID=8YFLogxK

U2 - 10.1186/s13063-017-1811-0

DO - 10.1186/s13063-017-1811-0

M3 - Article

C2 - 28193240

AN - SCOPUS:85013016903

VL - 18

JO - Trials

JF - Trials

SN - 1745-6215

IS - 1

M1 - 68

ER -