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    Clinical Trial Results:
    An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

    Summary
    EudraCT number
    		 2016-002804-14
    Trial protocol
    		 GB   BE   DE   IT   DK   ES   FR  
    Global end of trial date
    27 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2023
    First version publication date
    12 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZX008-1503
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02823145
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zogenix International Limited (a wholly owned subsidiary of Zogenix, Inc.)
    Sponsor organisation address
    5959 Horton Street, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long-term safety and tolerability of ZX008
    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
    08 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 145
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 29
    Worldwide total number of subjects
    375
    EEA total number of subjects
    161
    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)
    233
    Adolescents (12-17 years)
    100
    Adults (18-64 years)
    42
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study started to enroll participants in Jul 2016 and concluded in Jan 2023. Participants who completed 14 weeks treatment in any of the core studies ZX008-1501/ZX008-1502 (NCT02682927), or ZX008-1504 (NCT02926898) Cohort 2, or completed ZX008-1504 Cohort 1 study, and de novo participants were eligible to participate in this study.

    Pre-assignment
    Screening details
    		 The Participant Flow refers to the Safety (SAF) Population.

    Period 1
    Period 1 title
    Enrollment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Not Treated
    Arm description
    		 Participant (de novo) signed the informed consent form (ICF) but never received any study medication during the study.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Any ZX008 Open Label Dose
    Arm description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.
    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 to maximum of 30 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 42 months.

    Number of subjects in period 1
    		Not Treated Any ZX008 Open Label Dose
    Started
    1
    374
    Completed
    0
    374
    Not completed
    1
    0
         Unknown
    1
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Any ZX008 Open Label Dose
    Arm description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.
    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 to maximum of 30 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 42 months.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: As pre-specified in the SAP, participant Demographics and Baseline Characteristics were summarized for the safety population. In Period 1, no participant received study medication therefore, Period 2 is considered as Baseline Period.
    Number of subjects in period 2 [2]
    		Any ZX008 Open Label Dose
    Started
    374
    Completed
    49
    Not completed
    325
         Adverse event, serious fatal
    3
         Physician decision
    2
         Subject needed to take prohibited medication
    1
         Withdrawal by sponsor due to lack of compliance
    1
         Family Decision
    1
         Subject has transitioned to study 1900 OLE study
    225
         Transitioned to commercial supply of medication
    1
         Reason unknown
    1
         IP approved and subject moved to commercial drug
    1
         Non-Compliance With E-Diary
    1
         Withdrawal By Caregiver
    1
         Consent withdrawn by subject
    16
         Adverse event, non-fatal
    11
         Subject transferred to direct access programme
    1
         Switching to commercially available drug
    11
         Lack of efficacy
    48
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant enrolled but discontinued the study without receiving study medication and Demographics were planned for participants who received at least one dose of ZX008 during OLE.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Any ZX008 Open Label Dose
    Reporting group description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.

    Reporting group values
    		 Any ZX008 Open Label Dose Total
    Number of subjects
    		 374 374
    Age Categorical
    Units: participants
        <6 years
    		 92 92
        6-18 years
    		 250 250
        >18 years
    		 32 32
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.3 ( 6.12 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 172 172
        Male
    		 202 202

    End points

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    End points reporting groups
    Reporting group title
    Not Treated
    Reporting group description
    		 Participant (de novo) signed the informed consent form (ICF) but never received any study medication during the study.

    Reporting group title
    Any ZX008 Open Label Dose
    Reporting group description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.
    Reporting group title
    Any ZX008 Open Label Dose
    Reporting group description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.

    Primary: Percentage of participants with treatment-emergent adverse events (TEAEs) leading to withdrawal from investigational medicinal product (IMP) during the OLE Treatment Period

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    End point title
    		 Percentage of participants with treatment-emergent adverse events (TEAEs) leading to withdrawal from investigational medicinal product (IMP) during the OLE Treatment Period [1]
    End point description
    A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
    End point type
    Primary
    End point timeframe
    From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    374
    Units: percentage of participants
        number (not applicable)
    3.5
    No statistical analyses for this end point

    Primary: Percentage of participants with treatment-emergent adverse events (TEAEs) during the Open-label extension (OLE) Treatment Period

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    End point title
    		 Percentage of participants with treatment-emergent adverse events (TEAEs) during the Open-label extension (OLE) Treatment Period [2]
    End point description
    Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
    End point type
    Primary
    End point timeframe
    From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    374
    Units: percentage of participants
        number (not applicable)
    98.1
    No statistical analyses for this end point

    Primary: Percentage of participants with Serious treatment-emergent adverse events (TEAEs) during the OLE Treatment Period

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    End point title
    		 Percentage of participants with Serious treatment-emergent adverse events (TEAEs) during the OLE Treatment Period [3]
    End point description
    Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
    End point type
    Primary
    End point timeframe
    From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    374
    Units: percentage of participants
        number (not applicable)
    26.5
    No statistical analyses for this end point

    Secondary: Convulsive Seizure Frequency (CSF) per 28 days during the OLE Treatment Period (to Month 36)

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    End point title
    		 Convulsive Seizure Frequency (CSF) per 28 days during the OLE Treatment Period (to Month 36)
    End point description
    Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where,i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, 'n' signifies participants who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    324
    Units: seizure frequency per 28 days
    median (full range (min-max))
        Month 1 (n=324)
    6.53 (0.0 to 4876.9)
        Month 2 (n= 323)
    4.67 (0.0 to 3392.7)
        Month 3 (n= 320)
    4.67 (0.0 to 2593.7)
        Month 4-6 (n= 316)
    4.36 (0.0 to 1725.5)
        Month 7-9 (n= 299)
    3.82 (0.0 to 310.8)
        Month 10-12 (n= 284)
    4.04 (0.0 to 362.4)
        Month 13-15 (n= 280)
    3.11 (0.0 to 215.0)
        Month 16-18 (n= 262)
    3.42 (0.0 to 243.3)
        Month 19-21 (n= 247)
    3.42 (0.0 to 372.4)
        Month 22-24 (n= 234)
    2.80 (0.0 to 489.5)
        Month 25-27 (n= 187)
    2.80 (0.0 to 747.3)
        Month 28-30 (n= 151)
    2.80 (0.0 to 242.5)
        Month 31-33 (n= 116)
    3.21 (0.0 to 224.0)
        Month 34-36 (n= 73)
    2.74 (0.0 to 56.0)
    No statistical analyses for this end point

    Secondary: Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period

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    End point title
    		 Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period
    End point description
    Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo subjects (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. Modified Intent-to-Treat (mITT) population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
    End point type
    Secondary
    End point timeframe
    From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    324
    Units: seizure frequency per 28 days
        median (full range (min-max))
    -6.67 (-1757.8 to 751.3)
    No statistical analyses for this end point

    Secondary: Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Month 2 to EOS (Month 42) in the OLE Treatment Period

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    End point title
    		 Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Month 2 to EOS (Month 42) in the OLE Treatment Period
    End point description
    Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    323
    Units: seizure frequency per 28 days
        median (full range (min-max))
    -7.04 (-1986.9 to 816.4)
    No statistical analyses for this end point

    Secondary: Convulsive Seizure Frequency (CSF) by Mean Daily Dose during the overall OLE Treatment Period

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    End point title
    		 Convulsive Seizure Frequency (CSF) by Mean Daily Dose during the overall OLE Treatment Period
    End point description
    Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to <0.4 mg/kg), medium (0.4 to <0.6 mg/kg), and high dose (>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, 'n' represents the number of participants categorized by mean daily dose.
    End point type
    Secondary
    End point timeframe
    From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    324
    Units: seizure frequency per 28 days
    median (full range (min-max))
        ZX008 Low Dose (0 - <0.4 mg/kg/day) (n=90)
    3.94 (0.0 to 2215.3)
        ZX008 Medium Dose (0.4 - <0.6 mg/kg/day) (n=113)
    4.80 (0.0 to 113.6)
        ZX008 High Dose (>=0.6 mg/kg/day) (n=121)
    6.00 (0.1 to 942.8)
    No statistical analyses for this end point

    Secondary: Percentage of participants With Changes in antiepileptic drug (AED) medications during first 6 months of OLE Treatment Period

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    End point title
    		 Percentage of participants With Changes in antiepileptic drug (AED) medications during first 6 months of OLE Treatment Period
    End point description
    Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
    End point type
    Secondary
    End point timeframe
    At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period
    End point values
    		 Any ZX008 Open Label Dose
    Number of subjects analysed
    324
    Units: percentage of participants
    number (not applicable)
        OLE Month 1
    5.2
        OLE Month 2
    7.1
        OLE Month 3
    7.4
        OLE Month 4
    8.3
        OLE Month 5
    6.8
        OLE Month 6
    9.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to 42 months
    Adverse event reporting additional description
    A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. The Safety (SAF) population was the set of all enrolled subjects who received at least one dose of ZX008 during the OLE. As pre-specified in the SAP, safety analyses were performed on the SAF Population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Any ZX008 Open Label Dose
    Reporting group description
    		 Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period.

    Serious adverse events
    		 Any ZX008 Open Label Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 374 (26.47%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Labial frenectomy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abasia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Apnoea
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Tic
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Apathy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Insomnia
         subjects affected / exposed
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug dose omission
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Near drowning
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Change in seizure presentation
         subjects affected / exposed
    5 / 374 (1.34%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Dystonia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hyperkinesia
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Movement disorder
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    21 / 374 (5.61%)
         occurrences causally related to treatment / all
    2 / 26
         deaths causally related to treatment / all
    0 / 0
    Seizure cluster
         subjects affected / exposed
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    15 / 374 (4.01%)
         occurrences causally related to treatment / all
    1 / 18
         deaths causally related to treatment / all
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth disorder
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Aneurysmal bone cyst
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    7 / 374 (1.87%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 374 (3.21%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    5 / 374 (1.34%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Feeding intolerance
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Any ZX008 Open Label Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 374 (91.44%)
    Investigations
    Echocardiogram abnormal
         subjects affected / exposed
    67 / 374 (17.91%)
         occurrences all number
    82
    Blood glucose decreased
         subjects affected / exposed
    88 / 374 (23.53%)
         occurrences all number
    115
    Weight decreased
         subjects affected / exposed
    31 / 374 (8.29%)
         occurrences all number
    33
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    25 / 374 (6.68%)
         occurrences all number
    26
    Nervous system disorders
    Seizure
         subjects affected / exposed
    46 / 374 (12.30%)
         occurrences all number
    60
    Somnolence
         subjects affected / exposed
    35 / 374 (9.36%)
         occurrences all number
    38
    Tremor
         subjects affected / exposed
    21 / 374 (5.61%)
         occurrences all number
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 374 (9.09%)
         occurrences all number
    49
    Pyrexia
         subjects affected / exposed
    112 / 374 (29.95%)
         occurrences all number
    229
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    23 / 374 (6.15%)
         occurrences all number
    34
    Diarrhoea
         subjects affected / exposed
    73 / 374 (19.52%)
         occurrences all number
    102
    Vomiting
         subjects affected / exposed
    39 / 374 (10.43%)
         occurrences all number
    50
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 374 (9.09%)
         occurrences all number
    55
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    20 / 374 (5.35%)
         occurrences all number
    20
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    19 / 374 (5.08%)
         occurrences all number
    23
    Abnormal behaviour
         subjects affected / exposed
    22 / 374 (5.88%)
         occurrences all number
    28
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    20 / 374 (5.35%)
         occurrences all number
    21
    Gastroenteritis
         subjects affected / exposed
    32 / 374 (8.56%)
         occurrences all number
    34
    Ear infection
         subjects affected / exposed
    39 / 374 (10.43%)
         occurrences all number
    56
    Influenza
         subjects affected / exposed
    45 / 374 (12.03%)
         occurrences all number
    50
    Viral upper respiratory tract infection
         subjects affected / exposed
    19 / 374 (5.08%)
         occurrences all number
    36
    Viral infection
         subjects affected / exposed
    27 / 374 (7.22%)
         occurrences all number
    40
    Upper respiratory tract infection
         subjects affected / exposed
    65 / 374 (17.38%)
         occurrences all number
    117
    Nasopharyngitis
         subjects affected / exposed
    104 / 374 (27.81%)
         occurrences all number
    224
    Rhinitis
         subjects affected / exposed
    32 / 374 (8.56%)
         occurrences all number
    62
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    32 / 374 (8.56%)
         occurrences all number
    35
    Decreased appetite
         subjects affected / exposed
    100 / 374 (26.74%)
         occurrences all number
    112

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2016
    Amendment 1.2-Important clarifications and changes were made to the protocol and included the following: • Addition of Study 1504 as a core study contributing subjects to this study, including updates/additions as appropriate in exploratory objectives, planned number of subjects/study centers, inclusion/exclusion criteria, study design, treatment administration, prohibited concomitant medication, study visits, assessments specific to Study 1504 subjects only, statistical methods, etc. • Clarified the use of concomitant AED treatments • Clarified the dose adjustment parameters in the first month of the study • Updated risk-benefit for the study • Updated prohibited medication/food section to include the prohibition of alcohol • Clarified how ongoing AEs from the core studies were to be handled in this study
    01 Nov 2016
    Amendment 2.0- Clarifications and changes were made to the protocol, including changes requested based on feedback received from the United States Food and Drug Administration, and included the following: • Added the criteria for dose adjustments outside the protocol-specified range for safety and/or efficacy • Clarified the criteria on inclusion for subjects who did not complete the 12-week Maintenance period of the core study • Added Pediatric Quality of Life Inventory (PedsQL) Family Impact module as an effectiveness endpoint • Reproduction requirements were updated and clarified • Clarified the transition from the core study to the OLE study • Clarified the timing of the echocardiogram (ECHO) - moved from Week 6 to Month 1 • Clarified the timing of the cardiac follow-up visits • Added guidance consistent with the Seattle Children’s Research Foundation for volume of blood collected from children • Severity of valve regurgitation (tricuspid or pulmonary) was changed • Clarified the process for SAE reporting • Added the requirement for pharmacokinetic (PK) as soon as feasible after an SAE
    05 May 2017
    Amendment 3.0- Clarifications and changes were made to the protocol, and included the following: • Extend the study duration to 2 years (24 months) • Clarified the methodology sections regarding dosing for subjects who entered the open label extension trial from core studies and increased the study duration to 24 months • Updated the Risk Benefit Assessment with regards to ZX008 doses administered in the core studies • Increased number of subjects expected to enroll in the study • Clarified the timing for cardiac follow up visits and increased study duration to 2 years (24 months) • Updated the study drug doses for open-label Treatment period • Added visit windows for year 2 visits and clarified timing of the cardiac follow up visits in Table 6 “Time Windows for Assessments” • Clarified the timing and observation period for reporting of AEs • Clarified the process for SAE reporting
    02 Feb 2018
    Amendment 4.0- Clarifications and changes were made to the protocol, and included the following: • Updated number of enrolled subjects to 340 from the core studies and up to 50 subjects who did not participate in the core studies (de novo) • Included eligibility criteria for de novo subjects aged > 18 to 35 years of age; provided summary of eligibility, clarified language, for de novo adult subjects • Adjusted duration of study to approximately 36 months • Updated rationale to provide risk-benefit assessment that included results from Study 1. • Clarified that seizure comparisons would include the time when dose was stable • Included clinical data results from double-blind, controlled study (Study 1) • Clarified dose changes for subjects receiving and not receiving stiripentol • Corrected procedures for postdose Visit 13 • Clarified cardiac follow-up visits • Updated estimated blood volume to be collected • Clarified age range for PedsQL • Clarified how to code and report SAEs • Clarified ECHO reading severity (trace and mild) and oversight based on patient age
    03 Aug 2020
    Amendment 5.0- Clarifications and changes were made to the protocol, and included the following: • Included study conduct information for the COVID-19 pandemic • Updated background information related to existing treatments for Dravet and additional clinical and pre-clinical study data available in the updated ZX008 Investigator’s Brochure (IB) • Updated language for subjects transitioning to another extension study or to commercial drug • Updated number of study centers to include Japan

    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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