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 change in ALS Functional Rating Scale- Revised (ALSFRS-R) score from baseline up to Week 48:
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 75 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects must provide a signed and dated informed consent form (ICF) to participate in the study. 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. Subjects must be willing to cooperate and comply with all protocol restrictions and requirements. 2. Subjects will be male or female, ≥ 18 to 75 years of age at the time the ICF is signed. 3. Subjects will be diagnosed with Definite ALS or Probable ALS according to the El Escorial revised criteria for the diagnosis of ALS. 4. Subjects with a baseline score ≥ 2 points on each individual item of the ALSFRS- R at screening and baseline visits. 5. Subjects have a screening and baseline %forced vital capacity (FVC) ≥ 70%. 6. Subjects with 1- to 4-point decline for 8 weeks (±7 days) in ALSFRS-R total score between screening and baseline visits. 7. Subjects whose first symptom of ALS has occurred within 2 years of providing written informed consent.
Exclusion criteria
Exclusions Related to Primary Diagnosis 1. Subjects with a history of spinal surgery after the onset of ALS, such as surgery for cervical spondylosis or a herniated disc, or plans for such surgery during the study period. Exclusions Related to Other Neurological Disorders (including, but not limited to the following) 2. Subjects with the possibility that the current symptoms may be symptoms of a disease requiring differential diagnosis, such as cervical spondylosis and multifocal motor neuropathy, cannot be ruled out. Exclusions Related to General Health or Concomitant Conditions 3. Subjects undergoing treatment for a malignancy. 4. Subjects with a complication that could have a significant effect on efficacy evaluations, such as Parkinson's disease or syndrome, schizophrenia, bipolar disorder, and dementia. 5. Subjects who have the presence or history of any clinically significant (CS) disease (except ALS) that could interfere with the objectives of the study (the assessment of safety and efficacy) or the safety of the subject, as judged by the Investigator. 6. Subjects who are female, of childbearing potential, and pregnant (a positive pregnancy test) or lactating at the screening visit (Visit 1). 7. Subjects of childbearing potential unwilling to use acceptable method of contraception from the 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. 8. Subjects who have a significant risk of suicidality. 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) within the 3 months before the screening visit. 9. Subjects who have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations greater than 2 times the upper limit of normal (ULN) at screening. 10. Subjects with a Glomerular Filtration Rate (GFR) \< 30 mL/Min Per 1.73 m2 at screening, using the Larsson Equation. Exclusions Related to Medications 11. Subjects with history of hypersensitivity to edaravone, any of the additives or inactive ingredients of edaravone, or sulfites. 12. Subjects with hereditary problems of fructose intolerance (eg, fructose, sucrose, invert sugar, and sorbitol). 13. Subjects who participated in another study and were administered an investigational product within 1 month or 5 half-lives of the investigational agent, whichever is longer, before providing informed consent for the present study. 14. Subjects who have received any previous treatment with edaravone. 15. Subjects who have received stem cell therapy. 16. Subjects who are unable to take their medications orally at baseline (Visit 2).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CAFS Score at Week 48 | up to 48 Weeks | CAFS ranks patients' clinical outcomes based on survival time and change in the ALSFRS-R score. To calculate a patient's CAFS, each patient is compared individually to all other patients in the study. The summary score for each patient is the sum of the comparisons ( 1, 0, 1) against all other patients. After that, patients' summary scores are ranked. The CAFS rank is 1-383 and a higher CAFS rank indicates a better outcome than does a lower CAFS. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in % Slow Vital Capacity (SVC) at Week 48 | up to 48 Weeks | SVC measurements will be conducted in clinic at around the same time of day where possible with the subject in sitting upright position. Subjects should make at least 3 attempts to generate acceptable and reproducible SVC data. The highest value was selected and recorded. |
| Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)40 at Week 48 | up to 48 Weeks | 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 to Death, Tracheostomy or Permanent Assisted Mechanical Ventilation (≥ 23 Hours/Day) | up to 48 Weeks | — |
| Time to Death or PAMV (≥ 23 Hours/Day) | up to 48 Weeks | — |
| Time to Death | up to 48 Weeks | — |
Countries
Canada, Germany, Italy, 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 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12 | 192 |
| Edaravone 105mg (2 Weeks On/Off ) Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1.
Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12 | 192 |
| Total | 384 |
Baseline characteristics
| Characteristic | Edaravone 105 mg (Once Daily) | Edaravone 105mg (2 Weeks On/Off ) | Total |
|---|---|---|---|
| Age, Customized 18-64 years | 134 Participants | 122 Participants | 256 Participants |
| Age, Customized 65-84 years | 58 Participants | 70 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 183 Participants | 187 Participants | 370 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 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 | 9 / 192 | 16 / 192 |
| other Total, other adverse events | 118 / 192 | 131 / 191 |
| serious Total, serious adverse events | 52 / 192 | 55 / 191 |
Outcome results
Primary
CAFS Score at Week 48
CAFS ranks patients' clinical outcomes based on survival time and change in the ALSFRS-R score. To calculate a patient's CAFS, each patient is compared individually to all other patients in the study. The summary score for each patient is the sum of the comparisons ( 1, 0, 1) against all other patients. After that, patients' summary scores are ranked. The CAFS rank is 1-383 and a higher CAFS rank indicates a better outcome than does a lower CAFS. 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: up to 48 Weeks
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 | Value (MEAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | CAFS Score at Week 48 | 187.2 Units on a scale |
| Edaravone 105mg (2 Weeks On/Off ) | CAFS Score at Week 48 | 184.2 Units on a scale |
p-value: 0.777ANCOVA
Secondary
Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)40 at Week 48
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: up to 48 Weeks
Population: Those patients reached to Week 48 and conducted ALSAQ-40 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Edaravone 105 mg (Once Daily) | Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)40 at Week 48 | 2.35 Point | Standard Error 0.25 |
| Edaravone 105mg (2 Weeks On/Off ) | Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)40 at Week 48 | 1.79 Point | Standard Error 0.25 |
Secondary
Change From Baseline in % Slow Vital Capacity (SVC) at Week 48
SVC measurements will be conducted in clinic at around the same time of day where possible with the subject in sitting upright position. Subjects should make at least 3 attempts to generate acceptable and reproducible SVC data. The highest value was selected and recorded.
Time frame: up to 48 Weeks
Population: Those patients reached to Week 48 and conducted SVC assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Edaravone 105 mg (Once Daily) | Change From Baseline in % Slow Vital Capacity (SVC) at Week 48 | -26.94 percentage of SVC | Standard Error 2.45 |
| Edaravone 105mg (2 Weeks On/Off ) | Change From Baseline in % Slow Vital Capacity (SVC) at Week 48 | -22.15 percentage of SVC | Standard Error 2.48 |
p-value: 0.169Mixed Model for Repeated Measures (MMRM)
Secondary
Time to Death
Time frame: up to 48 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time to Death | NA Months |
| Edaravone 105mg (2 Weeks On/Off ) | Time to Death | NA Months |
Secondary
Time to Death or PAMV (≥ 23 Hours/Day)
Time frame: up to 48 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time to Death or PAMV (≥ 23 Hours/Day) | NA Months |
| Edaravone 105mg (2 Weeks On/Off ) | Time to Death or PAMV (≥ 23 Hours/Day) | NA Months |
Secondary
Time to Death, Tracheostomy or Permanent Assisted Mechanical Ventilation (≥ 23 Hours/Day)
Time frame: up to 48 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Edaravone 105 mg (Once Daily) | Time to Death, Tracheostomy or Permanent Assisted Mechanical Ventilation (≥ 23 Hours/Day) | NA Months |
| Edaravone 105mg (2 Weeks On/Off ) | Time to Death, Tracheostomy or Permanent Assisted Mechanical Ventilation (≥ 23 Hours/Day) | NA Months |