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    Clinical Trial Results:
    Open-label, 2-dose level trial to evaluate pharmacokinetics, safety, and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in infants with refractory epilepsy with partial-onset seizures aged from 1 month to <2 years

    Summary
    EudraCT number
    		 2012-001091-11
    Trial protocol
    		 CZ   PT   IT   HR   RO  
    Global end of trial date
    03 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-211
    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
    Joana Moreira, BIAL - Portela & Cª, S.A., 00351 229866100, joana.moreira@bial.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000696-PIP02-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To evaluate the steady state pharmacokinetic (PK) profile of ESL. Secondary: To assess the safety and tolerability of ESL in the defined patient population at the doses used and to perform exploratory analyses of efficacy.
    Protection of trial subjects
    This study was conducted in compliance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice, including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Apr 2018
    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
    Czechia: 3
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Ukraine: 11
    Worldwide total number of subjects
    23
    EEA total number of subjects
    3
    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)
    23
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patient recruitment period lasted approximately 66 months. The actual overall study duration or patient recruitment period may vary.

    Pre-assignment
    Screening details
    		 Subjects who met all the inclusion criteria and none of the exclusion criteria. 23 subjects were enrolled to the trial and 1 subject experienced an SAE of status epilepticus during the Screening Period that led to study discontinuation (recorded as a screen failure).

    Pre-assignment period milestones
    Number of subjects started
    		 23
    Number of subjects completed
    		 23

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Overall - Group 1 - Age Cohort A
    Arm description
    		 Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After a Screening Period of up to 3 weeks, Group 1 began treatment. For Age cohort A, there was no titration and subjects were treated with 5 mg/kg once daily (QD) for 5 days in a 6-day Evaluation Period.

    Arm title
    		 Overall - Group 1 - Age Cohort B
    Arm description
    		 Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    After a Screening Period of up to 3 weeks, Group 1 began treatment. For Age cohort B, subjects had a 5-day Up-titration Period at 5 mg/kg QD before increasing to 10 mg/kg QD for the Evaluation Period and a 5-day Down-titration Period if subjects did not continue in the extension study or discontinued the study early.

    Arm title
    		 Overall - Group 2 - Age Cohort A
    Arm description
    		 Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    After a Screening Period of up to 3 weeks, subjects in Group 2 began a 5-day Up-titration Period at 5 mg/kg QD, followed by a second 5-day Up-titration Period at 12.5 mg/kg QD, before proceeding to the evaluation dose at 20 mg/kg QD for 5 days in a 6-day Evaluation Period. If subjects did not continue in the subsequent extension study or discontinued the study early, down-titration was to occur as follows: one 5-day down-titration step at 12.5 mg/kg QD.

    Arm title
    		 Overall - Group 2 - Age Cohort B
    Arm description
    		 Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    After a Screening Period of up to 3 weeks, subjects in Group 2 began a 5-day Up-titration Period at 5 mg/kg QD, followed by a second 5-day Up-titration Period at 12.5 mg/kg QD, before proceeding to the evaluation dose at 20 mg/kg QD for 5 days in a 6-day Evaluation Period. If subjects did not continue in the subsequent extension study or discontinued the study early, down-titration was to occur as follows: two 5-day down-titration steps, starting at 12.5 mg/kg QD followed by 5 mg/kg QD.

    Number of subjects in period 1
    		Overall - Group 1 - Age Cohort A Overall - Group 1 - Age Cohort B Overall - Group 2 - Age Cohort A Overall - Group 2 - Age Cohort B
    Started
    4
    10
    4
    5
    Completed
    4
    10
    4
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall - Group 1 - Age Cohort A
    Reporting group description
    		 Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5).

    Reporting group title
    Overall - Group 1 - Age Cohort B
    Reporting group description
    		 Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.

    Reporting group title
    Overall - Group 2 - Age Cohort A
    Reporting group description
    		 Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.

    Reporting group title
    Overall - Group 2 - Age Cohort B
    Reporting group description
    		 Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study.

    Reporting group values
    		 Overall - Group 1 - Age Cohort A Overall - Group 1 - Age Cohort B Overall - Group 2 - Age Cohort A Overall - Group 2 - Age Cohort B Total
    Number of subjects
    		 4 10 4 5 23
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0 0 0
        Newborns (0-27days)
    		 0 0 0 0 0
        Infants and toddlers (28days – 23months)
    		 4 10 4 5 23
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 year)
    		 0 0 0 0 0
        From 18 - 64 years
    		 0 0 0 0 0
        From 65 – 84 years
    		 0 0 0 0 0
        Over 85 years
    		 0 0 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Months
        arithmetic mean (standard deviation)
    		 3.8 ( 0.5 ) 14.7 ( 6.75 ) 3.8 ( 1.5 ) 16.2 ( 5.81 ) -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 2 5 3 2 12
        Male
    		 2 5 1 3 11

    End points

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    End points reporting groups
    Reporting group title
    Overall - Group 1 - Age Cohort A
    Reporting group description
    		 Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5).

    Reporting group title
    Overall - Group 1 - Age Cohort B
    Reporting group description
    		 Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.

    Reporting group title
    Overall - Group 2 - Age Cohort A
    Reporting group description
    		 Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study.

    Reporting group title
    Overall - Group 2 - Age Cohort B
    Reporting group description
    		 Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study.

    Subject analysis set title
    Group 1 - Age Cohort A x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP

    Subject analysis set title
    Group 1 - Age Cohort B x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP

    Subject analysis set title
    Group 2 - Age Cohort A x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP

    Subject analysis set title
    Group 2 - Age Cohort B x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP

    Subject analysis set title
    Group 1 - Age Cohort A x PK Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data

    Subject analysis set title
    Group 1 - Age Cohort B x PK Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data

    Subject analysis set title
    Group 2 - Age Cohort A x PK Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data

    Subject analysis set title
    Group 2 - Age Cohort B x PK Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data

    Primary: Steady state PK profile of ESL - Cmax

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    End point title
    		 Steady state PK profile of ESL - Cmax [1]
    End point description
    Cmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    10
    3
    5
    Units: [ng/mL]
    geometric mean (geometric coefficient of variation)
        Cmax
    3960 ( 63.1 )
    10400 ( 43 )
    10800 ( 92.1 )
    19800 ( 8.39 )
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - Cmax/dose

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    End point title
    		 Steady state PK profile of ESL - Cmax/dose [2]
    End point description
    Dose-normalised Cmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    10
    3
    5
    Units: [ng/mL]/[mg/kg]
    geometric mean (geometric coefficient of variation)
        Cmax/dose
    792 ( 63.1 )
    1040 ( 43 )
    542 ( 92.1 )
    992 ( 8.39 )
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - tmax

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    End point title
    		 Steady state PK profile of ESL - tmax [3]
    End point description
    tmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    10
    3
    5
    Units: [h]
    median (full range (min-max))
        tmax
    2.25 (0.5 to 3.0)
    2.25 (0.5 to 4.5)
    1.5 (0.5 to 3.0)
    2 (0.5 to 6.0)
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - AUCτ

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    End point title
    		 Steady state PK profile of ESL - AUCτ [4]
    End point description
    AUCτ, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    9
    3
    5
    Units: [h*ng/mL]
    geometric mean (geometric coefficient of variation)
        AUCτ
    42100 ( 65.2 )
    122000 ( 62.8 )
    128000 ( 117 )
    229000 ( 23.1 )
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - AUCτ/dose

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    End point title
    		 Steady state PK profile of ESL - AUCτ/dose [5]
    End point description
    Dose-normalised AUCτ, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    9
    3
    5
    Units: [h*ng/mL]/[mg(kg]
    geometric mean (geometric coefficient of variation)
        AUCτ/dose
    8430 ( 65.2 )
    12200 ( 62.8 )
    6410 ( 117 )
    11500 ( 23.1 )
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - t1/2

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    End point title
    		 Steady state PK profile of ESL - t1/2 [6]
    End point description
    t1/2, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    7
    3
    4
    Units: [h]
    geometric mean (geometric coefficient of variation)
        t1/2
    6.36 ( 29.7 )
    7.25 ( 24.7 )
    7.37 ( 29.7 )
    6.98 ( 20.4 )
    No statistical analyses for this end point

    Primary: Steady state PK profile of ESL - CL/F

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    End point title
    		 Steady state PK profile of ESL - CL/F [7]
    End point description
    CL/F, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
    End point type
    Primary
    End point timeframe
    6 day Evaluation Period
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: please refer to synopsis
    End point values
    		 Group 1 - Age Cohort A x PK Set Group 1 - Age Cohort B x PK Set Group 2 - Age Cohort A x PK Set Group 2 - Age Cohort B x PK Set
    Number of subjects analysed
    4
    9
    3
    5
    Units: [mL/h/kg]
    geometric mean (geometric coefficient of variation)
        CL/F
    119 ( 65.2 )
    82 ( 62.8 )
    156 ( 117 )
    87.2 ( 23.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until the date of the EOT visit/EDV.
    Adverse event reporting additional description
    From informed consent until EOT visit/EDV. This period was extended to follow-up on all ongoing AEs after the EOT visit/EDV until the AE was finally resolved or it was medically justifiable to stop further follow up (e.g. a chronic condition is reached). In case of death, AE(s) that were ongoing and did not cause death could be left ongoing.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Group 1 - Age Cohort A x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Reporting group title
    Group 1 - Age Cohort B x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Reporting group title
    Group 2 - Age Cohort A x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Reporting group title
    Group 2 - Age Cohort B x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Serious adverse events
    		 Group 1 - Age Cohort A x Safety Set Group 1 - Age Cohort B x Safety Set Group 2 - Age Cohort A x Safety Set Group 2 - Age Cohort B x Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1 - Age Cohort A x Safety Set Group 1 - Age Cohort B x Safety Set Group 2 - Age Cohort A x Safety Set Group 2 - Age Cohort B x Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 10 (30.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Electrocardiogram PR prolongation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2017
    Local Amendment#1, Czech Republic This protocol amendment amends Protocol Final Version No. 2.0 (21-DEC-2016). It was prepared in order to comply with the requirements issued by the Czech State Institute for Drug Control dated 20.03.2017. • The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European ancestry. Thus, although there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine or chemically-related compounds treatment, and the use of carbamazepine or chemicallyrelated compounds may be considered if the benefits are thought to exceed the risks, subjects who are known to be positive for HLA-A*3101 allele are not considered eligible due to safety reasons [1,2]. A new exclusion criterion was added. • Due to safety reasons, subjects with worsening of liver function must be withdrawn from the trial. • If an overnight stay/hospitalisation is required due to the subject’s study participation, one parent will have the opportunity to stay together with his/her child as required. The resulting accommodation costs will be covered by the sponsor.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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