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    Clinical Trial Results:
    EFFECTS OF ESLICARBAZEPINE ACETATE (BIA 2-093) ON COGNITIVE FUNCTION IN CHILDREN WITH PARTIAL ONSET SEIZURES: AN ADD-ON, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER CLINICAL TRIAL

    Summary
    EudraCT number
    		 2008-005606-39
    Trial protocol
    		 NL   PL   IT  
    Global end of trial date
    27 May 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1
    Version creation reason
    Summary report(s)
    		 BIA-2093-208_Synopsis_part I-II
    BIA-2093-208_Synopsis_part III

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-208
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01527513
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BIAL - Portela & Ca SA
    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)
    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
    04 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To evaluate the effects of ESL on cognition in comparison with placebo as adjunctive therapy in children aged 6 to 16 years old with refractory partial-onset seizures over a 12-week DB period.
    Protection of trial subjects
    The trial was conducted in accordance with the International Conference on Harmonisation (ICH), Good Clinical Practices (GCP), Good Manufacturing Practice (GMP), the ethical principles of the Declaration of Helsinki and with applicable local regulations. This trial was conducted by qualified persons who respected the rights and welfare of the subjects and after the review and approval of the protocol by an EC. Adverse events were collected throughout the trial and subject was followed by 28 days after the completion of the study.
    Background therapy
    		 Concomitant AED therapy (1 or 2 AEDs). Concomitant AED therapy will be kept stable during the whole study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Ukraine: 40
    Worldwide total number of subjects
    123
    EEA total number of subjects
    36
    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)
    54
    Adolescents (12-17 years)
    69
    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
    		 Patients were enrolled in 27 sites in Italy, Poland, Russia and the Ukraine.

    Pre-assignment
    Screening details
    		 Subjects who met all the inclusion criteria and none of the exclusion criteria. 133 subjects were enrolled to the trial and 10 subjects were screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 133 [1]
    Number of subjects completed
    		 123

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet the inclusion/exclusion criteria: 10
    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 is number of treated subjects.
    Period 1
    Period 1 title
    Part I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part I - ESL
    Arm description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate (BIA 2-093)
    Investigational medicinal product code
    Other name
    Eslicarbazepine acetate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosages were as follows: • During the 4-week titration period, ESL 10 mg/kg/day for 2 weeks followed by 20 mg/kg/day for 2 weeks, to a maximum dose of 1200 mg/day. • During the 8-week maintenance period, ESL 30 mg/kg/day to a maximum dose of 1200 mg/day. • During the tapering-off period, patients were tapered off in 10 mg/kg/day steps every 2 weeks. The duration of this period depended on the dose that the patient was taking at the end of the maintenance period (30, 20, or 10 mg/kg/day). ESL was provided as 200 mg tablets. Doses were rounded to the nearest 100 mg unit. Half tablets could be used for dosage adjustment, if necessary (tablets were scored).

    Arm title
    		 Part I - Placebo
    Arm description
    		 Placebo Once-Daily (QD)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosages were as follows: • During the 4-week titration period, Placebo 10 mg/kg/day for 2 weeks followed by 20 mg/kg/day for 2 weeks, to a maximum dose of 1200 mg/day. • During the 8-week maintenance period, Placebo 30 mg/kg/day to a maximum dose of 1200 mg/day. • During the tapering-off period, patients were tapered off in 10 mg/kg/day steps every 2 weeks. The duration of this period depended on the dose that the patient was taking at the end of the maintenance period (30, 20, or 10 mg/kg/day). Placebo was provided as 200 mg tablets. Doses were rounded to the nearest 100 mg unit. Half tablets could be used for dosage adjustment, if necessary (tablets were scored).

    Number of subjects in period 1
    		Part I - ESL Part I - Placebo
    Started
    83
    40
    Completed
    75
    37
    Not completed
    8
    3
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    4
    -
         Other
    -
    1
         Non-Compliance of Patient
    1
    1
    Period 2
    Period 2 title
    Part II
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part II - ESL
    Arm description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate (BIA 2-093)
    Investigational medicinal product code
    Other name
    Eslicarbazepine acetate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosages were as follows: All patients who entered Period II initially received a dose of 10 mg/kg/day ESL, but this dose was titrated by the investigator according to clinical response, with a dose range from 10 to 30 mg/kg/day (maximum allowed dose of 1200 mg QD). Doses were rounded to the nearest 100 mg unit. Half tablets could be used for dosage adjustment, if necessary (tablets were scored). Down-titration was allowed according to clinical response or in case of intolerable AEs, as often as needed.

    Number of subjects in period 2
    		Part II - ESL
    Started
    112
    Completed
    95
    Not completed
    17
         Consent withdrawn by subject
    12
         Physician decision
    1
         Other
    2
         Non-Compliance of Patient
    1
         Lack of efficacy
    1
    Period 3
    Period 3 title
    Part III
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part III - ESL
    Arm description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate (BIA 2-093)
    Investigational medicinal product code
    Other name
    Eslicarbazepine acetate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosages were as follows: The dose range was 10 to 30 mg/kg/day (maximum allowed ESL dose of 1200 mg QD), and was titrated up or down by the investigator according to clinical response or in case of intolerable adverse events (AEs). Upon completion of this extension, patients were tapered off ESL in 10 mg/kg/day steps every 2 weeks.

    Number of subjects in period 3 [2]
    		Part III - ESL
    Started
    42
    Completed
    31
    Not completed
    11
         Switches to commercial ESL
    1
         Consent withdrawn by subject
    6
         Physician decision
    1
         Adverse event, non-fatal
    1
         Completion status was not recorded
    1
         Lost to follow-up
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects 95 completed the Part II and 53 of them did not start Part III.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I - ESL
    Reporting group description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).

    Reporting group title
    Part I - Placebo
    Reporting group description
    		 Placebo Once-Daily (QD)

    Reporting group values
    		 Part I - ESL Part I - Placebo Total
    Number of subjects
    		 83 40 123
    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)
    		 36 18 54
        Adolescents (12-17 year)
    		 47 22 69
        From 18 - 64 years
    		 0 0 0
        From 65 – 84 years
    		 0 0 0
        Over 85 years
    		 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 11.8 ± 3.14 11.6 ± 2.79 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 36 14 50
        Male
    		 47 26 73

    End points

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    End points reporting groups
    Reporting group title
    Part I - ESL
    Reporting group description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).

    Reporting group title
    Part I - Placebo
    Reporting group description
    		 Placebo Once-Daily (QD)
    Reporting group title
    Part II - ESL
    Reporting group description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).
    Reporting group title
    Part III - ESL
    Reporting group description
    		 Eslicarbazepine acetate (BIA 2-093): ESL 10-30 mg/kg/day QD (maximum 1200 mg/day).

    Subject analysis set title
    Part I - ESL x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization.

    Subject analysis set title
    Part I - Placebo x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization.

    Subject analysis set title
    Part II - ESL x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who entered Part II and who received at least one dose of study treatment.

    Subject analysis set title
    Part I - ESL x Modified Cognitive ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline assessment of cognition.

    Subject analysis set title
    Part I - Placebo x Modified Cognitive ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline assessment of cognition.

    Subject analysis set title
    Part I - ESL x Cognitive PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients in the Modified Cognitive ITT population who completed the 8-week maintenance period and were not IPDs with respect to the primary cognitive endpoint.

    Subject analysis set title
    Part I - Placebo x Cognitive PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients in the Modified Cognitive ITT population who completed the 8-week maintenance period and were not IPDs with respect to the primary cognitive endpoint.

    Subject analysis set title
    Part I - ESL x Modified Efficacy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.

    Subject analysis set title
    Part I - Placebo x Modified Efficacy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.

    Subject analysis set title
    Part II - ESL x Modified Efficacy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who entered Part II, who received at least one dose of study treatment and had at least one post-baseline seizure frequency assessment during Part II

    Subject analysis set title
    Part III - ESL x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who entered Part III and who received at least one dose of study treatment.

    Subject analysis set title
    Part III - ESL x Modified Efficacy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who entered Part III, who received at least one dose of study treatment and had at least one post-baseline Clinical Global Impression-Severity (CGI-S) scale assessment during Part III.

    Primary: Change from baseline to the end of the Part I (DB period) in the composite Power of Attention measure, in order to assess information processing speed and attention/psychomotor speed.

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    End point title
    		 Change from baseline to the end of the Part I (DB period) in the composite Power of Attention measure, in order to assess information processing speed and attention/psychomotor speed.
    End point description
    Change from baseline to the end of the Part I (DB period) in the composite Power of Attention measure, in order to assess information processing speed and attention/psychomotor speed by treatment group for the Modified Cognitive ITT
    End point type
    Primary
    End point timeframe
    From baseline to the end of the Part I
    End point values
    		 Part I - ESL x Modified Cognitive ITT Part I - Placebo x Modified Cognitive ITT Part I - ESL x Cognitive PP Part I - Placebo x Cognitive PP
    Number of subjects analysed
    73
    37
    59
    33
    Units: Power of Attention measure
    arithmetic mean (standard deviation)
        Baseline(V2)
    1733.976 ± 582.46
    1724.103 ± 443.4066
    1699.186 ± 531.0453
    1759.848 ± 456.0726
        End of Part I
    1818.474 ± 605.688
    1824.383 ± 568.5121
    1759.485 ± 544.0179
    1868.03 ± 584.2275
        Change from Baseline at End of Part I
    84.013 ± 403.3595
    101.937 ± 422.4147
    59.122 ± 403.4904
    111.085 ± 445.6327
    Statistical analysis title
    		 Non-Inferiority: ESL vs Placebo Mod. Cognitive ITT
    Statistical analysis description
    Analysis of change from baseline at end of double-blind period based on an ANCOVA model including treatment and country as fixed effects, baseline Power of Attention (ms) score and sex as covariates.
    Comparison groups
    Part I - ESL x Modified Cognitive ITT v Part I - Placebo x Modified Cognitive ITT
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.977
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.2085
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -154.451
         upper limit
    		 150.034
    Statistical analysis title
    		 Non-Inferiority: ESL vs Placebo Cognitive PP
    Statistical analysis description
    Analysis of change from baseline at end of double-blind period based on an ANCOVA model including treatment and country as fixed effects, baseline Power of Attention (ms) score and sex as covariates.
    Comparison groups
    Part I - ESL x Cognitive PP v Part I - Placebo x Cognitive PP
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    33.2001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -137.593
         upper limit
    		 203.993

    Secondary: Change From Baseline in Standardized Seizure Frequency- Part I

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    End point title
    		 Change From Baseline in Standardized Seizure Frequency- Part I
    End point description
    Standardized seizure frequency change from baseline in Part I by treatment group for the Modified Efficacy ITT
    End point type
    Secondary
    End point timeframe
    Baseline, Maintenance Period
    End point values
    		 Part I - ESL x Modified Efficacy ITT Part I - Placebo x Modified Efficacy ITT
    Number of subjects analysed
    83
    40
    Units: Number of seizures
    arithmetic mean (standard deviation)
        Number of seizures
    -31.03 ± 87.963
    -9.13 ± 75.602
    Statistical analysis title
    		 Equivalence: ESL vs Placebo Mod. Efficacy ITT
    Statistical analysis description
    Results from the non-parametric analysis are based on an ANCOVA model on ranked data with ranked baseline, age group and sex as covariates and treatment and country as fixed effects.
    Comparison groups
    Part I - ESL x Modified Efficacy ITT v Part I - Placebo x Modified Efficacy ITT
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change From Baseline in Seizure Frequency During OL period (Part II)

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    End point title
    		 Change From Baseline in Seizure Frequency During OL period (Part II)
    End point description
    Standardized seizure frequency change from baseline during OL period (Part II) for the Modified Efficacy ITT
    End point type
    Secondary
    End point timeframe
    Weeks 1 to ≥ 41 weeks
    End point values
    		 Part II - ESL x Modified Efficacy ITT
    Number of subjects analysed
    112
    Units: Number of seizures
    arithmetic mean (standard deviation)
        Number of seizures
    -3.03 ± 31.37
    No statistical analyses for this end point

    Secondary: Treatment retention time as actual time treated (Part III)

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    End point title
    		 Treatment retention time as actual time treated (Part III)
    End point description
    Treatment retention time as actual time on treatment during Part III of the study using Kaplan-Meier methods for the Modified Efficacy ITT
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Part III - ESL x Modified Efficacy ITT
    Number of subjects analysed
    41
    Units: Treatment retention time
    median (confidence interval 95%)
        Overall
    735 (728 to 741)
        6-11 years
    738 (716 to 770)
        12-16 years
    735 (728 to 755)
    No statistical analyses for this end point

    Secondary: CGI-S scale change from baseline (Part III)

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    End point title
    		 CGI-S scale change from baseline (Part III)
    End point description
    Change from baseline (OL7) to last assessment in continuous CGI-S scale score during the 2-year open-label extension for the Modified Efficacy ITT
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Part III - ESL x Modified Efficacy ITT
    Number of subjects analysed
    41
    Units: CGI-S Scale Score
    arithmetic mean (standard deviation)
        Severity of Illness
    -0.5 ± 0.85
        Global Improvement
    -0.1 ± 0.69
        Therapeutic Effect
    0 ± 0.56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment up to 28 days after the completion of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Part I - ESL x Safety
    Reporting group description
    		 Subject in the Safety Set treated with ESL in Part I

    Reporting group title
    Part III - ESL x Safety
    Reporting group description
    		 Subject in the Safety Set treated with ESL in Part III

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

    Reporting group title
    Part I - Placebo x Safety
    Reporting group description
    		 Subject in the Safety Set treated with Palcebo in Part I

    Serious adverse events
    		 Part I - ESL x Safety Part III - ESL x Safety Part II - ESL x Safety Part I - Placebo x Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 42 (4.76%)
    8 / 112 (7.14%)
    2 / 40 (5.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Mitral valve incompetence
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Brain operation
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Complex partial seizures
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    3 / 112 (2.68%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis infectious mononucleosis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part I - ESL x Safety Part III - ESL x Safety Part II - ESL x Safety Part I - Placebo x Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 83 (39.76%)
    8 / 42 (19.05%)
    41 / 112 (36.61%)
    19 / 40 (47.50%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeling abnormal
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 42 (7.14%)
    4 / 112 (3.57%)
    2 / 40 (5.00%)
         occurrences all number
    1
    3
    6
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Hypomenorrhoea
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 42 (4.76%)
    2 / 112 (1.79%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    2
    2
    Respiratory disorder
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Apathy
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    2
    Nervousness
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Face injury
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Foot fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin laceration
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Convulsion
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dizziness
         subjects affected / exposed
    3 / 83 (3.61%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    1 / 40 (2.50%)
         occurrences all number
    3
    0
    2
    1
    Headache
         subjects affected / exposed
    8 / 83 (9.64%)
    1 / 42 (2.38%)
    6 / 112 (5.36%)
    6 / 40 (15.00%)
         occurrences all number
    8
    1
    7
    8
    Hemianopia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mental retardation
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    0
    1
    Somnolence
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    5
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Monocytosis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Splenomegaly
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    3 / 112 (2.68%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diplopia
         subjects affected / exposed
    3 / 83 (3.61%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    1 / 40 (2.50%)
         occurrences all number
    5
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    2 / 40 (5.00%)
         occurrences all number
    2
    0
    4
    2
    Vomiting
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 42 (0.00%)
    4 / 112 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    6
    0
    5
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    4 / 83 (4.82%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    1
    Rash pruritic
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypothalamo-pituitary disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Bronchitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    3 / 112 (2.68%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    2 / 112 (1.79%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    3 / 112 (2.68%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Laryngitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    3 / 112 (2.68%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Pharyngitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 42 (2.38%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    4 / 83 (4.82%)
    0 / 42 (0.00%)
    3 / 112 (2.68%)
    2 / 40 (5.00%)
         occurrences all number
    4
    0
    3
    3
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 42 (2.38%)
    5 / 112 (4.46%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    5
    0
    Rhinitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    1
    Rubella
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scarlet fever
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Varicella
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 42 (0.00%)
    1 / 112 (0.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Obesity
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 42 (0.00%)
    0 / 112 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2010
    Amendment 1: •The list of participating countries were changed. •The list of Inclusion/exclusion criterion was updated. •Some wording and definitions in the protocol was changed •A few tests were added to the applicable study visits. •A few analyses were clarified/ updated/ added.
    24 Mar 2011
    Amendment 2: •The list of Inclusion/exclusion criterion was updated. •Some therapy was deleted/added. •Clarification for some procedures, IMP dosing and concomitant medication use were added. •Changed subject(s) to patient(s) throughout the protocol except in the Introduction.
    03 Oct 2011
    Amendment 3: •Added an additional two-year, OL treatment extension (Part III) with ESL. •Added changes arising from the inclusion of Part III. • Criteria for patient withdrawal/Statistical analysis/Informed Consent and Assent were updated.

    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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