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

Sponsor

Seoul National University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02619994

Collaborator

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

238

Enrollment

Location

Arms

Duration (Months)

3.7

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Multidrug-Resistant	Drug: Linezolid Drug: Delamanid Drug: Levofloxacin Drug: Pyrazinamide Drug: Locally-used WHO-approved MDR-TB regimen in Korea	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

238 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Jan 1, 2016

Anticipated Primary Completion Date :

Jun 1, 2021

Anticipated Study Completion Date :

Jun 1, 2021

Arms and Interventions

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: Linezolid Drug: Delamanid Drug: Levofloxacin Drug: Pyrazinamide

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: Linezolid

Drug: Delamanid

Drug: Levofloxacin

Drug: Pyrazinamide

Outcome Measures

Primary Outcome Measures

Treatment success rate [24 months after treatment start]
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 [through study completion, 24 months after enrollment]
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 [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 85 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine	Seoul		Korea, Republic of	110-744