Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial

Myungsun Lee, Jeongha Mok, Deog Kyeom Kim, Tae Sun Shim, Won Jung Koh, Doosoo Jeon, Taehoon Lee, Seung Heon Lee, Ju Sang Kim, Jae Seuk Park, Ji Yeon Lee, Song Yee Kim, Jae Ho Lee, Kyung Wook Jo, Byung Woo Jhun, youngae kang, Joong Hyun Ahn, Chang Ki Kim, Soyoun Shin, Taeksun SongSungJae Shin, Young Ran Kim, Heejung Ahn, Seokyung Hahn, Ho Jeong Won, Ji Yeon Jang, Sang Nae Cho, Jae Joon Yim

Research output: Contribution to journalArticle

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Abstract

Background: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. Methods: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/(0.50 × 0.95), resulting in 102 persons per group (204 in total). Discussion: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. Trial registration: ClincalTrials.gov, NCT02619994. Registered on 2 December 2015.

Original languageEnglish
Article number57
JournalTrials
Volume20
Issue number1
DOIs
Publication statusPublished - 2019 Jan 16

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Linezolid
Pyrazinamide
Multidrug-Resistant Tuberculosis
Levofloxacin
Fluoroquinolones
Clinical Trials
Pharmaceutical Preparations
Sputum
Therapeutics
OPC-67683

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology (medical)

Cite this

Lee, Myungsun ; Mok, Jeongha ; Kim, Deog Kyeom ; Shim, Tae Sun ; Koh, Won Jung ; Jeon, Doosoo ; Lee, Taehoon ; Lee, Seung Heon ; Kim, Ju Sang ; Park, Jae Seuk ; Lee, Ji Yeon ; Kim, Song Yee ; Lee, Jae Ho ; Jo, Kyung Wook ; Jhun, Byung Woo ; kang, youngae ; Ahn, Joong Hyun ; Kim, Chang Ki ; Shin, Soyoun ; Song, Taeksun ; Shin, SungJae ; Kim, Young Ran ; Ahn, Heejung ; Hahn, Seokyung ; Won, Ho Jeong ; Jang, Ji Yeon ; Cho, Sang Nae ; Yim, Jae Joon. / Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END) : Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial. In: Trials. 2019 ; Vol. 20, No. 1.
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title = "Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial",
abstract = "Background: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. Methods: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80{\%}, and a < 10{\%} difference in treatment success rate between the control and investigational arms (80{\%} vs. 70{\%}) when the anticipated actual success rate in the treatment group is assumed to be 90{\%}, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50{\%}, and 5{\%} loss to follow-up, the number of participants is calculated as N/(0.50 × 0.95), resulting in 102 persons per group (204 in total). Discussion: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. Trial registration: ClincalTrials.gov, NCT02619994. Registered on 2 December 2015.",
author = "Myungsun Lee and Jeongha Mok and Kim, {Deog Kyeom} and Shim, {Tae Sun} and Koh, {Won Jung} and Doosoo Jeon and Taehoon Lee and Lee, {Seung Heon} and Kim, {Ju Sang} and Park, {Jae Seuk} and Lee, {Ji Yeon} and Kim, {Song Yee} and Lee, {Jae Ho} and Jo, {Kyung Wook} and Jhun, {Byung Woo} and youngae kang and Ahn, {Joong Hyun} and Kim, {Chang Ki} and Soyoun Shin and Taeksun Song and SungJae Shin and Kim, {Young Ran} and Heejung Ahn and Seokyung Hahn and Won, {Ho Jeong} and Jang, {Ji Yeon} and Cho, {Sang Nae} and Yim, {Jae Joon}",
year = "2019",
month = "1",
day = "16",
doi = "10.1186/s13063-018-3053-1",
language = "English",
volume = "20",
journal = "Trials",
issn = "1745-6215",
publisher = "BioMed Central",
number = "1",

}

Lee, M, Mok, J, Kim, DK, Shim, TS, Koh, WJ, Jeon, D, Lee, T, Lee, SH, Kim, JS, Park, JS, Lee, JY, Kim, SY, Lee, JH, Jo, KW, Jhun, BW, kang, Y, Ahn, JH, Kim, CK, Shin, S, Song, T, Shin, S, Kim, YR, Ahn, H, Hahn, S, Won, HJ, Jang, JY, Cho, SN & Yim, JJ 2019, 'Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial', Trials, vol. 20, no. 1, 57. https://doi.org/10.1186/s13063-018-3053-1

Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END) : Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial. / Lee, Myungsun; Mok, Jeongha; Kim, Deog Kyeom; Shim, Tae Sun; Koh, Won Jung; Jeon, Doosoo; Lee, Taehoon; Lee, Seung Heon; Kim, Ju Sang; Park, Jae Seuk; Lee, Ji Yeon; Kim, Song Yee; Lee, Jae Ho; Jo, Kyung Wook; Jhun, Byung Woo; kang, youngae; Ahn, Joong Hyun; Kim, Chang Ki; Shin, Soyoun; Song, Taeksun; Shin, SungJae; Kim, Young Ran; Ahn, Heejung; Hahn, Seokyung; Won, Ho Jeong; Jang, Ji Yeon; Cho, Sang Nae; Yim, Jae Joon.

In: Trials, Vol. 20, No. 1, 57, 16.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END)

T2 - Study protocol for a phase II/III, multicenter, randomized, open-label clinical trial

AU - Lee, Myungsun

AU - Mok, Jeongha

AU - Kim, Deog Kyeom

AU - Shim, Tae Sun

AU - Koh, Won Jung

AU - Jeon, Doosoo

AU - Lee, Taehoon

AU - Lee, Seung Heon

AU - Kim, Ju Sang

AU - Park, Jae Seuk

AU - Lee, Ji Yeon

AU - Kim, Song Yee

AU - Lee, Jae Ho

AU - Jo, Kyung Wook

AU - Jhun, Byung Woo

AU - kang, youngae

AU - Ahn, Joong Hyun

AU - Kim, Chang Ki

AU - Shin, Soyoun

AU - Song, Taeksun

AU - Shin, SungJae

AU - Kim, Young Ran

AU - Ahn, Heejung

AU - Hahn, Seokyung

AU - Won, Ho Jeong

AU - Jang, Ji Yeon

AU - Cho, Sang Nae

AU - Yim, Jae Joon

PY - 2019/1/16

Y1 - 2019/1/16

N2 - Background: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. Methods: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/(0.50 × 0.95), resulting in 102 persons per group (204 in total). Discussion: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. Trial registration: ClincalTrials.gov, NCT02619994. Registered on 2 December 2015.

AB - Background: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. Methods: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/(0.50 × 0.95), resulting in 102 persons per group (204 in total). Discussion: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. Trial registration: ClincalTrials.gov, NCT02619994. Registered on 2 December 2015.

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U2 - 10.1186/s13063-018-3053-1

DO - 10.1186/s13063-018-3053-1

M3 - Article

C2 - 30651149

AN - SCOPUS:85060154506

VL - 20

JO - Trials

JF - Trials

SN - 1745-6215

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