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    Clinical Trial Results:
    An open-label extension study following a double-blind, randomised, placebo-controlled, multi-centre study to assess the efficacy and safety of adjunctive zonisamide in paediatric partial onset seizures.

    Summary
    EudraCT number
    		 2007-000198-53
    Trial protocol
    		 HU   BE   LV   IT   EE   PL   ES   FR   GB  
    Global end of trial date
    08 Mar 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    E2090-E044-313
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01136954
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, United States, 07677
    Public contact
    Eisai Call Center, Eisai Inc., 888 422-4743,
    Scientific contact
    Eisai Call Center, Eisai 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
    08 Mar 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long-term safety of zonisamide used as an adjunctive treatment in paediatric subjects treated 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 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 Conference on 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
    10 Jul 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
    Poland: 16
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Latvia: 18
    Country: Number of subjects enrolled
    Ukraine: 66
    Worldwide total number of subjects
    144
    EEA total number of subjects
    78
    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)
    67
    Adolescents (12-17 years)
    77
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who completed E2090-E044-312 (NCT00566254)"Study 312" core study were invited to participate in this extension study.

    Pre-assignment
    Screening details
    		 Of the 183 participants who completed Study 312 and were eligible to enter into this study, E2090-E044-313 (Study 313), 144 participants entered into Study 313.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    To preserve the blind for Study 312, participants entering into Study 313 started with a double-blind Transition Period during which participants already on zonisamide continued on the same dose of zonisamide for their weight, and those who were taking placebo during Study 312 were up-titrated to an appropriate dose of zonisamide. At the end of the Transition Period, participants entered the Open-label Period, in which all participants took zonisamide at a known dose level.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zonisamide (placebo during core study)
    Arm description
    		 Participants previously receiving placebo in Study 312, started dosing with zonisamide with a dose of 1 mg/kg/day and titrated upwards with weekly dose increases until a dose of 8 mg/kg/day was reached at the end of the Transition Period (weeks 2 -11). Down-titration was allowed between the limits of 1 to 8 mg/kg/day during the Open-label Period. Subsequently, a 45-57 week Open-label period followed. Placebo dosing ceased in Open-label Period. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zonisamide
    Investigational medicinal product code
    Other name
    Zonegran, E2090
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Titration Period: Participants were started on oral zonisamide at approximately 1 mg/kg/day. The total daily dose of zonisamide was gradually increased until it equaled the maintenance dose of placebo they had been receiving at the end of Study 312. When this point was reached, the participant stopped taking placebo. Open-label Period: All participants took zonisamide at a known dose level. Participants could be down-titrated, if necessary, and as often as needed until the minimum dose at each level was reached. Participants who down-titrated could be re up-titrated, if required, to control seizures: this could be repeated until the maximum dose in that weight group was reached. At the end of the Open-label Period, participants either down-titrated or continued taking zonisamide under Eisai's Compassionate Use policy; participants who down-titrated were permitted to up-titrate a replacement AED at the same time.

    Arm title
    		 Zonisamide (zonisamide during core study)
    Arm description
    		 Participants previously receiving zonisamide in Study 312 continued taking the same dose of study drug (8 mg/kg/day),supplemented with an increasing number of placebo capsules to mirror the up-titration regimen being followed by those previously receiving placebo.Down-titration was allowed between the limits of 1 to 8 mg/kg/day during Transition Period. Subsequently, a 45-57 week Open-label period followed. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zonisamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Titration Period: Participants continued on oral zonisamide at the dose they received in Study 312, supplemented with an increasing number of placebo capsules, thereby mirroring the up-titration regimen being followed by those participants previously randomized to placebo in Study 312. Open-label Period: All participants took zonisamide at a known dose level. Participants could be down-titrated, if necessary, and as often as needed until the minimum dose at each level was reached. Participants who down-titrated could be re up-titrated, if required, to control seizures: this could be repeated until the maximum dose in that weight group was reached. At the end of the Open-label Period, participants either down-titrated or continued taking zonisamide under Eisai's Compassionate Use policy; participants who down-titrated were permitted to up-titrate a replacement AED at the same time.

    Number of subjects in period 1
    		Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Started
    72
    72
    Completed
    48
    51
    Not completed
    24
    21
         Consent withdrawn by subject
    6
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    3
    2
         Not specified
    1
    3
         Lack of efficacy
    14
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zonisamide (placebo during core study)
    Reporting group description
    		 Participants previously receiving placebo in Study 312, started dosing with zonisamide with a dose of 1 mg/kg/day and titrated upwards with weekly dose increases until a dose of 8 mg/kg/day was reached at the end of the Transition Period (weeks 2 -11). Down-titration was allowed between the limits of 1 to 8 mg/kg/day during the Open-label Period. Subsequently, a 45-57 week Open-label period followed. Placebo dosing ceased in Open-label Period. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Reporting group title
    Zonisamide (zonisamide during core study)
    Reporting group description
    		 Participants previously receiving zonisamide in Study 312 continued taking the same dose of study drug (8 mg/kg/day),supplemented with an increasing number of placebo capsules to mirror the up-titration regimen being followed by those previously receiving placebo.Down-titration was allowed between the limits of 1 to 8 mg/kg/day during Transition Period. Subsequently, a 45-57 week Open-label period followed. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Reporting group values
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study) Total
    Number of subjects
    		 72 72 144
    Age categorical
    Units: Subjects
        6 - 11 Years
    		 34 33 67
        12 - 18 Years
    		 38 39 77
    Gender categorical
    Units: Subjects
        Female
    		 32 41 73
        Male
    		 40 31 71

    End points

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    End points reporting groups
    Reporting group title
    Zonisamide (placebo during core study)
    Reporting group description
    		 Participants previously receiving placebo in Study 312, started dosing with zonisamide with a dose of 1 mg/kg/day and titrated upwards with weekly dose increases until a dose of 8 mg/kg/day was reached at the end of the Transition Period (weeks 2 -11). Down-titration was allowed between the limits of 1 to 8 mg/kg/day during the Open-label Period. Subsequently, a 45-57 week Open-label period followed. Placebo dosing ceased in Open-label Period. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Reporting group title
    Zonisamide (zonisamide during core study)
    Reporting group description
    		 Participants previously receiving zonisamide in Study 312 continued taking the same dose of study drug (8 mg/kg/day),supplemented with an increasing number of placebo capsules to mirror the up-titration regimen being followed by those previously receiving placebo.Down-titration was allowed between the limits of 1 to 8 mg/kg/day during Transition Period. Subsequently, a 45-57 week Open-label period followed. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Primary: Treatment Emergent Non-Serious Adverse Events with greater than 5% Frequency

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    End point title
    		 Treatment Emergent Non-Serious Adverse Events with greater than 5% Frequency [1]
    End point description
    Treatment Emergent Adverse Event (TEAE) is defined as an Adverse Event with a start date on or after Day 1 and within 15 days of last dose. For each event, each participant experiencing an event is only counted once even if they had multiple episodes.
    End point type
    Primary
    End point timeframe
    Week 1 through Week 59
    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: Statistical analyses are not available for this data.
    End point values
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Number of subjects analysed
    72 [2]
    72 [3]
    Units: Participants
    number (not applicable)
        Nasopharyngitis
    6
    9
        Bronchitis
    4
    3
        Respiratory tract infection
    2
    4
        Headache
    4
    7
        Weight decreased
    6
    6
        Abdominal pain
    1
    4
        Decreased appetite
    5
    4
    Notes
    [2] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    [3] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Decrease from Baseline in 28-day Seizure

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    End point title
    		 Percentage of Participants with a Decrease from Baseline in 28-day Seizure
    End point description
    A participant with a decrease from baseline in 28-day seizure frequency of greater than or equal to 50% was considered a responder. Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. The primary analysis assessed the percent of responders from Baseline in the Open Label Visit Period. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 59
    End point values
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Number of subjects analysed
    72 [4]
    72 [5]
    Units: Percentage of participants
        number (not applicable)
    55.6
    56.9
    Notes
    [4] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    [5] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    No statistical analyses for this end point

    Secondary: Median Change from Study 312 Baseline in the 28-day Seizure Frequency

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    End point title
    		 Median Change from Study 312 Baseline in the 28-day Seizure Frequency
    End point description
    Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of Study 312 through the Open Label Visit Period.
    End point type
    Secondary
    End point timeframe
    Baseline of Study 312 (Week -8 to Week 0) to Week 59 of Study 313
    End point values
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Number of subjects analysed
    72 [6]
    72 [7]
    Units: Seizures
        median (full range (min-max))
    -3.8 (-89 to 73)
    -4.7 (-95 to 50)
    Notes
    [6] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    [7] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    No statistical analyses for this end point

    Secondary: Median Percent Change from Study 312 Baseline in the 28-day Seizure Frequency during the Open Label Period

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    End point title
    		 Median Percent Change from Study 312 Baseline in the 28-day Seizure Frequency during the Open Label Period
    End point description
    Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of Study 312 through the Open Label Visit Period. Percentage change = 100% x (seizure frequency at period - seizure frequency at Study 312 baseline)/seizure frequency at Study 312 baseline.
    End point type
    Secondary
    End point timeframe
    Baseline of Study 312 (Week -8 to Week 0) to Week 59 of Study 313
    End point values
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Number of subjects analysed
    72 [8]
    72 [9]
    Units: Percentage change
        median (full range (min-max))
    -64.6 (-100 to 174)
    -67.9 (-100 to 262)
    Notes
    [8] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    [9] - Safety population-all participants who entered the study and received at least 1 dose of study drug
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    "Treatment-Emergent Adverse Events (TEAE) were collected, and includes all Adverse Events (AE) with a start date on or after Day 1 and within 15 Days of last dose, including AEs with missing start dates. Participants were followed for up to 61 weeks.
    Adverse event reporting additional description
    Treatment-emergent AEs were summarized by period (Transition, Open-label, Down-titration), treatment group, body system, and preferred term (PT).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11
    Reporting groups
    Reporting group title
    Zonisamide (placebo during core study)
    Reporting group description
    		 Participants previously receiving placebo in Study 312, started dosing with zonisamide at a dose of 1 mg/kg/day and titrated upwards with weekly dose increases until a dose of 8 mg/kg/day was reached at the end of the Transition Period (weeks 2 -11). Down-titration was allowed between the limits of 1 to 8 mg/kg/day during the Open-label Period. Subsequently, a 45-57 week Open-label period followed. Placebo dosing ceased in Open-label Period. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Reporting group title
    Zonisamide (zonisamide during core study)
    Reporting group description
    		 Participants previously receiving zonisamide in Study 312 continued taking the same dose of study drug (8 mg/kg/day),supplemented with an increasing number of placebo capsules to mirror the up-titration regimen being followed by those previously receiving placebo. Down-titration was allowed between the limits of 1 to 8 mg/kg/day during the Open-label Period. Subsequently, a 45-57 week Open-label period followed. In the event of dose-limiting adverse events during the Transition Period, the dose of both placebo and zonisamide could be down-titrated to one level above the minimal dose.

    Serious adverse events
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 72 (9.72%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Foreign body aspiration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zonisamide (placebo during core study) Zonisamide (zonisamide during core study)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 72 (25.00%)
    25 / 72 (34.72%)
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 72 (8.33%)
    6 / 72 (8.33%)
         occurrences all number
    6
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 72 (5.56%)
    7 / 72 (9.72%)
         occurrences all number
    4
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 72 (8.33%)
    9 / 72 (12.50%)
         occurrences all number
    8
    14
    Bronchitis
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 72 (4.17%)
         occurrences all number
    4
    3
    Respiratory tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 72 (5.56%)
         occurrences all number
    5
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 72 (6.94%)
    4 / 72 (5.56%)
         occurrences all number
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2009
    Additional safety text was included regarding management of rashes, monitoring subjects for signs of suicidal ideation, and monitoring/managing hyperchloremic, non-anion gap metabolic acidosis. This was due to a safety update of the SmPC.
    28 Apr 2009
    ● A criterion was added to stipulate that if a female subject became pregnant she must be withdrawn from the study. ● Additional safety text was included regarding management of rashes, monitoring subjects for signs of suicidal ideation, and monitoring/managing hyperchloremic, non-anion gap metabolic acidosis. This was due to a safety update of the SmPC.
    21 Jul 2009
    ● To harmonise pregnancy withdrawal criteria with other ongoing zonisamide studies a criterion was added stipulating that if a female subject became pregnant she must be withdrawn from the study. ● To ensure adequate blinding of the study, laboratory bicarbonate results were to remain blinded to investigators unless they were of potential clinical significance. Since zonisamide is a carbonic anhydrase inhibitor and can be associated with decreased bicarbonate levels, it may have been possible for investigators to determine which treatment a subject was receiving by reviewing their bicarbonate results.
    19 Mar 2010
    ● The following changes were made (in accordance with changes made to the Study 312 protocol) as agreed with the EMA. - The duration of the Open-label Period was reduced from up to 72 weeks to 45 through 57 weeks and the total study duration was reduced from a maximum of 87 weeks to a maximum of 59 weeks. - At the end of the study, subjects who wished to continue taking zonisamide could apply for the treatment in accordance with Eisai’s compassionate use policy; subjects for whom the treatment was stopped were down-titrated. - The number of subjects was reduced from 266 to 204. - The frequency of use of rescue benzodiazepines which led to exclusion was amended to greater than once a week from one or more times a month. - The exclusion criterion for concomitant use of felbamate was amended to within 3 months of Visit 1 from within 2 months of Visit 1. - The frequency of visits and scheduled assessments/events in the double-blind Transition Period and the Open-label Period was reduced. - The cognitive testing battery was modified to comprise only COWAT; it was to be assessed at Study Entry and the Final Visit/Early Termination Visit. Completion of the school performance letter was made optional. - The vital signs assessment was no longer to be performed. - Pregnancy status was to be established using a urine pregnancy test. - For subjects who stopped treatment at the end of the study, the Follow-Up Visit after down-titration was removed and the assessments completed during the follow-up telephone call were amended. - The definition of baseline, for the purposes of the efficacy parameters, and for the purposes of the safety parameters was clarified. - Vital signs and cognitive testing data (other than COWAT data) were to be analyzed only for data collected prior to the implementation of Protocol Amendment 03. Medication compliance was to be summarized. Safety parameters were to be plotted as appropriate.
    19 Mar 2010
    Amendment 3 continued. ● Blinding of bicarbonate results to investigators was only required at the Study Entry Visit (Visit 1) since in the Open-label Period all subjects took zonisamide. ● The guidelines for monitoring/managing hyperchloremic, non-anion gap metabolic acidosis were modified to ensure consistency with the current version of the SmPC. ● Additional exploratory analyses were to be conducted at the end of the study to compare subjects who entered the study pre- and post- Protocol Amendment 03, to explore whether the primary and secondary efficacy endpoints were affected by the increased limit on benzodiazepine use that was introduced in Protocol Amendment 03.

    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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