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    Clinical Trial Results:
    A Phase 3b, Multicenter, Randomized, Double-blind Extension Study to Evaluate the Continued Efficacy and Safety of Oral Edaravone Administered for an Additional Period of up to 48 Weeks Following Study MT-1186-A02 in Subjects with Amyotrophic Lateral Sclerosis (ALS)

    Summary
    EudraCT number
    		 2021-003900-42
    Trial protocol
    		 DE   IT  
    Global end of trial date
    05 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Oct 2024
    First version publication date
    03 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MT-1186-A04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05151471
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 jRCT: 2071210117
    Sponsors
    Sponsor organisation name
    Mitsubishi Tanabe Pharma America Inc.
    Sponsor organisation address
    525 Washington Boulevard, Suite 1100, Jersey City, New Jersey, United States, 07310
    Public contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd, +44 2070655000, regulatory@mt-pharma-eu.com
    Scientific contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd, +44 2070655000, regulatory@mt-pharma-eu.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate and compare the efficacy of the following 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 the oral Edaravone is commercially available in that country: - Oral Edaravone 105 mg administered once daily - Oral Edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as on/off).
    Protection of trial subjects
    The Investigator ensured that this study was conducted in compliance with the 2013 (Fortaleza, Brazil) revision of the 1964 Declaration of Helsinki. This study was conducted in accordance with GCP requirements described in the current revision of ICH of Technical Requirements of Pharmaceuticals for Human Use Guidelines. This study was carried out in accordance with regional and local legal requirements. Before the first subject was enrolled in the study, all ethical and legal requirements were met. Prior to undergoing any study-specific procedure, all subjects or their Legally authorized representative (LAR) must consent in writing to participate. An ICF was given to each subject, which contained all regulatory required elements, all ICH-required elements, and data protection information, when applicable, in a language that is understandable to the subject or their LAR. The Sponsor had taken out an insurance policy to cover any costs that arise during the research study. Any compensation payable for any injury caused to patients by taking part in this research study would be in line with local guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jan 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    United States: 82
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    Japan: 128
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Worldwide total number of subjects
    384
    EEA total number of subjects
    95
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    256
    From 65 to 84 years
    128
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited upon completion of the MT-1186-A02 study. Only subjects who were eligible for the study based upon their Week 48 procedures from the MT-1186-A02 study were enrolled. The recruitment was conducted in North America, Europe, and Asia Pacific and the first subject was screened on 11 January 2022.

    Pre-assignment
    Screening details
    		 The duration of study for individual subjects comprised of a Screening/Day 1, the Week 48 study procedures from Study MT-1186-A02 were used as the Screening/entry criteria for Study MT-1186-A04.

    Period 1
    Period 1 title
    MT-1186-A02(overall)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A02_edaravone 105 mg (once daily)
    Arm description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).
    Arm type
    		 Experimental

    Investigational medicinal product name
    edaravone (MT-1186)
    Investigational medicinal product code
    MT-1186
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Oral edaravone 105 mg administered once daily

    Arm title
    		 A02_edaravone 105 mg (on/off)
    Arm description
    		 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) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    edaravone (MT-1186)
    Investigational medicinal product code
    MT-1186
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Oral edaravone 105 mg for 14 days, followed by placebo for 14 days. Subsequently, repeat oral edaravone 105 mg for 10 days followed by placebo for 18 days in Cycles 2 through 12 (48 weeks).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Oral edaravone 105 mg for 14 days, followed by placebo for 14 days. Subsequently, repeat oral edaravone 105 mg for 10 days followed by placebo for 18 days in Cycles 2 through 12 (48 weeks).

    Number of subjects in period 1
    		A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Started
    192
    192
    Completed
    125
    121
    Not completed
    67
    71
         Adverse event, serious fatal
    2
    3
         Consent withdrawn by subject
    20
    21
         Physician decision
    3
    3
         Adverse event, non-fatal
    10
    14
         Other
    3
    5
         Study terminated by sponsor
    26
    23
         Lost to follow-up
    1
    1
         Protocol deviation
    2
    1
    Period 2
    Period 2 title
    MT-1186-A04 (overall)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    During the double-blind treatment period, neither the subject nor the Investigator site personnel knew which treatment was being taken. Each subject maintained their unique randomization number assigned from Study MT-1186-A02. The codes were only accessible to authorized IVRS/IWRS users.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A04_edaravone 105 mg (once daily)
    Arm description
    		 Oral edaravone 105 mg dose once daily in each 28-day cycle for up to 48 weeks or until the drug is commercially available in that country. Subjects who met study MT-1186-A04 eligibility criteria, continued in the same treatment group/regimen that they were in during Study MT-1186-A02.
    Arm type
    		 Experimental

    Investigational medicinal product name
    edaravone (MT-1186)
    Investigational medicinal product code
    MT-1186
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Oral edaravone 105 mg administered once daily

    Arm title
    		 A04_edaravone 105 mg (on/off)
    Arm description
    		 Oral edaravone 105 mg dose for 10 days followed by 18-day placebo (regimen denoted as on/off) in each 28-day cycle for up to 48 weeks or until the drug is commercially available in that country. Subjects who met study MT-1186-A04 eligibility criteria, continued in the same treatment group/regimen that they were in during Study MT-1186-A02.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    edaravone (MT-1186)
    Investigational medicinal product code
    MT-1186
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use, Enteral use
    Dosage and administration details
    Oral edaravone 105 mg for 14 days, followed by placebo for 14 days. Subsequently, repeat oral edaravone 105 mg for 10 days followed by placebo for 18 days in Cycles 2 through 12 (48 weeks).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use, Enteral use
    Dosage and administration details
    Oral edaravone 105 mg for 14 days, followed by placebo for 14 days. Subsequently, repeat oral edaravone 105 mg for 10 days followed by placebo for 18 days in Cycles 2 through 12 (48 weeks).

    Number of subjects in period 2 [1]
    		A04_edaravone 105 mg (once daily) A04_edaravone 105 mg (on/off)
    Started
    104
    98
    Completed
    24
    24
    Not completed
    80
    74
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    7
    9
         Adverse event, non-fatal
    21
    16
         Other
    2
    1
         Study terminated by sponsor
    49
    47
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only Subjects who completed MT-1186-A02 and signed ICF for rollover into MT-1186-A04 were able to join to MT-1186-A04.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A02_edaravone 105 mg (once daily)
    Reporting group description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).

    Reporting group title
    A02_edaravone 105 mg (on/off)
    Reporting group description
    		 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) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).

    Reporting group values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off) Total
    Number of subjects
    		 192 192 384
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 134 122 256
        From 65-84 years
    		 58 70 128
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ( 10.6 ) 60.0 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 69 70 139
        Male
    		 123 122 245
    Race
    Units: Subjects
        White
    		 115 109 224
        Black or African American
    		 3 2 5
        Asian - Japanese
    		 63 64 127
        Asian - Not Japanese
    		 8 13 21
        American Indian or Alaska Native
    		 0 1 1
        Native Hawaiian or Pacific Islander
    		 0 1 1
        Not Reported
    		 0 1 1
        Other
    		 3 1 4
    Country
    Units: Subjects
        United States
    		 38 44 82
        Canada
    		 28 21 49
        Germany
    		 24 28 52
        Italy
    		 23 20 43
        Switzerland
    		 9 6 15
        Japan
    		 63 65 128
        South Korea
    		 7 8 15
    Region
    Units: Subjects
        North America- NA
    		 66 65 131
        Europe - EU
    		 56 54 110
        Asia Pacific - AP
    		 70 73 143
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 9 5 14
        Not Hispanic or Latino
    		 183 187 370
        Not reported
    		 0 0 0
        Unknown
    		 0 0 0
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.50 ( 9.69 ) 169.17 ( 9.79 ) -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 69.90 ( 14.59 ) 67.78 ( 15.27 ) -
    BMI
    Units: kg/㎡
        arithmetic mean (standard deviation)
    		 24.61 ( 4.27 ) 23.57 ( 3.83 ) -

    End points

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    End points reporting groups
    Reporting group title
    A02_edaravone 105 mg (once daily)
    Reporting group description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).

    Reporting group title
    A02_edaravone 105 mg (on/off)
    Reporting group description
    		 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) from MT-1186-A02 Baseline to Week 96 (A04 Week 48).
    Reporting group title
    A04_edaravone 105 mg (once daily)
    Reporting group description
    		 Oral edaravone 105 mg dose once daily in each 28-day cycle for up to 48 weeks or until the drug is commercially available in that country. Subjects who met study MT-1186-A04 eligibility criteria, continued in the same treatment group/regimen that they were in during Study MT-1186-A02.

    Reporting group title
    A04_edaravone 105 mg (on/off)
    Reporting group description
    		 Oral edaravone 105 mg dose for 10 days followed by 18-day placebo (regimen denoted as on/off) in each 28-day cycle for up to 48 weeks or until the drug is commercially available in that country. Subjects who met study MT-1186-A04 eligibility criteria, continued in the same treatment group/regimen that they were in during Study MT-1186-A02.

    Primary: Time to at least a 12-point Decrease in ALSFRS-R or Death

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    End point title
    		 Time to at least a 12-point Decrease in ALSFRS-R or Death
    End point description
    The primary efficacy endpoint assessed the time from the randomization date in Study MT- 1186-A02 to at least a 12-point decrease in ALSFRS-R or death, whichever happened first.
    End point type
    Primary
    End point timeframe
    96 weeks
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    86
    82
    Units: months
        median (confidence interval 80%)
    13.90 (13.40 to 16.59)
    15.05 (13.80 to 16.62)
    Statistical analysis title
    		 Time to ≥12-point Decrease in ALSFRS-R or Death
    Comparison groups
    A02_edaravone 105 mg (once daily) v A02_edaravone 105 mg (on/off)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Logrank
    Confidence interval

    Secondary: Change in the ALSAQ 40 score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04

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    End point title
    		 Change in the ALSAQ 40 score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    31
    27
    Units: points
        least squares mean (standard error)
    54.83 ( 4.05 )
    57.91 ( 4.13 )
    Statistical analysis title
    		 Change in the ALSAQ40 score at all visits
    Comparison groups
    A02_edaravone 105 mg (once daily) v A02_edaravone 105 mg (on/off)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.591
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Mixed Model for Repeated Measures (MMRM)
    Confidence interval

    Secondary: Change in ALSFRS-R score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04

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    End point title
    		 Change in ALSFRS-R score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    31
    29
    Units: points
        least squares mean (standard error)
    -18.21 ( 1.31 )
    -20.95 ( 1.32 )
    Statistical analysis title
    		 Changes from Baseline in ALSFRS-R Total Score
    Comparison groups
    A02_edaravone 105 mg (once daily) v A02_edaravone 105 mg (on/off)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.142
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Confidence interval

    Secondary: The CAFS score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04

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    End point title
    		 The CAFS score at all visits from baseline in Study MT-1186-A02 to the end of Study MT-1186-A04
    End point description
    End point type
    Secondary
    End point timeframe
    Up to week 96
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    192
    191
    Units: Rank
        number (not applicable)
    200.8
    181.6
    Statistical analysis title
    		 The CAFS score at all visits from baseline
    Comparison groups
    A02_edaravone 105 mg (once daily) v A02_edaravone 105 mg (on/off)
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.131
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Time from the randomization date in Study MT-1186-A02 to death, tracheostomy, or PAMV (≥23 hours/day)

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    End point title
    		 Time from the randomization date in Study MT-1186-A02 to death, tracheostomy, or PAMV (≥23 hours/day)
    End point description
    The median survival for the time to death could not be calculated due to the low number of events (only 33 and 32 events of death, tracheostomy, or PAMV in the Once Daily and On/Off groups, respectively), resulting in 159 and 160 censored observations in respective group.
    End point type
    Secondary
    End point timeframe
    From the randomization date in Study MT-1186-A02 through EOT/ET in Study MT-1186-A04
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [1] - The median survival for the time to death could not be calculated due to the low number of events.
    [2] - The median survival for the time to death could not be calculated due to the low number of events.
    No statistical analyses for this end point

    Secondary: Time from the randomization date in Study MT-1186-A02 to death or PAMV (≥23 hours/day)

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    End point title
    		 Time from the randomization date in Study MT-1186-A02 to death or PAMV (≥23 hours/day)
    End point description
    The median survival for the time to death could not be calculated due to the low number of events (only 30 and 31 events of death or PAMV in the Once Daily and On/Off groups, respectively), resulting in 162 and 161 censored observations in respective group.
    End point type
    Secondary
    End point timeframe
    From the randomization date in Study MT-1186-A02 through EOT/ET in Study MT-1186-A04
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [3] - The median survival for the time to death could not be calculated due to the low number of events.
    [4] - The median survival for the time to death could not be calculated due to the low number of events.
    No statistical analyses for this end point

    Secondary: Time from the randomization date in Study MT-1186-A02 to death

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    End point title
    		 Time from the randomization date in Study MT-1186-A02 to death
    End point description
    The median survival for the time to death could not be calculated due to the low number of events (only 24 and 28 events of death in the Once Daily and On/Off groups, respectively), resulting in 168 and 164 censored observations in respective group.
    End point type
    Secondary
    End point timeframe
    From the randomization date in Study MT-1186-A02 through EOT/ET in Study MT-1186-A04
    End point values
    		 A02_edaravone 105 mg (once daily) A02_edaravone 105 mg (on/off)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [5] - The median survival for the time to death could not be calculated due to the low number of events.
    [6] - The median survival for the time to death could not be calculated due to the low number of events.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs and SAEs that occur from the time written ICF was obtained until the end of the Safety Follow-up Period or the withdrawal of the subject from the study. Safety assessments made on the data from MT-1186-A04.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    edaravone 105 mg (once daily)
    Reporting group description
    		 -

    Reporting group title
    edaravone 105mg (2 weeks On/Off )
    Reporting group description
    		 -

    Serious adverse events
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 104 (31.73%)
    27 / 98 (27.55%)
         number of deaths (all causes)
    15
    12
         number of deaths resulting from adverse events
    13
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thermal burn
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Gastrostomy
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    4 / 104 (3.85%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    14 / 104 (13.46%)
    5 / 98 (5.10%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asphyxia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    10 / 104 (9.62%)
    10 / 98 (10.20%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 6
    0 / 5
    Sputum retention
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric symptom
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 104 (23.08%)
    25 / 98 (25.51%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 104 (7.69%)
    13 / 98 (13.27%)
         occurrences all number
    13
    24
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 104 (6.73%)
    6 / 98 (6.12%)
         occurrences all number
    7
    6
    Diarrhoea
         subjects affected / exposed
    4 / 104 (3.85%)
    5 / 98 (5.10%)
         occurrences all number
    8
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 104 (4.81%)
    5 / 98 (5.10%)
         occurrences all number
    5
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 98 (1.02%)
         occurrences all number
    6
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2022
    • Secondary Efficacy Endpoints were updated to clarify timing of endpoint analyses. • Exploratory efficacy endpoints were updated to clarify timing of endpoint analyses. • Updated to allow subjects to remain in a sitting position. • Updated to allow for when corrected QT interval is unavailable. • Updated pregnancy test requirements. • Updated compliance definition and recording requirements. • Updated menopause confirmation requirements.
    20 Oct 2022
    • Updates based on AMX0035 use: • Updates based on allowing AMX0035 use for subjects if it becomes commercially available via prescription in their respective country. AMX0035 was to be taken at least 1 hour after MT-1186/oral edaravone dosing. • The primary estimand construction elements were: Treatment of interest, population, variable, ICE handling strategy and population-level summary. • The secondary estimand was to be tested as supportive analysis for the primary endpoint. • Supportive analysis for the secondary estimand was updated from sensitivity analysis. • Updated secondary efficacy endpoints: • Time from the randomization

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Oct 2023
    The MT-1186-A02 study was prematurely terminated as it met the futility criteria following a pre-planned interim futility analysis. As a result of the pre-planned futility analysis of MT-1186-A02, the Sponsor endorsed the IDMC recommendation and decided to also terminate the MT-1186-A04 study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of the study, a low number of the subjects completed the 48-week DBT period of MT-1186-A04. Of the subjects who discontinued study treatment, the most common reason for discontinuation was study terminated by Sponsor.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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