Tuberculosis, Multidrug-Resistant
Conditions
Keywords
Multidrug-resistant tuberculosis, Linezolid, Delamanid, Multicenter randomized trial, Non-inferiority, Shorter regimen
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).
Interventions
DRUGLinezolid
DRUGDelamanid
DRUGLevofloxacin
DRUGPyrazinamide
DRUGLocally-used WHO-approved MDR-TB regimen in Korea
Sponsors
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 Ansan Hospital
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Sputum Culture Conversion Proportion | At 2 months of treatment | Culture conversion rate at month 2 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 |
| 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. |
| 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 |
| Treatment Success According to Pyrazinamide Resistance (1) | At 24months after treatment start | Treatment success rate of participants with pyrazinamide resistance in the mITT analysis |
Countries
South Korea
Participant flow
Pre-assignment details
Of the 443 eligible patients, 229 were excluded for the following reasons: * By the investigators' decision (n=102) * Declined to participate (n=65) * Met one of the exclusion criteria (n=58) * Laboratory abnormalities (n=42) * Ongoing use of prohibited drugs (n=10) * Unwilling to use proper contraceptives (n=3) * History of optic or peripheral neuropathy (n=3) * Other unspecified reason (n=4)
Participants by arm
| Arm | Count |
|---|---|
| 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
Locally-used WHO-approved MDR-TB regimen in Korea | 89 |
| 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)
Linezolid
Delamanid
Levofloxacin
Pyrazinamide | 79 |
| Total | 168 |
Baseline characteristics
| Characteristic | Control Arm | Experimental Arm | Total |
|---|---|---|---|
| Age, Continuous | 46 years | 49 years | 47 years |
| Baseline Characteristics of Participants | 89 Participants | 79 Participants | 168 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 89 Participants | 79 Participants | 168 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Korea | 89 participants | 79 participants | 168 participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 63 Participants | 53 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 89 | 5 / 79 |
| other Total, other adverse events | 87 / 89 | 78 / 79 |
| serious Total, serious adverse events | 19 / 89 | 20 / 79 |
Outcome results
Primary
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. (primary consideration for the modified intention-to-treat results)
Time frame: 24 months after treatment start
Population: mITT population Participant with \[not assessable\] was not included in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Treatment Success Rate | 60 Participants |
| Experimental Arm | Treatment Success Rate | 54 Participants |
Secondary
Proportion of Death Between the Control and Investigational Arms
The proportion of participants who died in the control and experimental arm mITT population
Time frame: At 24months after treatment start
Population: mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Proportion of Death Between the Control and Investigational Arms | 2 Participants |
| Experimental Arm | Proportion of Death Between the Control and Investigational Arms | 5 Participants |
Secondary
Proportion of Reverting to Positive Sputum Culture After the End of Treatment
The proportion of patients who experienced a reversion between the end of treatment and up to 24 months after treatment start
Time frame: At 24months after treatment start
Population: mITT population Participant with \[not assessable\] was not included in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Proportion of Reverting to Positive Sputum Culture After the End of Treatment | 0 Participants |
| Experimental Arm | Proportion of Reverting to Positive Sputum Culture After the End of Treatment | 1 Participants |
Secondary
Sputum Culture Conversion Proportion
Culture conversion rate at month 2 of treatment in participants with positive baseline sputum culture (liquid media).
Time frame: At 2 months of treatment
Population: mITT population Participants with positive baseline sputum culture
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Sputum Culture Conversion Proportion | 42 Participants |
| Experimental Arm | Sputum Culture Conversion Proportion | 35 Participants |
Secondary
Sputum Culture Conversion Proportion
Culture conversion rate at month 6 of treatment in participants with positive baseline sputum culture (liquid media).
Time frame: At 6 months of treatment start
Population: mITT population participants with positive baseline sputum culture (liquid media)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Sputum Culture Conversion Proportion | 45 Participants |
| Experimental Arm | Sputum Culture Conversion Proportion | 39 Participants |
Secondary
Time to Sputum Culture Conversion 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.
Time frame: through study completion (24 months after treatment start)
Population: Participants with a positive baseline M.tuberculosis culture (liquid media) in the mITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm | Time to Sputum Culture Conversion After Treatment Start | 24 day |
| Experimental Arm | Time to Sputum Culture Conversion After Treatment Start | 27 day |
Secondary
Treatment Success According to Pyrazinamide Resistance (1)
Treatment success rate of participants with pyrazinamide resistance in the mITT analysis
Time frame: At 24months after treatment start
Population: mITT population Participant with \[not assessable\] was not included in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Treatment Success According to Pyrazinamide Resistance (1) | 13 Participants |
| Experimental Arm | Treatment Success According to Pyrazinamide Resistance (1) | 19 Participants |
Secondary
Treatment Success According to Pyrazinamide Resistance (2)
Treatment success rate of participants without pyrazinamide resistance in the mITT analysis
Time frame: At 24 months after treatment start
Population: mITT population Participant with \[not assessable\] was not included in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Treatment Success According to Pyrazinamide Resistance (2) | 41 Participants |
| Experimental Arm | Treatment Success According to Pyrazinamide Resistance (2) | 32 Participants |
Secondary
Treatment Success at the End of Treatment
Treatment success rate at the end of treatment. * control arm (20-24 months) * experimental arm (40 or 52 weeks)
Time frame: At the end of treatment
Population: mITT populration One participant of experimental arm who became pregnant during the treatment was excluded
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm | Treatment Success at the End of Treatment | 64 Participants |
| Experimental Arm | Treatment Success at the End of Treatment | 61 Participants |