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    Clinical Trial Results:
    A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in Pediatric Patients with Developmental and/or Epileptic Encephalopathies (ELEKTRA)

    Summary
    EudraCT number
    2018-002484-25
    Trial protocol
    PT   PL  
    Global end of trial date
    20 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Mar 2021
    First version publication date
    12 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-935-2002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03650452
    WHO universal trial number (UTN)
    U1111-1206-5522
    Sponsors
    Sponsor organisation name
    Ovid Therapeutics Inc.
    Sponsor organisation address
    1460 Broadway, New York, NY, United States, 10036
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002572-PIP02-19
    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
    20 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect on the frequency of all seizures (convulsive and drop) in participants treated with TAK-935 as an adjunctive therapy compared to placebo in the Maintenance Period.
    Protection of trial subjects
    All study participant’s parents, or their guardians were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Aug 2018
    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
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 41
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    141
    EEA total number of subjects
    53
    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)
    94
    Adolescents (12-17 years)
    47
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 45 investigative sites globally from 8 August 2018 to 20 July 2020.

    Pre-assignment
    Screening details
    Participants with a diagnosis of Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) were enrolled and randomized in a 1:1 ratio to double-blind treatment with TAK-935 or matching placebo for up to the 20-week Treatment Period (8-week Dose Optimization Period and 12-week Maintenance Period).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    TAK-935 placebo-matching tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-935 placebo-matching tablets or mini-tablets.

    Arm title
    TAK-935
    Arm description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-935
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-935 tablets or mini-tablets.

    Number of subjects in period 1
    Placebo TAK-935
    Started
    70
    71
    Completed
    60
    66
    Not completed
    10
    5
         Physician decision
    1
    -
         Early Withdrawal from Study Treatment
    3
    -
         Adverse event, non-fatal
    3
    4
         Withdrawal by Parent/Guardian
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    TAK-935 placebo-matching tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20.

    Reporting group title
    TAK-935
    Reporting group description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.

    Reporting group values
    Placebo TAK-935 Total
    Number of subjects
    70 71 141
    Age categorical
    Units: Subjects
        Children (2-11 years)
    46 48 94
        Adolescents (12-17 years)
    24 23 47
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    9.5 ( 3.93 ) 9.6 ( 4.14 ) -
    Sex: Female, Male
    Units: participants
        Female
    28 22 50
        Male
    42 49 91
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    10 11 21
        Not Hispanic or Latino
    60 60 120
        Unknown or Not Reported
    0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    22 22 44
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    1 0 1
        White
    47 49 96
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Region of Enrollment
    Units: Subjects
        Australia
    2 2 4
        Canada
    3 3 6
        China
    20 21 41
        Spain
    11 8 19
        Israel
    5 4 9
        Poland
    12 17 29
        Portugal
    2 3 5
        United States
    15 13 28
    Height
    Units: cm
        arithmetic mean (standard deviation)
    ( ) 134.7 ( 21.34 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    32.8 ( 15.98 ) 33.3 ( 15.11 ) -
    Body Mass Index (BMI)
    BMI= weight (km)/height (m^2)
    Units: (kg/m^2)
        arithmetic mean (standard deviation)
    ( ) 17.43 ( 4.048 ) -
    Clinical Global Impression of Severity (CGI-S) Responses of Investigator
    The CGI-Severity (CGI-S) focuses on clinicians’ observations of the participant’s cognitive, functional, and behavioral performance since the beginning of the study. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill participants).
    Units: score on a scale
        arithmetic mean (full range (min-max))
    -
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 placebo-matching tablets, orally or via G-tube/PEG, BID up to Week 20. Number analyzed are the number of participants with data available for Height and BMI at Baseline.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 placebo-matching tablets, orally or via G-tube/PEG, BID up to Week 20. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2.

    Subject analysis set title
    TAK-935
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2.

    Subject analysis sets values
    Placebo Placebo TAK-935
    Number of subjects
    68
    59
    64
    Age categorical
    Units: Subjects
        Children (2-11 years)
        Adolescents (12-17 years)
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Sex: Female, Male
    Units: participants
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Region of Enrollment
    Units: Subjects
        Australia
        Canada
        China
        Spain
        Israel
        Poland
        Portugal
        United States
    Height
    Units: cm
        arithmetic mean (standard deviation)
    132.4 ( 20.34 )
    ( )
    ( )
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Body Mass Index (BMI)
    BMI= weight (km)/height (m^2)
    Units: (kg/m^2)
        arithmetic mean (standard deviation)
    17.63 ( 4.378 )
    ( )
    ( )
    Clinical Global Impression of Severity (CGI-S) Responses of Investigator
    The CGI-Severity (CGI-S) focuses on clinicians’ observations of the participant’s cognitive, functional, and behavioral performance since the beginning of the study. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill participants).
    Units: score on a scale
        arithmetic mean (full range (min-max))
    4.8 (3 to 7)
    4.5 (2 to 7)

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    TAK-935 placebo-matching tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20.

    Reporting group title
    TAK-935
    Reporting group description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 placebo-matching tablets, orally or via G-tube/PEG, BID up to Week 20. Number analyzed are the number of participants with data available for Height and BMI at Baseline.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 placebo-matching tablets, orally or via G-tube/PEG, BID up to Week 20. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2.

    Subject analysis set title
    TAK-935
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2.

    Primary: Percent Change from Baseline in Seizure Frequency Per 28 Days During the Maintenance Period

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    End point title
    Percent Change from Baseline in Seizure Frequency Per 28 Days During the Maintenance Period
    End point description
    Seizure frequency per 28 days is defined as total number of seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during maintenance period – frequency of seizures per 28 days at baseline) divided by frequency of seizures per 28 days at baseline multiplied by 100. Negative percent change from Baseline indicates improvement. Efficacy Analysis Set included all Modified Intent-to-Treat (mITT) participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline; Maintenance Period: Weeks 9 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    56
    64
    Units: percent change
        median (full range (min-max))
    3.11 (-78.8 to 163.0)
    -27.76 (-100.0 to 160.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v TAK-935
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0007 [2]
    Method
    Ranked ANCOVA
    Parameter type
    Hodges-Lehmann Estimation
    Point estimate
    -30.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.99
         upper limit
    -13.19
    Notes
    [1] - The location shift (TAK-935 - Placebo) and Asymptotic 95% confidence interval between TAK-935 and Placebo (TAK-935 - Placebo) were based on Hodges-Lehmann Estimation from un-adjusted rank statistics.
    [2] - The p-value is 2-sided and it is for the difference of percent change from baseline between TAK-935 and Placebo were computed using Rank Transformed Analysis of Covariance (ANCOVA) adjusting for baseline seizure frequency and indication.

    Secondary: Percent Change from Baseline in Seizure Frequency Per 28 Days During the Treatment period

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    End point title
    Percent Change from Baseline in Seizure Frequency Per 28 Days During the Treatment period
    End point description
    Seizure Frequency per 28 days is defined as total number of Seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent Change from Baseline is defined as (frequency of seizures per 28 days during treatment period – frequency of seizures per 28 days at baseline) divided by frequency of seizures per 28 days at baseline multiplied by 100. Negative percent change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2.
    End point type
    Secondary
    End point timeframe
    Baseline; Treatment Period: Weeks 0 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    59
    64
    Units: percent change
        median (full range (min-max))
    0.75 (-60.1 to 437.8)
    -30.05 (-100.0 to 347.5)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v TAK-935
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0024 [4]
    Method
    Ranked ANCOVA
    Parameter type
    Hodges-Lehmann Estimate
    Point estimate
    -25.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -43.96
         upper limit
    -10.69
    Notes
    [3] - The location shift (TAK-935 - Placebo) and Asymptotic 95% confidence interval between TAK-935 and Placebo (TAK-935 - Placebo) were based on Hodges-Lehmann Estimation from un-adjusted rank statistics.
    [4] - The p-value is 2-sided and it is for the difference of percent change from baseline between TAK-935 and Placebo were computed using Rank Transformed ANCOVA adjusting for baseline seizure frequency and indication.

    Secondary: Percent Change from Baseline in Convulsive Seizure Frequency Per 28 Days in Participants with Dravet Syndrome Stratum During the Maintenance Period

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    End point title
    Percent Change from Baseline in Convulsive Seizure Frequency Per 28 Days in Participants with Dravet Syndrome Stratum During the Maintenance Period
    End point description
    Convulsive seizure frequency per 28 days is defined as total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent Change from Baseline (%) is defined as [(Maintenance Period Convulsive Seizure Frequency - Baseline Period Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Negative percent change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance Period: Weeks 9 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    21
    24
    Units: percent change
        median (full range (min-max))
    9.38 (-47.3 to 153.5)
    -36.50 (-100.0 to 84.1)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v TAK-935
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0001 [6]
    Method
    Ranked ANCOVA
    Parameter type
    Hodges-Lehmann Estimate
    Point estimate
    -50
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -75.03
         upper limit
    -25.09
    Notes
    [5] - The location shift (TAK-935 - Placebo) and Asymptotic 95% confidence interval between TAK-935 and Placebo (TAK-935 - Placebo) were based on Hodges-Lehmann Estimation from un-adjusted rank statistics.
    [6] - The p-value is 2-sided and it is for the difference of percent change from baseline between TAK-935 and Placebo were computed using Rank Transformed ANCOVA adjusting for baseline seizure frequency.

    Secondary: Percent Change from Baseline in Drop Seizure Frequency Per 28 Days in Participants with the Lennox-Gastaut Syndrome (LGS) Stratum During the Maintenance Period

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    End point title
    Percent Change from Baseline in Drop Seizure Frequency Per 28 Days in Participants with the Lennox-Gastaut Syndrome (LGS) Stratum During the Maintenance Period
    End point description
    Drop seizure frequency per 28 days is defined as total number of drop seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent Change from Baseline (%) is defined as [(Maintenance Period Drop Seizure Frequency - Baseline Period Drop Seizure Frequency) divided by Baseline Drop Seizure Frequency] multiplied by 100. Negative percent change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance Period: Weeks 9 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    35
    40
    Units: percent change
        median (full range (min-max))
    -1.90 (-78.8 to 163.0)
    -18.46 (-100.0 to 160.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v TAK-935
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.147 [8]
    Method
    Ranked ANCOVA
    Parameter type
    Hodges-Lehmann Estimate
    Point estimate
    -16.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.5
         upper limit
    4.49
    Notes
    [7] - The location shift (TAK-935 - Placebo) and Asymptotic 95% confidence interval between TAK-935 and Placebo (TAK-935 - Placebo) were based on Hodges-Lehmann Estimation from un-adjusted rank statistics.
    [8] - The p-value is 2-sided and it is for the difference of percent change from baseline between TAK-935 and Placebo were computed using Rank Transformed ANCOVA adjusting for baseline seizure frequency.

    Secondary: Percentage of Participants with LGS Stratum Considered Treatment Responders Throughout the Maintenance Period

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    End point title
    Percentage of Participants with LGS Stratum Considered Treatment Responders Throughout the Maintenance Period
    End point description
    Responders are defined as having over 50% drop seizure reduction compared to Baseline. Percent Reduction from Baseline (%) is defined as [(Maintenance Period Drop Seizure Frequency - Baseline Period Drop Seizure Frequency) divided by Baseline Drop Seizure Frequency] multiplied by 100. Data is reported as reduction of 25%, 50%, 75% and 100% or more in drop seizures from Baseline. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Only participants with LGS stratum indication were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance Period: Weeks 9 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    37
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Reduction of >=25% in Drop Seizures from Baseline
    29.7 (15.9 to 47.0)
    42.5 (27.0 to 59.1)
        Reduction of >=50% in Drop Seizures from Baseline
    16.2 (6.2 to 32.0)
    27.5 (14.6 to 43.9)
        Reduction of >=75% in Drop Seizures from Baseline
    2.7 (0.1 to 14.2)
    10.0 (2.8 to 23.7)
        Reduction of 100% in Drop Seizures from Baseline
    0 (0.0 to 9.5)
    5.0 (0.6 to 16.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Dravet Syndrome Stratum Considered Treatment Responders Throughout the Maintenance Period

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    End point title
    Percentage of Participants with Dravet Syndrome Stratum Considered Treatment Responders Throughout the Maintenance Period
    End point description
    Responders are defined as having over 50% convulsive seizure reduction compared to Baseline. Percent Reduction from Baseline (%) is defined as [(Maintenance Period Convulsive Seizure Frequency - Baseline Period Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Data is reported as reduction of 25%, 50%, 75% and 100% or more in drop seizures from Baseline. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Only participants with Dravet syndrome stratum indication were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Maintenance Period: Weeks 9 to 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    22
    24
    Units: percentage of participants
    number (confidence interval 95%)
        Reduction of >=25% in Convulsive Seizures from BL
    13.6 (2.9 to 34.9)
    66.7 (44.7 to 84.4)
        Reduction of >=50% in Convulsive Seizures from BL
    0 (0.0 to 15.4)
    41.7 (22.1 to 63.4)
        Reduction of >=75% in Convulsive Seizures from BL
    0 (0.0 to 15.4)
    20.8 (7.1 to 42.2)
        Reduction of 100% in Convulsive Seizures from BL
    0 (0.0 to 15.4)
    8.3 (1.0 to 27.0)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinician’s Clinical Global Impression of Severity (CGI-S) Responses of Investigator Reported Impression of Efficacy and Tolerability of Study Drug

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    End point title
    Change from Baseline in Clinician’s Clinical Global Impression of Severity (CGI-S) Responses of Investigator Reported Impression of Efficacy and Tolerability of Study Drug
    End point description
    The CGI-Severity (CGI-S) focuses on clinicians’ observations of the participant’s cognitive, functional, and behavioral performance since the beginning of the study. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill participants). A negative change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    49
    58
    Units: score on scale
        least squares mean (standard deviation)
    -0.3 ( 0.15 )
    -0.2 ( 0.14 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v TAK-935
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    P-value
    = 0.6829 [10]
    Method
    Mixed-Model Repeated Measure (MMRM)
    Parameter type
    Least Square (LS) Mean
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.49
    Variability estimate
    Standard deviation
    Dispersion value
    0.21
    Notes
    [9] - The MMRM model included treatment and visit as factors along with treatment*visit interaction and baseline score as a covariate; and visit as repeated measure.
    [10] - The p-value is 2-sided and it is for the difference (TAK-935 - Placebo) of change from baseline between TAK-935 and Placebo was computed using MMRM.

    Secondary: Percentage of Participants with Clinical Global Impression of Change (CGI-C) Responses as per the Investigator Reported Impression of Efficacy and Tolerability TAK-935

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    End point title
    Percentage of Participants with Clinical Global Impression of Change (CGI-C) Responses as per the Investigator Reported Impression of Efficacy and Tolerability TAK-935
    End point description
    CGI-Change (CGI-C) treatment response ratings should take account of both therapeutic efficacy and treatment-related AEs. Each component of the CGI is rated separately; the instrument does not yield a global score. The CGI-C is rated on a 7-point scale, where, 0 = Marked improvement and no side-effects, 1 = Marked improvement and minimal side-effects, 2 = No Change, 3 = Minimal improvement and marked side-effects and 4 = Unchanged or worse and side-effects outweigh the therapeutic effect. Lower scores indicated improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    49
    58
    Units: percentage of participants
    number (not applicable)
        Week 20, Score 0
    12.2
    17.2
        Week 20, Score 1
    2.0
    15.5
        Week 20, Score 2
    85.7
    65.5
        Week 20, Score 3
    0
    0
        Week 20, Score 4
    0
    1.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Caregiver Global Impression of Change (Care GI-C) Responses as Per the Parent/Family Reported Impression of Efficacy and Tolerability of TAK-935

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    End point title
    Percentage of Participants with Caregiver Global Impression of Change (Care GI-C) Responses as Per the Parent/Family Reported Impression of Efficacy and Tolerability of TAK-935
    End point description
    The Care GI-C is rated on a 7-point scale, with the severity of illness scale where, 1 = Very much improved, 2 = Much improved, 3 = Slightly improved, 4 = No change, 5 = Slightly worse, 6 = Much worse and 7 = Very much worse. Lower scores indicated improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2. Number of participants analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 20
    End point values
    Placebo TAK-935
    Number of subjects analysed
    49
    58
    Units: percentage of participants
    number (not applicable)
        Week 20, Score 1
    2.0
    13.8
        Week 20, Score 2
    12.2
    10.3
        Week 20, Score 3
    18.4
    32.8
        Week 20, Score 4
    55.1
    37.9
        Week 20, Score 5
    8.2
    3.4
        Week 20, Score 6
    4.1
    1.7
        Week 20, Score 7
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Plasma 24S-Hydroxycholesterol (24HC) Levels Participants Treated with TAK-935 as an Adjunctive Therapy

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    End point title
    Change from Baseline in Plasma 24S-Hydroxycholesterol (24HC) Levels Participants Treated with TAK-935 as an Adjunctive Therapy
    End point description
    A negative change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2, with available data. n=the number of participants with Baseline and Week 24 data available for analyses. 9999 indicated that the mean and standard deviation was not estimable as there were no evaluable participants for analyses. 99999 indicated that the standard deviation was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo TAK-935
    Number of subjects analysed
    57
    61
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline (n=57, 61)
    102.77 ( 50.385 )
    102.20 ( 62.332 )
        Change from Baseline at Week 24 (n=0, 1)
    9999 ( 9999 )
    -0.10 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Seizure Frequency in Participants Treated with TAK-935 as an Adjunctive Therapy

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    End point title
    Change from Baseline in Seizure Frequency in Participants Treated with TAK-935 as an Adjunctive Therapy
    End point description
    Seizure frequency was based on convulsive seizures for the participants in the Dravet Syndrome Indication and Drop Seizures for the participants in the LGS Indication. Seizure frequency per 28 days = (total number of seizures reported during the period) / (number of days during the period seizures were assessed) * 28. A negative change from Baseline indicates improvement. Efficacy Analysis Set included all mITT participants whose efficacy assessments were compliant with Protocol Amendment 2, with available data. n=the number of participants with Baseline and Week 24 data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo TAK-935
    Number of subjects analysed
    57
    61
    Units: seizures per 28 days
    median (full range (min-max))
        Baseline (n=57, 61)
    31.00 (3.1 to 1040.1)
    32.12 (2.6 to 5187.7)
        Change from Baseline at Week 24 (n=33, 40)
    0.30 (-84.9 to 520.4)
    -6.29 (-1024.3 to 77.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose to 30 days post-last dose of study treatment (Up to 24 weeks)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    TAK-935 placebo-matching tablets, orally or via G-tube/PEG, BID up to Week 20.

    Reporting group title
    TAK-935
    Reporting group description
    TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.

    Serious adverse events
    Placebo TAK-935
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 70 (18.57%)
    11 / 71 (15.49%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding disorder
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         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: 0%
    Non-serious adverse events
    Placebo TAK-935
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 70 (74.29%)
    55 / 71 (77.46%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 70 (11.43%)
    11 / 71 (15.49%)
         occurrences all number
    13
    13
    Asthenia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Decreased activity
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    3 / 70 (4.29%)
    4 / 71 (5.63%)
         occurrences all number
    3
    4
    Influenza like illness
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Erection increased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    3 / 70 (4.29%)
    1 / 71 (1.41%)
         occurrences all number
    3
    1
    Epistaxis
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    3
    Dysphonia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Agitation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Apathy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Impulsive behaviour
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Initial insomnia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    2
    Insomnia
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Middle insomnia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Irritability
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 71 (5.63%)
         occurrences all number
    3
    4
    Negativism
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Poverty of speech
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Defiant behaviour
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 71 (2.82%)
         occurrences all number
    3
    2
    Benzodiazepine drug level increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Drug level increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Electrocardiogram P wave abnormal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Nitrite urine present
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Protein urine present
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Red blood cells urine
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Urine output decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 71 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    3
    Contusion
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 71 (4.23%)
         occurrences all number
    4
    3
    Fall
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Head injury
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 71 (0.00%)
         occurrences all number
    4
    0
    Joint injury
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Soft tissue injury
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Tibia fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Nervous system disorders
    Seizure
         subjects affected / exposed
    7 / 70 (10.00%)
    4 / 71 (5.63%)
         occurrences all number
    8
    4
    Somnolence
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 71 (8.45%)
         occurrences all number
    3
    8
    Aphasia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Ataxia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Cerebellar ataxia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    2
    Change in seizure presentation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Chorea
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Drooling
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 71 (4.23%)
         occurrences all number
    1
    3
    Clonic convulsion
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Epilepsy
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 71 (0.00%)
         occurrences all number
    5
    0
    Headache
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 71 (4.23%)
         occurrences all number
    0
    3
    Hypotonia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Hypersomnia
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Myoclonic epilepsy
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Partial seizures
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Poor quality sleep
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 71 (4.23%)
         occurrences all number
    0
    4
    Seizure cluster
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Tonic convulsion
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Lethargy
         subjects affected / exposed
    0 / 70 (0.00%)
    5 / 71 (7.04%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Basophilia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Coagulopathy
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 71 (4.23%)
         occurrences all number
    0
    3
    Granulocytopenia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Monocytosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Eye disorders
    Amblyopia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Blepharitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Excessive eye blinking
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Periorbital swelling
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 71 (7.04%)
         occurrences all number
    4
    7
    Vomiting
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 71 (8.45%)
         occurrences all number
    5
    7
    Aphthous ulcer
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 71 (5.63%)
         occurrences all number
    0
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Gingival swelling
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Lip swelling
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Umbilical hernia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Hepatomegaly
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 71 (2.82%)
         occurrences all number
    1
    3
    Pruritus
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Hypercalciuria
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 70 (14.29%)
    12 / 71 (16.90%)
         occurrences all number
    11
    20
    Nasopharyngitis
         subjects affected / exposed
    6 / 70 (8.57%)
    6 / 71 (8.45%)
         occurrences all number
    8
    7
    Acute sinusitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Bronchitis viral
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Gastroenteritis viral
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 71 (1.41%)
         occurrences all number
    3
    1
    Gingival abscess
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Gingivitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Herpes simplex
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Infectious mononucleosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 71 (2.82%)
         occurrences all number
    6
    5
    Laryngitis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Nail infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Otitis media acute
         subjects affected / exposed
    3 / 70 (4.29%)
    1 / 71 (1.41%)
         occurrences all number
    7
    1
    Otitis media
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Peritonsillar abscess
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 71 (4.23%)
         occurrences all number
    1
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 71 (4.23%)
         occurrences all number
    1
    3
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    2
    Sepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 71 (1.41%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 70 (7.14%)
    6 / 71 (8.45%)
         occurrences all number
    5
    6
    Abnormal loss of weight
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 71 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Electrolyte imbalance
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2018
    Protocol Amendment 1: The primary purpose of this amendment was to make following changes. Removal of ‘Non-Dravet patients with convulsive seizures”. To change name of ‘Drop seizure’ stratum to ‘LGS stratum’. To increase duration of maintenance period from 10 weeks to 12 weeks. To allow administration of TAK-935 via gastrostomy tube (G tube)/percutaneous endoscopic gastrostomy (PEG) tube. The total sample size was changed from 152 to 112. Remove exclusion criterion for status epilepticus (exclusion criterion #1). Remove exclusion criterion for inability to swallow study drug safety (exclusion criterion #3). Remove exclusion criterion for positive drug screen at screening. BMI assessment removed. Participants with Hepatitis B and C are excluded.
    14 Feb 2019
    Protocol Amendment 2: The primary purpose of this amendment was to make following changes. Clarified that iDMC will review the AE profiles of the first 12 patients aged ≥9 years completing 4 weeks of treatment. Renamed the Titration Period to the Dose Optimization Period and increased the period duration from 2 weeks to 8 weeks. Added additional phone calls to monitor dose optimization and safety. Removed hepatitis B and C serology panel. Changed the follow-up visit from a phone call to a clinic visit. Revised the PK collection timepoints and added sampling windows. Updated the approximate total blood volume collected. Revised the primary, secondary and exploratory objectives. Updated language regarding patient’s legal representative. Clarified diagnosis of Dravet syndrome and Lennox-Gastaut syndrome for Inclusion. Clarified that convulsive status epilepticus requiring hospitalization is an exclusion criterion for this study. Revised the exclusion criterion related to ocular conditions. Added malignancy (including progressive tumors) as an exclusionary condition. Revised the primary, secondary and exploratory endpoints. Revised the pharmacokinetic endpoints. Revised and added analysis sets. Updated study rationale. Add new section to define end of the study. Clarified the handling of missed doses. Changed demographic collection from “date of birth” to “year of birth”. Added a formula for assessment of seizure frequency. Clarified that the Exit survey is a separate questionnaire from the Care GI-C. Added statement about AEs or SAEs associated with overdose. Clarified reporting seizures as AEs/SAEs. Removed text that stated that expected SAEs were provided in the Investigators Brochure. Clarified SAE reporting process. Added text stating that TAK-935 should not be administered to pregnant or lactating females. Updated the schedule of assessments. Updated Appendix 2. Updated the Appendix 3 study sampling summary. Replaced table in Appendix 3.

    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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