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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 – 1-YEAR EXTENSION

    Summary
    EudraCT number
    		 2016-001072-29
    Trial protocol
    		 CZ   PT   IT   HR   RO  
    Global end of trial date
    11 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2022
    First version publication date
    20 Mar 2022
    Other versions
    Summary report(s)
    		 CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-211/EXT
    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)
    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
    12 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of 1 year of adjunctive treatment with eslicarbazepine acetate (ESL) in the defined patient population and to perform exploratory analyses of efficacy. No primary or secondary objectives were defined for this study. Instead, all objectives were used to collect long-term data and were evaluated descriptively
    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
    15 May 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
    		 All 23 subjects who completed the BIA-2093-211 study continued in the BIA-2093-211/EXT study.

    Pre-assignment
    Screening details
    		 All 23 subjects were screened in BIA-2093-211 study before enrolled in BIA-2093-211/EXT study. There was no separate screening done in the BIA-2093-211/EXT study.

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

    Period 1
    Period 1 title
    Open-label ESL extension (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 ≤20 mg/kg/day
    Arm description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was ≤20 mg/kg/day. In Down-titration Period (1 step of 5 days), Dose (QD) was reduced by half.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was ≤20 mg/kg/day. In Down-titration Period (1 step of 5 days), Dose (QD) was reduced by half.

    Arm title
    		 Overall - Group >20 - ≤25 mg/kg/day
    Arm description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >20 - ≤25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >20 - ≤25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Arm title
    		 Overall - Group >25 mg/kg/day
    Arm description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2‑093
    Other name
    Zebinix
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Number of subjects in period 1
    		Overall - Group ≤20 mg/kg/day Overall - Group >20 - ≤25 mg/kg/day Overall - Group >25 mg/kg/day
    Started
    12
    7
    4
    Completed
    9
    5
    4
    Not completed
    3
    2
    0
         Consent withdrawn by subject
    2
    1
    -
         Adverse event, serious non-fatal
    -
    1
    -
         Violation of an inclusion/exclusion criterion
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall - Group ≤20 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was ≤20 mg/kg/day. In Down-titration Period (1 step of 5 days), Dose (QD) was reduced by half.

    Reporting group title
    Overall - Group >20 - ≤25 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >20 - ≤25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Reporting group title
    Overall - Group >25 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Reporting group values
    		 Overall - Group ≤20 mg/kg/day Overall - Group >20 - ≤25 mg/kg/day Overall - Group >25 mg/kg/day Total
    Number of subjects
    		 12 7 4 23
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0 0
        Newborns (0-27days)
    		 0 0 0 0
        Infants and toddlers (28days – 23months)
    		 12 7 4 23
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 year)
    		 0 0 0 0
        From 18 - 64 years
    		 0 0 0 0
        From 65 – 84 years
    		 0 0 0 0
        Over 85 years
    		 0 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Months
        arithmetic mean (standard deviation)
    		 8 ± 6.32 14 ± 8.64 16 ± 5.35 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 7 3 1 11
        Male
    		 5 4 3 12

    End points

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    End points reporting groups
    Reporting group title
    Overall - Group ≤20 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was ≤20 mg/kg/day. In Down-titration Period (1 step of 5 days), Dose (QD) was reduced by half.

    Reporting group title
    Overall - Group >20 - ≤25 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >20 - ≤25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Reporting group title
    Overall - Group >25 mg/kg/day
    Reporting group description
    		 Age ≥1 to <24 months. Subjects who received at least 1 dose of investigational medicinal product, Dose in Treatment Period was >25 mg/kg/day. In Down-titration Period (2 steps of 5 days), Dose (QD) was reduced by half at each step.

    Subject analysis set title
    Overall - Group ≤20 mg/kg/day x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP. Treatment for each subject was to begin on Day 1, which was Day 6 of Study BIA-2093-211 and continue for 1 year.

    Subject analysis set title
    Overall - Group >20 - ≤25 mg/kg/day x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP. Treatment for each subject was to begin on Day 1, which was Day 6 of Study BIA-2093-211 and continue for 1 year.

    Subject analysis set title
    Overall - Group >25 mg/kg/day x Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP. Treatment for each subject was to begin on Day 1, which was Day 6 of Study BIA-2093-211 and continue for 1 year.

    Primary: Number of subjects with at least one TAE

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    End point title
    		 Number of subjects with at least one TAE [1]
    End point description
    Absolute number of subjects with at least one Treatment-emergent Adverse Event (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        TAE
    11
    7
    2
    No statistical analyses for this end point

    Primary: Number of subjects with at least one serious TAE

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    End point title
    		 Number of subjects with at least one serious TAE [2]
    End point description
    Absolute number of subjects with at least one seriousTreatment-emergent Adverse Event (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        Serious TAE
    3
    1
    0
    No statistical analyses for this end point

    Primary: Number of subjects with at least one related TAE

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    End point title
    		 Number of subjects with at least one related TAE [3]
    End point description
    Absolute number of subjects with at least one related Treatment-emergent Adverse Event (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        Related TAE
    2
    3
    1
    No statistical analyses for this end point

    Primary: Number of subjects with at least one severe TAE

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    End point title
    		 Number of subjects with at least one severe TAE [4]
    End point description
    Absolute number of subjects with at least one severe Treatment-emergent Adverse Event (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        Severe TAE
    2
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects with at least one TAE leading to discontinuation of IMP

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    End point title
    		 Number of subjects with at least one TAE leading to discontinuation of IMP [5]
    End point description
    Absolute number of subjects with at least one Treatment-emergent Adverse Event leading to discontinuation of IMP (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        TAE leading to discontinuation of IMP
    0
    1
    0
    No statistical analyses for this end point

    Primary: Number of subjects with at least one TAE leading to death

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    End point title
    		 Number of subjects with at least one TAE leading to death [6]
    End point description
    Absolute number of subjects with at least one Treatment-emergent Adverse Event leading to death (Safety Set)
    End point type
    Primary
    End point timeframe
    overall
    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: This is the a safety and tolerability study with no primary efficacy endpoint. Instead, all objectives were used to collect long-term data and were evaluated descriptively. Primary endpoints were added for upload due to EudraCT technical reasons
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        TAE leading to death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Seizure-free subjects at Baseline (Safety Set)

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    End point title
    		 Number of Seizure-free subjects at Baseline (Safety Set)
    End point description
    Absolute number of Seizure-free subjects at Baseline (Safety Set)
    End point type
    Secondary
    End point timeframe
    at baseline
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        seizure-free
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Seizure-free subjects in Treatment Period (Safety Set)

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    End point title
    		 Number of Seizure-free subjects in Treatment Period (Safety Set)
    End point description
    Absolute number of Seizure-free subjects in Treatment Period (Safety Set)
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    12
    7
    4
    Units: Participants
    number (not applicable)
        seizure-free
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Seizure-free subjects in Down-titration Period (Safety Set)

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    End point title
    		 Number of Seizure-free subjects in Down-titration Period (Safety Set)
    End point description
    Absolute number of Seizure-free subjects in Down-titration Period (Safety Set)
    End point type
    Secondary
    End point timeframe
    5 days after treatment period if ≤20 mg/kg/day, 10 days after treatment period else
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    11
    7
    4
    Units: Participants
    number (not applicable)
        seizure-free
    6
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Seizure-free subjects in Follow-up Period (Safety Set)

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    End point title
    		 Number of Seizure-free subjects in Follow-up Period (Safety Set)
    End point description
    Absolute number of Seizure-free subjects in Follow-up Period (Safety Set)
    End point type
    Secondary
    End point timeframe
    4 weeks after downtitration
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    10
    7
    4
    Units: Participants
    number (not applicable)
        seizure-free
    5
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Standardised Seizure Frequency Change (Safety Set)

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    End point title
    		 Standardised Seizure Frequency Change (Safety Set)
    End point description
    Standardised Seizure Frequency - Relative change from baseline in Treatment Period (%)
    End point type
    Other pre-specified
    End point timeframe
    1 year
    End point values
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set
    Number of subjects analysed
    10
    6
    4
    Units: [%]
    median (geometric coefficient of variation)
        seizure frequency change
    -86.01 ± -124.96
    -75.91 ± -57.18
    -12.68 ± 446.1390000000
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE with onset or worsening after the first IMP intake during BIA-2093-211 until 4 weeks after the last IMP intake during BIA-2093-211/EXT
    Adverse event reporting additional description
    AE with onset or worsening after the first IMP intake during BIA-2093-211 until 4 weeks after the last IMP intake during BIA-2093-211/EXT.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Overall - Group ≤20 mg/kg/day x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Reporting group title
    Overall - Group >25 mg/kg/day x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Reporting group title
    Overall - Group >20 - ≤25 mg/kg/day x Safety Set
    Reporting group description
    		 Subjects in the Safety Set treated with ESL

    Serious adverse events
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma, low grade
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Exposure to toxic agent
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall - Group ≤20 mg/kg/day x Safety Set Overall - Group >25 mg/kg/day x Safety Set Overall - Group >20 - ≤25 mg/kg/day x Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    2 / 4 (50.00%)
    7 / 7 (100.00%)
    Surgical and medical procedures
    Cleft palate repair
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Ear tube insertion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Vasomotor rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    2
    Electrocardiogram PR prolongation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Change in seizure presentation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Epilepsy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Infantile spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Intellectual disability
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Non-24-hour sleep-wake disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Seizure
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    4
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Hypochromic anaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Strabismus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Enterocolitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Teething
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    Dermatitis atopic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    6
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Exanthema subitum
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    6
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    5
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    7
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Subglottic laryngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    3
    Viral infection
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Viral rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    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.
    14 Jun 2017
    Global Amendment This protocol amendment amends Protocol Final Version No. 2.0 (21-DEC-2016). It was prepared since it was decided that during the Treatment Period, on-site visits will be performed every 4 weeks after Visit 2. The visits will be performed to adequately follow up the safety of the subjects and if necessary to adjust the volume of ESL suspension according to the subject’s body weight. Safety laboratory tests will be performed at each visit during the Treatment Period.

    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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