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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 Adult Subjects With Lennox-Gastaut Syndrome (LGS)

    Summary
    EudraCT number
    		 2021-002481-40
    Trial protocol
    		 Outside EU/EEA   IT   FR   ES   LV   GR   NL   BE   PL   HU   DE  
    Global end of trial date
    25 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2024
    First version publication date
    10 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-935-3002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04938427
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, N/A N/A, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, N/A N/A, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000491-PIP20-21
    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
    25 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to assess the efficacy of soticlestat in reducing major motor drop (MMD) seizure frequency as add-on therapy to standard of care (SOC) as compared with placebo during the full treatment period (titration + maintenance) and maintenance period.
    Protection of trial subjects
    Each participant signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    08 Nov 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: 3
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 40
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Japan: 34
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Serbia: 24
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    United States: 58
    Worldwide total number of subjects
    270
    EEA total number of subjects
    88
    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)
    129
    Adolescents (12-17 years)
    83
    Adults (18-64 years)
    58
    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 84 investigative sites in Australia, Belgium, Canada, China, France, Germany, Greece, Hungary, Italy, Japan, Latvia, Netherlands, Poland, Russian Federation, Serbia, Spain, Ukraine and the United States from 08 November 2021 to 25 January 2024.

    Pre-assignment
    Screening details
    		 A total of 270 participants with a diagnosis of Lennox-Gastaut syndrome 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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm 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 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
    Other name
    Pharmaceutical forms
    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 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 the 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 the dose tapered down if participants decided to discontinue the treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Soticlestat
    Investigational medicinal product code
    Other name
    TAK-935
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered for 16 weeks in the treatment period.

    Number of subjects in period 1
    		Placebo Soticlestat
    Started
    136
    134
    Completed
    126
    114
    Not completed
    10
    20
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    5
    19
         Reason Not Specified
    2
    1
         Withdrawal by Parent/Guardian
    2
    -

    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 G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive 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 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 the 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 the dose tapered down if participants decided to discontinue the treatment.

    Reporting group values
    		 Placebo Soticlestat Total
    Number of subjects
    		 136 134
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.5 ( 6.68 ) 13.4 ( 9.35 ) -
    Gender categorical
    Units: Subjects
        Gender Female
    		 52 55 107
        Gender Male
    		 84 79 163
    Race (NIH/OMB)
    Units: Subjects
        Race American Indian or Alaska Native
    		 0 0 0
        Race Asian
    		 44 42 86
        Race Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Race Black or African American
    		 2 1 3
        Race White
    		 81 86 167
        Race More than one race
    		 2 0 2
        Race Unknown or Not Reported
    		 6 5 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Ethnicity Hispanic or Latino
    		 4 7 11
        Ethnicity Not Hispanic or Latino
    		 130 124 254
        Ethnicity Unknown or Not Reported
    		 2 3 5

    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 G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive 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 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 the 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 the dose tapered down if participants decided to discontinue the treatment.

    Primary: Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period

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    End point title
    		 Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period
    End point description
    MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by the 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 the 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 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -6.69 (-26.41 to 24.26)
    -6.11 (-38.02 to 31.99)
    Statistical analysis title
    		 Percent Change from Baseline in Seizure Frequency
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.785 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.02
         upper limit
    		 9.99
    Notes
    [1] - The p-value was calculated 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 Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period

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    End point title
    		 Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period
    End point description
    MMD seizure frequency per 28 days was defined as the total number of MMD 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 the 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 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    132
    124
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -9.63 (-30.15 to 23.71)
    -5.24 (-41.94 to 42.29)
    Statistical analysis title
    		 Percent Change from Baseline in Seizure Frequency
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.778 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.86
         upper limit
    		 15.14
    Notes
    [2] - The p-value was calculated using the Rank ANCOVA model using the treatment group, age stratum (≤6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors.

    Secondary: Percentage of Responders During the Maintenance Period

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    End point title
    		 Percentage of Responders During the Maintenance Period
    End point description
    Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    132
    124
    Units: percentage of participants
        number (not applicable)
    11.4
    19.4
    Statistical analysis title
    		 Percentage of Responders
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 3.87

    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 are defined as those with ≥50% reduction from Baseline in MMD seizures during the Full Treatment Period. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: percentage of participants
        number (not applicable)
    9.6
    16.4
    Statistical analysis title
    		 Percentage of Responders
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 4.05

    Secondary: Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure 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%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period
    End point description
    Percent reduction from Baseline (%) is defined as [(Full Treatment Period MMD Seizure Frequency - Baseline MMD Seizure Frequency) divided by Baseline MMD Seizure Frequency] multiplied by 100. Data is reported as reduction of ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% or more in seizures from Baseline. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: percentage of participants
    number (not applicable)
        ≤0% Reduction
    43.4
    43.3
        >0% to ≤ 25% Reduction
    29.4
    24.6
        >25% to ≤ 50% Reduction
    17.6
    15.7
        >50% to ≤ 75% Reduction
    6.6
    11.2
        >75% to ≤ 100% Reduction
    2.9
    5.2
    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 the 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 completed the Care GI-I via interview. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    130
    122
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    0.8
    1.6
        Score 2: Much Improved
    13.1
    20.5
        Score 3: Minimally Improved
    25.4
    26.2
        Score 4: No Change
    46.2
    36.9
        Score 5: Minimally Worse
    11.5
    6.6
        Score 6: Much Worse
    3.1
    5.7
        Score 7: Very Much Worse
    0.0
    2.5
    Statistical analysis title
    		 Percentage of Participants With Care GI-I Response
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.13

    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 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 the 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 will complete the CGI-I. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    133
    132
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    1.5
    3.0
        Score 2: Much Improved
    11.3
    15.9
        Score 3: Minimally Improved
    17.3
    24.2
        Score 4: No Change
    60.2
    43.2
        Score 5: Minimally Worse
    5.3
    7.6
        Score 6: Much Worse
    4.5
    4.5
        Score 7: Very Much Worse
    0.0
    1.5
    Statistical analysis title
    		 Percentage of Participants with CGI-I Responses
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.21

    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). Lower scores indicate improvement. Data for percentage of participants categorized based on the responses for each domain are presented. Percentages are rounded off to the nearest single decimal place.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    133
    132
    Units: percentage of participants
    number (not applicable)
        Alertness: Score 1: Very Much Improved
    1.5
    1.5
        Alertness: Score 2: Much Improved
    7.5
    13.6
        Alertness: Score 3: Minimally improved
    12.8
    16.7
        Alertness: Score 4: No Change
    71.4
    59.1
        Alertness: Score 5: Minimally Worse
    4.5
    8.3
        Alertness: Score 6: Much Worse
    2.3
    0.8
        Alertness: Score 7: Very Much Worse
    0.0
    0.0
        Communication: Score 1: Very Much Improved
    1.5
    2.3
        Communication: Score 2: Much Improved
    7.5
    10.6
        Communication: Score 3: Minimally improved
    12.8
    18.9
        Communication: Score 4: No Change
    71.4
    61.4
        Communication: Score 5: Minimally Worse
    4.5
    6.1
        Communication: Score 6: Much Worse
    2.3
    0.8
        Communication: Score 7: Very Much Worse
    0.0
    0.0
        Disruptive Behaviors: Score 1: Very Much Improved
    0.0
    1.5
        Disruptive Behaviors: Score 2: Much Improved
    1.5
    6.1
        Disruptive Behaviors: Score 3: Minimally improved
    8.3
    10.6
        Disruptive Behaviors: Score 4: No Change
    79.7
    75.0
        Disruptive Behaviors: Score 5: Minimally Worse
    6.8
    3.8
        Disruptive Behaviors: Score 6: Much Worse
    3.8
    2.3
        Disruptive Behaviors: Score 7: Very Much Worse
    0.0
    0.8
    Statistical analysis title
    		 Alertness Domain
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.3
    Statistical analysis title
    		 Communication Domain
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 2.48
    Statistical analysis title
    		 Disruptive Behaviors Domain
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 3.43

    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 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). Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    131
    122
    Units: percentage of participants
    number (not applicable)
        Score 1: Very Much Improved
    0.8
    1.6
        Score 2: Much Improved
    9.9
    18.9
        Score 3: Minimally Improved
    24.4
    28.7
        Score 4: No Change
    51.1
    39.3
        Score 5: Minimally Worse
    9.9
    4.1
        Score 6: Much Worse
    3.8
    5.7
        Score 7: Very Much Worse
    0.0
    1.6
    Statistical analysis title
    		 CGI-I Seizure Intensity and Duration
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.65

    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
    QI-Disability tool is parent/caregiver-reported questionnaire evaluated quality of life(QoL) in children with intellectual disabilities.It contains 32 items with 6 domains of QoL:physical health,positive & negative emotions,social interaction,leisure,outdoors & independence.Each item is rated on Likert scale of:Never,Rarely,Sometimes,Often,& Very Often. Items were linearly transformed to scale of 0-100,higher scores=better QoL. Domain scores=average of item scores. Domain scores are summed & divided by 6 to yield total score. Total score ranges from 0-100,with higher scores=better QoL. A negative change from Baseline implies deteriorating QoL Mixed-effects model for repeated measures (MMRM) was used for analysis. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects analysed indicates the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Placebo Soticlestat
    Number of subjects analysed
    112
    107
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.66 ( 10.314 )
    -1.17 ( 12.042 )
    Statistical analysis title
    		 QI-Disability Total Score
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 3.24

    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 was defined as the total number of seizures reported during the period divided by the 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 the 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 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Subjects 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
    132
    124
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -9.92 (-30.55 to 15.55)
    -16.82 (-40.93 to 20.60)
    Statistical analysis title
    		 Percent Change From Baseline in Frequency
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -6.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.83
         upper limit
    		 4.16

    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 was defined as the total number of seizures reported during the period divided by the 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 the 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. mITT Analysis Set included all randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -6.45 (-28.11 to 16.16)
    -16.71 (-39.84 to 18.53)
    Statistical analysis title
    		 Percent Change from Baseline in Frequency
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hodges-Lehmann Location Shift Estimate
    Point estimate
    -6.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.67
         upper limit
    		 3.12

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

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    End point title
    		 Change From Baseline in Percentage of MMD Seizure-free Days During the Full Treatment Period
    End point description
    MMD Seizure-free days was defined as the number of days the participant remained MMD seizure free after initiation of the treatment. The change from baseline in percentage of MMD seizure-free days, was defined as the percentage of seizure-free days during the Full Treatment Period minus the percentage of seizure-free days during the Baseline. 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 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: percentage of days
        least squares mean (standard error)
    5.37 ( 1.661 )
    7.84 ( 1.676 )
    Statistical analysis title
    		 Percentage of MMD Seizure-free Days
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 6.67

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

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    End point title
    		 Longest MMD Seizure-free Interval During the Full Treatment Period
    End point description
    Longest MMD Seizure-free Interval was defined as the longest time period that the participant remained MMD 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 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: days
        least squares mean (standard error)
    5.5 ( 1.39 )
    10.9 ( 1.41 )
    Statistical analysis title
    		 Longest MMD Seizure-free Interval
    Comparison groups
    Soticlestat v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 8.9

    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 randomised participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 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
    136
    134
    Units: days
        least squares mean (standard error)
    3.4 ( 1.12 )
    2.5 ( 1.14 )
    Statistical analysis title
    		 Number of Days Rescue ASM is used
    Comparison groups
    Placebo v Soticlestat
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 2

    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 took at least 1 dose of the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    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 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 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 the 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 the dose tapered down if participants decided to discontinue the treatment.

    Serious adverse events
    		 Placebo Soticlestat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 136 (7.35%)
    11 / 134 (8.21%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue injury
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Change in seizure presentation
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         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
    Negative pressure pulmonary oedema
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (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 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (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 / 136 (0.74%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Soticlestat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 136 (37.50%)
    69 / 134 (51.49%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 136 (3.68%)
    7 / 134 (5.22%)
         occurrences all number
    6
    8
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    10 / 136 (7.35%)
    19 / 134 (14.18%)
         occurrences all number
    10
    22
    Change in seizure presentation
         subjects affected / exposed
    7 / 136 (5.15%)
    17 / 134 (12.69%)
         occurrences all number
    10
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 136 (3.68%)
    8 / 134 (5.97%)
         occurrences all number
    5
    9
    Pyrexia
         subjects affected / exposed
    11 / 136 (8.09%)
    10 / 134 (7.46%)
         occurrences all number
    14
    10
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 136 (2.21%)
    7 / 134 (5.22%)
         occurrences all number
    3
    7
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 136 (2.21%)
    8 / 134 (5.97%)
         occurrences all number
    3
    15
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 136 (5.15%)
    11 / 134 (8.21%)
         occurrences all number
    12
    13
    Nasopharyngitis
         subjects affected / exposed
    11 / 136 (8.09%)
    10 / 134 (7.46%)
         occurrences all number
    13
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 136 (2.21%)
    8 / 134 (5.97%)
         occurrences all number
    3
    10

    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) Increased maximum age to 55 years. 3) Required prior treatment failure of 1 ASM rather than 2 for enrolment in the study. 5) Changed MMD seizures to the most impactful seizure.

    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.
    Not Specified
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