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    Clinical Trial Results:
    A Phase 3b, Multicenter, Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Oral Edaravone Administered for a Period of 48 Weeks in Subjects with Amyotrophic Lateral Sclerosis (ALS)

    Summary
    EudraCT number
    		 2019-004256-11
    Trial protocol
    		 DE   IT  
    Global end of trial date
    29 Sep 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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MT-1186-A02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04569084
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Japan Registry of Clinical Trials (jRCT): jRCT2031200301
    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
    29 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2023
    Was the trial ended prematurely?
    No
    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 ALS based on Combined Assessment of Function and Survival (CAFS) at Week 48: - Oral edaravone 105 mg administered once daily (regimen denoted as daily) in Cycles 1 through 12 - Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1, and 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.
    Protection of trial subjects
    The study was conducted in accordance with the 2013 (Fortaleza) revision of the 1964 Declaration of Helsinki, Good Clinical Practice (GCP) as required by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regional and local legislation, and standard operating procedures (SOPs) in place at Mitsubishi Tanabe Pharma America, Inc. (MTPA). Clinical monitoring was conducted to confirm the ethical conduct of the study at the investigational site(s) and was performed according to the SOPs of the Contract Research Organization (CRO) which had been delegated the responsibility for those activities. 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
    16 Nov 2020
    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 via a variety of methods including, but not limited to, site review of subject records, media advertising, and recruitment vendors, if appropriate. All recruitment material was approved by an IRB/IEC prior to implementation. The recruitment was started from November 2020 and conducted in 96 sites globally.

    Pre-assignment
    Screening details
    		 Screening assessments was performed 8 weeks (± 7 days) prior to Day 1. All screening evaluations must be completed and reviewed to confirm that potential subjects meet all eligibility criteria(e.g., inclusion criteria %FVC ≥ 70% versus %FVC ≥ 80%). Sites completed a diagnosis verification process for each subject prior to enrollment into the study

    Period 1
    Period 1 title
    MT-1186-A02 (overall) (overall period)
    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
    		 edaravone 105 mg (once daily)
    Arm description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
    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
    Oral use, Enteral use
    Dosage and administration details
    Dose: 105 mg dose Administration: Oral/percutaneous endoscopic gastrostomy (PEG)/radiologically inserted gastrostomy (RIG) tube. The mode of administration could be switched from oral to PEG/RIG tube dosing dependent on disease progression.

    Arm title
    		 edaravone 105mg (2 weeks 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) in Cycles 2 through 12
    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
    Dose: 105 mg dose or placebo Administration: Oral/PEG/RIG tube. The mode of administration could be switched from oral to PEG/RIG tube dosing dependent on disease progression.

    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
    Dose: 105 mg dose or placebo Administration: Oral/PEG/RIG tube. The mode of administration could be switched from oral to PEG/RIG tube dosing dependent on disease progression.

    Number of subjects in period 1
    		edaravone 105 mg (once daily) edaravone 105mg (2 weeks 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
         Protocol violation
    2
    1
         Adverse event, non-fatal
    10
    14
         Other
    3
    5
         Study terminated by sponsor
    26
    23
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    edaravone 105 mg (once daily)
    Reporting group description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12

    Reporting group title
    edaravone 105mg (2 weeks 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) in Cycles 2 through 12

    Reporting group values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks 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
    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
    Hight
    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
    edaravone 105 mg (once daily)
    Reporting group description
    		 Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12

    Reporting group title
    edaravone 105mg (2 weeks 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) in Cycles 2 through 12

    Primary: CAFS score at Week 48

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    End point title
    		 CAFS score at Week 48
    End point description
    CAFS results at Week 48. The CAFS score is composed of change of ALSFRS-R score and time to death. A higher CAFS rank indicates a better outcome than does a lower CAFS rank.
    End point type
    Primary
    End point timeframe
    at Week 48
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    192
    191
    Units: points
        number (not applicable)
    187.2
    184.2
    Statistical analysis title
    		 CAFS score at Week 48
    Statistical analysis description
    More than a few death events (≥5% death percentage for all randomized subjects, eg, ≥19 death events) were observed in the data review meeting, the primary endpoint analysis using mixed model repeated measures (MMRM) was replaced with the ranking score on CAFS score at Week 48 based on a joint rank score derived from change from baseline in ALSFRS-R score and time to death through Week 48 with analysis of covariance (ANCOVA) specified in the secondary endpoint analysis.
    Comparison groups
    edaravone 105 mg (once daily) v edaravone 105mg (2 weeks On/Off )
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.777
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) 40

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    End point title
    		 Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) 40
    End point description
    End point type
    Secondary
    End point timeframe
    at Week 48
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    128
    125
    Units: Points
        least squares mean (standard error)
    2.35 ( 0.25 )
    1.79 ( 0.25 )
    Statistical analysis title
    		 Change from baseline in ALSAQ 40
    Comparison groups
    edaravone 105 mg (once daily) v edaravone 105mg (2 weeks On/Off )
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.793
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Confidence interval

    Secondary: Change from baseline in % slow vital capacity (SVC)

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    End point title
    		 Change from baseline in % slow vital capacity (SVC)
    End point description
    End point type
    Secondary
    End point timeframe
    at Week 48
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    116
    117
    Units: %
        least squares mean (standard error)
    -26.94 ( 2.45 )
    -22.15 ( 2.48 )
    Statistical analysis title
    		 Change from baseline in % SVC
    Comparison groups
    edaravone 105 mg (once daily) v edaravone 105mg (2 weeks On/Off )
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.169
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Confidence interval

    Secondary: Time to death, tracheostomy, or PAMV (≥ 23 hours/day)

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    End point title
    		 Time to death, tracheostomy, or PAMV (≥ 23 hours/day)
    End point description
    The median survival time to death, tracheostomy, or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 11 events; On/Off group: 17 events), resulting in 181 and 175 censored observations in respective group.
    End point type
    Secondary
    End point timeframe
    On Day 1 of study treatment with edaravone through EOT/ET
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - The median survival time could not be calculated in either group due to the low number of events.
    [2] - The median survival time could not be calculated in either group due to the low number of events.
    No statistical analyses for this end point

    Secondary: Time to death or PAMV (≥ 23 hours/day)

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    End point title
    		 Time to death or PAMV (≥ 23 hours/day)
    End point description
    The median survival time to death or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 10 events; On/Off group: 17 events).
    End point type
    Secondary
    End point timeframe
    On Day 1 of study treatment with edaravone through EOT/ET
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - The median survival time could not be calculated in either group due to the low number of events.
    [4] - The median survival time could not be calculated in either group due to the low number of events.
    No statistical analyses for this end point

    Secondary: Time to death

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    End point title
    		 Time to death
    End point description
    The median survival time to death at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 9 events; On/Off group: 16 events).
    End point type
    Secondary
    End point timeframe
    On Day 1 of study treatment with edaravone through EOT/ET
    End point values
    		 edaravone 105 mg (once daily) edaravone 105mg (2 weeks On/Off )
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - The median survival time could not be calculated in either group due to the low number of events.
    [6] - The median survival time could not be calculated in either group 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, regardless of the relationship to the IMP, occurring from date of subject’s written informed consent until the end of the safety FU period or the withdrawal of the subject from the study, were recorded on an AE form in the eCRF (AE eCRF).
    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 105 mg (2 weeks On/Off )
    Reporting group description
    		 -

    Serious adverse events
    		 edaravone 105 mg (once daily) edaravone 105 mg (2 weeks On/Off )
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 192 (27.08%)
    55 / 191 (28.80%)
         number of deaths (all causes)
    8
    16
         number of deaths resulting from adverse events
    8
    13
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Artery dissection
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastrostomy
         subjects affected / exposed
    3 / 192 (1.56%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunostomy
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 192 (1.56%)
    2 / 191 (1.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (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
    1 / 192 (0.52%)
    3 / 191 (1.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    2 / 192 (1.04%)
    5 / 191 (2.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    9 / 192 (4.69%)
    10 / 191 (5.24%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Sputum retention
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Embedded device
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swallow study
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vital capacity decreased
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Benign familial pemphigus
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 192 (0.52%)
    2 / 191 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 192 (0.52%)
    5 / 191 (2.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 192 (0.52%)
    2 / 191 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    16 / 192 (8.33%)
    15 / 191 (7.85%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Salivary hypersecretion
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (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
    4 / 192 (2.08%)
    4 / 191 (2.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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 105 mg (2 weeks On/Off )
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 192 (61.46%)
    131 / 191 (68.59%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    17 / 192 (8.85%)
    14 / 191 (7.33%)
         occurrences all number
    23
    18
    Fall
         subjects affected / exposed
    36 / 192 (18.75%)
    34 / 191 (17.80%)
         occurrences all number
    57
    64
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 192 (7.81%)
    9 / 191 (4.71%)
         occurrences all number
    18
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 192 (6.25%)
    10 / 191 (5.24%)
         occurrences all number
    14
    15
    Oedema peripheral
         subjects affected / exposed
    10 / 192 (5.21%)
    9 / 191 (4.71%)
         occurrences all number
    10
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    24 / 192 (12.50%)
    27 / 191 (14.14%)
         occurrences all number
    24
    27
    Diarrhoea
         subjects affected / exposed
    20 / 192 (10.42%)
    14 / 191 (7.33%)
         occurrences all number
    25
    15
    Dysphagia
         subjects affected / exposed
    11 / 192 (5.73%)
    12 / 191 (6.28%)
         occurrences all number
    12
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 192 (7.81%)
    11 / 191 (5.76%)
         occurrences all number
    15
    13
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    11 / 192 (5.73%)
    8 / 191 (4.19%)
         occurrences all number
    13
    8
    Rash
         subjects affected / exposed
    13 / 192 (6.77%)
    4 / 191 (2.09%)
         occurrences all number
    16
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 192 (4.69%)
    10 / 191 (5.24%)
         occurrences all number
    9
    10
    Insomnia
         subjects affected / exposed
    11 / 192 (5.73%)
    14 / 191 (7.33%)
         occurrences all number
    11
    14
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 192 (4.17%)
    20 / 191 (10.47%)
         occurrences all number
    10
    22
    Muscle spasms
         subjects affected / exposed
    3 / 192 (1.56%)
    10 / 191 (5.24%)
         occurrences all number
    4
    13
    Muscular weakness
         subjects affected / exposed
    15 / 192 (7.81%)
    13 / 191 (6.81%)
         occurrences all number
    36
    24
    Musculoskeletal pain
         subjects affected / exposed
    10 / 192 (5.21%)
    9 / 191 (4.71%)
         occurrences all number
    10
    9
    Pain in extremity
         subjects affected / exposed
    4 / 192 (2.08%)
    10 / 191 (5.24%)
         occurrences all number
    4
    10
    Infections and infestations
    COVID-19
         subjects affected / exposed
    24 / 192 (12.50%)
    26 / 191 (13.61%)
         occurrences all number
    24
    26
    Nasopharyngitis
         subjects affected / exposed
    11 / 192 (5.73%)
    8 / 191 (4.19%)
         occurrences all number
    17
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2021
    • Addition of preliminary results of Study MT-1186-Z-101. • Permission to switch from oral administration to PEG/RIG tube post-baseline due to disease progression. • Updated dosing schedule rationale including the following information: The currently marketed dosing regimen is the On/Off regimen, with patients taking medication for 10 out of 14 days followed by a 14-day medication-free period, resulting in 28-day cycles. This dosing regimen was based on the treatment regimen of edaravone indicated for acute ischemic stroke. The daily dose and the overall design of this study was chosen in conjunction with the FDA as a postmarketing commitment, in hopes of providing patients with a more convenient dosing regimen. • Updated COVID-19 procedures due to COVID-19 restrictions related to site visits and safety assessments such as routine blood sampling or other assessments may be performed at the discretion of the Investigator and the site’s abilities, including the performance of complete study visits in the subject’s home or questionnaires via telephone. • Permission of COVID-19 and other vaccines that have received emergency use authorization.
    24 Nov 2022
    • Addition of secondary efficacy endpoints: o Time to death or permanent assisted mechanical ventilation (≥ 23 hours/day) o Time to death • Permission to use AMX0035 for subjects if it becomes commercially available via prescription in their respective country. • Updates based on allowing use of AMX0035: o Adjustments to primary estimand construction elements o Adjustments to secondary estimand construction elements o Changes to primary analysis: All available ALSFRS-R scores regardless of use of additional/new AMX0035 treatment (ICE1) and all available ALSFRS-R scores up to early discontinuation (ICE2) were included for the primary analysis. o Updated criteria in terms of defined cutoff for minimal number of deaths required for replacing the primary endpoint with the ranking score on CAFS at Week 48. o Addition of sensitivity analyses for the primary efficacy endpoint o Addition of supportive analysis for the secondary estimand • Updated study information: Study MT-1186-J03, Study MT-1186-A01 • Updates concerning responsibilities for legally authorized representatives (informed consent form)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Aug 2023
    The study was prematurely terminated due to meeting the futility criteria following a pre-planned IA. The futility IA was conducted after 50% of the planned study population (N=190) had completed the 48-week DBT period and assessed the study’s primary endpoint and the conditional probability of the study results to show a statistically significant difference in change from baseline in ALSFRS-R total score at Week 48 between the two treatment groups at the final analysis. Through that IA, the IDMC concluded that there was a low conditional probability for the investigational Once Daily regimen to show superiority to the current On/Off regimen as measured by the ALSFRS-R score at study completion, taking into account the results from other efficacy endpoints; therefore, study discontinuation was recommended by the IDMC. Based on the results of the IA and the recommendation from the IDMC, the Sponsor decided to discontinue the study early. As part of this decision, the global, multi-center, double-blind, Phase 3b MT-1186-A04 study, an extension to MT-1186-A02, was also discontinued prematurely. The premature termination of the study was not based on safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Of the 35.9% subjects who discontinued study treatment, the most common reason for discontinuation was study terminated by Sponsor (12.8% of subjects), which was driven by the decision to terminate the study prematurely due to futility.
    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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