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    Clinical Trial Results:
    A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults with Dravet Syndrome (Cohort 2)

    Summary
    EudraCT number
    2016-000474-38
    Trial protocol
    NL   DE   GB   ES  
    Global end of trial date
    05 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jun 2022
    First version publication date
    23 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZX008-1504
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02926898
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Zogenix International Limited
    Sponsor organisation address
    Siena Court, Broadway, Maidenhead, United Kingdom, SL6 1NJ
    Public contact
    Zogenix International Limited, Zogenix International Limited, Zogenixeu@druginfo.com
    Scientific contact
    Zogenix International Limited, Zogenix International Limited, Zogenixeu@druginfo.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
    02 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that fenfluramine hydrochloride was superior to placebo for the treatment of Dravet syndrome in children and young adults stabilized on a STP regimen based on the change in convulsive seizure frequency (CSF) from Baseline to the combined Titration and Maintenance Periods (T+M period)
    Protection of trial subjects
    The study procedures set out in the protocol were designed to ensure that the Sponsor and the Investigators abided by the principles of the current International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guideline on the conduct, evaluation and documentation of this study, as described in ICH Topic E6 Guideline. The study was also carried out according to all applicable international and national regulatory requirements. The Sponsor ensured that all ethical and legal requirements were met before the first subject was enrolled into the study. The Investigator was responsible for obtaining a subject’s informed consent to participate in the study. A Subject Information Sheet and study master ICFs, including a subject ICF (for adult subjects), subject assent form (for subjects under the age of consent), and an ICF for the parent/caregiver, were prepared by the Sponsor according to the provisions of ICH GCP and local legal requirements. For pediatric subjects (<18 years of age), or young adult subjects (18 years of age) unable to provide consent due to intellectual disability, the written informed consent of a legally acceptable representative was required. Pediatric and young adult subjects who could understand the nature, scope, and possible consequences of the study must also have given their assent, orally and/or in writing via the assent document, as appropriate.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jan 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Canada: 7
    Worldwide total number of subjects
    87
    EEA total number of subjects
    58
    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)
    57
    Adolescents (12-17 years)
    28
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 28 study sites in Canada, France, Germany, the Netherlands, Spain, the United Kingdom, and the United States enrolled participants for Study 1504 Cohort 2.

    Pre-assignment
    Screening details
    A total of 115 subjects were screened for eligibility to participate in Study 1504 Cohort 2. Of these, 87 subjects were enrolled and randomized.

    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer
    Blinding implementation details
    Matching fenfluramine placebo was supplied as an oral solution.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
    Arm description
    Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food.
    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
    Upon completion of the 6-week Baseline Period, subjects received fenfluramine hydrochloride (at a dose of 0.5 mg/kg/day; maximum dose of 20 mg/day). All subjects were titrated to their randomized dose during the Titration Period. The duration of the titration period was 21 days. Following titration, subjects continued treatment at their assigned dose of fenfluramine 0.5 mg/kg/day over a 12-week Maintenance Period. The total treatment time from the beginning of the Titration Period through the end of the maintenance period was a maximum of 15 weeks.

    Arm title
    Cohort 2: Placebo
    Arm description
    Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food.
    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
    Upon completion of the 6-week Baseline Period, subjects received placebo, volume matched to the 0.4 mg/kg/day dose level. To maintain the blinded aspect of the study, subjects titrated the placebo dose over 21 days and remained at this dose for the 12-week Maintenance Period.

    Number of subjects in period 1
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day Cohort 2: Placebo
    Started
    43
    44
    Completed
    36
    41
    Not completed
    7
    3
         Worsening of seizures
    1
    -
         Uncontrolled seizures
    -
    1
         Patient decision
    1
    -
         Physician decision
    1
    -
         Early transition to OLE
    -
    1
         Adverse event, non-fatal
    2
    1
         Protocol deviation
    1
    -
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
    Reporting group description
    Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food.

    Reporting group values
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day Cohort 2: Placebo Total
    Number of subjects
    43 44 87
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    31 26 57
        Adolescents (12-17 years)
    11 17 28
        Adults (18-64 years)
    1 1 2
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.8 ( 4.56 ) 9.4 ( 5.05 ) -
    Gender categorical
    Units: Subjects
        Female
    20 17 37
        Male
    23 27 50

    End points

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    End points reporting groups
    Reporting group title
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
    Reporting group description
    Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food.

    Primary: Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period

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    End point title
    Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
    End point description
    Baseline-adjusted in CSF (mean number of convulsive seizures per 28 days) from Baseline to the T + M Period in ZX008 0.5 mg/kg/day vs placebo. Modified intent-to-treat (mITT) Population, defined as all randomized subjects 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
    15 weeks (combined Titration + Maintenance Period)
    End point values
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day Cohort 2: Placebo
    Number of subjects analysed
    43
    44
    Units: Baseline-adjusted CSF per 28 days
        least squares mean (confidence interval 95%)
    7.0 (5.4 to 8.9)
    15.1 (11.7 to 19.5)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day v Cohort 2: Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    ANCOVA
    Parameter type
    percent difference
    Point estimate
    -54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -67.2
         upper limit
    -35.6
    Notes
    [1] - ANCOVA model with treatment group (ZX008 or placebo) and age group (< 6 years, ≥ 6 years) as factors, and with log baseline frequency as a covariate, and log CSF as the outcome variable.

    Secondary: Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period

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    End point title
    Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
    End point description
    Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups. Modified intent-to-treat (mITT) Population, defined as all randomized subjects 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
    15 weeks (combined Titration + Maintenance Period)
    End point values
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day Cohort 2: Placebo
    Number of subjects analysed
    43
    44
    Units: percentage of participants
        number (not applicable)
    53.5
    4.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day v Cohort 2: Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [2] - A logistic regression model using a categorical response variable as a function of Treatment group, Baseline seizure frequency, and age group.

    Secondary: Longest Convulsive Seizure-Free Interval (Days)

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    End point title
    Longest Convulsive Seizure-Free Interval (Days)
    End point description
    Comparison of the duration of the longest convulsive seizure–free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups. Modified intent-to-treat (mITT) Population, defined as all randomized subjects 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
    15 weeks (combined Titration + Maintenance Period)
    End point values
    Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day Cohort 2: Placebo
    Number of subjects analysed
    43
    44
    Units: Days
        median (full range (min-max))
    22.00 (3.0 to 105.0)
    13.00 (1.0 to 40.0)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 2: Placebo v Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of observation for Adverse Events extended from the time the subject gave informed consent until the end of the Follow-up Visit (up to Day 120 [Visit 13]).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort 2: fenfluramine 0.5 mg/kg/day
    Reporting group description
    Subjects received fenfluramine 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum STP plus CLB and/or VPA. Study medication was administered twice daily (BID) in equally divided doses with food.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to standard-of-care treatment that included STP. Study medication was administered twice daily (BID) in equally divided doses with food.

    Serious adverse events
    Cohort 2: fenfluramine 0.5 mg/kg/day Cohort 2: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 43 (13.95%)
    7 / 44 (15.91%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 44 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondritis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 2: fenfluramine 0.5 mg/kg/day Cohort 2: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 43 (97.67%)
    42 / 44 (95.45%)
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    6 / 43 (13.95%)
    2 / 44 (4.55%)
         occurrences all number
    6
    3
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    6
    Blood pressure increased
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    4
    Echocardiogram abnormal
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 44 (0.00%)
         occurrences all number
    4
    0
    Weight decreased
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 44 (2.27%)
         occurrences all number
    4
    1
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    4
    Lethargy
         subjects affected / exposed
    6 / 43 (13.95%)
    2 / 44 (4.55%)
         occurrences all number
    6
    2
    Seizure
         subjects affected / exposed
    2 / 43 (4.65%)
    7 / 44 (15.91%)
         occurrences all number
    2
    14
    Somnolence
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 44 (6.82%)
         occurrences all number
    4
    3
    Status epilepticus
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 44 (0.00%)
         occurrences all number
    21
    0
    Tremor
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 44 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 44 (4.55%)
         occurrences all number
    3
    2
    Fatigue
         subjects affected / exposed
    11 / 43 (25.58%)
    2 / 44 (4.55%)
         occurrences all number
    11
    2
    Pyrexia
         subjects affected / exposed
    11 / 43 (25.58%)
    4 / 44 (9.09%)
         occurrences all number
    21
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 44 (2.27%)
         occurrences all number
    4
    1
    Diarrhoea
         subjects affected / exposed
    10 / 43 (23.26%)
    3 / 44 (6.82%)
         occurrences all number
    12
    5
    Vomiting
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 44 (6.82%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 44 (2.27%)
         occurrences all number
    4
    1
    Irritability
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 44 (4.55%)
         occurrences all number
    4
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 44 (4.55%)
         occurrences all number
    5
    2
    Ear infection
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 44 (4.55%)
         occurrences all number
    5
    2
    Nasopharyngitis
         subjects affected / exposed
    7 / 43 (16.28%)
    15 / 44 (34.09%)
         occurrences all number
    7
    19
    Rhinitis
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 44 (2.27%)
         occurrences all number
    7
    1
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 44 (6.82%)
         occurrences all number
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 44 (6.82%)
         occurrences all number
    4
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 43 (44.19%)
    5 / 44 (11.36%)
         occurrences all number
    23
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2016
    - Addition of chest x-ray prior to and after 13 weeks of treatment with study medication (France and The Netherlands) - Addition of 24-month cardiac safety follow-up for subjects who have completed more than 13 weeks of double-blind or open-label treatment with study medication (France, The Netherlands, and Germany) - Updated prohibited medication/food section to include the prohibition of alcohol - Added new section of transition for subjects who will enter the open-label extension study, including updates as appropriate in inclusion/exclusion criteria, study design, study visits, blood volumes to be taken, statistical methods, etc. - Increased the number of sites and countries - Clarified the use of midazolam and diazepam as rescue medication did not require Medical Monitor approval prior to use - Clarified that QOLCE was to be administered to all children - Clarified seizure type definitions -The participating countries were expanded to include Canada and Germany
    30 Sep 2016
    - The participating countries were expanded to include Belgium, Italy, Spain, and United States - The number of participating sites was updated. - The required number of seizures during the Baseline period was corrected due to a typographical error. - The Screening was extended to 21 days - Corrections were made to state that ECGs were to be read centrally - SAE reporting process was updated
    13 Dec 2016
    Clarifications and changes were made to the various sections of the protocol based on the selected dose of ZX008 0.5 mg/kg/day, maximum 20 mg/day for Cohort 2, including the Schedule of Assessments, risk-benefit rationale, and description of the primary outcome.
    02 Feb 2018
    - Sample size was updated (sample size had been expanded to include approximately 90 subjects) - Updates were made to statistical analysis and efficacy objectives to align with the SAP. - The AESI list was updated to 1) remove cardiovascular/respiratory items, including discontinuation of the reporting of ECHOs with trace mitral regurgitation as AESIs; 2) remove serotonin syndrome; 3) remove hallucinations, psychosis, euphoria, mood disorders; 4) remove galactorrhea, gynecomastia, priapism; and 5) remove fasting serum blood glucose ≥2×ULN

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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