Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   37227   clinical trials with a EudraCT protocol, of which   6125   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Efficacy and safety of Eslicarbazepine Acetate (BIA 2 093) as adjunctive therapy for refractory partial seizures in children: a double-blind, randomised, placebo-controlled, parallel-group, multicentre clinical trial

    Summary
    EudraCT number
    2007-001887-55
    Trial protocol
    PT   HU   CZ   AT   FR   SK   IT   ES   GB   DE  
    Global end of trial date
    24 Aug 2017

    Results information
    Results version number
    v3(current)
    This version publication date
    11 Mar 2018
    First version publication date
    07 Aug 2015
    Other versions
    v1 , v2
    Version creation reason
    Summary report(s)
    BIA-2093-305_Synopsis_part I-II
    BIA-2093-305_Synopsis_part III-V
    BIA-2093-305_Synopsis Part III- V final

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BIA-2093-305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00988156
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    BIAL - Portela & CA, S.A.
    Sponsor organisation address
    À Av. Siderurgia Nacional, Coronado, Portugal, 4745-457
    Public contact
    André Garrido, BIAL - Portela & Cª, S.A., 00351 229866100, andre.garrido@bial.com
    Scientific contact
    Helena Gama, BIAL - Portela & Cª, S.A., 00351 229866100, helena.gama@bial.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000696-PIP02-10
    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
    19 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: The primary objective of the study is to assess the efficacy of Eslicarbazepine Acetate as adjunctive therapy in children and adolescents with refractory partial seizures. The primary analysis variables for the assessment of efficacy will be: 1. the responder rate, defined as the proportion of patients with at least a 50% decrease in the standardised seizure frequency 2. the relative reduction in the standardised seizure frequency
    Protection of trial subjects
    The trial was conducted in accordance with the International Conference on Harmonisation (ICH), Good Clinical Practices (GCP), Good Manufacturing Practice (GMP), the ethical principles of the Declaration of Helsinki and with applicable local regulations. This trial was conducted by qualified persons who respected the rights and welfare of the subjects and after the review and approval of the protocol by an EC. Adverse events were collected throughout the trial and subject was followed by 4 weeks after last treatment visit in the double blind phase and 4 weeks after last treatment visit in the open blind phase.
    Background therapy
    Concomitant AED therapy (1 or 2 AEDs).
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Dec 2007
    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
    Austria: 3
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 4
    Country: Number of subjects enrolled
    Czech Republic: 31
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Hungary: 38
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Serbia: 37
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Ukraine: 63
    Worldwide total number of subjects
    304
    EEA total number of subjects
    160
    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)
    207
    Adolescents (12-17 years)
    96
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The patient recruitment period will last approximately 66 months. The actual overall study duration or patient recruitment period may vary.

    Pre-assignment
    Screening details
    Subjects who met all the inclusion criteria and none of the exclusion criteria. 370 subjects were enrolled to the trial and 66 subjects were screening failures including 5 IMP recalls and 41 randomised subjects were IMP recall.

    Pre-assignment period milestones
    Number of subjects started
    370 [1]
    Number of subjects completed
    263

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 2
    Reason: Number of subjects
    Consent withdrawn by subject: 3
    Reason: Number of subjects
    Physician decision: 1
    Reason: Number of subjects
    Ineligibility: 44
    Reason: Number of subjects
    Treatment with > 2 conc. AEDs at the same time: 5
    Reason: Number of subjects
    IMP recall: 46
    Reason: Number of subjects
    Sponsor decision: 6
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to have started the pre-assignment period is the number of enrolled subjects; The worldwide number of subjects enrolled in the trial is number of randomised subjects.
    Period 1
    Period 1 title
    PART I: DOUBLE-BLIND TREATMENT
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part I - Placebo
    Arm description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL placebo oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg placebo tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Titration period: First 2 weeks: 10 mg/kg/day; Next 4 weeks: 20 mg/kg/day (maximum 1200 mg/day) (if no AE occurred), 10 mg/kg/day (if AE occurred); Maintenance period: Next 12 weeks: 20 mg/kg/day (if acceptable tolerability), 30 mg/kg/day (maximum 1200 mg/day) (if unsatisfactory response), 10 mg/kg/day (if during the previous period will receive this dose) Tapering-off \follow-up period: After the 12-week maintenance period, the study treatment will be tapered off in 10 mg/kg/day steps every 2 weeks, followed by a 4 week observational follow-up period.

    Arm title
    Part I - ESL
    Arm description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Arm type
    Active comparator

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Titration period: First 2 weeks: 10 mg/kg/day; Next 4 weeks: 20 mg/kg/day (maximum 1200 mg/day) (if no AE occurred), 10 mg/kg/day (if AE occurred); Maintenance period: Next 12 weeks: 20 mg/kg/day (if acceptable tolerability), 30 mg/kg/day (maximum 1200 mg/day) (if unsatisfactory response), 10 mg/kg/day (if during the previous period will receive this dose) Tapering-off \follow-up period: After the 12-week maintenance period, the study treatment will be tapered off in 10 mg/kg/day steps every 2 weeks, followed by a 4 week observational follow-up period.

    Number of subjects in period 1 [2]
    Part I - Placebo Part I - ESL
    Started
    129
    134
    Completed
    118
    120
    Not completed
    11
    14
         Physician decision
    2
    2
         Lack of efficacy
    1
    -
         Other reason
    1
    -
         Adverse event, serious fatal
    1
    1
         Not serious AE and lack of efficacy
    -
    1
         Adverse event, non-fatal
    1
    2
         Consent withdrawn by subject
    5
    5
         Adverse event, serious non-fatal
    -
    2
         Treatment with > 2 conc. AEDs at the same time
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period does not include 41 subjects with IMP recall.
    Period 2
    Period 2 title
    PART II: OPEN-LABEL EXTENSION PERIOD
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Part II - ESL
    Arm description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Arm type
    Active comparator

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. The starting dose will be 10 mg/kg/day or 800 mg/day for patients with high body weight. The daily dose will be titrated by the investigator according to clinical response in the dose range from 10 mg/kg/day to 30 mg/kg/day (or 800 mg/day to maximum 1200 mg/day for patients with high body weight). Down-titration will be allowed during Part II according to clinical response or in case of intolerable AEs.

    Number of subjects in period 2 [3]
    Part II - ESL
    Started
    226
    Completed
    163
    Not completed
    63
         Physician decision
    3
         At the specific request of the sponsor
    2
         Lack of efficacy
    30
         Other reason
    3
         Adverse event, non-fatal
    6
         Consent withdrawn by subject
    16
         Adverse event, serious non-fatal
    3
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects 238 completed double blind part and 12 of them did not start open label part.
    Period 3
    Period 3 title
    PART III-V: OPEN-LABEL EXTENSION PERIOD
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Part III - V - ESL
    Arm description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Arm type
    Active comparator

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Part III starting dose will be the same dose of Eslicarbazepine Acetate that patient was receiving at the end of the Part II, unless investigator decides to titrate this dose to achieve further reduction in seizure frequency or due to the occurrence of any intolerable AEs. Eslicarbazepine Acetate dose titration schema during this study extension (Part III) will be the same defined for study Part II. The daily dose will be titrated by the investigator according to clinical response in the dose range from 10 mg/kg/day to 30 mg/kg/day (or 800 mg/day to maximum 1200 mg/day for patients with high body weight). The maximum Eslicarbazepine Acetate dosage will be 1200 mg once daily. Down-titration will be allowed during Part III according to clinical response or in case of intolerable AEs. The same dosage will be applied in the Part IV and Part V as in the Part III.

    Number of subjects in period 3 [4]
    Part III - V - ESL
    Started
    152
    Completed
    14
    Not completed
    138
         Physician decision
    1
         Discontinued after Part IV
    6
         At the specific request of the sponsor
    82
         Lack of efficacy
    10
         Other reason
    4
         Adverse event, serious fatal
    2
         Switched to Zebinix
    3
         Consent withdrawn by subject
    13
         Discontinued after Part III
    13
         Lost to follow-up
    4
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects 183 completed Part II and 31 of them did not start Part III-V.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part I - Placebo
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL placebo oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg placebo tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.

    Reporting group title
    Part I - ESL
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.

    Reporting group values
    Part I - Placebo Part I - ESL Total
    Number of subjects
    129 134 263
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    0 0 0
        Preterm newborn- gestational age < 37 wk
    0 0 0
        Newborns (0-27days)
    0 0 0
        Infants and toddlers (28days – 23months)
    0 0 0
        Children (2-11 years)
    84 82 166
        Adolescents (12-17 year)
    45 51 96
        From 18 - 64 years
    0 1 1
        From 65 – 84 years
    0 0 0
        Over 85 years
    0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    9.5 ± 3.85 9.9 ± 4.22 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    67 70 137
        Male
    62 64 126

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Part I - Placebo
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL placebo oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg placebo tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.

    Reporting group title
    Part I - ESL
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Reporting group title
    Part II - ESL
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.
    Reporting group title
    Part III - V - ESL
    Reporting group description
    Patients aged 2–6 years will receive the study treatment as 50 mg/mL Eslicarbazepine Acetate oral suspension. Patients aged 7 or over will receive the study treatment in the form of 200 mg Eslicarbazepine Acetate tablets. The study treatment should be administered once daily, preferably at the same time of the day. The maximum absolute dosage will be 1200 mg once daily. Subjects without IMP recall.

    Subject analysis set title
    Part I - Placebo x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of double-blind study treatment excluding those stratum I patients who were randomised before the IMP recall

    Subject analysis set title
    Part I - ESL x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of double-blind study treatment excluding those stratum I patients who were randomised before the IMP recall

    Subject analysis set title
    Part I - Placebo x Intent-to-treat Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients randomised, treated with at least one dose of study medication after randomisation, and with at least one post-baseline seizure frequency assessment excluding those stratum I patients who were randomised before the IMP recall

    Subject analysis set title
    Part I - ESL x Intent-to-treat Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients randomised, treated with at least one dose of study medication after randomisation, and with at least one post-baseline seizure frequency assessment excluding those stratum I patients who were randomised before the IMP recall

    Subject analysis set title
    Part I - Placebo x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the ITT without any major protocol deviations

    Subject analysis set title
    Part I - ESL x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the ITT without any major protocol deviations

    Subject analysis set title
    Part II - ESL x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients entering Part II who received at least one dose of Eslicarbazepine Acetate during the open-label extension period excluding stratum I patients randomised before the IMP recall irrespective of treatment with suspension or tablets in Part II

    Subject analysis set title
    Part II - ESL x Intent-to-treat Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients entering Part II, treated with at least one dose of Eslicarbazepine Acetate during the open-label extension period, and with at least one seizure frequency assessment during the extension period excluding stratum I patients randomised before the IMP recall irrespective of treatment with suspension or tablets in Part II

    Subject analysis set title
    Part III-V - ESL x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients entering Part III – V, treated with at least one dose of Eslicarbazepine Acetate during the open-label extension period (Part III – V)

    Subject analysis set title
    Part III-V - ESL x Intent-to-treat Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients entering Part III – V, treated with at least one dose of Eslicarbazepine Acetate during the open-label extension period (Part III – V), and with at least one seizure frequency assessment during the extension period (Part III – V)

    Primary: Responder rate in the Part I

    Close Top of page
    End point title
    Responder rate in the Part I
    End point description
    Responder rate defined as the number of patients with at least a 50% decrease in the standardised 4-week seizure frequency from the baseline period to the 12-week maintenance period
    End point type
    Primary
    End point timeframe
    Baseline up to Visit 7 in the Part I
    End point values
    Part I - Placebo x Intent-to-treat Set Part I - ESL x Intent-to-treat Set
    Number of subjects analysed
    129
    134
    Units: Participants
    number (not applicable)
        Participants
    40
    41
    Statistical analysis title
    Cochran—Mantel—Haenszel—test strat. by age stratum
    Statistical analysis description
    The responder rate during the 12-week maintenance period were analysed by a Cochran-Mantel-Haenszel (CMH) test with age stratum as stratification factor.
    Comparison groups
    Part I - ESL x Intent-to-treat Set v Part I - Placebo x Intent-to-treat Set
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.9017
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.63

    Primary: Relative Reduction From Baseline in Seizure Frequency in the Part I

    Close Top of page
    End point title
    Relative Reduction From Baseline in Seizure Frequency in the Part I
    End point description
    Relative reduction in the standardised 4-week seizure frequency from the baseline period to the 12-week maintenance period
    End point type
    Primary
    End point timeframe
    Baseline up to Visit 7 in the Part I
    End point values
    Part I - Placebo x Intent-to-treat Set Part I - ESL x Intent-to-treat Set
    Number of subjects analysed
    129
    134
    Units: Seizures
    least squares mean (standard error)
        Seizures
    -8.6 ± 5.93
    -18.1000000000 ± 5.84
    Statistical analysis title
    ANCOVA model for comparison
    Statistical analysis description
    ANCOVA model with treatment and stratum group as fixed effects and baseline seizure frequency as a covariate.
    Comparison groups
    Part I - Placebo x Intent-to-treat Set v Part I - ESL x Intent-to-treat Set
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.249
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.71
         upper limit
    25.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.25

    Primary: Relative Change From Baseline in Seizure Frequency in the Part I

    Close Top of page
    End point title
    Relative Change From Baseline in Seizure Frequency in the Part I [1]
    End point description
    Relative change in the standardised 4-week seizure frequency from the baseline period to the 12-week maintenance period
    End point type
    Primary
    End point timeframe
    Baseline up to Visit 7 in the Part I
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Part I - Placebo x Intent-to-treat Set Part I - ESL x Intent-to-treat Set
    Number of subjects analysed
    129
    134
    Units: Seizures
    arithmetic mean (standard deviation)
        Seizures
    -9.6 ± 70.1500000000
    -19.2 ± 64.1000000000
    No statistical analyses for this end point

    Primary: Responder rate in the Part II

    Close Top of page
    End point title
    Responder rate in the Part II [2]
    End point description
    Responder rate defined as the number of patients with at least a 50% decrease in the standardised 4-week seizure frequency
    End point type
    Primary
    End point timeframe
    Baseline till the end of Part II
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Part II - ESL x Intent-to-treat Set
    Number of subjects analysed
    225
    Units: Participants
    number (not applicable)
        Participants
    105
    No statistical analyses for this end point

    Primary: Relative Change From Baseline in Seizure Frequency in the Part II

    Close Top of page
    End point title
    Relative Change From Baseline in Seizure Frequency in the Part II [3]
    End point description
    Relative change in the standardised 4-week seizure frequency
    End point type
    Primary
    End point timeframe
    Baseline till the end of Part II
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Part II - ESL x Intent-to-treat Set
    Number of subjects analysed
    225
    Units: Seizures
    arithmetic mean (standard deviation)
        Seizures
    -33.9 ± 58.65
    No statistical analyses for this end point

    Primary: Responder rate in the Part III-V

    Close Top of page
    End point title
    Responder rate in the Part III-V [4]
    End point description
    Responder rate defined as the number of patients with at least a 50% decrease in the standardised 4-week seizure frequency
    End point type
    Primary
    End point timeframe
    Baseline till the end of Part III-V
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Part III-V - ESL x Intent-to-treat Set
    Number of subjects analysed
    148
    Units: Participants
    number (not applicable)
        Participants
    104
    No statistical analyses for this end point

    Primary: Relative Change From Baseline in Seizure Frequency in the Part III

    Close Top of page
    End point title
    Relative Change From Baseline in Seizure Frequency in the Part III [5]
    End point description
    Relative change in the standardised 4-week seizure frequency
    End point type
    Primary
    End point timeframe
    Baseline till the end of Part III
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Part III-V - ESL x Intent-to-treat Set
    Number of subjects analysed
    148
    Units: Seizures
    arithmetic mean (standard deviation)
        Seizures
    -59.3 ± 50.37
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the date of first study treatment up to 28 days after the last dose of study medication in the corresponding part.
    Adverse event reporting additional description
    Part I: up to the date of visit FU1 for patients continuing if the visit occurs within these 28 days Part II: up to 28 days after the last dose of IMP for patients discontinuing treatment during Part II or the date of Visit OL6 for patients continuing with treatment in Part III of the study Part III-V: up to 28 days after the last dose of IMP
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Part I - Placebo x Safety Set
    Reporting group description
    Subjects in the Safety Set treated with placebo during Part I

    Reporting group title
    Part I - ESL x Safety Set
    Reporting group description
    Subjects in the Safety Set treated with ESL during Part I

    Reporting group title
    Part II - ESL x Safety Set
    Reporting group description
    Subjects in the Safety Set treated with ESL during Part II

    Reporting group title
    Part III-V - ESL x Safety Set
    Reporting group description
    Subjects in the Safety Set treated with ESL during Part III - V

    Serious adverse events
    Part I - Placebo x Safety Set Part I - ESL x Safety Set Part II - ESL x Safety Set Part III-V - ESL x Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 129 (6.98%)
    15 / 134 (11.19%)
    23 / 226 (10.18%)
    19 / 152 (12.50%)
         number of deaths (all causes)
    1
    1
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device change
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Conduct disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 134 (1.49%)
    6 / 226 (2.65%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nystagmus
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 134 (2.24%)
    2 / 226 (0.88%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otosalpingitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash vesicular
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular purpura
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dengue fever
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Infectious mononucleosis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 129 (2.33%)
    1 / 134 (0.75%)
    4 / 226 (1.77%)
    4 / 152 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part I - Placebo x Safety Set Part I - ESL x Safety Set Part II - ESL x Safety Set Part III-V - ESL x Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 129 (71.32%)
    108 / 134 (80.60%)
    172 / 226 (76.11%)
    97 / 152 (63.82%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    2
    Clavicle fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Concussion
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 134 (2.24%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    1
    3
    0
    2
    Drug toxicity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Excoriation
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Face injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    3
    1
    Fall
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    7
    0
    Foot fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Forearm fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Hand fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Head injury
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    4 / 226 (1.77%)
    1 / 152 (0.66%)
         occurrences all number
    1
    2
    4
    1
    Injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    2
    Ligament sprain
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Lip injury
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Overdose
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Poisoning
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Radius fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    2
    Skin injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Skin wound
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Tibia fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Tooth fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth injury
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toxicity to various agents
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wrist fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    2
    0
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    5 / 152 (3.29%)
         occurrences all number
    2
    2
    1
    5
    Blood glucose decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    1
    0
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Blood triglycerides increased
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    2
    0
    1
    1
    Body temperature increased
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    1
    1
    0
    2
    Breath sounds abnormal
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ecg p wave inverted
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Electrocardiogram pr shortened
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Electrocardiogram pr prolongation
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Electrocardiogram qrs complex prolonged
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Electrocardiogram qt prolonged
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    1
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    7 / 226 (3.10%)
    9 / 152 (5.92%)
         occurrences all number
    1
    1
    7
    10
    Haemoglobin decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Platelet count increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Positive rombergism
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Rheumatoid factor increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thyroxine decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thyroxine increased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    2
    2
    Weight decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    4 / 152 (2.63%)
         occurrences all number
    0
    0
    1
    5
    Weight increased
         subjects affected / exposed
    2 / 129 (1.55%)
    5 / 134 (3.73%)
    3 / 226 (1.33%)
    2 / 152 (1.32%)
         occurrences all number
    2
    5
    3
    2
    White blood cell count increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Bradyarrhythmia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Bundle branch block right
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Wolff-parkinson-white syndrome
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Phimosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    0
    1
    1
    2
    Leukopenia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pancytopenia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    2
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 134 (2.24%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Balance disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cerebellar ataxia
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 134 (2.24%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    1
    3
    3
    0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Circadian rhythm sleep disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    4
    Cognitive disorder
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    1
    0
    1
    2
    Convulsion
         subjects affected / exposed
    13 / 129 (10.08%)
    11 / 134 (8.21%)
    29 / 226 (12.83%)
    20 / 152 (13.16%)
         occurrences all number
    18
    15
    47
    28
    Coordination abnormal
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 129 (1.55%)
    5 / 134 (3.73%)
    6 / 226 (2.65%)
    2 / 152 (1.32%)
         occurrences all number
    2
    5
    10
    2
    Epilepsy
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Head titubation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    8 / 129 (6.20%)
    18 / 134 (13.43%)
    20 / 226 (8.85%)
    12 / 152 (7.89%)
         occurrences all number
    14
    22
    26
    18
    Hypotonia
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Intention tremor
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    1
    1
    1
    1
    Intracranial haematoma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mental impairment
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Migraine
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nystagmus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Paraesthesia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Poor quality sleep
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Postictal headache
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Postictal state
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Somnolence
         subjects affected / exposed
    6 / 129 (4.65%)
    15 / 134 (11.19%)
    20 / 226 (8.85%)
    3 / 152 (1.97%)
         occurrences all number
    8
    16
    25
    3
    Speech disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Status epilepticus
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tremor
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 134 (1.49%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Unresponsive to stimuli
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Astigmatism
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chalazion
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diplopia
         subjects affected / exposed
    2 / 129 (1.55%)
    8 / 134 (5.97%)
    12 / 226 (5.31%)
    2 / 152 (1.32%)
         occurrences all number
    2
    12
    14
    2
    Eye pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eye swelling
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Optic atrophy
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    1
    1
    Visual impairment
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 129 (0.00%)
    5 / 134 (3.73%)
    5 / 226 (2.21%)
    0 / 152 (0.00%)
         occurrences all number
    0
    11
    9
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    4 / 129 (3.10%)
    3 / 134 (2.24%)
    6 / 226 (2.65%)
    2 / 152 (1.32%)
         occurrences all number
    7
    4
    8
    6
    Abdominal pain upper
         subjects affected / exposed
    0 / 129 (0.00%)
    4 / 134 (2.99%)
    3 / 226 (1.33%)
    1 / 152 (0.66%)
         occurrences all number
    0
    4
    4
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Constipation
         subjects affected / exposed
    2 / 129 (1.55%)
    3 / 134 (2.24%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    2
    3
    6
    1
    Dental caries
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 129 (2.33%)
    1 / 134 (0.75%)
    4 / 226 (1.77%)
    10 / 152 (6.58%)
         occurrences all number
    3
    1
    4
    14
    Dyspepsia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Enteritis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    1
    Enterocolitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    5 / 152 (3.29%)
         occurrences all number
    0
    0
    0
    6
    Flatulence
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Food poisoning
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroduodenitis
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Gingivitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 129 (0.78%)
    7 / 134 (5.22%)
    5 / 226 (2.21%)
    1 / 152 (0.66%)
         occurrences all number
    1
    9
    7
    1
    Odynophagia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pancreatic disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Periodontitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Peritonitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rectal fissure
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Stomatitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Tooth disorder
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    1
    1
    0
    2
    Vomiting
         subjects affected / exposed
    8 / 129 (6.20%)
    8 / 134 (5.97%)
    21 / 226 (9.29%)
    10 / 152 (6.58%)
         occurrences all number
    9
    11
    32
    14
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Enuresis
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    2
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Incontinence
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Leukocyturia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Nephropathy
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal failure acute
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Alopecia
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    2 / 152 (1.32%)
         occurrences all number
    3
    2
    2
    2
    Dermatitis atopic
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    10
    10
    Dermatitis contact
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Heat rash
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Onychomadesis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Papule
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pityriasis rosea
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Rash
         subjects affected / exposed
    4 / 129 (3.10%)
    2 / 134 (1.49%)
    3 / 226 (1.33%)
    1 / 152 (0.66%)
         occurrences all number
    5
    2
    3
    1
    Rash erythematous
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Solar dermatitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Ankle deformity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    1
    2
    0
    2
    Arthritis reactive
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Chest wall mass
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Elbow deformity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Foot deformity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Groin pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemarthrosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Joint swelling
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    2
    1
    1
    2
    Rhabdomyolysis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    2
    1
    Hypothalamo-pituitary disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    4 / 152 (2.63%)
         occurrences all number
    0
    2
    2
    4
    Precocious puberty
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    1
    2
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Decreased appetite
         subjects affected / exposed
    1 / 129 (0.78%)
    6 / 134 (4.48%)
    2 / 226 (0.88%)
    2 / 152 (1.32%)
         occurrences all number
    1
    8
    2
    2
    Dehydration
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Feeding disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Hyperphagia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Obesity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight gain poor
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Acute sinusitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    2
    0
    0
    3
    Acute tonsillitis
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    6 / 226 (2.65%)
    2 / 152 (1.32%)
         occurrences all number
    1
    2
    7
    2
    Appendicitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    7 / 129 (5.43%)
    5 / 134 (3.73%)
    8 / 226 (3.54%)
    13 / 152 (8.55%)
         occurrences all number
    7
    5
    10
    27
    Bronchopneumonia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    0
    2
    Bullous impetigo
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    2
    0
    1
    Ear infection
         subjects affected / exposed
    3 / 129 (2.33%)
    0 / 134 (0.00%)
    6 / 226 (2.65%)
    0 / 152 (0.00%)
         occurrences all number
    4
    0
    6
    0
    Febrile infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Furuncle
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    3 / 152 (1.97%)
         occurrences all number
    0
    0
    0
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 134 (2.24%)
    8 / 226 (3.54%)
    8 / 152 (5.26%)
         occurrences all number
    1
    4
    9
    10
    Gastroenteritis viral
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    2 / 152 (1.32%)
         occurrences all number
    0
    1
    2
    3
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Herpes simplex
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infected bites
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    1 / 129 (0.78%)
    4 / 134 (2.99%)
    6 / 226 (2.65%)
    5 / 152 (3.29%)
         occurrences all number
    2
    9
    14
    7
    Laryngitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    2
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mastitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    15 / 129 (11.63%)
    15 / 134 (11.19%)
    31 / 226 (13.72%)
    16 / 152 (10.53%)
         occurrences all number
    23
    22
    43
    31
    Onychomycosis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    2 / 152 (1.32%)
         occurrences all number
    1
    2
    2
    2
    Otitis media acute
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    0
    1
    Parasitic gastroenteritis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    9 / 129 (6.98%)
    9 / 134 (6.72%)
    10 / 226 (4.42%)
    9 / 152 (5.92%)
         occurrences all number
    9
    10
    14
    18
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    3 / 226 (1.33%)
    5 / 152 (3.29%)
         occurrences all number
    1
    2
    3
    6
    Pneumonia
         subjects affected / exposed
    2 / 129 (1.55%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    5 / 152 (3.29%)
         occurrences all number
    2
    1
    2
    14
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    7 / 129 (5.43%)
    7 / 134 (5.22%)
    13 / 226 (5.75%)
    8 / 152 (5.26%)
         occurrences all number
    7
    10
    28
    17
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 129 (2.33%)
    2 / 134 (1.49%)
    6 / 226 (2.65%)
    0 / 152 (0.00%)
         occurrences all number
    3
    3
    14
    0
    Rhinitis
         subjects affected / exposed
    7 / 129 (5.43%)
    4 / 134 (2.99%)
    5 / 226 (2.21%)
    11 / 152 (7.24%)
         occurrences all number
    7
    5
    7
    22
    Sinusitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    0
    0
    1
    2
    Subcutaneous abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Tinea infection
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    4 / 129 (3.10%)
    2 / 134 (1.49%)
    4 / 226 (1.77%)
    5 / 152 (3.29%)
         occurrences all number
    4
    2
    5
    7
    Tracheitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    2
    Tracheobronchitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 129 (3.88%)
    6 / 134 (4.48%)
    10 / 226 (4.42%)
    13 / 152 (8.55%)
         occurrences all number
    8
    8
    18
    32
    Urinary tract infection
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    4 / 226 (1.77%)
    2 / 152 (1.32%)
         occurrences all number
    1
    0
    4
    2
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Varicella
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    3 / 152 (1.97%)
         occurrences all number
    2
    2
    2
    3
    Viral infection
         subjects affected / exposed
    6 / 129 (4.65%)
    5 / 134 (3.73%)
    12 / 226 (5.31%)
    9 / 152 (5.92%)
         occurrences all number
    7
    5
    13
    11
    Viral pharyngitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Viral rash
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 129 (2.33%)
    5 / 134 (3.73%)
    7 / 226 (3.10%)
    1 / 152 (0.66%)
         occurrences all number
    6
    6
    9
    1
    Vulvitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Systolic hypertension
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Surgical and medical procedures
    Adenoidectomy
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    0
    1
    Brain operation
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Plastic surgery to the face
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Suture insertion
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tenotomy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth extraction
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oral papilloma
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyogenic granuloma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Sebaceous adenoma
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    1
    1
    1
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Immunodeficiency
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Social circumstances
    Learning disability
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    3 / 226 (1.33%)
    2 / 152 (1.32%)
         occurrences all number
    0
    2
    3
    3
    Chest pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Device malfunction
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    0
    2
    Face oedema
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 129 (2.33%)
    5 / 134 (3.73%)
    6 / 226 (2.65%)
    3 / 152 (1.97%)
         occurrences all number
    3
    7
    6
    5
    Feeling hot
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    4 / 226 (1.77%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Hyperthermia
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    2 / 226 (0.88%)
    1 / 152 (0.66%)
         occurrences all number
    1
    2
    2
    1
    Irritability
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    4 / 226 (1.77%)
    1 / 152 (0.66%)
         occurrences all number
    1
    2
    4
    2
    Malaise
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Oedema
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    7 / 129 (5.43%)
    10 / 134 (7.46%)
    20 / 226 (8.85%)
    16 / 152 (10.53%)
         occurrences all number
    13
    14
    27
    38
    Sluggishness
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thirst
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    3 / 226 (1.33%)
    1 / 152 (0.66%)
         occurrences all number
    1
    2
    3
    1
    Affect lability
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Agitation
         subjects affected / exposed
    1 / 129 (0.78%)
    5 / 134 (3.73%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Apathy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Attention deficit/Hyperactivity disorder
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    1
    0
    1
    1
    Bradyphrenia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bruxism
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyslogia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysthymic disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Emotional distress
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Encopresis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Inappropriate affect
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    1
    4
    1
    2
    Listless
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Mood swings
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 134 (1.49%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Obsessive-compulsive disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Restlessness
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    1
    1
    Sleep talking
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somatoform disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    2
    Epididymal cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Labia enlarged
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Polycystic ovaries
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaginal discharge
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 134 (2.24%)
    1 / 226 (0.44%)
    2 / 152 (1.32%)
         occurrences all number
    0
    6
    3
    12
    Bronchospasm
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    4 / 129 (3.10%)
    2 / 134 (1.49%)
    6 / 226 (2.65%)
    7 / 152 (4.61%)
         occurrences all number
    4
    3
    8
    18
    Epistaxis
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 134 (0.75%)
    3 / 226 (1.33%)
    0 / 152 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Laryngospasm
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasal septum deviation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 134 (2.24%)
    4 / 226 (1.77%)
    3 / 152 (1.97%)
         occurrences all number
    1
    3
    5
    7
    Respiratory disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 134 (0.75%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    3 / 152 (1.97%)
         occurrences all number
    0
    0
    1
    4
    Rhinorrhoea
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tonsillar inflammation
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vasomotor rhinitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 134 (0.00%)
    2 / 226 (0.88%)
    0 / 152 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Hepatic cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    0 / 226 (0.00%)
    1 / 152 (0.66%)
         occurrences all number
    0
    0
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 134 (0.00%)
    1 / 226 (0.44%)
    0 / 152 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2007
    Global Amendment#1 The reason for this study global protocol amendment is to harmonized the requests from different Ethics Committees and/or Regulatory Authorities
    29 Apr 2009
    Global Amendment#2 The reason is to define a study extension (Part III) in order to allow patients who participated in study SCO/BIA-2093-305 to continue receiving the study medication
    17 May 2010
    Global Amendment#3 The reason is to define a study extension (Part IV) in order to allow patients who participated in study SCO/BIA-2093-305 to continue receiving the study medication
    07 Jun 2010
    Global Amendment#4 The reason is the recall of the oral suspension formulation of the investigational medicinal product (50 mg/mL) used in the age group of 2-6 years children for Part I and Part II.
    16 Sep 2010
    Global Amendment#4 The reason is the recall of the oral suspension formulation of the investigational medicinal product (50 mg/mL) used in the age group of 2-6 years children for Part I and Part II.
    12 May 2011
    Global Amendment#3 The reason is to define a study extension (Part V) in order to allow patients who participated in study SCO/BIA-2093-305 to continue receiving the study medication

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA