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Treatment Shortening of MDR-TB Using Existing and New Drugs (MDR-END)

Primary Purpose

Tuberculosis, Multidrug-Resistant

Status
Unknown status
Phase
Phase 2
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Linezolid
Delamanid
Levofloxacin
Pyrazinamide
Locally-used WHO-approved MDR-TB regimen in Korea
Sponsored by
Seoul National University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis, Multidrug-Resistant focused on measuring Multidrug-resistant tuberculosis, Linezolid, Delamanid, Multicenter randomized trial, Non-inferiority, Shorter regimen

Eligibility Criteria

19 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Males and females aged from 19 to 85 years
  • Confirmed MDR-TB or RR-TB
  • On current TB therapy for ≤14 days at the time of enrollment.

Exclusion Criteria:

  • Known any quinolone-resistant MDR-TB
  • Known XDR-TB
  • who are pregnant or who are unwilling to use proper contraceptives at childbearing age
  • Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption
  • The need for ongoing use of prohibited drugs while on study drugs
  • History of optic neuropathy or peripheral neuropathy
  • With any of the following test results: i.Absolute neutrophil count < 2000 cells/mL, ii.White blood cell count (WBC) < 3.0 X 103/µL, iii.Hemoglobin < 7.0 g/dL, iv.Serum creatinine > 2.0 mg/dL, v.Aspartate aminotransferase (AST or SGOT) >100 IU/L, vi.Alanine aminotransferase (ALT or SGPT) >100 IU/L, vii.Total bilirubin > 2.0 mg/dL, viii.Albumin < 2.8g/dL, ix.QTcF > 500ms
  • History of hypersensitivity reaction to the study drugs

Sites / Locations

  • Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Control Arm

Experimental Arm

Arm Description

Regimen is the locally-used WHO-approved MDR-TB regimen in Korea based on 2014 Korean guideline of TB management. Intensive phase regimen consists of four effective second-line anti-TB drugs (including injectables) and pyrazinamide. Treatment duration: for at least 20 months

Regimen consists of only oral medication using delamanid, linezolid, levofloxacin, and pyrazinamide, for nine or twelve months depending on the time of sputum culture conversion to negative. Delamanid (100 mg bid for the entire treatment period) Linezolid (600mg/day for 2 months and 300mg/day afterwards until the end of treatment) Levofloxacin (750 ~1000 mg/day) Pyrazinamide (1000~ 2000 mg/day)

Outcomes

Primary Outcome Measures

Treatment success rate
To test for non-inferiority of the investigational arm, when the lower limit of the one-sided 97.5% confidence interval of the difference (PT - PC) between investigational and control arms is larger than the non-inferiority margin of - 10%, it will be concluded that the treatment success rate of the investigational arm shows non-inferiority to the treatment success rate of the control arm.

Secondary Outcome Measures

Time to sputum culture conversion after treatment start
To determine whether time to sputum culture conversion after treatment start is statis- tically different between the control and investigational arms, the median time will be estimated in each group using the Kaplan-Meier method, and the difference in the distribution of time to culture conversion of the two arms will be compared using the log-rank test.
Sputum culture conversion proportion
Treatment success
proportion of reverting to positive sputum culture after the end of treatment
Treatment success according to pyrazinamide resistance
proportion of death between the control and investigational arms

Full Information

First Posted
November 24, 2015
Last Updated
January 31, 2019
Sponsor
Seoul National University Hospital
Collaborators
Asan Medical Center, Dankook University, International Tuberculosis Research Center, Pusan National University Yangsan Hospital, Pusan National University Hospital, Samsung Medical Center, Severance Hospital, SMG-SNU Boramae Medical Center, Incheon St.Mary's Hospital, Ulsan University Hospital, Korean Institute of Tuberculosis, National Medical Center, Seoul, Korean Center for Disease Control and Prevention, Korea University
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1. Study Identification

Unique Protocol Identification Number
NCT02619994
Brief Title
Treatment Shortening of MDR-TB Using Existing and New Drugs
Acronym
MDR-END
Official Title
Delamanid, Linezolid, Levofloxacin, and Pyrazinamide for the Treatment of Patients With Fluoroquinolone-sensitive MDR-TB: A Phase 2/3, Multicenter, Randomized, Open-label, Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Unknown status
Study Start Date
January 2016 (undefined)
Primary Completion Date
June 2021 (Anticipated)
Study Completion Date
June 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
Collaborators
Asan Medical Center, Dankook University, International Tuberculosis Research Center, Pusan National University Yangsan Hospital, Pusan National University Hospital, Samsung Medical Center, Severance Hospital, SMG-SNU Boramae Medical Center, Incheon St.Mary's Hospital, Ulsan University Hospital, Korean Institute of Tuberculosis, National Medical Center, Seoul, Korean Center for Disease Control and Prevention, Korea University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to compare the efficacy of a 'new treatment regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for nine or twelve months (investigational arm)' and 'the standard treatment regimen including injectables for 20 to 24 months (control arm)' for treating fluoroquinolone-sensitive multidrug-resistant tuberculosis.
Detailed Description
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. The population number is calculated as 102 per group (204 in total).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Multidrug-Resistant
Keywords
Multidrug-resistant tuberculosis, Linezolid, Delamanid, Multicenter randomized trial, Non-inferiority, Shorter regimen

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
238 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control Arm
Arm Type
Active Comparator
Arm Description
Regimen is the locally-used WHO-approved MDR-TB regimen in Korea based on 2014 Korean guideline of TB management. Intensive phase regimen consists of four effective second-line anti-TB drugs (including injectables) and pyrazinamide. Treatment duration: for at least 20 months
Arm Title
Experimental Arm
Arm Type
Experimental
Arm Description
Regimen consists of only oral medication using delamanid, linezolid, levofloxacin, and pyrazinamide, for nine or twelve months depending on the time of sputum culture conversion to negative. Delamanid (100 mg bid for the entire treatment period) Linezolid (600mg/day for 2 months and 300mg/day afterwards until the end of treatment) Levofloxacin (750 ~1000 mg/day) Pyrazinamide (1000~ 2000 mg/day)
Intervention Type
Drug
Intervention Name(s)
Linezolid
Intervention Type
Drug
Intervention Name(s)
Delamanid
Intervention Type
Drug
Intervention Name(s)
Levofloxacin
Intervention Type
Drug
Intervention Name(s)
Pyrazinamide
Intervention Type
Drug
Intervention Name(s)
Locally-used WHO-approved MDR-TB regimen in Korea
Primary Outcome Measure Information:
Title
Treatment success rate
Description
To test for non-inferiority of the investigational arm, when the lower limit of the one-sided 97.5% confidence interval of the difference (PT - PC) between investigational and control arms is larger than the non-inferiority margin of - 10%, it will be concluded that the treatment success rate of the investigational arm shows non-inferiority to the treatment success rate of the control arm.
Time Frame
24 months after treatment start
Secondary Outcome Measure Information:
Title
Time to sputum culture conversion after treatment start
Description
To determine whether time to sputum culture conversion after treatment start is statis- tically different between the control and investigational arms, the median time will be estimated in each group using the Kaplan-Meier method, and the difference in the distribution of time to culture conversion of the two arms will be compared using the log-rank test.
Time Frame
through study completion, 24 months after enrollment
Title
Sputum culture conversion proportion
Time Frame
At 2 months or 6 months of treatment
Title
Treatment success
Time Frame
At 24months after enrollment
Title
proportion of reverting to positive sputum culture after the end of treatment
Time Frame
At 24months after enrollment
Title
Treatment success according to pyrazinamide resistance
Time Frame
At 24months after enrollment
Title
proportion of death between the control and investigational arms
Time Frame
At 24months after enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females aged from 19 to 85 years Confirmed MDR-TB or RR-TB On current TB therapy for ≤14 days at the time of enrollment. Exclusion Criteria: Known any quinolone-resistant MDR-TB Known XDR-TB who are pregnant or who are unwilling to use proper contraceptives at childbearing age Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption The need for ongoing use of prohibited drugs while on study drugs History of optic neuropathy or peripheral neuropathy With any of the following test results: i.Absolute neutrophil count < 2000 cells/mL, ii.White blood cell count (WBC) < 3.0 X 103/µL, iii.Hemoglobin < 7.0 g/dL, iv.Serum creatinine > 2.0 mg/dL, v.Aspartate aminotransferase (AST or SGOT) >100 IU/L, vi.Alanine aminotransferase (ALT or SGPT) >100 IU/L, vii.Total bilirubin > 2.0 mg/dL, viii.Albumin < 2.8g/dL, ix.QTcF > 500ms History of hypersensitivity reaction to the study drugs
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jae-Joon Yim, MD
Phone
+82-2-2072-2059
Email
yimjj@snu.ac.kr
Facility Information:
Facility Name
Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jae-Joon Yim, MD
Phone
+82-2-2072-2059
Email
yimjj@snu.ac.kr

12. IPD Sharing Statement

Citations:
PubMed Identifier
30651149
Citation
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 YA, Ahn JH, Kim CK, Shin S, Song T, Shin SJ, Kim YR, Ahn H, Hahn S, Won HJ, Jang JY, Cho SN, Yim JJ. 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. 2019 Jan 16;20(1):57. doi: 10.1186/s13063-018-3053-1.
Results Reference
derived

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Treatment Shortening of MDR-TB Using Existing and New Drugs

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