ALS
Conditions
Brief summary
To evaluate and compare the efficacy of two dosing regimens of oral edaravone in subjects with amyotrophic lateral sclerosis (ALS), based on the time from the randomization date in Study MT-1186-A02 to at least a 12-point decrease in Revised ALS Functional Rating Score (ALSFRS-R) or death, whichever happens first, over the course of the study or until oral edaravone is commercially available in that country
Interventions
DRUGMT-1186
Oral edaravone
DRUGPlacebo
Oral
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects or their legally authorized representative must provide a signed and dated informed consent form to participate in the study. 2. Subjects must be able (in the judgment of the Investigator) to understand the nature of the study and all risks involved with participation in the study. 3. Subjects must be willing to cooperate and comply with all protocol restrictions and requirements. 4. Subjects must have successfully completed all Study MT-1186-A02 visits and have been compliant with study drug.
Exclusion criteria
1. Subjects of childbearing potential unwilling to use an acceptable method of contraception from the Day 1/screening visit until 3 months after the last dose of study medication. Subjects who are sexually active who do not agree to use contraception during the study period. 2. Subjects who are female, of childbearing potential, and pregnant (a positive pregnancy test) or lactating at the Day 1/screening visit. 3. Subjects who have a significant risk of suicide. Subjects with any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to act, without a specific plan) or type 5 (active suicidal ideation with specific plan and intent) based on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Week 48 of Study MT-1186-A02. 4. Subjects who are not eligible to continue in the study, as judged by the Investigator in conjunction with the MTDA medical monitor. 5. Subjects who are unable to take their medications orally or through a PEG/RIG tube.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From the Randomization Date in Study MT-1186-A02 to at Least a 12-point Decrease in ALSFRS-R or Death, Whichever Happens First. | Up to 96 weeks | The ASLFRS-R is Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised. The ALSFRS-R measures 12 aspects of physical function, ranging from one's ability to swallow and use utensils to climbing stairs and breathing. Each function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Baseline, Week 72 and Week 96 | CAFS analysis ranks clinical outcomes on the basis of survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. A subject's score will be calculated by comparing each subject to every other subject within each treatment group in the study, resulting in a score of +1 if the outcome was better than the subject being compared, -1 if worse, and 0 if the same. The subject's score will then be calculated by summing up their comparison to all of the other subjects within each treatment group in the study as CAFS score. Patients' summary scores are ranked; a higher score indicates a better performance. The score range is from 1 to N, where N is the total sample size. Since CAFS were calculated using the imputed ALSFRS-R scores with multiple imputation method, and the maximum varies for each simulation, 383 is the maximum possible value of full range for measure of dispersion. |
| Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Baseline, Week 72 and Week 96 | The ALSAQ-40 is a questionnaire that consists of 40 questions/items with 5 discrete scales: physical mobility, activities of daily living and independence, eating and drinking, communication, emotional reactions, ranging from 0 (best health as assessed by the scale) to 100 (worse health as assessed by the measure). |
| Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Baseline, Week 72, Week 84 and Week 96 | The ALSFRS-R is rating scale (ratings 0 = can't do, to 4 = normal ability) used to determine participants' assessment of their capability and independence in 12 functional activities. |
| Time From the Randomization Date in Study MT-1186-A02 to Death, Tracheostomy, or Permanent Assisted Mechanical Ventilation (≥23 Hours/Day) | Up to 96 weeks | — |
| Time From the Randomization Date in Study MT-1186-A02 to Death or Permanent Assisted Mechanical Ventilation (>23 Hours/Day) | Up to 96 weeks | — |
| Time From the Randomization Date in Study MT-1186-A02 to Death | Up to 96 weeks | — |
Countries
Canada, Germany, Japan, South Korea, Switzerland, United States
Contacts
STUDY_DIRECTORShionogi Clinical Trials Administrator Clinical Support Help Line
Shionogi
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Edaravone 105 mg (Once Daily) Oral edaravone administered once daily for up to 48 weeks or until the drug is commercially available in that country.
MT-1186: Oral edaravone | 192 |
| Edaravone 105 mg (on/Off) Oral edaravone administered for 10 days followed by 18-day placebo (regimen denoted as on/off) for up to 48 weeks or until the drug is commercially available in that country.
MT-1186: Oral edaravone
Placebo: Oral | 192 |
| Total | 384 |
Baseline characteristics
| Characteristic | Edaravone 105 mg (Once Daily) | Edaravone 105 mg (on/Off) | Total |
|---|---|---|---|
| Age, Customized Adults (18-64 years) | 134 Participants | 122 Participants | 256 Participants |
| Age, Customized From 65-84 years | 58 Participants | 70 Participants | 128 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Japanese | 63 Participants | 64 Participants | 127 Participants |
| Race/Ethnicity, Customized Asian - Not Japanese | 8 Participants | 13 Participants | 21 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 115 Participants | 109 Participants | 224 Participants |
| Sex: Female, Male Female | 69 Participants | 70 Participants | 139 Participants |
| Sex: Female, Male Male | 123 Participants | 122 Participants | 245 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 104 | 12 / 98 |
| other Total, other adverse events | 24 / 104 | 25 / 98 |
| serious Total, serious adverse events | 33 / 104 | 27 / 98 |
Outcome results
Primary
Time From the Randomization Date in Study MT-1186-A02 to at Least a 12-point Decrease in ALSFRS-R or Death, Whichever Happens First.
The ASLFRS-R is Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised. The ALSFRS-R measures 12 aspects of physical function, ranging from one's ability to swallow and use utensils to climbing stairs and breathing. Each function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0.
Time frame: Up to 96 weeks
Population: The outcome measure time frame is from the randomization date in Study MT- 1186-A02 to at least a 12-point decrease in ALSFRS-R or death, whichever happened first.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time From the Randomization Date in Study MT-1186-A02 to at Least a 12-point Decrease in ALSFRS-R or Death, Whichever Happens First. | 13.9 Month |
| Edaravone 105 mg (on/Off) | Time From the Randomization Date in Study MT-1186-A02 to at Least a 12-point Decrease in ALSFRS-R or Death, Whichever Happens First. | 15.05 Month |
p-value: 0.78Log Rank
Secondary
Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04
The ALSFRS-R is rating scale (ratings 0 = can't do, to 4 = normal ability) used to determine participants' assessment of their capability and independence in 12 functional activities.
Time frame: Baseline, Week 72, Week 84 and Week 96
Population: Those patients reached to Week 72, Week 84 and Week 96, and conducted ALSFRS-R assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone 105 mg (Once Daily) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | -15.02 Point | Standard Error 0.95 |
| Edaravone 105 mg (Once Daily) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 84 | -16.79 Point | Standard Error 1.11 |
| Edaravone 105 mg (Once Daily) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | -18.21 Point | Standard Error 1.31 |
| Edaravone 105 mg (on/Off) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | -15.90 Point | Standard Error 0.95 |
| Edaravone 105 mg (on/Off) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 84 | -18.27 Point | Standard Error 1.1 |
| Edaravone 105 mg (on/Off) | Change in ALSFRS-R Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | -20.95 Point | Standard Error 1.32 |
Comparison: Week 72p-value: 0.513Mixed Model for Repeated Measures (MMRM)
Comparison: Week 84p-value: 0.344Mixed Model for Repeated Measures (MMRM)
Comparison: Week 96p-value: 0.142Mixed Model for Repeated Measures (MMRM)
Secondary
Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04
The ALSAQ-40 is a questionnaire that consists of 40 questions/items with 5 discrete scales: physical mobility, activities of daily living and independence, eating and drinking, communication, emotional reactions, ranging from 0 (best health as assessed by the scale) to 100 (worse health as assessed by the measure).
Time frame: Baseline, Week 72 and Week 96
Population: Those patients reached to Week 72 and Week 96, and conducted ALSAQ-40 assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone 105 mg (Once Daily) | Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | 45.71 Point | Standard Error 3.14 |
| Edaravone 105 mg (Once Daily) | Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | 54.83 Point | Standard Error 4.05 |
| Edaravone 105 mg (on/Off) | Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | 45.46 Point | Standard Error 3.11 |
| Edaravone 105 mg (on/Off) | Change in the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | 57.91 Point | Standard Error 4.13 |
Comparison: Week 72p-value: 0.954Mixed Model for Repeated Measures (MMRM)
Comparison: Week 96p-value: 0.591Mixed Model for Repeated Measures (MMRM)
Secondary
The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04
CAFS analysis ranks clinical outcomes on the basis of survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. A subject's score will be calculated by comparing each subject to every other subject within each treatment group in the study, resulting in a score of +1 if the outcome was better than the subject being compared, -1 if worse, and 0 if the same. The subject's score will then be calculated by summing up their comparison to all of the other subjects within each treatment group in the study as CAFS score. Patients' summary scores are ranked; a higher score indicates a better performance. The score range is from 1 to N, where N is the total sample size. Since CAFS were calculated using the imputed ALSFRS-R scores with multiple imputation method, and the maximum varies for each simulation, 383 is the maximum possible value of full range for measure of dispersion.
Time frame: Baseline, Week 72 and Week 96
Population: One subject randomized to the On/Off treatment group was excluded from this analysis because the subject did not receive any study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Edaravone 105 mg (Once Daily) | The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | 193.6 units on a scale |
| Edaravone 105 mg (Once Daily) | The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | 200.8 units on a scale |
| Edaravone 105 mg (on/Off) | The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 72 | 189.1 units on a scale |
| Edaravone 105 mg (on/Off) | The Combined Assessment of Function and Survival (CAFS) Score at All Visits From Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04 | Week 96 | 181.6 units on a scale |
Comparison: Week 72p-value: 0.704ANCOVA
Comparison: Week 96p-value: 0.131ANCOVA
Secondary
Time From the Randomization Date in Study MT-1186-A02 to Death
Time frame: Up to 96 weeks
Population: The outcome measure time frame is from Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time From the Randomization Date in Study MT-1186-A02 to Death | NA Month |
| Edaravone 105 mg (on/Off) | Time From the Randomization Date in Study MT-1186-A02 to Death | NA Month |
Secondary
Time From the Randomization Date in Study MT-1186-A02 to Death or Permanent Assisted Mechanical Ventilation (>23 Hours/Day)
Time frame: Up to 96 weeks
Population: The outcome measure time frame is from Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time From the Randomization Date in Study MT-1186-A02 to Death or Permanent Assisted Mechanical Ventilation (>23 Hours/Day) | NA Month |
| Edaravone 105 mg (on/Off) | Time From the Randomization Date in Study MT-1186-A02 to Death or Permanent Assisted Mechanical Ventilation (>23 Hours/Day) | NA Month |
Secondary
Time From the Randomization Date in Study MT-1186-A02 to Death, Tracheostomy, or Permanent Assisted Mechanical Ventilation (≥23 Hours/Day)
Time frame: Up to 96 weeks
Population: The outcome measure time frame is from Baseline in Study MT-1186-A02 to the End of Study MT-1186-A04.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time From the Randomization Date in Study MT-1186-A02 to Death, Tracheostomy, or Permanent Assisted Mechanical Ventilation (≥23 Hours/Day) | NA Month |
| Edaravone 105 mg (on/Off) | Time From the Randomization Date in Study MT-1186-A02 to Death, Tracheostomy, or Permanent Assisted Mechanical Ventilation (≥23 Hours/Day) | NA Month |