Treatment Shortening of MDR-TB Using Existing and New Drugs

Phase 2

Completed

Conditions: Tuberculosis, Multidrug-Resistant

Interventions: Drug: Locally-used WHO-approved MDR-TB regimen in Korea
Drug: Linezolid
Drug: Delamanid
Drug: Levofloxacin
Drug: Pyrazinamide

Registration Number: NCT02619994

Lead Sponsor: Seoul National University Hospital

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 214

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Arm	Locally-used WHO-approved MDR-TB regimen in Korea	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
Experimental Arm	Levofloxacin	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)
Experimental Arm	Linezolid	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)
Experimental Arm	Delamanid	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)
Experimental Arm	Pyrazinamide	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)

Primary Outcome Measures

Name	Time	Method
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. (primary consideration for the modified intention-to-treat results)

Secondary Outcome Measures

Name	Time	Method
Time to Sputum Culture Conversion After Treatment Start	through study completion (24 months after treatment start)	To determine whether time to sputum culture conversion after treatment start is statistically 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 6 months of treatment start	Culture conversion rate at month 6 of treatment in participants with positive baseline sputum culture (liquid media).
Treatment Success at the End of Treatment	At the end of treatment	Treatment success rate at the end of treatment. * control arm (20-24 months) * experimental arm (40 or 52 weeks)
Proportion of Reverting to Positive Sputum Culture After the End of Treatment	At 24months after treatment start	The proportion of patients who experienced a reversion between the end of treatment and up to 24 months after treatment start
Treatment Success According to Pyrazinamide Resistance (1)	At 24months after treatment start	Treatment success rate of participants with pyrazinamide resistance in the mITT analysis
Proportion of Death Between the Control and Investigational Arms	At 24months after treatment start	The proportion of participants who died in the control and experimental arm mITT population
Treatment Success According to Pyrazinamide Resistance (2)	At 24 months after treatment start	Treatment success rate of participants without pyrazinamide resistance in the mITT analysis

Trial Locations

Locations (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