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    Clinical Trial Results:
    A double-blind, randomised, placebo-controlled, multicentre study to assess the efficacy and safety of adjunctive zonisamide in primary generalised tonic clonic seizures.

    Summary
    EudraCT number
    		 2007-003557-91
    Trial protocol
    		 DE   HU   LT   FI   CZ   EE  
    Global end of trial date
    09 Jan 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2090-E044-315
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00692003
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Limited
    Sponsor organisation address
    European Knowledge Centre, Mosquito Way, Hatfield, Herts, , Woodcliff Lake, United States, AL10 9SN
    Public contact
    Eisai Call Center, Eisai Limited (Eisai Inc.), 888 422-4743,
    Scientific contact
    Eisai Call Center, Eisai Limited (Eisia Inc.), 888 422-4743,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    15 Jul 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2009
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this study is to assess the efficacy of adjunctive zonisamide in idiopathic generalised epilepsy (IGE) in reducing the frequency of tonic-clonic seizures in subjects with continuing primary generalised tonic clonic seizures (PGTCS) despite treatment with one or two other anti-epileptic drugs (AEDs).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Romania: 3
    Worldwide total number of subjects
    6
    EEA total number of subjects
    5
    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)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was recruited at 6 centers (3 in Romania and 1 in Australia, Hungary, and Lithuania) during the period of 01 August 2008 to 28 January 2009.

    Pre-assignment
    Screening details
    		 Twenty-one subjects were screened and 14 subjects did not continue the study after screening. Seven subjects entered the study but 1 subject did not receive any treatment. Consequently, 6 subjects were enrolled and treated during the study. None of the 6 subjects completed treatment & all discontinued due to the Sponsor's decision.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zonisamide
    Arm description
    		 25-400 mg zonisamide capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide and ≥12 years old: 50 mg zonisamide daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zonisamide
    Investigational medicinal product code
    E2090
    Other name
    Zonegran
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25-400 mg zonisamide capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide and ≥12 years old: 50 mg zonisamide daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Arm title
    		 Placebo
    Arm description
    		 25-400 mg zonisamide placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide placebo and ≥12 years old: 50 mg zonisamide placebo daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matched zonisamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25-400 mg zonisamide placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide placebo and ≥12 years old: 50 mg zonisamide placebo daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Number of subjects in period 1
    		Zonisamide Placebo
    Started
    5
    1
    Completed
    0
    0
    Not completed
    5
    1
         Sponsor decision
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 25-400 mg zonisamide capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide and ≥12 years old: 50 mg zonisamide daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Reporting group title
    Placebo
    Reporting group description
    		 25-400 mg zonisamide placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide placebo and ≥12 years old: 50 mg zonisamide placebo daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Reporting group values
    		 Zonisamide Placebo Total
    Number of subjects
    		 5 1 6
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.4 ± 18.66 27 ± 27 -
    Gender categorical
    Units: Subjects
        Female
    		 3 0 3
        Male
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 25-400 mg zonisamide capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide and ≥12 years old: 50 mg zonisamide daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Reporting group title
    Placebo
    Reporting group description
    		 25-400 mg zonisamide placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide placebo and ≥12 years old: 50 mg zonisamide placebo daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Primary: Number of Participants Considered Responders as Assessed During the Maintenance Period

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    End point title
    		 Number of Participants Considered Responders as Assessed During the Maintenance Period [1]
    End point description
    The number of participants who were considered responders during the 12 week Maintenance Period (Week 4 to Week 16). A responder was defined as a participant with a decrease from baseline in Primary Generalised Tonic-Clonic Seizures (PGTCS) frequency of ≥ 50% (i.e. 28-day PGTC seizure frequency in the period from Week 4 to the Week 16 visit compared to Week -8 to randomization at Week 0). Each participant's response to treatment was assessed on the basis of their seizure diaries. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) through out the titration and maintenance treatment periods until the Early termination Visit at Week 16. Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    End point type
    Primary
    End point timeframe
    Baseline (Week -8/-4 to Week 0) and Maintenance Phase (Week 4 to Week 16)
    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: Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    End point values
    		 Zonisamide Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Participants
        number (not applicable)
    Notes
    [2] - Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    [3] - Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in 28-day PGTC Seizure Frequency

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    End point title
    		 Absolute Change From Baseline in 28-day PGTC Seizure Frequency
    End point description
    Absolute Change from Baseline in 28-day PGTC Seizure Frequency was assessed both for the Maintenance Period alone (Week 4 to Week 16) and for the entire double-blind treatment period (Week 0 to Week 16). Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 16 weeks
    End point values
    		 Zonisamide Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Absolute Change
        number (not applicable)
    Notes
    [4] - Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    [5] - Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected for approximately 3 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11
    Reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 25-400 mg zonisamide capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide and ≥12 years old: 50 mg zonisamide daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Reporting group title
    Placebo
    Reporting group description
    		 25-400 mg zonisamide placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment; Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg zonisamide placebo and ≥12 years old: 50 mg zonisamide placebo daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4; Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events); Down Titration Period (4 weeks).

    Serious adverse events
    		 Zonisamide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Zonisamide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Postictal headache
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Nov 2008
    This study was terminated early at the Sponsor’s discretion. When this study was discontinued, only 6 subjects had been treated. Data from the 5 subjects treated with zonisamide were insufficient to draw firm conclusions regarding efficacy.
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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