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    Clinical Trial Results:
    Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation

    Summary
    EudraCT number
    		 2016-004957-33
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 May 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2017
    First version publication date
    12 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2090-S082-405
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01127256
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Korea Inc.
    Sponsor organisation address
    10F Revessant, Bongeunsa-ro 86 gil 6, Gangnam-gu, Seoul, Korea, Republic of, 06163
    Public contact
    Eisai Korea Inc. Medical Department, Eisai Korea Inc., 82-2 34515538,
    Scientific contact
    Eisai Korea Inc. Medical Department, Eisai Korea Inc., 82-2 34515538,
    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
    05 May 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to help with the therapeutic guideline of epileptic participants by establishing the efficacy and safety of Zonisamide in Korean participants through its comparison with Carbamazepine which is widely used as the first line drug in epileptic participants, and establishing the use of titration of Zonisamide to deduce the maximum efficacy while increasing the safety on participants.
    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 Council 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 Council for Harmonisation of Technical Requirements for Registration 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
    19 Jul 2006
    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
    Korea, Republic of: 200
    Worldwide total number of subjects
    200
    EEA total number of subjects
    0
    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)
    0
    Adults (18-64 years)
    200
    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 12 centers in Korea during the period of May 2006 to May 2009.

    Pre-assignment
    Screening details
    		 A total of 200 participants enrolled; 96 participants were in the zonisamide group and 104 in the carbamazepine group. The zonisamide participants was divided into 52 participants in the slow titration group and 44 participants in the fast titration group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zonisamide
    Arm description
    		 Initial dose was 100 mg/day, increased by 100 mg. The maximum dose was 600 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zonisamide
    Investigational medicinal product code
    E2090
    Other name
    Zonegran, Excegran
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose was 100 mg/day, increased by 100 mg. The maximum dose was 600 mg/day.

    Arm title
    		 Carbamazepine
    Arm description
    		 Initial dose was 100 mg/day, increased by 200 mg every 1 week to 600 mg/day. The maximum dose was 1200 mg/day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Carbamazepine
    Investigational medicinal product code
    Other name
    Tegretol, Carbatrol, Equetro, Epitol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose was 100 mg/day, increased by 200 mg every 1 week to 600 mg/day. The maximum dose was 1200 mg/day.

    Number of subjects in period 1
    		Zonisamide Carbamazepine
    Started
    96
    104
    Completed
    57
    65
    Not completed
    39
    39
         Consent withdrawn by subject
    5
    9
         Adverse event, non-fatal
    13
    13
         Protocol violation
    1
    -
         Lost to follow-up
    16
    17
         Lack of efficacy
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 100 mg. The maximum dose was 600 mg/day.

    Reporting group title
    Carbamazepine
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 200 mg every 1 week to 600 mg/day. The maximum dose was 1200 mg/day.

    Reporting group values
    		 Zonisamide Carbamazepine Total
    Number of subjects
    		 96 104 200
    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)
    		 39.8 ± 15.9 35.7 ± 15.1 -
    Gender categorical
    Units: Subjects
        Female
    		 49 53 102
        Male
    		 47 51 98
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 96 104 200
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 0 0 0
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 100 mg. The maximum dose was 600 mg/day.

    Reporting group title
    Carbamazepine
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 200 mg every 1 week to 600 mg/day. The maximum dose was 1200 mg/day.

    Primary: The Percentage of Participants With Seizure Free Rate

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    End point title
    		 The Percentage of Participants With Seizure Free Rate [1]
    End point description
    The percentage of participants who had no seizure during the trial.
    End point type
    Primary
    End point timeframe
    24 weeks
    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: Did not perform the Statistics Analysis for this endpoint.
    End point values
    		 Zonisamide Carbamazepine
    Number of subjects analysed
    96
    104
    Units: Percentage of participants
        number (not applicable)
    73.7
    83.1
    No statistical analyses for this end point

    Secondary: The Percentage of Participants With Retention Rate

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    End point title
    		 The Percentage of Participants With Retention Rate
    End point description
    The percentage of participants who completed the trial.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Zonisamide Carbamazepine
    Number of subjects analysed
    96
    104
    Units: Percentage of participants
        number (not applicable)
    59.4
    62.5
    No statistical analyses for this end point

    Secondary: Quality of Life in Epilepsy (QoL-QOLIE31)

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    End point title
    		 Quality of Life in Epilepsy (QoL-QOLIE31)
    End point description
    Quality of life assessment tool. Overall scores is calculated by summing subsections, and it ranges from 0 to 100. Higher score presents higher quality of life.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Zonisamide Carbamazepine
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Pre-QOLIE 31
    60.72 ± 14.69
    61.96 ± 16.67
        Post-QOLIE 31
    67.27 ± 16.34
    69.51 ± 17.61
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug, to approximately up to approximately 3 years 1 month.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 WHO-ART
    Dictionary version
    061
    Reporting groups
    Reporting group title
    Zonisamide
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 100 mg. The maximum dose was 600 mg/day.

    Reporting group title
    Carbamazepine
    Reporting group description
    		 Initial dose was 100 mg/day, increased by 200 mg every 1 week to 600 mg/day. The maximum dose was 1200 mg/day.

    Serious adverse events
    		 Zonisamide Carbamazepine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 96 (5.21%)
    9 / 104 (8.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Sgot Increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sgpt Increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cervical Sprain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Shoulder Injury
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Fibroid
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 96 (0.00%)
    4 / 104 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depressive Mood
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory And Judgement Disturbance
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Torpor
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual Hallucination
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Worsening Insomnia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Zonisamide Carbamazepine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 96 (77.08%)
    70 / 104 (67.31%)
    Investigations
    Weight Decrease
         subjects affected / exposed
    16 / 96 (16.67%)
    2 / 104 (1.92%)
         occurrences all number
    17
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    28 / 96 (29.17%)
    23 / 104 (22.12%)
         occurrences all number
    30
    24
    Headache
         subjects affected / exposed
    14 / 96 (14.58%)
    14 / 104 (13.46%)
         occurrences all number
    14
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 96 (7.29%)
    6 / 104 (5.77%)
         occurrences all number
    7
    6
    Pyrexia
         subjects affected / exposed
    6 / 96 (6.25%)
    8 / 104 (7.69%)
         occurrences all number
    6
    9
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    20 / 96 (20.83%)
    5 / 104 (4.81%)
         occurrences all number
    21
    5
    Constipation
         subjects affected / exposed
    1 / 96 (1.04%)
    7 / 104 (6.73%)
         occurrences all number
    1
    7
    Diarrhoea
         subjects affected / exposed
    5 / 96 (5.21%)
    2 / 104 (1.92%)
         occurrences all number
    6
    2
    Dyspepsia
         subjects affected / exposed
    1 / 96 (1.04%)
    6 / 104 (5.77%)
         occurrences all number
    1
    7
    Gastrointestinal Pain
         subjects affected / exposed
    7 / 96 (7.29%)
    2 / 104 (1.92%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    11 / 96 (11.46%)
    12 / 104 (11.54%)
         occurrences all number
    11
    14
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    7 / 96 (7.29%)
    4 / 104 (3.85%)
         occurrences all number
    7
    5
    Rash
         subjects affected / exposed
    6 / 96 (6.25%)
    4 / 104 (3.85%)
         occurrences all number
    6
    4
    Urticaria
         subjects affected / exposed
    0 / 96 (0.00%)
    5 / 104 (4.81%)
         occurrences all number
    0
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 104 (1.92%)
         occurrences all number
    4
    2
    Drowsiness
         subjects affected / exposed
    25 / 96 (26.04%)
    24 / 104 (23.08%)
         occurrences all number
    25
    25
    Memory Impairment
         subjects affected / exposed
    9 / 96 (9.38%)
    5 / 104 (4.81%)
         occurrences all number
    9
    5
    Mental Torpor
         subjects affected / exposed
    7 / 96 (7.29%)
    12 / 104 (11.54%)
         occurrences all number
    7
    12
    Sleep Disorder
         subjects affected / exposed
    6 / 96 (6.25%)
    4 / 104 (3.85%)
         occurrences all number
    6
    4

    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? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination leading to small numbers of subjects analyzed
    For support, Contact us.
    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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