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    Clinical Trial Results:
    Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy (MIT-E)

    Summary
    EudraCT number
    		 2020-002100-39
    Trial protocol
    		 ES   FR   IT   SE   PL  
    Global end of trial date
    27 Dec 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Feb 2025
    First version publication date
    19 Jul 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PTC743-MIT-001-EP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04378075
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PTC Therapeutics, Inc.
    Sponsor organisation address
    500 Warren Corp Centre Dr, Warren, United States, NJ 07059
    Public contact
    Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.com
    Scientific contact
    Medical Information, PTC Therapeutics International Limited, +353 19068700, medinfo@ptcbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001238-PIP02-20
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the effect of vatiquinone (PTC743) on reduction in observable motor seizure frequency in participants with genetically confirmed mitochondrial disease, as assessed by a seizure diary.
    Protection of trial subjects
    This study was designed and monitored in accordance with sponsor procedures, which comply with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    68
    EEA total number of subjects
    22
    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)
    5
    Children (2-11 years)
    47
    Adolescents (12-17 years)
    15
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 82 participants were screened, of which 14 were not randomized due to screen failure.

    Period 1
    Period 1 title
    Double-blind (24 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-blind Period: Vatiquinone
    Arm description
    		 Participants received vatiquinone 15 milligrams (mg)/kilogram (kg) if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, 3 times per day (TID) for up to 24 weeks during the double-blind period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vatiquinone
    Investigational medicinal product code
    Other name
    PTC743, EPI-743
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Vatiquinone was administered per the treatment arm description.

    Arm title
    		 Double-blind Period: Placebo
    Arm description
    		 Participants received vatiquinone-matched placebo, administered orally, TID for up to 24 weeks during the double-blind period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Vatiquinone-matching placebo was administered per the treatment arm description

    Number of subjects in period 1
    		Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Started
    34
    34
    Received at least 1 dose of study drug
    34
    34
    Completed
    28
    29
    Not completed
    6
    5
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    2
         Other than specified
    -
    2
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Long-term Extension (48 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Long-term Extension: Vatiquinone/Vatiquinone
    Arm description
    		 Participants who received vatiquinone for 24 weeks in the double-blind period continued to received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vatiquinone
    Investigational medicinal product code
    Other name
    PTC743, EPI-743
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Vatiquinone was administered per the treatment arm description.

    Arm title
    		 Long-term Extension: Placebo/Vatiquinone
    Arm description
    		 Participants who received placebo for 24 weeks in the double-blind period, received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vatiquinone
    Investigational medicinal product code
    Other name
    PTC743, EPI-743
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Vatiquinone was administered per the treatment arm description.

    Number of subjects in period 2
    		Long-term Extension: Vatiquinone/Vatiquinone Long-term Extension: Placebo/Vatiquinone
    Started
    28
    29
    Completed
    16
    18
    Not completed
    12
    11
         Sponsor's decision
    1
    1
         Adverse event, serious fatal
    2
    2
         Other than specified
    9
    7
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-blind Period: Vatiquinone
    Reporting group description
    		 Participants received vatiquinone 15 milligrams (mg)/kilogram (kg) if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, 3 times per day (TID) for up to 24 weeks during the double-blind period.

    Reporting group title
    Double-blind Period: Placebo
    Reporting group description
    		 Participants received vatiquinone-matched placebo, administered orally, TID for up to 24 weeks during the double-blind period.

    Reporting group values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo Total
    Number of subjects
    		 34 34 68
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.7 ( 5.34 ) 6.6 ( 4.84 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 14 20 34
        Male
    		 20 14 34
    Race
    Units: Subjects
        American Indian/Alaska Native
    		 0 1 1
        Asian
    		 3 9 12
        Black/African American
    		 1 3 4
        White/Caucasian
    		 24 20 44
        Other
    		 1 0 1
        Not Reported
    		 5 1 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 26 30 56
        Not Reported
    		 5 1 6
        Unknown
    		 1 2 3
    Number of Observable Motor Seizures per 28 Days
    The 28-day motor seizure frequency in the double-blind period was calculated as the (number of motor seizures)/ (the number of valid days where motor seizure count information is present) * 28 within the double-blind period.
    Units: motor seizures/28 days
        median (full range (min-max))
    		 112.5 (6 to 3139) 237.0 (15 to 2918) -

    End points

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    End points reporting groups
    Reporting group title
    Double-blind Period: Vatiquinone
    Reporting group description
    		 Participants received vatiquinone 15 milligrams (mg)/kilogram (kg) if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, 3 times per day (TID) for up to 24 weeks during the double-blind period.

    Reporting group title
    Double-blind Period: Placebo
    Reporting group description
    		 Participants received vatiquinone-matched placebo, administered orally, TID for up to 24 weeks during the double-blind period.
    Reporting group title
    Long-term Extension: Vatiquinone/Vatiquinone
    Reporting group description
    		 Participants who received vatiquinone for 24 weeks in the double-blind period continued to received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.

    Reporting group title
    Long-term Extension: Placebo/Vatiquinone
    Reporting group description
    		 Participants who received placebo for 24 weeks in the double-blind period, received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.

    Subject analysis set title
    Overall Period: Vatiquinone/Vatiquinone
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for up to 72 weeks.

    Subject analysis set title
    Overall Period: Placebo/Vatiquinone
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received vatiquinone-matched placebo, administered orally, TID for up to 24 weeks followed by vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for up to 48 weeks.

    Primary: Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days During the Double-blind Period

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    End point title
    		 Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days During the Double-blind Period
    End point description
    The 28-day motor seizure frequency in the double-blind period was calculated as the (number of motor seizures)/ (the number of valid days where motor seizure count information is present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation. Intent-to-treat (ITT) population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: percent change
        median (confidence interval 95%)
    -12.74 (-28.67 to 9.42)
    -0.33 (-28.97 to 17.06)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-blind Period: Vatiquinone v Double-blind Period: Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.173
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -8.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.3
         upper limit
    		 16.4

    Secondary: Change From Baseline to Week 72 in Number of Disease-Related Hospitalization Days Per 28 days in Overall Period

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    End point title
    		 Change From Baseline to Week 72 in Number of Disease-Related Hospitalization Days Per 28 days in Overall Period
    End point description
    The disease-related hospitalization days per 28 days in the overall period was calculated as the (number of disease-related hospitalizations)/(the number of days within the overall treatment period) * 28. The baseline hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: days
        median (confidence interval 95%)
    0.363 (0 to 1.304)
    0.166 (0 to 0.515)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in Number of Disease-Related Hospitalization Days per 28 Days in Double-Blind Period

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    End point title
    		 Change From Baseline to Week 24 in Number of Disease-Related Hospitalization Days per 28 Days in Double-Blind Period
    End point description
    The disease-related hospitalization days per 28 days in the double-blind period was calculated as the (number of disease-related hospitalizations)/(the number of days within the double-blind period) * 28. The baseline hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: days
        median (confidence interval 95%)
    0 (0 to 1.160)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in Occurrence/Recurrence of Status Epilepticus per 28 Days in Double-blind Period

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    End point title
    		 Change From Baseline to Week 24 in Occurrence/Recurrence of Status Epilepticus per 28 Days in Double-blind Period
    End point description
    The status epilepticus per 28 Days in the double-blind period was calculated as the (number of status epilepticus incidences)/(the number of days in the double-blind period) * 28. The baseline status epilepticus incidences used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: status epilepticus per 28 days
        arithmetic mean (standard deviation)
    0.039 ( 0.9564 )
    -0.026 ( 1.1083 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Disease-Related In-Patient Hospitalizations in Double-Blind Period

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    End point title
    		 Number of Participants with Disease-Related In-Patient Hospitalizations in Double-Blind Period
    End point description
    In-patient hospitalization per 28 days in the double-blind period was calculated as the (number of in-patient hospitalization)/(the number of days in the double-blind period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with in-patient hospitalizations for either seizure or epilepticus per 28 days in double-blind period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
    6
    2
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 72 in Occurrence/Recurrence of Status Epilepticus per 28 Days in Overall Period

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    End point title
    		 Change From Baseline to Week 72 in Occurrence/Recurrence of Status Epilepticus per 28 Days in Overall Period
    End point description
    The status epilepticus per 28 Days in the overall period was calculated as the (number of status epilepticus incidences)/(the number of days in the overall period) * 28. The baseline status epilepticus incidences used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: status epilepticus per 28 days
        arithmetic mean (standard deviation)
    0.036 ( 0.6444 )
    -0.102 ( 1.0094 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Disease-Related Emergency Room Visits in Double-Blind Period

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    End point title
    		 Number of Participants With Disease-Related Emergency Room Visits in Double-Blind Period
    End point description
    Disease-related emergency room visits per 28 days in the double-blind period was calculated as the (number of disease-related emergency room visits)/(the number of days in the double-blind period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with disease-related emergency room visits for either seizure or epilepticus per 28 days in double-blind period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
    9
    4
    No statistical analyses for this end point

    Secondary: Number of Disease-Related In-Patient Hospitalizations in Double-Blind Period

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    End point title
    		 Number of Disease-Related In-Patient Hospitalizations in Double-Blind Period
    End point description
    In-patient hospitalization per 28 days in the double-blind period was calculated as the (number of in-patient hospitalization)/(the number of days in the double-blind period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of in-patient hospitalizations for either seizure or epilepticus per 28 days in double-blind period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
        0 Hospitalization
    28
    32
        1 Hospitalization
    4
    1
        2 Hospitalizations
    1
    0
        7 Hospitalizations
    0
    1
        10 Hospitalizations
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Disease-Related Emergency Room Visits in Overall Period

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    End point title
    		 Number of Participants With Disease-Related Emergency Room Visits in Overall Period
    End point description
    Disease-related emergency room visits per 28 days in the overall period was calculated as the (number of disease-related emergency room visits)/(the number of days in the overall period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with disease-related emergency room visits for either seizure or epilepticus per 28 days in overall period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
    14
    5
    No statistical analyses for this end point

    Secondary: Number of Participants with Disease-Related In-Patient Hospitalizations in Overall Period

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    End point title
    		 Number of Participants with Disease-Related In-Patient Hospitalizations in Overall Period
    End point description
    In-patient hospitalization per 28 days in the overall period was calculated as the (number of in-patient hospitalization)/(the number of days in the overall period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with in-patient hospitalizations for either seizure or epilepticus per 28 days in overall period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
    11
    3
    No statistical analyses for this end point

    Secondary: Number of Disease-Related In-Patient Hospitalizations in Overall Period

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    End point title
    		 Number of Disease-Related In-Patient Hospitalizations in Overall Period
    End point description
    In-patient hospitalization per 28 days in the overall period was calculated as the (number of in-patient hospitalization)/(the number of days in the overall period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number in-patient hospitalizations for either seizure or epilepticus per 28 days in overall period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
        0 Hospitalization
    23
    31
        1 Hospitalization
    7
    1
        2 Hospitalizations
    0
    1
        5 Hospitalizations
    1
    0
        6 Hospitalizations
    1
    0
        7 Hospitalizations
    0
    1
        8 Hospitalizations
    1
    0
        10 Hospitalizations
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Disease-Related Emergency Room Visits in Double-Blind Period

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    End point title
    		 Number of Disease-Related Emergency Room Visits in Double-Blind Period
    End point description
    Disease-related emergency room visits per 28 days in the double-blind period was calculated as the (number of disease-related emergency room visits)/(the number of days in the double-blind period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of emergency room visits for either seizure or epilepticus per 28 days in double-blind period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
        0 Visit
    25
    30
        1 Visit
    7
    4
        2 Visits
    1
    0
        10 Visits
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Disease-Related Emergency Room Visits in Overall Period

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    End point title
    		 Number of Disease-Related Emergency Room Visits in Overall Period
    End point description
    Disease-related emergency room visits per 28 days in the overall period was calculated as the (number of disease-related emergency room visits)/(the number of days in the overall period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of emergency room visits for either seizure or epilepticus per 28 days in overall period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
        0 Visit
    20
    29
        1 Visit
    8
    4
        2 Visits
    2
    1
        6 Visits
    2
    0
        8 Visits
    1
    0
        10 Visits
    1
    0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to Week 24 in Total Seizure Frequency per 28 Days in Double-Blind Period

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    End point title
    		 Percent Change From Baseline to Week 24 in Total Seizure Frequency per 28 Days in Double-Blind Period
    End point description
    The total seizure frequency per 28 days in the double-blind period was calculated as the (number of total seizures)/(the number of valid days where total seizure count information is present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: percent change
        median (confidence interval 95%)
    -14.27 (-34.52 to 21.85)
    -5.73 (-31.59 to 7.79)
    No statistical analyses for this end point

    Secondary: Number of Participants Taking Rescue Medications in the Double-blind Period

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    End point title
    		 Number of Participants Taking Rescue Medications in the Double-blind Period
    End point description
    Number of participants taking rescue medications for epilepsy in double-blind period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
    24
    22
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to Week 72 in Total Seizure Frequency per 28 Days in Overall Period

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    End point title
    		 Percent Change From Baseline to Week 72 in Total Seizure Frequency per 28 Days in Overall Period
    End point description
    Overall period was defined as the period from the first dosing date of investigational product (IP) during double-blind period to the end of study (double-blind + open-label period). The 28 day total seizure frequency in the overall period was calculated as the (number of total seizures)/(the number of valid days where total seizure count information is present) * 28 within the overall period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: percent change
        median (confidence interval 95%)
    -17.03 (-42.38 to 0)
    -7.52 (-35.46 to 17.00)
    No statistical analyses for this end point

    Secondary: Number of Participants Taking Rescue Medications in the Overall Period

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    End point title
    		 Number of Participants Taking Rescue Medications in the Overall Period
    End point description
    Number of participants taking rescue medications for epilepsy in overall period are reported. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
    24
    23
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire Score in Double-blind Period

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    End point title
    		 Change From Baseline to Week 24 in Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire Score in Double-blind Period
    End point description
    The CarerQol-7D consists of 5 negative and 2 positive dimensions of providing informal care. The negative dimensions are relational problems, mental health problems, problems combining daily activities with care, financial problems and physical health problems because of providing informal care. The 2 positive dimensions are fulfilment from caregiving and support with lending care. For each dimension, there are 3 possible responses: no, some and a lot. Utility tariffs for CarerQol have been developed to calculate a weighted sum score of CarerQol-7D from the responses on the 7 dimensions, ranging from 0 (worst imaginable caregiving situation) to 100 (best imaginable caregiving situation), for which discrete choice experiments were used. Higher sum scores reflect better care-related quality of life. ITT population included all randomized participants who received at least 1 dose of treatment. 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    5
    2
    Units: units on a scale
        arithmetic mean (standard deviation)
    -10.38 ( 18.207 )
    -5.25 ( 10.112 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 72 in Health-Related Quality of Life as Measured by the CarerQoL-7D Questionnaire Score in Overall Period

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    End point title
    		 Change From Baseline to Week 72 in Health-Related Quality of Life as Measured by the CarerQoL-7D Questionnaire Score in Overall Period
    End point description
    The CarerQol-7D consists of 5 negative and 2 positive dimensions of providing informal care. The negative dimensions are relational problems, mental health problems, problems combining daily activities with care, financial problems and physical health problems because of providing informal care. The 2 positive dimensions are fulfilment from caregiving and support with lending care. For each dimension, there are 3 possible responses: no, some and a lot. Utility tariffs for CarerQol have been developed to calculate a weighted sum score of CarerQol-7D from the responses on the 7 dimensions, ranging from 0 (worst imaginable caregiving situation) to 100 (best imaginable caregiving situation), for which discrete choice experiments were used. Higher sum scores reflect better care-related quality of life. ITT population included all randomized participants who received at least 1 dose of treatment. 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    12
    10
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.95 ( 14.235 )
    -3.14 ( 13.675 )
    No statistical analyses for this end point

    Secondary: Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Motor Seizures per 28 Days During the Double-blind Period

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    End point title
    		 Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Motor Seizures per 28 Days During the Double-blind Period
    End point description
    Number of participants whose motor seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
        >30%
    7
    9
        30% to -30%
    17
    14
        < -30% to -60%
    7
    7
        < -60% to -100%
    3
    4
    No statistical analyses for this end point

    Secondary: Number of Participants with Motor Seizure Clusters in Overall Period

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    End point title
    		 Number of Participants with Motor Seizure Clusters in Overall Period
    End point description
    Seizure clusters were defined by “too many to count” entries in the seizure diaries. The motor seizure clusters per 28 days in the overall period was calculated as the (number of motor seizure clusters)/(the number of valid days where motor seizure clusters count information was present) * 28 within the overall period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 72
    End point values
    		 Overall Period: Vatiquinone/Vatiquinone Overall Period: Placebo/Vatiquinone
    Number of subjects analysed
    34
    34
    Units: participants
    21
    26
    No statistical analyses for this end point

    Secondary: Number of Participants with Motor Seizure Clusters in Double-Blind Period

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    End point title
    		 Number of Participants with Motor Seizure Clusters in Double-Blind Period
    End point description
    Seizure clusters were defined by “too many to count” entries in the seizure diaries. The motor seizure clusters per 28 days in the double-blind period was calculated as the (number of motor seizure clusters)/(the number of valid days where motor seizure clusters count information was present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation. ITT population included all randomized participants who received at least 1 dose of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
    19
    25
    No statistical analyses for this end point

    Secondary: Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Total Seizures per 28 Days During the Double-blind Period

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    End point title
    		 Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Total Seizures per 28 Days During the Double-blind Period
    End point description
    Number of participants whose total seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Double-blind Period: Vatiquinone Double-blind Period: Placebo
    Number of subjects analysed
    34
    34
    Units: participants
        >30%
    7
    7
        30% to -30%
    13
    15
        < -30% to -60%
    10
    9
        < -60% to -100%
    4
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 77
    Adverse event reporting additional description
    Double-blind phase: Safety analysis set included all randomized participants who received at least 1 dose of treatment. On-Vatiquinone period: On-Vatiquinone safety analysis set included all randomized participants who received at least 1 dose of Vatiquinone anytime during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Double-blind Period: Vatiquinone
    Reporting group description
    		 Participants received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for up to 24 weeks during the double-blind period.

    Reporting group title
    On-Vatiquinone Period: Placebo/Vatiquinone
    Reporting group description
    		 Participants who received placebo for 24 weeks in the double-blind period, received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.

    Reporting group title
    On-Vatiquinone Period: Vatiquinone/Vatiquinone
    Reporting group description
    		 Participants who received vatiquinone for 24 weeks in the double-blind period continued to received vatiquinone 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for 48 weeks during the long-term extension period.

    Reporting group title
    Double-blind Period: Placebo
    Reporting group description
    		 Participants received vatiquinone-matched placebo, administered orally, TID for up to 24 weeks during the double-blind period.

    Serious adverse events
    		 Double-blind Period: Vatiquinone On-Vatiquinone Period: Placebo/Vatiquinone On-Vatiquinone Period: Vatiquinone/Vatiquinone Double-blind Period: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 34 (52.94%)
    16 / 29 (55.17%)
    26 / 34 (76.47%)
    9 / 34 (26.47%)
         number of deaths (all causes)
    1
    1
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 29 (6.90%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis aspiration
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate affect
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Urine output decreased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 29 (3.45%)
    7 / 34 (20.59%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
    0 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Change in seizure presentation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Excessive granulation tissue
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
    5 / 34 (14.71%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 34 (5.88%)
    4 / 29 (13.79%)
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitochondrial cytopathy
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-blind Period: Vatiquinone On-Vatiquinone Period: Placebo/Vatiquinone On-Vatiquinone Period: Vatiquinone/Vatiquinone Double-blind Period: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 34 (76.47%)
    19 / 29 (65.52%)
    30 / 34 (88.24%)
    20 / 34 (58.82%)
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Fall
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Contusion
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
    4 / 34 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Nervous system disorders
    Change in seizure presentation
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    0
    3
    Headache
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Somnolence
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    2
    1
    Seizure
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 29 (3.45%)
    8 / 34 (23.53%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    10
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 29 (3.45%)
    9 / 34 (26.47%)
    1 / 34 (2.94%)
         occurrences all number
    6
    1
    12
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 29 (3.45%)
    10 / 34 (29.41%)
    0 / 34 (0.00%)
         occurrences all number
    7
    5
    14
    0
    Reproductive system and breast disorders
    Intermenstrual bleeding
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 29 (3.45%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Dyspnoea
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    2
    Eczema
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    3
    Agitation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 29 (6.90%)
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    2
    3
    COVID-19
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 29 (6.90%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Influenza
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 29 (10.34%)
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Pharyngitis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    3
    0
    3
    Hordeolum
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    3
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 29 (6.90%)
    1 / 34 (2.94%)
    1 / 34 (2.94%)
         occurrences all number
    2
    3
    2
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ear infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    4 / 34 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Sinusitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    4 / 34 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Rhinitis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 29 (3.45%)
    2 / 34 (5.88%)
    3 / 34 (8.82%)
         occurrences all number
    1
    1
    2
    5
    Pneumonia aspiration
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 34 (5.88%)
    7 / 29 (24.14%)
    5 / 34 (14.71%)
    3 / 34 (8.82%)
         occurrences all number
    3
    10
    10
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 29 (6.90%)
    4 / 34 (11.76%)
    2 / 34 (5.88%)
         occurrences all number
    4
    6
    11
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
    0 / 34 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2020
    The overall reason for this amendment was to change the name of the study Sponsor, subsequently the drug name, and to incorporate health authorities’ feedback on the previous version of the protocol.
    22 May 2020
    The overall reasons for this amendment were to add urinalysis assessment and an additional pharmacokinetic (PK) timepoint and to give additional training for seizure diaries, if needed.
    30 Sep 2020
    The overall reasons for this amendment were to revise the electrocariogram (ECG) collection schedule so as to time match it with the 4-hour postdose PK, to add PK samples to 4 hours postdose at Weeks 48 and 72, to revise the definition of compliance with study drug dosing, to separate the secondary endpoints into key and other endpoints, and refinement of statistical considerations.
    31 Mar 2021
    The overall reasons for this amendment were to add Pediatric Quality of Life Inventory (PedsQL) questionnaire at Weeks 24 and 72; revise the number of study sites from approximately 12 to approximately 30; clarify that historical electroencephalogram (EEG) may be within 6 months prior to the Screening Visit; revise inclusion and exclusion criteria to clarify genetic confirmation of mitochondrial disease, clarify use of antiepileptic drugs (AEDs), clarify aspartate aminotransferase (AST) and alanine aminotransferase (ALT) range for participants with underlying Alpers-Huttenlocher syndrome/DNA polymerase subunit gamma (POLG) subtypes, and clarify exclusion of artisanal (non-Epidiolex cannabidiol) cannabidiol; add a weight-based dosing table for study drug; and clarify that the statistical anlysis plan (SAP) will be finalized prior to unblinding of the study and revise the text regarding the sample size and statistical powering.
    04 Jun 2021
    The overall reasons for this amendment were to clarify that male participants must use contraception and that all participants must use contraceptive measures from the time consent was signed until 30 days after treatment discontinuation and to add an appendix of prohibited medications.
    06 Jan 2022
    The overall reason for this amendment was to incorporate feedback from health authorities.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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