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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

    Summary
    EudraCT number
    2015-004167-37
    Trial protocol
    GB   DE   BE   NO   DK   SE   ES   FR   IT  
    Global end of trial date
    29 Jul 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    24 Dec 2022
    First version publication date
    10 Jul 2022
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Alignment with final posting on ClinicalTrials.gov after NIH review.

    Trial information

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    Trial identification
    Sponsor protocol code
    ZX008-1502
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02826863
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Additional Sponsor Protocol Code: ZX008-1501
    Sponsors
    Sponsor organisation name
    Zogenix International Limited
    Sponsor organisation address
    5959 Horton Street, 5th Floor, Emeryville, United States, CA 94608
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001990-PIP01-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between Baseline and the combined Titration and Maintenance Periods (T+M).
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    15 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 120
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    262
    EEA total number of subjects
    92
    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)
    177
    Adolescents (12-17 years)
    76
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study 1501 started to enroll participants in January 2016 and concluded in July 2020. The study 1502 started to enroll participants in July 2016 and concluded in July 2020. The consolidated results of Study 1 and Study 3 are included in this record. The Participant Flow refers to the Randomized Population.

    Pre-assignment
    Screening details
    Due to slow enrollment into both trials, the databases for the two trials were combined. The first 72 enrolled participants from ZX008-1501 and first 47 from ZX008-1502 were combined for an analysis and reported as Study 1, whereas the final 55 participants from ZX008- 1501 and the final 88 from ZX008-1502 were combined and reported as Study 3.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Study 1: Placebo
    Arm description
    Participants received matching placebo as an oral solution, twice a day (bid) in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo as an oral solution, bid in equally divided doses with food for up to approximately 16 weeks.

    Arm title
    Study 1: ZX008 0.2 mg/kg/day
    Arm description
    Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Experimental

    Investigational medicinal product name
    Fenfluramine hydrochloride
    Investigational medicinal product code
    ZX008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

    Arm title
    Study 1: ZX008 0.8 mg/kg/day
    Arm description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Experimental

    Investigational medicinal product name
    Fenfluramine hydrochloride
    Investigational medicinal product code
    ZX008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

    Arm title
    Study 3: Placebo
    Arm description
    Participants received matching placebo as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo as an oral solution, bid in equally divided doses with food for up to approximately 16 weeks.

    Arm title
    Study 3: ZX008 0.2 mg/kg/day
    Arm description
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Experimental

    Investigational medicinal product name
    Fenfluramine hydrochloride
    Investigational medicinal product code
    ZX008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

    Arm title
    Study 3: ZX008 0.8 mg/kg/day
    Arm description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).
    Arm type
    Experimental

    Investigational medicinal product name
    Fenfluramine hydrochloride
    Investigational medicinal product code
    ZX008
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

    Number of subjects in period 1
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Started
    40
    39
    40
    48
    46
    49
    Completed
    37
    39
    34
    43
    45
    46
    Not completed
    3
    0
    6
    5
    1
    3
         Adverse event, serious fatal
    -
    -
    -
    1
    -
    -
         Consent withdrawn by subject
    2
    -
    1
    -
    1
    1
         Adverse event, non-fatal
    -
    -
    5
    1
    -
    2
         Unspecified
    -
    -
    -
    2
    -
    -
         Lack of efficacy
    1
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study 1: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, twice a day (bid) in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day Total
    Number of subjects
    40 39 40 48 46 49 262
    Age Categorical
    Units: participants
        24 Months - <12 Years
    27 28 31 31 30 30 177
        12 - < 18 Years
    10 11 7 17 15 16 76
        18 – < 65 Years
    3 0 2 0 1 3 9
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    9.2 ± 5.10 9.0 ± 4.52 8.8 ± 4.41 9.0 ± 4.29 9.6 ± 4.42 9.5 ± 5.29 -
    Sex: Female, Male
    Units: participants
        Female
    19 17 19 21 22 27 125
        Male
    21 22 21 27 24 22 137

    End points

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    End points reporting groups
    Reporting group title
    Study 1: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, twice a day (bid) in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Primary: Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo

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    End point title
    Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo [1]
    End point description
    Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. The modified intent-to-treat (mITT) population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Primary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The ZX008 0.2 mg/kg/day arm which was part of baseline period was not required for the primary endpoint assessment. Therefore, no data was reported for this arm.
    End point values
    Study 1: Placebo Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    40
    48
    48
    Units: seizure frequency per 28 days
        arithmetic mean (standard deviation)
    -6.71 ± 24.263
    -13.11 ± 25.500
    1.54 ± 21.966
    -3.54 ± 124.132
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    Method
    Parameter type
    Percentage difference from Placebo
    Point estimate
    64.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    51.85
         upper limit
    74.19
    Notes
    [2] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    Method
    Parameter type
    Percentage difference from Placebo
    Point estimate
    62.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    47.72
         upper limit
    72.8
    Notes
    [3] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

    Secondary: Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo

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    End point title
    Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo [4]
    End point description
    Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the ZX008 0.8 mg/kg/day arm was reported in primary endpoint therefore, this arm which was part of baseline period was not required for the secondary endpoint assessment. Hence, no data was reported for this arm.
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day
    Number of subjects analysed
    40
    39
    48
    46
    Units: seizure frequency per 28 days
        arithmetic mean (standard deviation)
    -6.71 ± 24.263
    -18.81 ± 90.640
    1.54 ± 21.966
    -5.89 ± 84.735
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    Method
    Parameter type
    Percentage difference from Placebo
    Point estimate
    49.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.31
         upper limit
    63.43
    Notes
    [5] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    Method
    Parameter type
    Percentage difference from Placebo
    Point estimate
    32.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.19
         upper limit
    51.33
    Notes
    [6] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

    Secondary: Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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    End point title
    Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period
    End point description
    Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 25% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    35.0
    66.7
    90.0
    27.1
    71.7
    83.3
    No statistical analyses for this end point

    Secondary: Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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    End point title
    Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period
    End point description
    Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 50% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    12.5
    38.5
    67.5
    6.3
    45.7
    72.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.773
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.475
         upper limit
    15.45
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    13.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.6
         upper limit
    49.8
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    53.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.9
         upper limit
    220.5
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    14.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.484
         upper limit
    49.915

    Secondary: Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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    End point title
    Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period
    End point description
    Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 75% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    2.5
    23.1
    50.0
    4.2
    28.3
    47.9
    No statistical analyses for this end point

    Secondary: Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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    End point title
    Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period
    End point description
    Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 100% reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    0
    7.7
    7.5
    0
    0
    12.5
    No statistical analyses for this end point

    Secondary: Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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    End point title
    Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period
    End point description
    The longest interval between convulsive seizures was calculated over the entire Titration and Maintenance Period and was derived as the maximum of the number of days between consecutive convulsive seizures. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: days
        median (full range (min-max))
    9.50 (2.0 to 23.0)
    15.00 (3.0 to 106.0)
    25.00 (2.0 to 97.0)
    10 (2 to 65)
    18.5 (2 to 100)
    30 (2 to 104)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Wilcoxon rank sum test
    Confidence interval

    Secondary: Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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    End point title
    Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period
    End point description
    A convulsive seizure free day was defined as a day for which diary data are available and no convulsive seizures were reported. Convulsive seizure free days were taken from the electronic diary data. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: seizure free days
        median (full range (min-max))
    15.14 (1.1 to 25.6)
    20.86 (2.2 to 28.0)
    24.43 (1.0 to 28.0)
    20.20 (1.4 to 27.1)
    23.36 (0.8 to 27.7)
    25.33 (0.3 to 28.0)
    No statistical analyses for this end point

    Secondary: Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo
    End point description
    Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The number of non-convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day non-convulsive seizure frequency. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    21
    23
    24
    26
    25
    30
    Units: seizure frequency per 28 days
        median (full range (min-max))
    -9.38 (-198.8 to 1886.1)
    -4.85 (-1940.8 to 192.3)
    -20.06 (-2064.8 to 9.4)
    -0.68 (-160.0 to 1313.1)
    -0.67 (-138.7 to 111.3)
    -4.35 (-1410.6 to 107.5)
    No statistical analyses for this end point

    Secondary: Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo
    End point description
    Total seizure frequency were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The seizure frequency was based on electronic diary data obtained for each participant. The number of all seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day convulsive or non-convulsive seizure frequency. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: seizure frequency per 28 days
        median (full range (min-max))
    -4.45 (-198.4 to 1850.1)
    -7.40 (-1955.1 to 187.1)
    -22.95 (-2069.3 to 44.5)
    -1.09 (-160.1 to 1310.5)
    -6.54 (-153.0 to 525.9)
    -11.39 (-1504.8 to 791.4)
    No statistical analyses for this end point

    Secondary: Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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    End point title
    Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period
    End point description
    Rescue medication was administered according to each participant’s usual or prescribed regimen consisting of 1 or more medications. The usage of rescue medication (number of days and number of medications used per seizure episode) was based on electronic diary data obtained for each participant. The number of days rescue medication was taken (normalized to 28 days) was calculated for each participant. Multiple medications taken on the same day were counted once for that day. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    77.5
    59.0
    45.0
    60.4
    65.2
    47.9
    No statistical analyses for this end point

    Secondary: Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study

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    End point title
    Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study
    End point description
    Participants who utilized medical center care to treat a seizure during the study were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    22.5
    17.9
    15.0
    12.5
    19.6
    14.6
    No statistical analyses for this end point

    Secondary: Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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    End point title
    Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period
    End point description
    The participants who either had SE episode recorded as an adverse event (AE) during treatment or a seizure greater than 10 minutes were reported for each treatment group. Additionally, a single participant who may had more than one episode of SE, and an episode of SE recorded as both an AE and as a seizure longer than 10 minutes was counted as a single event. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
        number (not applicable)
    27.5
    28.2
    35.0
    16.7
    19.6
    25.0
    No statistical analyses for this end point

    Secondary: Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period

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    End point title
    Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period
    End point description
    Duration of single convulsive seizures during the Baseline and the duration over the Titration and Maintenance Period were reported by treatment group using categories as <2 minutes, 2 to 10 minutes and > 10 minutes as collected in the seizure diary. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of seizures
    number (not applicable)
        <2 min (Baseline)
    69.28
    64.13
    71.61
    64.21
    63.90
    74.11
        2-10 min (Baseline)
    26.86
    34.95
    24.22
    34.83
    33.66
    22.78
        >10 min (Baseline)
    3.86
    0.93
    4.17
    0.96
    2.45
    3.10
        <2 min (Titration + Maintenance Period)
    71.31
    71.59
    72.27
    65.84
    63.45
    84.67
        2-10 min (Titration + Maintenance Period)
    26.31
    25.61
    22.91
    33.74
    31.34
    13.71
        >10 min (Titration + Maintenance Period)
    2.38
    2.79
    4.82
    0.43
    5.22
    1.62
    No statistical analyses for this end point

    Secondary: Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo

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    End point title
    Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo
    End point description
    CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), 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 Principal Investigator rated their global impression of the participant's condition during the study. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
    number (not applicable)
        1 = Very much improved (Visit 6)
    5.0
    23.1
    17.5
    4.2
    21.7
    16.7
        2 = Much improved (Visit 6)
    12.5
    12.8
    25.0
    2.1
    21.7
    27.1
        3 = Minimally improved (Visit 6)
    20.0
    20.5
    20.0
    27.1
    17.4
    27.1
        4 = No change (Visit 6)
    40.0
    25.6
    17.5
    54.2
    26.1
    12.5
        5 = Minimally worse (Visit 6)
    5.0
    7.7
    5.0
    4.2
    2.2
    2.1
        6 = Much worse (Visit 6)
    0
    0
    2.5
    0
    0
    4.2
        7 = Very much worse (Visit 6)
    0
    0
    0
    0
    0
    0
        1 = Very much improved (Visit 8)
    0
    5.1
    17.5
    4.2
    17.4
    29.2
        2 = Much improved (Visit 8)
    12.5
    30.8
    37.5
    6.3
    10.9
    31.3
        3 = Minimally improved (Visit 8)
    30.0
    20.5
    10.0
    16.7
    26.1
    14.6
        4 = No change (Visit 8)
    30.0
    17.9
    10.0
    50.0
    34.8
    8.3
        5 = Minimally worse (Visit 8)
    5.0
    5.1
    0
    4.2
    0
    4.2
        6 = Much worse (Visit 8)
    2.5
    5.1
    2.5
    2.1
    0
    0
        7 = Very much worse (Visit 8)
    0
    0
    2.5
    0
    0
    0
        1 = Very much improved (Visit 10)
    2.5
    17.9
    20.0
    4.2
    15.2
    35.4
        2 = Much improved (Visit 10)
    7.5
    17.9
    47.5
    10.4
    19.6
    18.8
        3 = Minimally improved (Visit 10)
    30.0
    25.6
    5.0
    12.5
    26.1
    16.7
        4 = No change (Visit 10)
    35.0
    28.2
    7.5
    60.4
    28.3
    4.2
        5 = Minimally worse (Visit 10)
    10.0
    7.7
    0
    0
    0
    0
        6 = Much worse (Visit 10)
    0
    2.6
    0
    0
    0
    2.1
        7 = Very much worse (Visit 10)
    0
    0
    0
    0
    0
    0
        1 = Very much improved (Visit 12)
    2.5
    12.8
    27.5
    4.2
    8.7
    33.3
        2 = Much improved (Visit 12)
    7.5
    28.2
    35.0
    4.2
    28.3
    31.3
        3 = Minimally improved (Visit 12)
    30.0
    17.9
    15.0
    16.7
    21.7
    10.4
        4 = No change (Visit 12)
    47.5
    28.2
    12.5
    58.3
    28.3
    16.7
        5 = Minimally worse (Visit 12)
    2.5
    10.3
    0
    6.3
    10.9
    6.3
        6 = Much worse (Visit 12)
    2.5
    2.6
    0
    0
    0
    0
        7 = Very much worse (Visit 12)
    0
    0
    2.5
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo

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    End point title
    Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo
    End point description
    CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), 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 rated their global impression of the participant's condition during the study. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: percentage of participants
    number (not applicable)
        1 = Very much improved (Visit 6)
    2.5
    17.9
    15.0
    6.3
    13.0
    16.7
        2 = Much improved (Visit 6)
    22.5
    20.5
    27.5
    2.1
    23.9
    31.3
        3 = Minimally improved (Visit 6)
    12.5
    28.2
    22.5
    25.0
    26.1
    31.3
        4 = No change (Visit 6)
    45.0
    12.8
    20.0
    45.8
    19.6
    2.1
        5 = Minimally worse (Visit 6)
    2.5
    7.7
    2.5
    10.4
    2.2
    6.3
        6 = Much worse (Visit 6)
    5.0
    2.6
    7.5
    2.1
    2.2
    2.1
        7 = Very much worse (Visit 6)
    0
    0
    2.5
    0
    0
    2.1
        1 = Very much improved (Visit 8)
    0
    15.4
    20.0
    4.2
    6.5
    39.6
        2 = Much improved (Visit 8)
    15.0
    25.6
    37.5
    8.3
    30.4
    29.2
        3 = Minimally improved (Visit 8)
    25.0
    25.6
    15.0
    20.8
    28.3
    14.6
        4 = No change (Visit 8)
    20.0
    12.8
    5.0
    47.9
    17.4
    6.3
        5 = Minimally worse (Visit 8)
    15.0
    10.3
    2.5
    6.3
    6.5
    0
        6 = Much worse (Visit 8)
    2.5
    5.1
    5.0
    4.2
    2.2
    2.1
        7 = Very much worse (Visit 8)
    0
    0
    2.5
    4.2
    0
    0
        1 = Very much improved (Visit 10)
    2.5
    20.5
    35.0
    2.1
    8.7
    41.7
        2 = Much improved (Visit 10)
    12.5
    17.9
    30.0
    6.3
    28.3
    22.9
        3 = Minimally improved (Visit 10)
    22.5
    20.5
    7.5
    25.0
    26.1
    8.3
        4 = No change (Visit 10)
    32.5
    25.6
    10.0
    45.8
    26.1
    6.3
        5 = Minimally worse (Visit 10)
    12.5
    7.7
    0
    6.3
    0
    4.2
        6 = Much worse (Visit 10)
    2.5
    7.7
    0
    0
    4.3
    0
        7 = Very much worse (Visit 10)
    2.5
    0
    2.5
    0
    0
    0
        1 = Very much improved (Visit 12)
    2.5
    20.5
    27.5
    2.1
    6.5
    33.3
        2 = Much improved (Visit 12)
    7.5
    20.5
    27.5
    6.3
    28.3
    29.2
        3 = Minimally improved (Visit 12)
    20.0
    15.4
    10.0
    18.8
    30.4
    20.8
        4 = No change (Visit 12)
    35.0
    20.5
    15.0
    50.0
    13.0
    4.2
        5 = Minimally worse (Visit 12)
    17.5
    15.4
    5.0
    10.4
    8.7
    4.2
        6 = Much worse (Visit 12)
    7.5
    7.7
    5.0
    2.1
    4.3
    2.1
        7 = Very much worse (Visit 12)
    0
    0
    2.5
    0
    2.2
    2.1
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo
    End point description
    QOLCE is a low-burden parent/caregiver completed assessment that evaluates how epilepsy affects day-to day functioning of the participant in various life areas, including physical activities, well being, cognition, social activities, behavior, and general health. QOLCE scores items on 16 subscales with possible 5-point response for each, where scores of 5 was best possible response and 1 was worst possible response. Item scores were then transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100. A score for each participant for each subscale was calculated by averaging that participant’s responses to each item in the subscale. Subscale scores per participant were averaged to obtain an overall QoL score for each participant. Higher the subscale and overall QoL scores, better the response. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 99
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.5 ± 8.73
    0.8 ± 11.77
    5.8 ± 11.70
    1.2 ± 9.01
    6.1 ± 12.47
    5.5 ± 13.22
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo
    End point description
    The Pediatric Quality of Life Inventory (PedsQL) is a pediatric modular measure of health related quality of life (QoL) completed by the parent/caregiver on behalf of the participant. It consisted of 23 items across 4 core scales that measure physical (8 items), emotional, social, and school functioning (5 items each). Each of the responses to the 23 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores are linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores correspond to better health-related QoL. The Overall Quality of Life is the average of all the items over the number of items answered on all the Scales. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 99
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    48
    46
    48
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.6 ± 10.43
    6.8 ± 11.25
    5.9 ± 15.11
    1.9 ± 13.26
    4.2 ± 17.65
    2.1 ± 14.73
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo
    End point description
    PedsQL Family Impact measured impact of pediatric chronic health conditions on parents and family by measuring parent self-reported physical, emotional, social, and cognitive functioning, communication, worry, and family daily activities and relationships. A total of 36 items in scale: 6 for Physical Functioning, 5 each for Emotional Functioning, Cognitive Functioning and Worry, 4 for Social Functioning, 3 for Communication, 3 questions for Daily Activities, and 5 for Family Relationships. Each of responses are initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always) and then linearly transformed to scale of 0 to 100,where 0=100,1=75,2=50,3=25 and 4=0, and higher scores mean better health-related QoL. mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 99
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    40
    39
    40
    47
    44
    48
    Units: score on a scale
        arithmetic mean (standard deviation)
    -4.4 ± 13.00
    3.9 ± 9.44
    5.4 ± 15.60
    1.3 ± 14.88
    0.7 ± 15.78
    6.3 ± 14.64
    No statistical analyses for this end point

    Secondary: Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)

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    End point title
    Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)
    End point description
    The EuroQOL–5 Dimensions–5 Levels scale produced by European QOL Group (EQ-5D-5L) health questionnaire is health-related QOL instrument with 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The 5 dimensions of EQ-5D-5L health questionnaire were assessed on a Likert scale with 5 possible levels: no problems (NP), slight problems, moderate problems, severe problems, and extreme problems. The categories “slight problems”, “moderate problems”, “severe problems” and “extreme problems” are collapsed into one response category “problems” (Pb). The QOL of the parent/caregiver was assessed and percentage of participants was reported for each item. mITT population was used for analysis. Here, number of participants analyzed included those participants who were evaluable for the assessment and ‘n' signifies participants who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    At Baseline and Day 99
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    39
    37
    39
    42
    43
    45
    Units: percentage of participants
    number (not applicable)
        Mobility- NP (BL) (n=39,34,39,40,33,35)
    33.33
    52.94
    46.15
    40.00
    54.55
    28.57
        Mobility- Pb (BL) (n=39,34,39,40,33,35)
    66.67
    47.06
    53.85
    60.00
    45.45
    45.45
        Mobility- NP (D99) (n=35,37,37,42,43,45)
    40.00
    45.95
    51.35
    52.38
    51.16
    46.67
        Mobility- Pb (D99) (n=35,37,37,42,43,45)
    60.00
    54.05
    48.65
    47.62
    48.84
    53.33
        Self-care- NP (BL) (n=39,34,39,40,33,35)
    25.64
    41.18
    38.46
    22.50
    36.36
    22.86
        Self-care- Pb (BL) (n=39,34,39,40,33,35)
    74.36
    58.82
    61.54
    77.50
    63.64
    77.14
        Self-care- NP (D99) n=35,37,37,42,43,45)
    28.57
    43.24
    48.65
    30.95
    34.88
    35.56
        Self-care- Pb (D99) n=35,37,37,42,43,45)
    71.43
    56.76
    51.35
    69.05
    65.12
    64.44
        Usual activities- NP (BL)(n=39,34,39,40,33,35)
    23.08
    41.18
    35.90
    25.00
    39.39
    20.00
        Usual activities- Pb (BL) (n=39,34,39,40,33,35)
    76.92
    58.82
    64.10
    75.00
    60.61
    80.00
        Usual activities- NP (D99)(n=35,37,37,42,43,45)
    25.71
    32.43
    48.65
    30.95
    25.58
    35.56
        Usual activities- Pb (D99)(n=35,37,37,42,43,45)
    74.29
    67.57
    51.35
    69.05
    74.42
    64.44
        Pain/discomfort- NP (BL)(n=39,34,39,40,33,35)
    48.72
    41.18
    46.15
    45.00
    51.52
    51.43
        Pain/discomfort- Pb (BL)(n=39,34,39,40,33,35)
    51.28
    58.82
    53.85
    55.00
    48.48
    48.57
        Pain/discomfort- NP (D99)(n=35,37,37,42,43,45)
    48.57
    51.35
    64.86
    76.19
    46.51
    64.44
        Pain/discomfort- Pb (D99)(n=35,37,37,42,43,45)
    51.43
    48.65
    35.14
    45.24
    53.49
    35.56
        Anxiety/depression- NP (BL)(n=39,34,39,40,33,35)
    74.36
    61.76
    56.41
    60.00
    63.64
    74.29
        Anxiety/depression- Pb (BL)(n=39,34,39,40,33,35)
    25.64
    38.24
    43.59
    40.00
    36.36
    25.71
        Anxiety/depression- NP (D99)(n=35,37,37,42,43,45)
    65.71
    67.57
    67.57
    69.05
    67.44
    73.33
        Anxiety/depression- Pb (D99)(n=35,37,37,42,43,45)
    34.29
    32.43
    32.43
    30.95
    32.56
    26.67
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo

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    End point title
    Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo
    End point description
    The HADS is a tool that was validated to assess presence of anxiety or depression in an outpatient non-psychiatric population. The HADS a 14-item scale that generates ordinal data for 2 dimensions: 1) Anxiety (7 items), and 2) Depression (7 items). Each item has 4 possible answers rated 0 to 3, of which 0 = No distress and 3 = worst distress. All answers to the items for a dimension with their respective rating are added resulting in a range for each dimension from 0-21, out of which of 0-7 = normal; 8-10=borderline abnormal; 11-21=abnormal. Scores for the entire scale (emotional distress) range from 0 to 42, with higher scores indicating more distress. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 99
    End point values
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    31
    32
    35
    30
    31
    27
    Units: score on a scale
    arithmetic mean (standard deviation)
        Anxiety
    -0.4 ± 2.68
    -0.8 ± 2.84
    -0.8 ± 3.33
    -0.6 ± 3.62
    0.2 ± 3.89
    -0.7 ± 4.00
        Depression
    0.8 ± 4.50
    0.2 ± 4.52
    0.1 ± 4.35
    -0.7 ± 3.80
    2.0 ± 4.77
    -0.8 ± 4.03
        Total emotional distress
    0.4 ± 6.45
    -0.6 ± 6.60
    -0.7 ± 6.82
    -1.2 ± 6.42
    2.2 ± 7.52
    -1.5 ± 6.61
    No statistical analyses for this end point

    Secondary: Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state

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    End point title
    Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state [7]
    End point description
    Cmax is the maximum observed concentration determined directly from the concentration-time profile. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.
    End point values
    Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    39
    36
    45
    44
    Units: nanograms per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    17.7 ± 32.5
    67.9 ± 37.4
    17.4 ± 32.3
    64.5 ± 36.6
    No statistical analyses for this end point

    Secondary: Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state

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    End point title
    Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state [8]
    End point description
    AUC0-24 is the area under the concentration time curve from time zero to 24 hours. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis. PK samples at Visit 8 (Day 43) taken pre-dose to 6 hours post-dose were used to develop a population PK model. The model was utilized to generate plasma concentration-time curve over 24 hours at steady-state in study participants. AUC0-24 was calculated by numerical integration of the individual predicted concentration-time curve.
    End point type
    Secondary
    End point timeframe
    At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.
    End point values
    Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    39
    36
    45
    44
    Units: nanogram*hour per milliliter (ng*h/mL)
        geometric mean (geometric coefficient of variation)
    356 ± 37.0
    1390 ± 41.3
    348 ± 37.1
    1290 ± 42.6
    No statistical analyses for this end point

    Secondary: Time to maximum concentration [Tmax] of ZX008 at steady state

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    End point title
    Time to maximum concentration [Tmax] of ZX008 at steady state [9]
    End point description
    Tmax is the time to maximum concentration at steady state. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.
    End point values
    Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    39
    36
    45
    44
    Units: hours (h)
        median (full range (min-max))
    2.90 (2.80 to 3.10)
    3.00 (2.70 to 3.20)
    2.90 (2.80 to 3.10)
    2.90 (2.70 to 3.20)
    No statistical analyses for this end point

    Secondary: Elimination half-life [t1/2 beta] of ZX008 at steady state

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    End point title
    Elimination half-life [t1/2 beta] of ZX008 at steady state [10]
    End point description
    t1/2 beta is the elimination half-life. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.
    End point values
    Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Number of subjects analysed
    39
    36
    45
    44
    Units: hours (h)
        geometric mean (geometric coefficient of variation)
    18.4 ± 32.3
    21.1 ± 51.8
    18.1 ± 32.1
    18.6 ± 42.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Titration Period until the Safety Follow-up Visit (up to Day 113)
    Adverse event reporting additional description
    A Treatment emergent adverse event (TEAE) was defined as any AE that based on start date information occurred after the first dose of study drug. The safety population included all randomized participants who received at least 1 dose of ZX008 or placebo.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Study 1: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, twice a day (bid) in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 1: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: Placebo
    Reporting group description
    Participants received matching placebo as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.2 mg/kg/day
    Reporting group description
    Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Reporting group title
    Study 3: ZX008 0.8 mg/kg/day
    Reporting group description
    Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

    Serious adverse events
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 39 (10.26%)
    5 / 40 (12.50%)
    2 / 48 (4.17%)
    3 / 46 (6.52%)
    3 / 48 (6.25%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 39 (2.56%)
    2 / 40 (5.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Study 1: Placebo Study 1: ZX008 0.2 mg/kg/day Study 1: ZX008 0.8 mg/kg/day Study 3: Placebo Study 3: ZX008 0.2 mg/kg/day Study 3: ZX008 0.8 mg/kg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 40 (55.00%)
    35 / 39 (89.74%)
    36 / 40 (90.00%)
    37 / 48 (77.08%)
    41 / 46 (89.13%)
    41 / 48 (85.42%)
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    6 / 48 (12.50%)
    11 / 46 (23.91%)
    8 / 48 (16.67%)
         occurrences all number
    0
    0
    0
    7
    13
    8
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 39 (7.69%)
    3 / 40 (7.50%)
    3 / 48 (6.25%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences all number
    2
    3
    3
    3
    3
    1
    Echocardiogram abnormal
         subjects affected / exposed
    5 / 40 (12.50%)
    7 / 39 (17.95%)
    9 / 40 (22.50%)
    5 / 48 (10.42%)
    11 / 46 (23.91%)
    8 / 48 (16.67%)
         occurrences all number
    5
    7
    13
    5
    11
    8
    Blood pressure increased
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 39 (7.69%)
    2 / 40 (5.00%)
    4 / 48 (8.33%)
    2 / 46 (4.35%)
    2 / 48 (4.17%)
         occurrences all number
    0
    4
    2
    4
    2
    2
    Blood prolactin increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    3 / 40 (7.50%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Heart rate increased
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 39 (7.69%)
    1 / 40 (2.50%)
    3 / 48 (6.25%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    1
    3
    1
    4
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    4
    Weight decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    5 / 39 (12.82%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    1
    0
    1
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 39 (10.26%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    2
    5
    0
    0
    0
    1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 39 (10.26%)
    7 / 40 (17.50%)
    2 / 48 (4.17%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
         occurrences all number
    2
    6
    8
    2
    1
    4
    Somnolence
         subjects affected / exposed
    3 / 40 (7.50%)
    6 / 39 (15.38%)
    3 / 40 (7.50%)
    5 / 48 (10.42%)
    5 / 46 (10.87%)
    10 / 48 (20.83%)
         occurrences all number
    4
    6
    3
    5
    6
    10
    Ataxia
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    3 / 40 (7.50%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    3
    1
    0
    2
    Balance disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    1
    1
    0
    2
    Drooling
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 39 (7.69%)
    2 / 40 (5.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    2 / 48 (4.17%)
         occurrences all number
    0
    3
    2
    0
    1
    2
    Hypotonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    3 / 40 (7.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 39 (7.69%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    1
    5
    0
    1
    1
    0
    Sedation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Seizure
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 39 (7.69%)
    2 / 40 (5.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    4
    5
    4
    1
    0
    1
    Seizure cluster
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Status epilepticus
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    5
    0
    Tremor
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    6 / 48 (12.50%)
         occurrences all number
    1
    1
    1
    1
    1
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 39 (10.26%)
    4 / 40 (10.00%)
    1 / 48 (2.08%)
    3 / 46 (6.52%)
    5 / 48 (10.42%)
         occurrences all number
    1
    4
    4
    1
    3
    5
    Pyrexia
         subjects affected / exposed
    8 / 40 (20.00%)
    7 / 39 (17.95%)
    2 / 40 (5.00%)
    4 / 48 (8.33%)
    5 / 46 (10.87%)
    9 / 48 (18.75%)
         occurrences all number
    12
    12
    3
    5
    7
    11
    Asthenia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 40 (0.00%)
    1 / 48 (2.08%)
    2 / 46 (4.35%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    0
    1
    2
    3
    Gait disturbance
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 39 (10.26%)
    3 / 40 (7.50%)
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    5
    5
    3
    4
    0
    3
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    12 / 39 (30.77%)
    7 / 40 (17.50%)
    4 / 48 (8.33%)
    7 / 46 (15.22%)
    7 / 48 (14.58%)
         occurrences all number
    3
    14
    7
    4
    8
    7
    Salivary hypersecretion
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    4 / 40 (10.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    4
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 39 (2.56%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    2 / 46 (4.35%)
    3 / 48 (6.25%)
         occurrences all number
    2
    1
    1
    1
    2
    3
    Rhinorrhoea
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 39 (5.13%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences all number
    1
    2
    1
    0
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 39 (5.13%)
    2 / 40 (5.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    2
    2
    2
    1
    0
    4
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    3 / 40 (7.50%)
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    2 / 48 (4.17%)
         occurrences all number
    0
    0
    4
    1
    1
    2
    Enuresis
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    3
    2
    1
    Negativism
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 39 (5.13%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    1
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 39 (10.26%)
    7 / 40 (17.50%)
    5 / 48 (10.42%)
    4 / 46 (8.70%)
    1 / 48 (2.08%)
         occurrences all number
    6
    4
    8
    8
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 40 (12.50%)
    8 / 39 (20.51%)
    0 / 40 (0.00%)
    2 / 48 (4.17%)
    3 / 46 (6.52%)
    4 / 48 (8.33%)
         occurrences all number
    7
    13
    0
    3
    4
    5
    Croup infectious
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 39 (7.69%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    3
    1
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    1 / 40 (2.50%)
    2 / 48 (4.17%)
    3 / 46 (6.52%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    1
    2
    3
    0
    Influenza
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    2 / 48 (4.17%)
    1 / 46 (2.17%)
    1 / 48 (2.08%)
         occurrences all number
    4
    0
    0
    2
    3
    1
    Rhinitis
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 39 (7.69%)
    1 / 40 (2.50%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    1
    3
    1
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    1
    4
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    0
    0
    3
    3
    Viral infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    2 / 48 (4.17%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 40 (5.00%)
    8 / 39 (20.51%)
    14 / 40 (35.00%)
    3 / 48 (6.25%)
    12 / 46 (26.09%)
    18 / 48 (37.50%)
         occurrences all number
    2
    11
    15
    3
    12
    22
    Hypoglycaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    1 / 40 (2.50%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    1
    1
    0
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2015
    Protocol 1501 Amendment 1: Clarifications and changes were made to the protocol and included the following: • Sponsor name change • Added new section of transition for subjects who would be entering the open-label extension study • Removed the following clinical laboratory tests at Visits 1 and 6: luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, testosterone, growth hormone (GH), prolactin, and insulin-like growth factor-1 (IGF-1) • Clarified the maximum dose of ZX008 is 30 mg/day • Clarified the collection duration of prior and concomitant antiepileptic drug (AEDs) • Clarified data to be collected with the use of rescue medication • Moved the BRIEF-P description from the efficacy section to the safety section • Added new section of collection of data for AEs requiring hospitalization Additional clarifications and changes were made, based on feedback received from the US Food and Drug Administration (FDA), and included the following: • Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and adverse event of special interest (AESI) regarding valve regurgitation seen on echocardiogram (ECHO) • Clarified that the central cardiac reader would provide consultation to the Independent Data and Safety Monitoring Committee (IDSMC) when a subject was removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or pulmonary hypertension • Clarified expedited reporting of cardiac events other than serious adverse events (SAEs) • Added section on grading of and follow-up for ECHO findings.
    11 Jan 2016
    Protocol 1502 Amendment 1: Clarifications and changes were made to the protocol and included the following: • Sponsor name change • Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, testosterone, GH, prolactin, and IGF-1 • Clarified the maximum dose of ZX008 is 30 mg/day • Clarified the collection duration of prior and concomitant AEDs • Clarified data to be collected with the use of rescue medication • Added new section of collection of data for AEs requiring hospitalization • Replaced CHU9D with PedsQL • Updated statistical analysis section, to be consistent with the separate statistical analysis plan • Clarified study duration for participants • Clarified Inclusion Criterion regarding the requirement for a whole blood sample for a broad epilepsy-related gene panel • Added requirement that subjects qualified for and planned to enroll into the separate open-label extension study at the end of this study should be consented prior to Visit 12 • Clarified, for all questionnaires and rating scales, when rater substitution was acceptable for the clinic staff and the arent/caregiver Clarifications and changes were made based on feedback received from the US FDA, and included the following: • Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI regarding valve regurgitation seen on ECHO • Clarified that the central cardiac reader would provide consultation to the IDSMC when a subject was to be removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or pulmonary hypertension.
    11 Jan 2016
    Continuation of Protocol 1502 Amendment 1• Clarified expedited reporting of cardiac events other than SAEs • Added section on grading of and follow-up for ECHO findings • Added the assessment of cognition for subjects ≥5 years of age, so that all study participants were being assessed for cognition using the BRIEF. The description of the BRIEF was moved from the efficacy section to the safety section. Clarifications and changes were made based on feedback received from the European VHP Clinical Trials Group, and included the following: • Updated contraception requirements for the study • Clarified when subjects must have been discontinued from the study • Clarified that the investigator could discontinue a subject from the study in the case of a medical emergency • Added statistical information regarding sensitivity analyses for concomitant AED medication changes during the study.
    18 Jan 2016
    Protocol 1501 Amendment 2: Clarifications and changes were made to the protocol and included the following: • Replaced Child Health Utility Instrument (CHU9D) with PedsQL • Updated statistical analysis section, to be consistent with the separate statistical analysis plan • Clarified Inclusion Criterion regarding the requirement for a whole blood sample for a broad epilepsy-related gene panel A change was made based on feedback received from the US FDA, and included the following: • Added the assessment of cognition for subjects ≥5 years of age, so that all study participants were assessed for cognition using the BRIEF. The description of the BRIEF was moved from the efficacy section to the safety section. Clarifications and changes were made based on feedback received from the European Voluntary Harmonization Procedure (VHP) Clinical Trials Group, and included the following: • Updated contraception requirements for the study • Clarified when subjects must be discontinued from the study • Clarified that the investigator could discontinue a subject from the study in the case of a medical emergency • Added statistical information regarding sensitivity analyses for concomitant AED medication changes during the study.
    31 Oct 2016
    Protocol 1501 Amendment 3: Clarifications and changes were made to the protocol and included the following: • Removed atonic seizures from and added tonic-atonic to the types of convulsive seizures in Inclusion Criterion • Removal of Inclusion Criterion, to clarify that participation in the epilepsy-related genetic testing was not required at screening for participation • Updated the preclinical data information and, based on this information, revised the list of prohibited concomitant medications • Clarified that the number of convulsive seizures during the 6-week Baseline period is ≥ 6 versus > 6 as originally stated • Added PedsQL Family Impact module to the efficacy measures as intended • Clarified study days of Screening during the Baseline period and the timing of assessments in that period • Collection of blood sample for epilepsy genotype panel was mandatory but not required at screening. Added the list of countries in which Diacomit® (stiripentol) is approved • Added supporting references to existing citations of data • Clarified the safety objective • Specified that the number of study centers was approximate • Clarified the duration of use of contraception after the last dose of study drug • Removal of social media policy from the reason for removing a subject from therapy or assessment.
    31 Oct 2016
    Protocol 1502 Amendment 2: Clarifications and changes were made to the protocol and included the following: • Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in Inclusion Criterion • Removal of Inclusion Criterion to clarify that participation in the epilepsy-related genetic testing was not required at screening for participation. • Updated the preclinical data information and, based on this information, revised the list of prohibited concomitant medications. • Clarified that the number of convulsive seizures during the 6-week Baseline period was ≥6 versus >6 as originally stated. • Added PedsQL Family Impact module to the efficacy measures as intended • Clarified study days of Screening during the Baseline period and the timing of assessments in that period • Collection of blood sample for epilepsy genotype panel was mandatory but not required at screening.• Added the list of countries in which Diacomit® (stiripentol) is approved • Added supporting references to existing citations of data • Clarified the safety objective • Specified that the number of study centers was approximate. • Clarified the duration of use of contraception after the last dose of study drug. • Removal of social media policy from the reason for removing a subject from therapy or assessment.

    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.
    This posting consists of pooled analysis (PA) 1 and 2 of ZX008-1501 and ZX008-1502. PA1 is referenced as Study 1 in SAP and CSR. PA2 is referenced as Study 2 in respective SAP and Study 3 in corresponding CSR due to timing of regulatory submissions.
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