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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With Dravet Syndrome (DS)

    Summary
    EudraCT number
    		 2021-002480-22
    Trial protocol
    		 Outside EU/EEA   IT   FR   ES   LV   GR   NL   BE   PL   HU   DE  
    Global end of trial date
    11 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2024
    First version publication date
    26 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TAK-935-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04940624
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 jRCT: jRCT2051210074
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to Standard of Care (SOC) compared with placebo during the maintenance period only.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 NA
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2021
    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: 2
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 30
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 18
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    144
    EEA total number of subjects
    48
    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)
    95
    Adolescents (12-17 years)
    32
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 144 participants participated in the study at multiple investigative sites globally from 28 October 2021 to 11 April 2024.

    Pre-assignment
    Screening details
    		 A total of 144 participants with a diagnosis of Dravet Syndrome (DS) were randomized in a 1:1 ratio to receive either soticlestat or placebo.

    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, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (BID), up to 4 weeks during titration. Participants continued to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered for 16 weeks in the Treatment Period.

    Arm title
    		 Soticlestat
    Arm description
    		 Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Soticlestat
    Investigational medicinal product code
    TAK-935
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Gastroenteral use, Oral use
    Dosage and administration details
    Administered for 16 weeks in the Treatment Period.

    Number of subjects in period 1
    		Placebo Soticlestat
    Started
    71
    73
    Completed
    63
    60
    Not completed
    8
    13
         Physician decision
    1
    -
         Adverse event, non-fatal
    4
    11
         Reason Not Specified
    1
    -
         Withdrawal by Parent/Guardian
    1
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (BID), up to 4 weeks during titration. Participants continued to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.

    Reporting group title
    Soticlestat
    Reporting group description
    		 Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment.

    Reporting group values
    		 Placebo Soticlestat Total
    Number of subjects
    		 71 73
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.5 ( 5.06 ) 10.1 ( 5.04 ) -
    Gender categorical
    Units: Subjects
        Male
    		 36 36 72
        Female
    		 35 37 72
    Ethnicity categorical
    Units: Subjects
        Hispanic or Latino
    		 6 5 11
        Not Hispanic or Latino
    		 62 68 130
        Unknown or Not Reported
    		 3 0 3
    Race categorical
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 24 27 51
        Black or African American
    		 0 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 43 39 82
        Multiple
    		 0 1 1
        Not Reported
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (BID), up to 4 weeks during titration. Participants continued to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.

    Reporting group title
    Soticlestat
    Reporting group description
    		 Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment.

    Primary: Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Full Treatment Period

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    End point title
    		 Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Full Treatment Period
    End point description
    Convulsive seizure frequency per 28 days was 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 was defined as (frequency of seizures per 28 days during Full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100. Modified Intent-to-Treat (mITT) Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Primary
    End point timeframe
    Baseline; Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -8.64 (-30.13 to 14.83)
    -22.16 (-53.64 to 22.73)
    Statistical analysis title
    		 Full Treatment Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -15.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.3
         upper limit
    		 0.24
    Notes
    [1] - The p-value was computed using Rank Analysis of Covariance (ANCOVA) model using treatment group, age stratum (≤6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors.

    Primary: Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period

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    End point title
    		 Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period
    End point description
    Convulsive seizure frequency per 28 days was 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 was defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline; Maintenance Period: Weeks 5 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    68
    69
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -11.99 (-31.93 to 9.75)
    -23.29 (-56.92 to 14.15)
    Statistical analysis title
    		 Maintenance Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.089 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -14.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.51
         upper limit
    		 1.53
    Notes
    [2] - The p-value was computed using Rank ANCOVA model using treatment group, age stratum (≤6 years, >6 years), and rank of baseline seizure frequency per 28 days as predictors.

    Secondary: Percentage of Responders During Maintenance Period

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    End point title
    		 Percentage of Responders During Maintenance Period
    End point description
    Responders were defined as those with ≥50% reduction from Baseline in convulsive seizures during the Maintenance Period. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Maintenance Period: Weeks 5 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    68
    69
    Units: percentage of participants
        number (not applicable)
    11.8
    30.4
    Statistical analysis title
    		 Maintenance Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.3
         upper limit
    		 7.96
    Notes
    [3] - The p-value was based on Cochran-Mantel-Haenszel (CMH) test stratified by age stratum (≤6 years, >6 years).

    Secondary: Percentage of Responders During the Full Treatment Period

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    End point title
    		 Percentage of Responders During the Full Treatment Period
    End point description
    Responders were defined as those with ≥50% reduction from Baseline in convulsive seizures during the Full Treatment Period. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: percentage of participants
        number (not applicable)
    9.9
    27.4
    Statistical analysis title
    		 Full Treatment Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 9.49
    Notes
    [4] - The p-value was based on CMH test stratified by age stratum (<=6 years, >6 years).

    Secondary: Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to ≤100% Reduction in Convulsive Seizures During the Full Treatment Period

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    End point title
    		 Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to ≤100% Reduction in Convulsive Seizures During the Full Treatment Period
    End point description
    Percent reduction from Baseline (%) was defined as [(Full Treatment Period Convulsive Seizure Frequency - Baseline Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Data was reported as reduction of ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% or more in seizures from Baseline. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: percentage of participants
    number (not applicable)
        ≤0% Reduction
    39.4
    31.5
        >0% to ≤25% Reduction
    32.4
    20.5
        >25% to ≤50% Reduction
    18.3
    20.5
        >50% to ≤75% Reduction
    8.5
    13.7
        >75% to ≤100% Reduction
    1.4
    13.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16

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    End point title
    		 Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16
    End point description
    The Care GI-I is a 7-point Likert scale that the caregiver used to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The parent/caregiver will completed the Care GI-I via interview. Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    68
    66
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    1.5
    4.5
        Score 2: Much Improved
    11.8
    27.3
        Score 3: Minimally Improved
    22.1
    28.8
        Score 4: No Change
    47.1
    27.3
        Score 5: Minimally Worse
    10.3
    7.6
        Score 6: Much Worse
    5.9
    3.0
        Score 7: Very Much Worse
    1.5
    1.5
    Statistical analysis title
    		 Care GI-I Scale Responses
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [5]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 4.72
    Notes
    [5] - P-value was computed using Cumulative Logit model including treatment and age group as factors.

    Secondary: Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16

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    End point title
    		 Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16
    End point description
    The CGI-I (Clinician) is a 7-point Likert scale that the investigator used to rate a participant's change (improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of study drug relative to Baseline (before treatment with study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The investigator or designee completed the CGI-I. Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    71
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    2.8
    7.0
        Score 2: Much Improved
    8.5
    25.4
        Score 3: Minimally Improved
    15.5
    19.7
        Score 4: No Change
    59.2
    38.0
        Score 5: Minimally Worse
    5.6
    8.5
        Score 6: Much Worse
    8.5
    1.4
        Score 7: Very Much Worse
    0.0
    0.0
    Statistical analysis title
    		 CGI-I Scale Responses
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [6]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.37
         upper limit
    		 4.87
    Notes
    [6] - P-value was computed using Cumulative Logit model including treatment and age group as factors.

    Secondary: Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16

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    End point title
    		 Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16
    End point description
    The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select nonseizure domains (alertness, communication, and disruptive behaviors) since initiating the study drug. The participant was rated by the investigator for each domain as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    71
    Units: percentage of participants
    number (not applicable)
        Alertness: Score 1: Very Much Improved
    2.8
    7.0
        Alertness: Score 2: Much Improved
    8.5
    4.2
        Alertness: Score 3: Minimally Improved
    14.1
    14.1
        Alertness: Score 4: No Change
    67.6
    70.4
        Alertness: Score 5: Minimally Worse
    5.6
    4.2
        Alertness: Score 6: Much Worse
    1.4
    0.0
        Alertness: Score 7: Very Much Worse
    0.0
    0.0
        Communication: Score 1: Very Much Improved
    1.4
    4.2
        Communication: Score 2: Much Improved
    11.3
    5.6
        Communication: Score 3: Minimally Improved
    18.3
    22.5
        Communication: Score 4: No Change
    62.0
    62.0
        Communication: Score 5: Minimally Worse
    4.2
    4.2
        Communication: Score 6: Much Worse
    2.8
    1.4
        Communication: Score 7: Very Much Worse
    0.0
    0.0
        Disruptive Behaviors: Score 1: Very Much Improved
    1.4
    1.4
        Disruptive Behaviors: Score 2: Much Improved
    4.2
    5.6
        Disruptive Behaviors: Score 3: Minimally Improved
    14.1
    16.9
        Disruptive Behaviors: Score 4: No Change
    69.0
    64.8
        Disruptive Behaviors: Score 5: Minimally Worse
    11.3
    8.5
        Disruptive Behaviors: Score 6: Much Worse
    0.0
    1.4
        Disruptive Behaviors: Score 7: Very Much Worse
    0.0
    1.4
    Statistical analysis title
    		 CGI-I Nonseizure Symptoms Alertness Domain
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741 [7]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 2.26
    Notes
    [7] - P-value was computed using Cumulative Logit model including treatment and age group as factors.
    Statistical analysis title
    		 CGI-I Nonseizure Symptoms Behaviors Domain
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.693 [8]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 2.28
    Notes
    [8] - P-value was computed using Cumulative Logit model including treatment and age group as factors.
    Statistical analysis title
    		 CGI-I Nonseizure Symptoms Communication Domain
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.901 [9]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 2.02
    Notes
    [9] - P-value was computed using Cumulative Logit model including treatment and age group as factors.

    Secondary: Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16

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    End point title
    		 Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16
    End point description
    The CGI-I seizure Intensity and duration instrument was used by the parent/caregiver to rate changes in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms were rated on 7-point scale as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    69
    65
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    4.3
    10.8
        Score 2: Much Improved
    4.3
    24.6
        Score 3: Minimally Improved
    15.9
    23.1
        Score 4: No Change
    59.4
    33.8
        Score 5: Minimally Worse
    5.8
    1.5
        Score 6: Much Worse
    8.7
    6.2
        Score 7: Very Much Worse
    1.4
    0.0
    Statistical analysis title
    		 CGI-I Seizure Intensity and Duration
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Cumulative Logit Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 7.13
    Notes
    [10] - P-value was computed using Cumulative Logit model including treatment and age group as factors.

    Secondary: Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16

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    End point title
    		 Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16
    End point description
    The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluated the quality of life in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Each QI-Disability item is rated on a Likert scale of: Never, Rarely, Sometimes, Often, and Very Often. Items were linearly transformed to a scale of 0 to 100, with higher scores representing better quality of life. Domain scores are calculated by averaging item scores. The domain scores are summed and divided by 6 to yield a total score. The total score ranges from 0 to 100, with higher scores indicating a better quality of life. A negative change from Baseline implies deteriorating quality of life. Mixed-effects model for repeated measures (MMRM) was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    53
    56
    Units: score on a scale
        arithmetic mean (standard deviation)
    2.81 ( 10.119 )
    -1.23 ( 15.438 )
    Statistical analysis title
    		 Change From Baseline in QI-Disability Total Score
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.189 [11]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.59
         upper limit
    		 1.52
    Notes
    [11] - P-value was based on MMRM analysis with change from baseline as outcome and baseline score as fixed continuous effect; treatment group, age stratum, analysis visit, and analysis visit by treatment group interaction as fixed categorical effects.

    Secondary: Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period

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    End point title
    		 Percent Change From Baseline in Frequency of All Seizures 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 the frequency of seizures per 28 days at Baseline multiplied by 100. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance Period: Weeks 5 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    68
    69
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -11.89 (-33.78 to 10.50)
    -17.24 (-56.83 to 23.70)
    Statistical analysis title
    		 Maintenance Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.565 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -9.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.01
         upper limit
    		 7.87
    Notes
    [12] - The p-value was computed using rank ANCOVA model using treatment group, age stratum (<=6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors.

    Secondary: Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full Treatment Period

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    End point title
    		 Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full 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 the frequency of seizures per 28 days at Baseline multiplied by 100. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Baseline; Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -7.46 (-32.37 to 14.83)
    -9.27 (-54.11 to 30.00)
    Statistical analysis title
    		 Full Treatment Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.637 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -8.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.31
         upper limit
    		 10.13
    Notes
    [13] - The p-value was computed using rank ANCOVA model using treatment group, age stratum (<=6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors.

    Secondary: Change from Baseline in Percentage of Convulsive Seizure-free Days During the Full Treatment Period

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    End point title
    		 Change from Baseline in Percentage of Convulsive Seizure-free Days During the Full Treatment Period
    End point description
    Convulsive seizure-free days was defined as number of days a participant remained convulsive seizure free after initiation of the treatment. The percentage of convulsive seizure-free days during a period was defined as the number of non-missing seizure diary days when no convulsive seizures occurred during the period divided by the number of non-missing diary days during the period. The change from baseline was defined as the percentage of convulsive seizure -free days during the period minus the percentage of convulsive seizure-free days during the Baseline Period. A linear model with treatment group and age stratum as factors and baseline percentage as a covariate was used for analysis. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: percentage of days
        least squares mean (standard error)
    2.74 ( 1.784 )
    3.54 ( 1.719 )
    Statistical analysis title
    		 Full Treatment Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.81
         upper limit
    		 5.4

    Secondary: Longest Convulsive Seizure-free Interval During the Full Treatment Period

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    End point title
    		 Longest Convulsive Seizure-free Interval During the Full Treatment Period
    End point description
    Longest convulsive seizure-free interval was defined as the longest time period that the participant remained convulsive seizure free after initiation of the treatment. A linear model with treatment group and age stratum as factors was used for analysis. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: days
        least squares mean (standard error)
    16.7 ( 2.15 )
    22.3 ( 2.08 )
    Statistical analysis title
    		 Full Treatment Period
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 11.2

    Secondary: Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period

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    End point title
    		 Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period
    End point description
    Use of rescue ASM was recorded in the case report form (CRF) along with start and end date of medication. Based on the start and end dates for all rescue ASMs taken by a participant, the number of days during the Full Treatment Period when rescue ASM was used was derived. mITT Analysis Set included all randomized participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
    End point type
    Secondary
    End point timeframe
    Full Treatment Period: Weeks 1 to 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    71
    73
    Units: days
        least squares mean (standard error)
    4.0 ( 0.81 )
    2.9 ( 0.78 )
    Statistical analysis title
    		 Number of Days Rescue ASM is Used
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose up to Week 19
    Adverse event reporting additional description
    Safety Analysis Set included all participants who had taken at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Soticlestat
    Reporting group description
    		 Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.

    Serious adverse events
    		 Soticlestat Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 73 (9.59%)
    10 / 71 (14.08%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 73 (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
    Seizure cluster
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 73 (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
    Bronchitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 73 (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
    Infectious mononucleosis
         subjects affected / exposed
    0 / 73 (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
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    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
         subjects affected / exposed
    0 / 73 (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: 5%
    Non-serious adverse events
    		 Soticlestat Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 73 (54.79%)
    37 / 71 (52.11%)
    Nervous system disorders
    Change in seizure presentation
         subjects affected / exposed
    10 / 73 (13.70%)
    9 / 71 (12.68%)
         occurrences all number
    10
    10
    Somnolence
         subjects affected / exposed
    10 / 73 (13.70%)
    8 / 71 (11.27%)
         occurrences all number
    11
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 71 (5.63%)
         occurrences all number
    2
    4
    Pyrexia
         subjects affected / exposed
    8 / 73 (10.96%)
    9 / 71 (12.68%)
         occurrences all number
    8
    13
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 73 (8.22%)
    0 / 71 (0.00%)
         occurrences all number
    6
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 73 (8.22%)
    1 / 71 (1.41%)
         occurrences all number
    6
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 73 (12.33%)
    9 / 71 (12.68%)
         occurrences all number
    12
    12
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 73 (8.22%)
    8 / 71 (11.27%)
         occurrences all number
    7
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 73 (6.85%)
    4 / 71 (5.63%)
         occurrences all number
    6
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2022
    The following changes were made as per Amendment 2: 1. Changed the number of estimated sites from 65 to 100. 2. Removed ophthalmological evaluations from safety endpoints. 3. Changed "convulsive seizures" to the "most impactful seizures", increased the number of convulsive seizures from ≥4 to ≥12 over 12 weeks before screening. 4. Broadened option to have virtual visits to allow more flexibility for participants/parents or caregivers who may have difficulties with travel for clinic visits, such as coronavirus disease 2019 (COVID-19) restrictions or other extenuating circumstances. 5. Updated the inclusion/exclusion criteria.

    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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