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

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

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.

Study Overview

• Status: Unknown
• Conditions: Tuberculosis, Multidrug-Resistant
• Intervention / Treatment: Drug: Levofloxacin; Drug: Pyrazinamide; Drug: Linezolid; Drug: Locally-used WHO-approved MDR-TB regimen in Korea; Drug: Delamanid

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).

• Study Type: Interventional
• Enrollment (Anticipated): 238
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jae-Joon Yim, MD; Phone Number: +82-2-2072-2059; Email: yimjj@snu.ac.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Recruiting
    • Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine
    • Contact: Jae-Joon Yim, MD; Phone Number: +82-2-2072-2059; Email: yimjj@snu.ac.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control Arm; 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	Drug: Locally-used WHO-approved MDR-TB regimen in Korea
Experimental: Experimental Arm; 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)	Drug: Levofloxacin; Drug: Pyrazinamide; Drug: Linezolid; Drug: Delamanid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 months after treatment start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	through study completion, 24 months after enrollment
Sputum culture conversion proportion		At 2 months or 6 months of treatment
Treatment success		At 24months after enrollment
proportion of reverting to positive sputum culture after the end of treatment		At 24months after enrollment
Treatment success according to pyrazinamide resistance		At 24months after enrollment
proportion of death between the control and investigational arms		At 24months after enrollment

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Samsung Medical Center; Pusan National University Hospital; Asan Medical Center; Ulsan University Hospital; Korea University; SMG-SNU Boramae Medical Center; Severance Hospital; Korean Center for Disease Control and Prevention; Pusan National University Yangsan Hospital; Incheon St.Mary's Hospital; Dankook University; International Tuberculosis Research Center; National Medical Center, Seoul; Korean Institute of Tuberculosis

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: November 24, 2015
• First Submitted That Met QC Criteria: November 30, 2015
• First Posted (Estimate): December 2, 2015

Study Record Updates

• Last Update Posted (Actual): February 4, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Non-inferiority; Linezolid; Delamanid; Multidrug-resistant tuberculosis; Multicenter randomized trial; Shorter regimen
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antitubercular Agents; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Linezolid; Levofloxacin; Ofloxacin; Pyrazinamide
• Other Study ID Numbers: MDR-END