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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo Controlled, Fixed Dose-Ranging Study to Assess the Safety, Tolerability, and Efficacy of Topiramate Oral Liquid and Sprinkle Formulations as an Adjunct to Concurrent Anticonvulsant Therapy for Infants (1-24 Months of Age, Inclusive) With Refractory Partial-Onset Seizures, With Open-Label Extension

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2005-001338-33
    Trial protocol
    		 GB   FI   HU   CZ   ES   NO   BE   IT  
    Global end of trial date
    01 Nov 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jul 2016
    First version publication date
    15 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    TOPMAT-PEP-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00113815
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Johnson & Johnson Pharmaceutical Research & Development, L.L.C
    Sponsor organisation address
    Archimedsweg 29-2333CM, Leiden, Netherlands, B235-0
    Public contact
    Clinical Registry Group, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, ClinicalTrialsEU@its.jnj.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Nov 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the effectiveness of topiramate 5, 15, or 25 milligram per kilogram per day (mg/kg/day) with that of placebo as an adjunct to concurrent anticonvulsant therapy in reducing daily partial onset seizure (POS) rates in infants (1 to 24 months of age, inclusive) with refractory POS after 20 days of double-blind treatment.
    Protection of trial subjects
    The safety assessments included laboratory measurements (for example hematology, serum chemistry, and urinalysis), anthropometric measurements (body weight, body length, and head circumference), physical and neurological examinations, vineland scales of adaptive behavior, renal ultrasounds, vital sign measurements and electrocardiograms (ECGs). Adverse events were monitored throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 2005
    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
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    India: 76
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Russian Federation: 31
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Ukraine: 14
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    239
    EEA total number of subjects
    39
    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)
    236
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    0
    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
    		 -

    Pre-assignment
    Screening details
    		 Double blind treatment: A total of 120 participants were planned, however 149 participants were enrolled and randomized in the study at 52 participating centers in 19 countries. Open Label Phase: A total of 234 participants were enrolled.

    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, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were received placebo oral solution/capsule orally twice daily for 20 Days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received placebo oral solution twice daily for 20 Days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received placebo capsule orally twice daily for 20 Days.

    Arm title
    		 Topiramate 5 milligram (mg)/killogram (kg)
    Arm description
    		 Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Topiramate Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight oral solution twice daily for 20 Days.

    Investigational medicinal product name
    Topiramate Sprinkle Capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight sprinkle capsule orally twice daily for 20 Days.

    Arm title
    		 Topiramate 15 milligram (mg)/killogram (kg)
    Arm description
    		 Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Topiramate Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight oral solution twice daily for 20 Days.

    Investigational medicinal product name
    Topiramate Sprinkle Capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight sprinkle capsule orally twice daily for 20 Days.

    Arm title
    		 Topiramate 25 milligram (mg)/killogram (kg)
    Arm description
    		 Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Topiramate Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight oral solution twice daily for 20 Days.

    Investigational medicinal product name
    Topiramate Sprinkle Capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight sprinkle capsule orally twice daily for 20 Days.

    Arm title
    		 Open Label Phase: Topiramate
    Arm description
    		 Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Topiramate Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution twice daily for 1 Year.

    Investigational medicinal product name
    Topiramate Sprinkle Capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight sprinkle capsule orally twice daily for 1 Year.

    Number of subjects in period 1
    		Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg) Open Label Phase: Topiramate
    Started
    37
    38
    37
    37
    90
    Completed
    29
    34
    33
    34
    57
    Not completed
    8
    4
    4
    3
    33
         Adverse event, serious fatal
    -
    -
    -
    -
    2
         Consent withdrawn by subject
    1
    -
    -
    -
    12
         Adverse event, non-fatal
    1
    -
    1
    1
    -
         Other
    4
    3
    2
    2
    11
         Adverse event, serious non-fatal
    -
    -
    -
    -
    2
         Adverse event, serious non-fatal
    1
    1
    1
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    3
         Lack of efficacy
    1
    -
    -
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were received placebo oral solution/capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 5 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 15 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 25 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Open Label Phase: Topiramate
    Reporting group description
    		 Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.

    Reporting group values
    		 Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg) Open Label Phase: Topiramate Total
    Number of subjects
    		 37 38 37 37 90 239
    Title for AgeCategorical
    Units: subjects
        infants and toddlers(28 days-23 months)
    		 37 37 36 37 89 236
        Children (2-11 years)
    		 0 1 1 0 1 3
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65 to 84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Title for AgeContinuous
    Units: months
        arithmetic mean (standard deviation)
    		 11.8 ( 5.91 ) 13.3 ( 7.56 ) 12.4 ( 6.15 ) 10.2 ( 5.16 ) 12.7 ( 6.27 ) -
    Title for Gender
    Units: subjects
        Female
    		 23 16 18 14 40 111
        Male
    		 14 22 19 23 50 128

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were received placebo oral solution/capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 5 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 15 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Topiramate 25 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Open Label Phase: Topiramate
    Reporting group description
    		 Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.

    Primary: Percentage Reduction in Daily Partial Onset Seizure Rate From Baseline to End of the Double Blind Phase

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    End point title
    		 Percentage Reduction in Daily Partial Onset Seizure Rate From Baseline to End of the Double Blind Phase [1] [2]
    End point description
    Daily partial onset seizure (POS) rate was evaluated based on video electroencephalogram (vEEG) data. For participants who had zero baseline seizure and the postseizure number is more than zero, value -8999 was imputed as the percent reduction in accordance with the worst-rank analysis.
    End point type
    Primary
    End point timeframe
    Baseline and End of Double Blind Phase (Day 20)
    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: Descriptive statistics were done, no inferential statistical analyses were performed
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg)
    Number of subjects analysed
    28
    34
    34
    34
    Units: percentage (%)
        median (full range (min-max))
    13.06 (-8999 to 100)
    23.83 (-8999 to 100)
    5.53 (-8999 to 100)
    20.4 (-8999 to 100)
    No statistical analyses for this end point

    Secondary: Number of Treatment Responder Participants

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    End point title
    		 Number of Treatment Responder Participants [3]
    End point description
    A treatment responder was defined as a participant who had at least a 50 percent (%) reduction from baseline in seizure rate for a specific seizure type based on video electroencephalogram (vEEG) data.
    End point type
    Secondary
    End point timeframe
    End of Double Blind Phase (Day 20)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg)
    Number of subjects analysed
    28
    34
    34
    34
    Units: Participants
    10
    9
    13
    15
    No statistical analyses for this end point

    Secondary: Percentage Reduction in Daily Seizure Rate for All Seizure Types From Baseline to End of the Double-Blind Phase

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    End point title
    		 Percentage Reduction in Daily Seizure Rate for All Seizure Types From Baseline to End of the Double-Blind Phase [4]
    End point description
    Daily Seizure Rate for All Seizure Types was evaluated based on video electroencephalogram (vEEG) data. For participants who had zero baseline seizure and the postseizure number is more than zero, value -8999 was imputed as the percent reduction in accordance with the worst-rank analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Double Blind Phase (Day 20)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg)
    Number of subjects analysed
    28
    34
    34
    34
    Units: percentage (%)
        median (full range (min-max))
    15.68 (-8999 to 100)
    23.83 (-8999 to 100)
    5.53 (-8999 to 100)
    20.4 (-8999 to 100)
    No statistical analyses for this end point

    Secondary: Percent Reduction in Daily Seizure Rate for Partial Onset Seizure (POS) and All Seizure Types

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    End point title
    		 Percent Reduction in Daily Seizure Rate for Partial Onset Seizure (POS) and All Seizure Types [5]
    End point description
    Daily Seizure Rate for Partial Onset Seizure (POS) and All Seizure Types was evaluated based on participant take-home records. For participants who had zero baseline seizure and the postseizure number is more than zero, value -8999 was imputed as the percent reduction in accordance with the worst-rank analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Double Blind Phase (Day 20)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 Placebo Topiramate 5 milligram (mg)/killogram (kg) Topiramate 15 milligram (mg)/killogram (kg) Topiramate 25 milligram (mg)/killogram (kg)
    Number of subjects analysed
    37
    38
    37
    37
    Units: percentage (%)
        median (full range (min-max))
    9.87 (-8999 to 97.7)
    29.63 (-8999 to 100)
    0.08 (-8999 to 100)
    15.79 (-8999 to 100)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to follow-up (30 days after last treatment visit)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 WHOART
    Dictionary version
    SOC3
    Reporting groups
    Reporting group title
    Open Label Phase: Placebo/Topiramate
    Reporting group description
    		 Participants were received Placebo/Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.

    Reporting group title
    Open Label Phase: Topiramate
    Reporting group description
    		 Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.

    Reporting group title
    Open Label Phase: Topiramate/Topiramate
    Reporting group description
    		 Participants were received Topiramate up to 60 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 1 Year.

    Reporting group title
    Double Blind Phase: Placebo
    Reporting group description
    		 Participants were received placebo oral solution/capsule orally twice daily for 20 Days.

    Reporting group title
    Double Blind Phase: Topiramate 5 milligram (mg)/killogram (kg)
    Reporting group description
    		 Participants were received Topiramate 5 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Double Blind Phase: Topiramate 15 milligram (mg)/killogram(kg)
    Reporting group description
    		 Participants were received Topiramate 15 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Reporting group title
    Double Blind Phase: Topiramate 25 milligram (mg)/killogram(kg)
    Reporting group description
    		 Participants were received Topiramate 25 milligram (mg) per killigram (kg) of body weight oral solution/sprinkle capsule orally twice daily for 20 Days.

    Serious adverse events
    		 Open Label Phase: Placebo/Topiramate Open Label Phase: Topiramate Open Label Phase: Topiramate/Topiramate Double Blind Phase: Placebo Double Blind Phase: Topiramate 5 milligram (mg)/killogram (kg) Double Blind Phase: Topiramate 15 milligram (mg)/killogram(kg) Double Blind Phase: Topiramate 25 milligram (mg)/killogram(kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 36 (47.22%)
    34 / 90 (37.78%)
    45 / 108 (41.67%)
    3 / 37 (8.11%)
    3 / 38 (7.89%)
    4 / 37 (10.81%)
    4 / 37 (10.81%)
         number of deaths (all causes)
    0
    2
    6
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm Nos
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse Event Nos
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 90 (4.44%)
    5 / 108 (4.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    5 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Simplex
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    4 / 108 (3.70%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection Viral
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    5 / 108 (4.63%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 8
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unexpected Therapeutic Effect
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 90 (3.33%)
    7 / 108 (6.48%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 10
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 90 (1.11%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 90 (4.44%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 36 (11.11%)
    9 / 90 (10.00%)
    8 / 108 (7.41%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 15
    0 / 13
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 90 (1.11%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Insufficiency
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Resp Tract Infection
         subjects affected / exposed
    1 / 36 (2.78%)
    6 / 90 (6.67%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anorexia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    3 / 3
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomegaly
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory Failure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsions
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsions Aggravated
         subjects affected / exposed
    4 / 36 (11.11%)
    9 / 90 (10.00%)
    11 / 108 (10.19%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 16
    9 / 23
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsions Grand Mal
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 90 (4.44%)
    0 / 108 (0.00%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever Convulsions
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait Abnormal
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leucopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 90 (3.33%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 90 (1.11%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 90 (3.33%)
    8 / 108 (7.41%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroesophageal Reflux
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Enzymes Increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular Damage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Calculus
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 90 (2.22%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Development Abnormal
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 90 (0.00%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 90 (2.22%)
    4 / 108 (3.70%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    6 / 6
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 90 (3.33%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Growth Retarded
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight Decrease
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open Label Phase: Placebo/Topiramate Open Label Phase: Topiramate Open Label Phase: Topiramate/Topiramate Double Blind Phase: Placebo Double Blind Phase: Topiramate 5 milligram (mg)/killogram (kg) Double Blind Phase: Topiramate 15 milligram (mg)/killogram(kg) Double Blind Phase: Topiramate 25 milligram (mg)/killogram(kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 36 (91.67%)
    84 / 90 (93.33%)
    105 / 108 (97.22%)
    19 / 37 (51.35%)
    29 / 38 (76.32%)
    28 / 37 (75.68%)
    31 / 37 (83.78%)
    Nervous system disorders
    Convulsions Aggravated
         subjects affected / exposed
    4 / 36 (11.11%)
    11 / 90 (12.22%)
    21 / 108 (19.44%)
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    7
    17
    52
    1
    4
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 90 (4.44%)
    5 / 108 (4.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    4
    6
    9
    0
    0
    0
    0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    18 / 36 (50.00%)
    48 / 90 (53.33%)
    47 / 108 (43.52%)
    4 / 37 (10.81%)
    11 / 38 (28.95%)
    9 / 37 (24.32%)
    9 / 37 (24.32%)
         occurrences all number
    51
    121
    113
    11
    18
    11
    11
    Infection
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 90 (0.00%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    3
    0
    0
    1
    0
    Infection Viral
         subjects affected / exposed
    10 / 36 (27.78%)
    23 / 90 (25.56%)
    20 / 108 (18.52%)
    0 / 37 (0.00%)
    4 / 38 (10.53%)
    0 / 37 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    21
    33
    37
    0
    4
    0
    4
    Injury
         subjects affected / exposed
    4 / 36 (11.11%)
    8 / 90 (8.89%)
    4 / 108 (3.70%)
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    9
    12
    4
    2
    1
    0
    2
    Otitis Media
         subjects affected / exposed
    2 / 36 (5.56%)
    19 / 90 (21.11%)
    8 / 108 (7.41%)
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    2 / 37 (5.41%)
         occurrences all number
    3
    42
    25
    0
    4
    1
    5
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 36 (2.78%)
    8 / 90 (8.89%)
    7 / 108 (6.48%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    13
    9
    1
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 36 (8.33%)
    8 / 90 (8.89%)
    9 / 108 (8.33%)
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    7
    14
    15
    1
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    9 / 36 (25.00%)
    22 / 90 (24.44%)
    23 / 108 (21.30%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    4 / 37 (10.81%)
    3 / 37 (8.11%)
         occurrences all number
    11
    29
    46
    0
    1
    7
    4
    Gastroenteritis
         subjects affected / exposed
    5 / 36 (13.89%)
    12 / 90 (13.33%)
    13 / 108 (12.04%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    5
    12
    16
    0
    3
    0
    0
    Gastroesophageal Reflux
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 90 (2.22%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    2
    1
    0
    0
    0
    0
    Mouth Dry
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Saliva Increased
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 90 (1.11%)
    0 / 108 (0.00%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    2
    1
    0
    2
    0
    0
    3
    Tooth Disorder
         subjects affected / exposed
    3 / 36 (8.33%)
    10 / 90 (11.11%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    9
    14
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    11 / 36 (30.56%)
    15 / 90 (16.67%)
    26 / 108 (24.07%)
    2 / 37 (5.41%)
    7 / 38 (18.42%)
    3 / 37 (8.11%)
    6 / 37 (16.22%)
         occurrences all number
    38
    18
    95
    4
    15
    3
    10
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    7 / 36 (19.44%)
    9 / 90 (10.00%)
    18 / 108 (16.67%)
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    1 / 37 (2.70%)
    4 / 37 (10.81%)
         occurrences all number
    11
    13
    45
    0
    5
    1
    9
    Bronchospasm
         subjects affected / exposed
    0 / 36 (0.00%)
    8 / 90 (8.89%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    1 / 37 (2.70%)
         occurrences all number
    0
    13
    8
    0
    0
    2
    2
    Coughing
         subjects affected / exposed
    6 / 36 (16.67%)
    14 / 90 (15.56%)
    19 / 108 (17.59%)
    2 / 37 (5.41%)
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    4 / 37 (10.81%)
         occurrences all number
    8
    23
    26
    2
    4
    1
    6
    Pharyngitis
         subjects affected / exposed
    7 / 36 (19.44%)
    10 / 90 (11.11%)
    5 / 108 (4.63%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    7
    20
    12
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 36 (8.33%)
    6 / 90 (6.67%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    7
    3
    0
    0
    0
    0
    Respiratory Disorder
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 90 (3.33%)
    1 / 108 (0.93%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    5
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    6 / 36 (16.67%)
    17 / 90 (18.89%)
    13 / 108 (12.04%)
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    2 / 37 (5.41%)
         occurrences all number
    11
    33
    20
    0
    3
    1
    2
    Sinusitis
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 90 (5.56%)
    2 / 108 (1.85%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    12
    5
    0
    2
    0
    0
    Upper Resp Tract Infection
         subjects affected / exposed
    13 / 36 (36.11%)
    50 / 90 (55.56%)
    41 / 108 (37.96%)
    5 / 37 (13.51%)
    10 / 38 (26.32%)
    9 / 37 (24.32%)
    8 / 37 (21.62%)
         occurrences all number
    42
    174
    132
    8
    14
    13
    14
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    3 / 36 (8.33%)
    8 / 90 (8.89%)
    8 / 108 (7.41%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    2 / 37 (5.41%)
    0 / 37 (0.00%)
         occurrences all number
    3
    12
    9
    0
    1
    4
    0
    Dermatitis Contact
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 90 (3.33%)
    1 / 108 (0.93%)
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    7
    1
    4
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 90 (5.56%)
    9 / 108 (8.33%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences all number
    3
    8
    16
    0
    2
    1
    0
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 90 (0.00%)
    5 / 108 (4.63%)
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    9
    4
    0
    0
    0
    Skin Dry
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 90 (0.00%)
    3 / 108 (2.78%)
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    4
    0
    2
    0
    0
    Psychiatric disorders
    Anorexia
         subjects affected / exposed
    7 / 36 (19.44%)
    32 / 90 (35.56%)
    31 / 108 (28.70%)
    2 / 37 (5.41%)
    4 / 38 (10.53%)
    4 / 37 (10.81%)
    8 / 37 (21.62%)
         occurrences all number
    10
    74
    57
    3
    6
    11
    11
    Insomnia
         subjects affected / exposed
    1 / 36 (2.78%)
    10 / 90 (11.11%)
    4 / 108 (3.70%)
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    19
    6
    1
    2
    0
    1
    Nervousness
         subjects affected / exposed
    4 / 36 (11.11%)
    16 / 90 (17.78%)
    8 / 108 (7.41%)
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    3 / 37 (8.11%)
    1 / 37 (2.70%)
         occurrences all number
    11
    29
    13
    0
    3
    8
    1
    Somnolence
         subjects affected / exposed
    7 / 36 (19.44%)
    22 / 90 (24.44%)
    18 / 108 (16.67%)
    3 / 37 (8.11%)
    3 / 38 (7.89%)
    8 / 37 (21.62%)
    6 / 37 (16.22%)
         occurrences all number
    13
    52
    38
    5
    5
    13
    11
    Renal and urinary disorders
    Renal Calculus
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 90 (4.44%)
    5 / 108 (4.63%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    8
    7
    0
    0
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    7 / 90 (7.78%)
    4 / 108 (3.70%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    9
    5
    0
    0
    0
    0
    Infections and infestations
    Vaginitis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 90 (0.00%)
    0 / 108 (0.00%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    13 / 36 (36.11%)
    22 / 90 (24.44%)
    31 / 108 (28.70%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    3 / 37 (8.11%)
         occurrences all number
    20
    37
    64
    0
    0
    5
    4
    Growth Retarded
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 90 (0.00%)
    9 / 108 (8.33%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    14
    0
    0
    0
    2
    Hyperammonaemia
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 90 (3.33%)
    8 / 108 (7.41%)
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    4
    4
    14
    0
    0
    0
    0
    Hyperchloraemia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 90 (1.11%)
    4 / 108 (3.70%)
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    5
    2
    0
    2
    0
    Weight Decrease
         subjects affected / exposed
    3 / 36 (8.33%)
    9 / 90 (10.00%)
    20 / 108 (18.52%)
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    3 / 37 (8.11%)
    4 / 37 (10.81%)
         occurrences all number
    10
    19
    40
    2
    2
    6
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2005
    The overall reason for the amendment was to clarify exclusion criteria relating to seizure history and study procedures, including adjustment of blood volumes drawn, study drug storage conditions, entry into the open-label extension, and special instructions for prematurely born participants. One of the secondary efficacy variables of the statistical analysis was modified (included all seizure types), instructions for manual assignment to the open-label extension phase prior to starting the interactive voice response system (IVRS) were provided, and other minor errors were corrected.
    15 Apr 2005
    The overall reason for the amendment was to include additional safety measures or precautions, such as measurement of blood pressure, age limitation for enrollment, and documentation of inadequacy of current epilepsy treatment.
    03 May 2006
    The overall reason for the amendment was to incorporate investigator and regulatory authority feedback.
    14 Feb 2007
    The overall reason for the amendment was to write in response to a request from the United States Food and Drug Administration to reverse parts of Amendment INT-3. The time required after rescue treatment before the video electroencephalogram (vEEG) could begin was decreased from 48 to 12 hours in Amendment INT-3 and changed back to at least 48 hours after any rescue treatment with this amendment.

    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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    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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