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    Clinical Trial Results:
    Efficacy and safety of eslicarbazepine acetate (BIA 2-093) as monotherapy for patients with newly diagnosed partial-onset seizures: a double-blind, randomized, active-controlled, parallel-group, multicenter clinical study

    Summary
    EudraCT number
    2009-011135-13
    Trial protocol
    DE   IE   AT   FI   LT   PT   GB   SK   ES   IT   CZ   LV   BE   EE   HU   BG  
    Global end of trial date
    08 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Sep 2017
    First version publication date
    24 Sep 2017
    Other versions
    Summary report(s)
    bia-2093-311

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-311
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    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
    José Francisco Rocha, BIAL - Portela & Cª, S.A., 00351 229866100, jose.rocha@bial.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To demonstrate that monotherapy with eslicarbazepine acetate (ESL; 800 to 1600 mg once daily [QD]) is not inferior to monotherapy with controlled-release carbamazepine (CBZ-CR; 200 to 600 mg twice daily [BID]) in adults (≥18 years) with newly diagnosed epilepsy experiencing partial-onset seizures.
    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 IEC.
    Background therapy
    Concomitant AED therapy (1 or 2 AEDs).
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jan 2011
    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
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 54
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Chile: 16
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Estonia: 11
    Country: Number of subjects enrolled
    Finland: 36
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Hungary: 40
    Country: Number of subjects enrolled
    India: 67
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Latvia: 28
    Country: Number of subjects enrolled
    Peru: 13
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Romania: 44
    Country: Number of subjects enrolled
    Russian Federation: 104
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Ukraine: 43
    Worldwide total number of subjects
    815
    EEA total number of subjects
    456
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    753
    From 65 to 84 years
    61
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The patient recruitment period lasted 41 months. First subject was recruited on 27JAN2011, the last subject on 09JUN2014.

    Pre-assignment
    Screening details
    Subjects who met all the inclusion criteria and none of the exclusion criteria. 929 subjects were enrolled to the trial and 114 subjects were screening failures including 36 who met all the inclusion criteria and none of the exclusion criteria but were not randomised. 2 subjects were randomised but not treated.

    Pre-assignment period milestones
    Number of subjects started
    929 [1]
    Number of subjects completed
    813 [2]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    Consent withdrawn by subject: 25
    Reason: Number of subjects
    Pregnancy: 1
    Reason: Number of subjects
    Ineligibility: 72
    Reason: Number of subjects
    Subject's non compliance: 2
    Reason: Number of subjects
    Sponsor's discretion: 3
    Reason: Number of subjects
    Progressive disease: 1
    Reason: Number of subjects
    Randomised, but not treated: 2
    Reason: Number of subjects
    Other reason: 9
    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. 2 randomised subjects were not treated.
    [2] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: The arms are not mutually exclusive and number starting period 1 should be calculated as sum of the Eslicarbazepine acetate and CBZ-CR or as sum of ESL 800 mg QD, ESL 1200 mg QD, ESL 1600 mg QD, CBZ-CR 200 mg BID, CBZ-CR 400 mg BID, CBZ-CR 600 mg BID and not as sum of all arms groups. Therefore, the number of subjects starting period 1 consist with the number of subjects completing the pre-assignment period.
    Period 1
    Period 1 title
    DOUBLE-BLIND TREATMENT (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Eslicarbazepine acetate
    Arm description
    Patients will receive the study treatment in the form of 400-800 mg Eslicarbazepine Acetate capsules. The study treatment should be administered once daily. The maximum absolute daily dosage will be 1600 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2-093
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily in the evening. The maximum absolute dosage will be 1600 mg once daily. Dose Level A0 (during Titration Period): ESL 400 mg once daily Dose Level A: ESL 800 mg once daily Dose Level B0 (during Titration Period): ESL 1200 mg once daily Dose Level B: ESL 1200 mg once daily Dose Level C0 (during Titration Period): ESL 1600 mg once daily Dose Level C: ESL 1600 mg once daily

    Arm title
    CBZ-CR
    Arm description
    Patients will receive the study treatment in the form of 200-400 mg Carbamazepine controlled-release (Tegretal®-CR) capsules. The study treatment should be administered twice daily. The maximum absolute daily dosage will be 1200 mg. Carbatrol-XR (100 mg) capsules will be used during the 1-week Titration Period, when needed, because Tegretal-CR does not have a 100 mg capsule.
    Arm type
    Active comparator

    Investigational medicinal product name
    Carbamazepine controlled-release
    Investigational medicinal product code
    Other name
    Tegretal®-CR, Carbatrol®-XR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered twice daily in the morning and in the evening except for Dose Level A0 where morning dose is Placebo. The maximum absolute daily dosage will be 1200 mg. Dose Level A0 (during Titration Period): CBZ-CR 200 mg once daily Dose Level A: CBZ-CR 200 mg twice daily Dose Level B0 (during Titration Period): CBZ-CR 300 mg twice daily Dose Level B: CBZ-CR 400 mg twice daily Dose Level C0 (during Titration Period): CBZ-CR 500 mg twice daily Dose Level C: CBZ-CR 600 mg twice daily

    Arm title
    ESL 800 mg QD
    Arm description
    Patients with last evaluated dose 800 mg QD of Eslicarbazepine Acetate.
    Arm type
    Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2-093
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily in the evening.

    Arm title
    ESL 1200 mg QD
    Arm description
    Patients with last evaluated dose 1200 mg QD of Eslicarbazepine Acetate.
    Arm type
    Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2-093
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily in the evening.

    Arm title
    ESL 1600 mg QD
    Arm description
    Patients with last evaluated dose 1600 mg QD of Eslicarbazepine Acetate.
    Arm type
    Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2-093
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered once daily in the evening.

    Arm title
    CBZ-CR 200 mg BID
    Arm description
    Patients with last evaluated dose 200 mg BID of Carbamazepine controlled-release.
    Arm type
    Active comparator

    Investigational medicinal product name
    Carbamazepine controlled-release
    Investigational medicinal product code
    Other name
    Tegretal®-CR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered twice daily in the morning and in the evening.

    Arm title
    CBZ-CR 400 mg BID
    Arm description
    Patients with last evaluated dose 400 mg BID of Carbamazepine controlled-release.
    Arm type
    Active comparator

    Investigational medicinal product name
    Carbamazepine controlled-release
    Investigational medicinal product code
    Other name
    Tegretal®-CR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered twice daily in the morning and in the evening.

    Arm title
    CBZ-CR 600 mg BID
    Arm description
    Patients with last evaluated dose 600 mg BID of Carbamazepine controlled-release.
    Arm type
    Active comparator

    Investigational medicinal product name
    Carbamazepine controlled-release
    Investigational medicinal product code
    Other name
    Tegretal®-CR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment should be administered twice daily in the morning and in the evening.

    Number of subjects in period 1
    Eslicarbazepine acetate CBZ-CR ESL 800 mg QD ESL 1200 mg QD ESL 1600 mg QD CBZ-CR 200 mg BID CBZ-CR 400 mg BID CBZ-CR 600 mg BID
    Started
    401
    412
    271
    70
    60
    317
    61
    34
    Completed
    132
    148
    103
    21
    8
    114
    25
    9
    Not completed
    269
    264
    168
    49
    52
    203
    36
    25
         Progressive disease
    5
    6
    3
    1
    1
    6
    -
    -
         Protocol deviation
    3
    -
    3
    -
    -
    -
    -
    -
         Subject non compliance
    10
    14
    8
    2
    -
    10
    2
    2
         Lack of efficacy
    90
    56
    38
    14
    38
    30
    9
    17
         Other reason
    46
    67
    35
    8
    3
    59
    7
    1
         Adverse event, serious fatal
    2
    2
    2
    -
    -
    2
    -
    -
         Consent withdrawn by subject
    55
    41
    44
    8
    3
    35
    5
    1
         Ineligibility
    1
    1
    1
    -
    -
    1
    -
    -
         Investigator or sponsor discretion
    10
    12
    7
    2
    1
    9
    3
    -
         Unblinding of the IMP
    1
    1
    1
    -
    -
    1
    -
    -
         Pregnancy
    7
    4
    2
    2
    3
    3
    1
    -
         Adverse event, non-fatal
    32
    48
    21
    9
    2
    36
    8
    4
         Adverse event, serious non-fatal
    7
    12
    3
    3
    1
    11
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Eslicarbazepine acetate
    Reporting group description
    Patients will receive the study treatment in the form of 400-800 mg Eslicarbazepine Acetate capsules. The study treatment should be administered once daily. The maximum absolute daily dosage will be 1600 mg.

    Reporting group title
    CBZ-CR
    Reporting group description
    Patients will receive the study treatment in the form of 200-400 mg Carbamazepine controlled-release (Tegretal®-CR) capsules. The study treatment should be administered twice daily. The maximum absolute daily dosage will be 1200 mg. Carbatrol-XR (100 mg) capsules will be used during the 1-week Titration Period, when needed, because Tegretal-CR does not have a 100 mg capsule.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number reported to be in the baseline period is the number of treated subjects; The worldwide number of subjects enrolled in the trial is number of randomised subjects. Baseline period does not include 2 subjects who were randomised but not treated.
    Reporting group values
    Eslicarbazepine acetate CBZ-CR Total
    Number of subjects
    401 412 813
    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)
    0 0 0
        Adolescents (12-17 year)
    0 0 0
        From 18 - 64 years
    374 377 751
        From 65 – 84 years
    26 35 61
        Over 85 years
    1 0 1
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    37.6 ± 15.79 38.7 ± 16.29 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    173 192 365
        Male
    228 220 448

    End points

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    End points reporting groups
    Reporting group title
    Eslicarbazepine acetate
    Reporting group description
    Patients will receive the study treatment in the form of 400-800 mg Eslicarbazepine Acetate capsules. The study treatment should be administered once daily. The maximum absolute daily dosage will be 1600 mg.

    Reporting group title
    CBZ-CR
    Reporting group description
    Patients will receive the study treatment in the form of 200-400 mg Carbamazepine controlled-release (Tegretal®-CR) capsules. The study treatment should be administered twice daily. The maximum absolute daily dosage will be 1200 mg. Carbatrol-XR (100 mg) capsules will be used during the 1-week Titration Period, when needed, because Tegretal-CR does not have a 100 mg capsule.

    Reporting group title
    ESL 800 mg QD
    Reporting group description
    Patients with last evaluated dose 800 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    ESL 1200 mg QD
    Reporting group description
    Patients with last evaluated dose 1200 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    ESL 1600 mg QD
    Reporting group description
    Patients with last evaluated dose 1600 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    CBZ-CR 200 mg BID
    Reporting group description
    Patients with last evaluated dose 200 mg BID of Carbamazepine controlled-release.

    Reporting group title
    CBZ-CR 400 mg BID
    Reporting group description
    Patients with last evaluated dose 400 mg BID of Carbamazepine controlled-release.

    Reporting group title
    CBZ-CR 600 mg BID
    Reporting group description
    Patients with last evaluated dose 600 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    ESL x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment.

    Subject analysis set title
    CBZ-CR x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment.

    Subject analysis set title
    ESL 800 mg QD x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 600 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    ESL x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation.

    Subject analysis set title
    CBZ-CR x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation.

    Subject analysis set title
    ESL 800 mg QD x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation and the last evaluated dose was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation and the last evaluated dose was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment and the last evaluated dose was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation and the last evaluated dose was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation and the last evaluated dose was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomised and treated with at least one dose of study treatment after randomisation and the last evaluated dose was 600 mg BID of Carbamazepine controlled-release.

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

    Subject analysis set title
    CBZ-CR x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations

    Subject analysis set title
    ESL 800 mg QD x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations and the last evaluated dose was 600 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    ESL x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis.

    Subject analysis set title
    CBZ-CR x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis.

    Subject analysis set title
    ESL 800 mg QD x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Corrected Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PPS based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 600 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    ESL x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy.

    Subject analysis set title
    CBZ-CR x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy.

    Subject analysis set title
    ESL 800 mg QD x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the PP Set excluding all subjects discontinuing the study before reaching the end of the 26-week Evaluation Period for any reasons not linked to efficacy and the last evaluated dose was 600 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    ESL x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis.

    Subject analysis set title
    CBZ-CR x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis.

    Subject analysis set title
    ESL 800 mg QD x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 800 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1200 mg QD x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 1200 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    ESL 1600 mg QD x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 1600 mg QD of Eslicarbazepine Acetate.

    Subject analysis set title
    CBZ-CR 200 mg BID x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 200 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 400 mg BID x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 400 mg BID of Carbamazepine controlled-release.

    Subject analysis set title
    CBZ-CR 600 mg BID x Corrected Per Protocol Subset
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per Protocol Subset (SPP) based on data corrections identified after the snapshot for the primary statistical analysis and the last evaluated dose for patient was 600 mg BID of Carbamazepine controlled-release.

    Primary: Seizure freedom

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    End point title
    Seizure freedom
    End point description
    Proportion of subjects who are seizure free (seizure freedom) for the entire 26-week Evaluation Period (ESD 182) at the last evaluated dose level.
    End point type
    Primary
    End point timeframe
    26-week Evaluation Period of the last evaluated dose level
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set ESL x Corrected Per Protocol Set CBZ-CR x Corrected Per Protocol Set ESL x Per Protocol Subset CBZ-CR x Per Protocol Subset ESL x Corrected Per Protocol Subset CBZ-CR x Corrected Per Protocol Subset
    Number of subjects analysed
    401
    412
    388
    397
    389
    397
    316
    326
    317
    326
    Units: Subjects
    number (not applicable)
        Western Europe
    46
    57
    44
    55
    44
    55
    44
    55
    44
    55
        Central Europe
    62
    67
    62
    65
    62
    65
    62
    65
    62
    65
        Eastern Europe
    58
    68
    57
    67
    57
    67
    57
    67
    57
    67
        Russia
    45
    46
    44
    46
    44
    46
    44
    46
    44
    46
        GBR+Ireland+Australia
    18
    16
    17
    16
    17
    16
    17
    16
    17
    16
        South America
    30
    24
    29
    24
    29
    24
    29
    24
    29
    24
        India
    25
    27
    23
    27
    24
    27
    23
    27
    24
    27
        Total
    284
    305
    276
    300
    277
    300
    276
    300
    277
    300
    Statistical analysis title
    Average risk difference PP
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Per Protocol Set v CBZ-CR x Per Protocol Set
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -4.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.3
         upper limit
    1.74
    Notes
    [1] - Non-inferiority margin = -12%
    Statistical analysis title
    Average risk difference FAS
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Full Analysis Set v CBZ-CR x Full Analysis Set
    Number of subjects included in analysis
    813
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -3.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.04
         upper limit
    2.89
    Notes
    [2] - ESL is assumed to be superior to CBZ-CR if the lower limit of the CI > 0%
    Statistical analysis title
    Average risk difference SPP
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Per Protocol Subset v CBZ-CR x Per Protocol Subset
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -4.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.13
         upper limit
    0.1
    Notes
    [3] - Non-inferiority margin = -12%
    Statistical analysis title
    Average risk difference PPcor
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Corrected Per Protocol Set v CBZ-CR x Corrected Per Protocol Set
    Number of subjects included in analysis
    786
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -4.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.23
         upper limit
    1.8
    Notes
    [4] - Non-inferiority margin = -12%
    Statistical analysis title
    Average risk difference SPPcor
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Corrected Per Protocol Subset v CBZ-CR x Corrected Per Protocol Subset
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.1
         upper limit
    0.11
    Notes
    [5] - Non-inferiority margin = -12%

    Secondary: 1-year treatment effect

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    End point title
    1-year treatment effect
    End point description
    The proportion of seizure-free subjects during 1 year of treatment at the last evaluated dose
    End point type
    Secondary
    End point timeframe
    1 year after first day of Evaluation period
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set
    Number of subjects analysed
    401
    412
    388
    397
    Units: Subjects
    number (not applicable)
        Western Europe
    40
    55
    38
    54
        Central Europe
    58
    62
    58
    60
        Eastern Europe
    56
    58
    55
    57
        Russia
    38
    43
    37
    43
        GBR+Ireland+Australia
    15
    15
    15
    15
        South America
    26
    23
    26
    23
        India
    23
    27
    22
    27
        Total
    256
    283
    251
    279
    Statistical analysis title
    Average risk difference PP
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Per Protocol Set v CBZ-CR x Per Protocol Set
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -5.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.88
         upper limit
    0.97
    Notes
    [6] - Non-inferiority margin = -12%
    Statistical analysis title
    Average risk difference FAS
    Statistical analysis description
    The difference in proportions stratified by region etimated by the average risk difference (ARD) over the different regions and estimated from the coefficients of the logistic regression.
    Comparison groups
    ESL x Full Analysis Set v CBZ-CR x Full Analysis Set
    Number of subjects included in analysis
    813
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    Method
    P-value was not provided
    Parameter type
    Average Risk Difference (ARD)
    Point estimate
    -4.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.07
         upper limit
    1.64
    Notes
    [7] - Non-inferiority margin = -12%

    Secondary: Treatment failure time

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    End point title
    Treatment failure time
    End point description
    The time to first seizure at the last evaluated dose.
    End point type
    Secondary
    End point timeframe
    From the first day of Evaluation period till the last IMP intake of the target dose + 1 day
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set
    Number of subjects analysed
    401
    412
    388
    397
    Units: Days
    number (not applicable)
        25% Quartile
    572
    1217
    576
    1217
    Statistical analysis title
    Log-Rank Test for treatment failure time PP
    Comparison groups
    ESL x Per Protocol Set v CBZ-CR x Per Protocol Set
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0005 [8]
    Method
    Logrank
    Confidence interval
    Notes
    [8] - p-value (Log-Rank Test) - startified by region: 0.0003
    Statistical analysis title
    Log-Rank Test for treatment failure time FAS
    Comparison groups
    ESL x Full Analysis Set v CBZ-CR x Full Analysis Set
    Number of subjects included in analysis
    813
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0004 [9]
    Method
    Logrank
    Confidence interval
    Notes
    [9] - p-value (Log-Rank Test) - startified by region: 0.0003

    Secondary: Treatment retention time

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    End point title
    Treatment retention time
    End point description
    The time of the first occurrence of one of the following: Withdrawal of IMP due to AEs. Withdrawal of IMP due to lack of efficacy.
    End point type
    Secondary
    End point timeframe
    From the first dose of IMP till the last IMP intake of the target dose + 1day
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set
    Number of subjects analysed
    401
    412
    388
    397
    Units: Days
    number (confidence interval)
        25% Quartile
    398 (293 to 546)
    477 (384 to 723)
    420 (298 to 563)
    517 (392 to 790)
    Statistical analysis title
    Log-Rank Test for treatment retention time PP
    Comparison groups
    ESL x Per Protocol Set v CBZ-CR x Per Protocol Set
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1299 [10]
    Method
    Logrank
    Confidence interval
    Notes
    [10] - p-value (Log-Rank Test) - startified by region: 0.1151
    Statistical analysis title
    Log-Rank Test for retention failure time FAS
    Comparison groups
    ESL x Full Analysis Set v CBZ-CR x Full Analysis Set
    Number of subjects included in analysis
    813
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1438 [11]
    Method
    Logrank
    Confidence interval
    Notes
    [11] - p-value (Log-Rank Test) - startified by region: 0.1249

    Secondary: Dose-response relationship

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    End point title
    Dose-response relationship
    End point description
    The seizure frequency adjusted for the exposure time until end of evaluation, maintenance, and extension period
    End point type
    Secondary
    End point timeframe
    Evaluation, Maintenance and Extension periods
    End point values
    ESL 800 mg QD x Full Analysis Set ESL 1200 mg QD x Full Analysis Set ESL 1600 mg QD x Full Analysis Set CBZ-CR 200 mg BID x Full Analysis Set CBZ-CR 400 mg BID x Full Analysis Set CBZ-CR 600 mg BID x Full Analysis Set ESL 800 mg QD x Per Protocol Set ESL 1200 mg QD x Per Protocol Set ESL 1600 mg QD x Per Protocol Set CBZ-CR 200 mg BID x Per Protocol Set CBZ-CR 400 mg BID x Per Protocol Set CBZ-CR 600 mg BID x Per Protocol Set
    Number of subjects analysed
    271
    70
    60
    317
    61
    34
    262
    69
    57
    304
    60
    33
    Units: Subjects
    number (not applicable)
        Evaluation Period
    8
    8
    26
    5
    4
    12
    8
    8
    25
    4
    3
    12
        Maintenance Period
    12
    5
    7
    9
    6
    3
    11
    5
    6
    8
    5
    3
        Extension Phase
    28
    10
    3
    26
    4
    2
    26
    10
    3
    26
    3
    2
    No statistical analyses for this end point

    Secondary: Seizure occurrence

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    End point title
    Seizure occurrence
    End point description
    Number of subjects with at least 1 seizure during the respective phase / period of the last evaluated dose.
    End point type
    Secondary
    End point timeframe
    From Titration period till Extension phase
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set
    Number of subjects analysed
    401
    412
    388
    397
    Units: Subjects
    number (not applicable)
        Main Treatment Phase
    104
    74
    100
    71
        Titration Period
    35
    36
    34
    36
        Stabilization Period
    21
    21
    21
    21
        Evaluation Period
    42
    21
    41
    19
        Maintenance Period
    24
    16
    22
    15
        Extension Phase
    39
    31
    37
    30
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    Quality of life
    End point description
    The scores of the QOLIE-31
    End point type
    Secondary
    End point timeframe
    From Visit A1 (start of double-blind period) till the last Extension Phase Visit
    End point values
    ESL x Full Analysis Set CBZ-CR x Full Analysis Set ESL x Per Protocol Set CBZ-CR x Per Protocol Set
    Number of subjects analysed
    401
    412
    388
    397
    Units: Scale
    arithmetic mean (standard deviation)
        Final score: Screening
    64.5 ± 15.26
    63.9 ± 15.42
    64.6 ± 15.18
    63.9 ± 15.56
        Final score: Baseline
    65.4 ± 15.03
    66 ± 15.63
    65.7 ± 14.94
    65.9 ± 15.69
        Final score: Visit 4
    72 ± 14.27
    71.6 ± 14.78
    72.3 ± 14.1
    71.7 ± 14.82
        Final score: MPV2
    72.8 ± 14.21
    74.5 ± 14.62
    72.8 ± 14.09
    74.5 ± 14.71
        Final score: FEV
    72.7 ± 13.9
    75.5 ± 14.23
    72.8 ± 13.93
    75.5 ± 14.23
        Final score: EDV
    66.1 ± 17.42
    66.3 ± 18.48
    66.2 ± 17.61
    66.2 ± 18.58
        T-score: Screening
    51 ± 9.36
    50.6 ± 9.45
    51.1 ± 9.31
    50.7 ± 9.54
        T-score: Baseline
    51.6 ± 9.22
    51.9 ± 9.59
    51.7 ± 9.16
    51.8 ± 9.62
        T-score: Visit 4
    55.6 ± 8.75
    55.3 ± 9.06
    55.8 ± 8.64
    55.4 ± 9.09
        T-score: MPV2
    56.1 ± 8.71
    57.1 ± 8.96
    56.1 ± 8.64
    57.1 ± 9.02
        T-score: FEV
    56 ± 8.52
    57.8 ± 8.73
    56.1 ± 8.54
    57.8 ± 8.73
        T-score: EDV
    52 ± 10.68
    52.1 ± 11.33
    52.1 ± 10.8
    52 ± 11.39
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first study treatment up to 28 days after the last intake of the last evaluated dose of study medication.
    Adverse event reporting additional description
    Each AE has to be documented with reference to intensity, date of occurrence, duration, frequency, treatment, and outcome. Furthermore, each AE has to be classified as serious or non-serious. Additionally, the investigator has to assess whether the AE is drug related or not. Changes of AEs and dates of ending have to be documented.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    ESL x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment.

    Reporting group title
    CBZ-CR x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment.

    Reporting group title
    ESL 800 mg QD x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 800 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    ESL 1200 mg QD x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 1200 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    ESL 1600 mg QD x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 1600 mg QD of Eslicarbazepine Acetate.

    Reporting group title
    CBZ-CR 200 mg BID x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 200 mg BID of Carbamazepine controlled-release.

    Reporting group title
    CBZ-CR 400 mg BID x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 400 mg BID of Carbamazepine controlled-release.

    Reporting group title
    CBZ-CR 600 mg BID x Safety Set
    Reporting group description
    All patients who received at least one dose of study treatment and the last evaluated dose was 600 mg BID of Carbamazepine controlled-release.

    Serious adverse events
    ESL x Safety Set CBZ-CR x Safety Set ESL 800 mg QD x Safety Set ESL 1200 mg QD x Safety Set ESL 1600 mg QD x Safety Set CBZ-CR 200 mg BID x Safety Set CBZ-CR 400 mg BID x Safety Set CBZ-CR 600 mg BID x Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 401 (11.47%)
    50 / 412 (12.14%)
    24 / 271 (8.86%)
    9 / 70 (12.86%)
    13 / 60 (21.67%)
    45 / 317 (14.20%)
    4 / 61 (6.56%)
    1 / 34 (2.94%)
         number of deaths (all causes)
    2
    2
    2
    0
    0
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion late
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    High risk pregnancy
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site inflammation
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    2 / 401 (0.50%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    1 / 60 (1.67%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Adams-stokes syndrome
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral circulatory failure
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 401 (0.75%)
    4 / 412 (0.97%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    2 / 60 (3.33%)
    3 / 317 (0.95%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    2 / 60 (3.33%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epileptic psychosis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    3 / 401 (0.75%)
    0 / 412 (0.00%)
    2 / 271 (0.74%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    ESL x Safety Set CBZ-CR x Safety Set ESL 800 mg QD x Safety Set ESL 1200 mg QD x Safety Set ESL 1600 mg QD x Safety Set CBZ-CR 200 mg BID x Safety Set CBZ-CR 400 mg BID x Safety Set CBZ-CR 600 mg BID x Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    318 / 401 (79.30%)
    342 / 412 (83.01%)
    212 / 271 (78.23%)
    55 / 70 (78.57%)
    51 / 60 (85.00%)
    258 / 317 (81.39%)
    55 / 61 (90.16%)
    29 / 34 (85.29%)
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    2
    0
    0
    Animal bite
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    0
    0
    Ankle fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    1
    0
    Arthropod sting
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Brain contusion
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Concussion
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    Contusion
         subjects affected / exposed
    8 / 401 (2.00%)
    5 / 412 (1.21%)
    5 / 271 (1.85%)
    1 / 70 (1.43%)
    2 / 60 (3.33%)
    2 / 317 (0.63%)
    2 / 61 (3.28%)
    1 / 34 (2.94%)
         occurrences all number
    10
    5
    7
    1
    2
    2
    2
    1
    Craniocerebral injury
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    2
    0
    0
    Ear injury
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Excoriation
         subjects affected / exposed
    2 / 401 (0.50%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    1 / 60 (1.67%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    2
    0
    1
    1
    2
    0
    0
    Expired drug administered
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Face injury
         subjects affected / exposed
    3 / 401 (0.75%)
    2 / 412 (0.49%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    2
    2
    0
    1
    1
    0
    1
    Facial bones fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    5 / 401 (1.25%)
    12 / 412 (2.91%)
    3 / 271 (1.11%)
    1 / 70 (1.43%)
    1 / 60 (1.67%)
    8 / 317 (2.52%)
    1 / 61 (1.64%)
    3 / 34 (8.82%)
         occurrences all number
    7
    20
    5
    1
    1
    16
    1
    3
    Foot fracture
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Head injury
         subjects affected / exposed
    3 / 401 (0.75%)
    2 / 412 (0.49%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    2
    2
    0
    1
    1
    0
    1
    Injury
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    3
    0
    0
    Ligament rupture
         subjects affected / exposed
    2 / 401 (0.50%)
    1 / 412 (0.24%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 401 (0.25%)
    3 / 412 (0.73%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    1
    3
    1
    0
    0
    2
    1
    0
    Limb injury
         subjects affected / exposed
    5 / 401 (1.25%)
    5 / 412 (1.21%)
    3 / 271 (1.11%)
    1 / 70 (1.43%)
    1 / 60 (1.67%)
    4 / 317 (1.26%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    5
    5
    3
    1
    1
    4
    0
    1
    Lip injury
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Muscle rupture
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    4 / 401 (1.00%)
    0 / 412 (0.00%)
    3 / 271 (1.11%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    7
    0
    3
    4
    0
    0
    0
    0
    Nail injury
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Overdose
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 401 (0.00%)
    5 / 412 (1.21%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    4 / 317 (1.26%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    5
    1
    0
    Scratch
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Skeletal injury
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Soft tissue injury
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    1
    1
    Thermal burn
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    1
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Wrist fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    4 / 401 (1.00%)
    3 / 412 (0.73%)
    4 / 271 (1.48%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    4
    3
    4
    0
    0
    2
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 401 (2.24%)
    10 / 412 (2.43%)
    5 / 271 (1.85%)
    2 / 70 (2.86%)
    2 / 60 (3.33%)
    9 / 317 (2.84%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    9
    11
    5
    2
    2
    10
    1
    0
    Anti-gad antibody positive
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Anti-islet cell antibody positive
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 401 (1.50%)
    9 / 412 (2.18%)
    2 / 271 (0.74%)
    2 / 70 (2.86%)
    2 / 60 (3.33%)
    8 / 317 (2.52%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    6
    9
    2
    2
    2
    8
    1
    0
    Biopsy endometrium
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Blood 25-hydroxycholecalciferol decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 401 (0.25%)
    5 / 412 (1.21%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    4 / 317 (1.26%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    9
    3
    0
    0
    6
    0
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    4 / 412 (0.97%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    5
    0
    0
    0
    3
    0
    2
    Blood calcium increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Blood chloride decreased
         subjects affected / exposed
    5 / 401 (1.25%)
    1 / 412 (0.24%)
    5 / 271 (1.85%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    5
    1
    5
    0
    0
    0
    0
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 401 (0.25%)
    6 / 412 (1.46%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    5 / 317 (1.58%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    6
    1
    0
    0
    5
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    19 / 401 (4.74%)
    19 / 412 (4.61%)
    12 / 271 (4.43%)
    4 / 70 (5.71%)
    3 / 60 (5.00%)
    14 / 317 (4.42%)
    3 / 61 (4.92%)
    2 / 34 (5.88%)
         occurrences all number
    22
    20
    14
    4
    4
    15
    3
    2
    Blood creatinine decreased
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    1
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood folate decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Blood glucose decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    4 / 401 (1.00%)
    3 / 412 (0.73%)
    4 / 271 (1.48%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    4
    3
    4
    0
    0
    2
    1
    0
    Blood lactate dehydrogenase decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    7 / 401 (1.75%)
    2 / 412 (0.49%)
    5 / 271 (1.85%)
    0 / 70 (0.00%)
    2 / 60 (3.33%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    13
    2
    11
    0
    2
    2
    0
    0
    Blood parathyroid hormone decreased
         subjects affected / exposed
    4 / 401 (1.00%)
    1 / 412 (0.24%)
    4 / 271 (1.48%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    1
    4
    0
    0
    1
    0
    0
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 401 (0.00%)
    3 / 412 (0.73%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    3 / 317 (0.95%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    4
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 401 (0.50%)
    1 / 412 (0.24%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    3 / 401 (0.75%)
    2 / 412 (0.49%)
    2 / 271 (0.74%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    3
    2
    2
    1
    0
    0
    0
    2
    Blood pressure decreased
         subjects affected / exposed
    3 / 401 (0.75%)
    1 / 412 (0.24%)
    3 / 271 (1.11%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    3
    0
    0
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    1
    0
    0
    1
    0
    2
    Blood sodium decreased
         subjects affected / exposed
    5 / 401 (1.25%)
    2 / 412 (0.49%)
    4 / 271 (1.48%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    1 / 34 (2.94%)
         occurrences all number
    5
    2
    4
    0
    1
    0
    1
    1
    Blood sodium increased
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    3
    0
    0
    0
    2
    0
    1
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 401 (0.25%)
    3 / 412 (0.73%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    1 / 61 (1.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    1
    0
    0
    1
    1
    1
    Blood triglycerides
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    5 / 401 (1.25%)
    7 / 412 (1.70%)
    3 / 271 (1.11%)
    0 / 70 (0.00%)
    2 / 60 (3.33%)
    6 / 317 (1.89%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    8
    16
    6
    0
    2
    12
    0
    4
    Blood urea increased
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 412 (0.49%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    Blood urine present
         subjects affected / exposed
    2 / 401 (0.50%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    1
    1
    0
    1
    0
    0
    Body mass index decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Body mass index increased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    3
    0
    0
    1
    0
    0
    Body temperature increased
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    2
    2
    0
    0
    2
    0
    0
    Bone density increased
         subjects affected / exposed
    2 / 401 (0.50%)
    2 / 412 (0.49%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    2
    0
    0
    1
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    16 / 401 (3.99%)
    20 / 412 (4.85%)
    11 / 271 (4.06%)
    4 / 70 (5.71%)
    1 / 60 (1.67%)
    17 / 317 (5.36%)
    3 / 61 (4.92%)
    0 / 34 (0.00%)
         occurrences all number
    20
    26
    14
    5
    1
    22
    4
    0
    Coagulation test abnormal
         subjects affected / exposed
    2 / 401 (0.50%)
    0 / 412 (0.00%)
    2 / 271 (0.74%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    Coagulation time prolonged
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Colonoscopy
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Electrocardiogram qrs complex prolonged
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Electrocardiogram qt prolonged
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    1
    Eosinophil count decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    2
    0
    0
    0
    0
    2
    Gamma-glutamyltransferase abnormal
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    21 / 401 (5.24%)
    65 / 412 (15.78%)
    13 / 271 (4.80%)
    6 / 70 (8.57%)
    2 / 60 (3.33%)
    48 / 317 (15.14%)
    9 / 61 (14.75%)
    8 / 34 (23.53%)
         occurrences all number
    26
    76
    14
    10
    2
    53
    11
    12
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    2
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    4 / 401 (1.00%)
    4 / 412 (0.97%)
    3 / 271 (1.11%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    3 / 317 (0.95%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    8
    6
    6
    2
    0
    5
    1
    0
    Heart rate decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Heart rate increased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    4 / 401 (1.00%)
    4 / 412 (0.97%)
    3 / 271 (1.11%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    2 / 61 (3.28%)
    0 / 34 (0.00%)
         occurrences all number
    5
    4
    4
    1
    0
    2
    2
    0
    High density lipoprotein decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    4 / 412 (0.97%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    1 / 61 (1.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    5
    1
    0
    0
    3
    1
    1
    International normalised ratio decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    6 / 401 (1.50%)
    6 / 412 (1.46%)
    6 / 271 (2.21%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    5 / 317 (1.58%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    6
    7
    6
    0
    0
    6
    1
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    2 / 401 (0.50%)
    2 / 412 (0.49%)
    1 / 271 (0.37%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    1
    1
    0
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Monocyte count decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    N-telopeptide
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    N-telopeptide urine increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    2
    0
    Osteocalcin decreased
         subjects affected / exposed
    4 / 401 (1.00%)
    2 / 412 (0.49%)
    4 / 271 (1.48%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    2 / 317 (0.63%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    2
    4
    0
    0
    2
    0
    0
    Osteocalcin increased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    2 / 412 (0.49%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    2
    1
    0
    0
    1
    0
    1
    Positive rombergism
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Protein total decreased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Protein total increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    1 / 401 (0.25%)
    1 / 412 (0.24%)
    1 / 271 (0.37%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    1
    0
    0
    Serum ferritin increased
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Tandem gait test abnormal
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    1 / 61 (1.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Thyroid function test abnormal
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 412 (0.24%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Thyroxine decreased
         subjects affected / exposed
    4 / 401 (1.00%)
    1 / 412 (0.24%)
    2 / 271 (0.74%)
    2 / 70 (2.86%)
    0 / 60 (0.00%)
    1 / 317 (0.32%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    1
    2
    2
    0
    1
    0
    0
    Thyroxine free decreased
         subjects affected / exposed
    7 / 401 (1.75%)
    5 / 412 (1.21%)
    4 / 271 (1.48%)
    2 / 70 (2.86%)
    1 / 60 (1.67%)
    4 / 317 (1.26%)
    0 / 61 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    7
    6
    4
    2
    1
    5
    0
    1
    Transaminases increased
         subjects affected / exposed
    3 / 401 (0.75%)
    3 / 412 (0.73%)
    2 / 271 (0.74%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    3 / 317 (0.95%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    3
    2
    1
    0
    3
    0
    0
    Tri-iodothyronine free increased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    1 / 70 (1.43%)
    0 / 60 (0.00%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Tri-iodothyronine increased
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 412 (0.00%)
    0 / 271 (0.00%)
    0 / 70 (0.00%)
    1 / 60 (1.67%)
    0 / 317 (0.00%)
    0 / 61 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Urine analysis abnormal
         subjects affected