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    Clinical Trial Results:
    Double-Blind, Randomized, Historical Control Study of the Safety and Efficacy of Eslicarbazepine Acetate Monotherapy in Subjects with Partial Epilepsy Not Well Controlled by Current Antiepileptic Drugs

    Summary
    EudraCT number
    		 2010-018684-42
    Trial protocol
    		 CZ   ES   BG  
    Global end of trial date
    27 Nov 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Oct 2016
    First version publication date
    01 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    093-046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01091662
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sunovion Pharmaceuticals Inc.
    Sponsor organisation address
    84 Waterford Drive, Marlborough, United States, 01752
    Public contact
    Director, Sunovion Phamaceuticals Inc., 001 866-503-6351, clinicaltrialsdisclosure@sunovion.com
    Scientific contact
    Director, Sunovion Phamaceuticals Inc., 001 866-503-6351 , clinicaltrialsdisclosure@sunovion.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
    02 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is an 18-week, double-blind, multicenter study with gradual conversion from previous antiepileptic therapy to eslicarbazepine acetate monotherapy in subjects with partial epilepsy.
    Protection of trial subjects
    The study was conducted according to the protocol, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki. The study was conducted in accordance with applicable local law(s) and regulation(s).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2010
    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
    Czech Republic: 33
    Country: Number of subjects enrolled
    United States: 43
    Country: Number of subjects enrolled
    Ukraine: 68
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Serbia: 3
    Worldwide total number of subjects
    172
    EEA total number of subjects
    58
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    165
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 50 investigational sites (25 sites in US/25 sites non-US which included Bulgaria, Czech Republic, Serbia, Ukraine) screened subjects. 41 sites randomized subjects into the study which began on 30June2010

    Pre-assignment
    Screening details
    		 A total of 274 subjects were screened during the study of which 172 subjects were randomized (43 US subjects and 129 non-US subjects) into two dose groups: 1600 mg ESL (114 subjects) and 1200 mg ESL (58 subjects).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ESL 1200 mg
    Arm description
    		 Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg (Week 1) to 800 mg (Week 2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after the end of Week 18..
    Arm type
    		 Experimental

    Investigational medicinal product name
    eslicarbazepine acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    administered once daily

    Arm title
    		 ESL1600 mg
    Arm description
    		 Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after the end of Week 18.
    Arm type
    		 Experimental

    Investigational medicinal product name
    eslicarbazipane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    administered once daily

    Number of subjects in period 1
    		ESL 1200 mg ESL1600 mg
    Started
    58
    114
    Completed
    41
    80
    Not completed
    17
    34
         met exclusion criteria
    1
    -
         Consent withdrawn by subject
    7
    6
         Physician decision
    1
    1
         Adverse event, non-fatal
    1
    9
         Pregnancy
    -
    1
         unable to swallow capsule
    -
    1
         met exit criteria
    7
    13
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ESL 1200 mg
    Reporting group description
    		 Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg (Week 1) to 800 mg (Week 2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after the end of Week 18..

    Reporting group title
    ESL1600 mg
    Reporting group description
    		 Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after the end of Week 18.

    Reporting group values
    		 ESL 1200 mg ESL1600 mg Total
    Number of subjects
    		 58 114 172
    Age Categorical
    Units: participants
        <=18 years
    		 3 4 7
        Between 18 and 65 years
    		 55 110 165
        >=65 years
    		 0 0 0
    Age continuous
    Units:
        
    		3 ( 55 ) 4 ( 110 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 27 62 89
        Male
    		 31 52 83
    Age, Customized
    Units: Subjects
        <18 years
    		 3 4 7
        18-39 years
    		 32 59 91
        40-65 years
    		 23 51 74
        >65 years
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 7 8
        Not Hispanic or Latino
    		 57 107 164
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Czech Republic
    		 11 22 33
        United States
    		 15 28 43
        Ukraine
    		 26 42 68
        Bulgaria
    		 6 19 25
        Serbia
    		 0 3 3
    Subject analysis sets

    Subject analysis set title
    ESL1200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg (Week 1) to 800 mg (Week 2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after the end of Week 18..

    Subject analysis set title
    ESL 1600 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after the end of Week 18.

    Subject analysis sets values
    		 ESL1200 mg ESL 1600 mg
    Number of subjects
    58
    114
    Age Categorical
    Units: participants
        <=18 years
    3
    4
        Between 18 and 65 years
    55
    110
        >=65 years
    0
    0
    Age continuous
    Units:
        
    3 ( 55 )
    4 ( 110 )
    Gender, Male/Female
    Units: participants
        Female
    27
    62
        Male
    31
    52
    Age, Customized
    Units: Subjects
        <18 years
    3
    4
        18-39 years
    32
    59
        40-65 years
    23
    51
        >65 years
    0
    0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1
    7
        Not Hispanic or Latino
    57
    107
        Unknown or Not Reported
    0
    0
    Region of Enrollment
    Units: Subjects
        Czech Republic
    11
    22
        United States
    15
    28
        Ukraine
    26
    42
        Bulgaria
    6
    19
        Serbia
    0
    3

    End points

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    End points reporting groups
    Reporting group title
    ESL 1200 mg
    Reporting group description
    		 Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg (Week 1) to 800 mg (Week 2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after the end of Week 18..

    Reporting group title
    ESL1600 mg
    Reporting group description
    		 Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after the end of Week 18.

    Subject analysis set title
    ESL1200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg (Week 1) to 800 mg (Week 2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after the end of Week 18..

    Subject analysis set title
    ESL 1600 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after the end of Week 18.

    Primary: Cumulative 112-day exit rate as estimated by Kaplan-Meier method

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    End point title
    		 Cumulative 112-day exit rate as estimated by Kaplan-Meier method
    End point description
    Cumulative exit rate was defined as the proportion of subjects meeting at least one of the following five exit criteria over a 16-week study period (from start of AED taper/con. period (Wk 3) to end of double blind monotherapy period (Wk 18)).1.One episode of status epilepticus.2.One secondary gen. partial seizure (in subjects who did not have gen.seizures during 6 mo. prior to screening).3.A two fold increase in any consecutive 28 day seizure rate compared to the highest consecutive 28 day seizure rate during the 8 week baseline period. 4.A two fold increase in any consecutive 2 day seizure rate compared to the highest consecutive 2 day seizure rate during the 8 week baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 week baseline was 1 then 3 seizures in a consecutive 2 day period was required to exit. 5.Worsening of seizures or increase in seizure frequency considered serious or requiring intervention as judged by the investigator
    End point type
    Primary
    End point timeframe
    From beginning of Week 3 to end of Week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: proportion of participants
        number (confidence interval 95%)
    0.156 (0.081 to 0.2874)
    0.128 (0.075 to 0.2152)
    0.156 (0.081 to 0.2874)
    0.128 (0.075 to 0.2152)
    Statistical analysis title
    		 Cumulative 112-day exit rate as estimated by Kapla
    Statistical analysis description
    Cumulative 112-day exit rate as estimated by Kaplan-Meier method
    Comparison groups
    ESL1200 mg v ESL 1600 mg
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 number
    Point estimate
    0.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.081
         upper limit
    		 0.2874
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Cumulative 112-day exit rate as estimated by Kapla
    Statistical analysis description
    Cumulative 112-day exit rate as estimated by Kaplan-Meier method
    Comparison groups
    ESL 1600 mg v ESL1200 mg
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 number
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.075
         upper limit
    		 0.2152

    Secondary: Proportion (%) of subjects that are seizure-free during the 10-week double-blind monotherapy treatment period.

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    End point title
    		 Proportion (%) of subjects that are seizure-free during the 10-week double-blind monotherapy treatment period.
    End point description
    Seizure-free subjects during the monotherapy period were determined as subjects who had seizure assessments during the monotherapy period, and did not have any seizures in the 10 weeks between Visits 6 and 9 (Weeks 9 through 18). Subjects who discontinued during this period were considered not seizure-free even if they were seizure-free at the time of discontinuation, i.e., to be considered seizure-free, subjects must complete the 10-week period without any seizures.
    End point type
    Secondary
    End point timeframe
    Week 9 through 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
        number (confidence interval 95%)
    7.4 (2.1 to 17.9)
    10 (4.9 to 17.6)
    7.4 (2.1 to 17.9)
    10 (4.9 to 17.6)
    No statistical analyses for this end point

    Secondary: Percentage of subjects seizure-free during the last 4 weeks on eslicarbazepine acetate monotherapy.

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    End point title
    		 Percentage of subjects seizure-free during the last 4 weeks on eslicarbazepine acetate monotherapy.
    End point description
    Percentage of participants that were Seizure-free during the last four weeks of monotherapy were determined as subjects who had seizure assessments during the 4 weeks between Visits 8 and 9 (Weeks 15 through 18), and did not have any seizures.
    End point type
    Secondary
    End point timeframe
    Week 15 through 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
        number (confidence interval 95%)
    16.7 (7.9 to 29.3)
    17 (10.2 to 25.8)
    16.7 (7.9 to 29.3)
    17 (10.2 to 25.8)
    No statistical analyses for this end point

    Secondary: Completion rate (% of subjects completing the 18 weeks of double-blind treatment).

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    End point title
    		 Completion rate (% of subjects completing the 18 weeks of double-blind treatment).
    End point description
    Subjects completing the study were determined as subjects who completed the 18 weeks of double-blind treatment.
    End point type
    Secondary
    End point timeframe
    18 weeks
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
        number (confidence interval 95%)
    75.9 (62.4 to 86.5)
    80 (70.8 to 87.3)
    75.9 (62.4 to 86.5)
    80 (70.8 to 87.3)
    No statistical analyses for this end point

    Secondary: Completion rate during the 10 weeks of monotherapy (% of subjects entering the monotherapy period who complete).

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    End point title
    		 Completion rate during the 10 weeks of monotherapy (% of subjects entering the monotherapy period who complete).
    End point description
    Monotherapy completion rate was defined as the proportion (%) of subjects entering the monotherapy period who completed the 10 weeks of monotherapy treatment.
    End point type
    Secondary
    End point timeframe
    Week 8 through 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
        number (confidence interval 95%)
    85.4 (72.2 to 93.9)
    90.9 (82.9 to 96)
    85.4 (72.2 to 93.9)
    90.9 (82.9 to 96)
    No statistical analyses for this end point

    Secondary: Time on eslicarbazepine acetate monotherapy.

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    End point title
    		 Time on eslicarbazepine acetate monotherapy.
    End point description
    The start of the monotherapy period was defined as the date of termination of all other AEDs while taking study monotherapy medication. Time on monotherapy was defined from the start of monotherapy period to the last dose of monotherapy treatment.
    End point type
    Secondary
    End point timeframe
    Week 8 to Week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: days
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Change in seizure frequency from baseline.

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    End point title
    		 Change in seizure frequency from baseline.
    End point description
    The relative (%) change in standardized seizure frequency was evaluated for four periods: titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18).
    End point type
    Secondary
    End point timeframe
    18 weeks, Double-blind:weeks 1-18; Baseline: weeks -8to -1; titration: weeks 1 to 2; AED taper/conversion: weeks 3 to 8; monotherapy; weeks 9 to 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    98
    54
    98
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        Relative(%) change from baseline fo DB pd n=54,98
    -36.1 (-59.2 to -17.1)
    -47.5 (-70.8 to -11.3)
    -36.1 (-59.2 to -17.1)
    -47.5 (-70.8 to -11.3)
        Relative(%)chg from baseline for titrat pd n=54,98
    -19.3 (-57.9 to 3.3)
    -35.6 (-72.4 to -9.4)
    -19.3 (-57.9 to 3.3)
    -35.6 (-72.4 to -9.4)
        Relative (%) chg from baseline-AED t/c pd n=54,98
    -39.4 (-54 to 0)
    -42.9 (-73.8 to -12.1)
    -39.4 (-54 to 0)
    -42.9 (-73.8 to -12.1)
        Relative (%) change from baseline-mono pd n=48,87
    -45.7 (-72.1 to -20.1)
    -52.1 (-81.6 to -21.8)
    -45.7 (-72.1 to -20.1)
    -52.1 (-81.6 to -21.8)
    No statistical analyses for this end point

    Secondary: Responder rate (proportion [%] of subjects with a ≥50% reduction of seizure frequency from baseline).

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    End point title
    		 Responder rate (proportion [%] of subjects with a ≥50% reduction of seizure frequency from baseline).
    End point description
    Responder rate was defined as the proportion (%) of subjects with a ≥ 50% reduction of seizure frequency from baseline. This analysis was done for the titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18) periods.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 18, Double-blind weeks 1-18; baseline: weeks -8 to -1; Titration: weeks 1-2; AED taper/conversion; weeks 3-8; monotherapy weeks 9-18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
    number (confidence interval 95%)
        responder rate during the DB period
    38.9 (29.5 to 58.8)
    46 (36 to 56.3)
    35.2 (22.7 to 49.4)
    46 (36 to 56.3)
        responder rate during titration period
    35.2 (22.7 to 49.4)
    37 (27.6 to 47.2)
    29.6 (18 to 43.6)
    37 (27.6 to 47.2)
        responder rate during the AED
    29.6 (18 to 43.6)
    39 (29.4 to 49.3)
    29.6 (18 to 43.6)
    39 (29.4 to 49.3)
        responder rate during monotherapy period
    29.6 (18 to 43.6)
    46 (41.4 to 63)
    38.9 (29.5 to 58.8)
    46 (41.4 to 63)
    No statistical analyses for this end point

    Secondary: Proportion (%) of subjects reaching each exit criteria

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    End point title
    		 Proportion (%) of subjects reaching each exit criteria
    End point description
    The proportion (%) of subjects reaching each of the 5 exit criteria-1.One episode of status epilepticus.2.One secondary gen. partial seizure (in subjects who did not have gen.seizures during 6 mo. prior to screening).3.A two fold increase in any consecutive 28 day seizure rate compared to the highest consecutive 28 day seizure rate during the 8 week baseline period. 4.A two fold increase in any consecutive 2 day seizure rate compared to the highest consecutive 2 day seizure rate during the 8 week baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 week baseline was 1 then 3 seizures in a consecutive 2 day period was required to exit. 5.Worsening of seizures or increase in seizure frequency considered serious or requiring intervention as judged by the investigator
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 18, (beginning of week 1 to end of week 18)
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: percentage of participants
    number (not applicable)
        exit criterion 1
    0
    0
    0
    0
        exit criterion 2
    1.9
    0
    1.9
    0
        exit criterion investigator prog. assessment)
    5.6
    2
    5.6
    2
        exit criterion 3 (sponsors prog. assessment)
    3.7
    1
    3.7
    1
        exit criterion 4 (investigaor prog. assessment)
    1.9
    5
    1.9
    5
        exit criterion 4 (sponsor prog. assessment)
    3.7
    6
    3.7
    6
        exit criterion 5
    3.7
    5
    3.7
    5
    No statistical analyses for this end point

    Secondary: Change in total score from baseline in 31-Item Quality of Life in Epilepsy (QOLIE-31).

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    End point title
    		 Change in total score from baseline in 31-Item Quality of Life in Epilepsy (QOLIE-31).
    End point description
    The QOLIE-31 overall score was obtained by using a weighted average of multi-item scale scores. The recorded responses were converted to 0-100 point scales. The mean of the individual item scores in each subgroup were calculated, with higher converted scores reflecting better quality of life.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 18, Baseline: Day 0: End of AED taper/conversion period: end of week 8; End of monotherapy period: end of week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        chg from baseline-end of AED taper/covn.pd n=45,85
    3.4 ( 12.3 )
    5.8 ( 11.77 )
    3.4 ( 12.3 )
    5.8 ( 11.77 )
        change from baseline-end of monotherapy pd n=50,96
    4 ( 11.48 )
    4.7 ( 13.7 )
    4 ( 11.48 )
    4.7 ( 13.7 )
    No statistical analyses for this end point

    Secondary: Change in total score in Montgomery-Asberg Depression Rating Scale (MADRS),from baseline .

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    End point title
    		 Change in total score in Montgomery-Asberg Depression Rating Scale (MADRS),from baseline .
    End point description
    The total score of MADRS is defined as the sum of all individual item scores. From 0-60, high score indicates more severe
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 18,baseline day 0; end of AED taper/conversion period; end of week 8; end of monotherapy period; end of week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        chg from baseline-end of AED taper/covn.pd n=48,88
    -1.2 ( 3.69 )
    -1.8 ( 4.01 )
    -1.2 ( 3.69 )
    -1.8 ( 4.01 )
        chg from baseline-end of monotherapy pd n=54,98
    0 ( 6.47 )
    -1.6 ( 4.54 )
    0 ( 6.47 )
    -1.6 ( 4.54 )
    No statistical analyses for this end point

    Secondary: Change in total score of MADRS from baseline in those subjects with a MADRS score of ≥14 at randomization.

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    End point title
    		 Change in total score of MADRS from baseline in those subjects with a MADRS score of ≥14 at randomization.
    End point description
    The total score of MADRS is defined as the sum of all individual item scores. From 0-60, higher score indicates more severe
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 18, baseline:day 0;end of AED taper/conversion period; end of week 8; end of monotherapy period: end of week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    50
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        chge from baseline-end of AED taper/covn.pd n=7,16
    -3.9 ( 4.3 )
    -6.6 ( 4.15 )
    -3.9 ( 4.3 )
    -6.6 ( 4.15 )
        chg from baseline-end of monotherapy pd n=7,18
    -6.1 ( 6.72 )
    -4.1 ( 7.58 )
    -6.1 ( 6.72 )
    -4.1 ( 7.58 )
    No statistical analyses for this end point

    Secondary: Proportion (%) of subjects with increase of body weight >= 7% from baseline

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    End point title
    		 Proportion (%) of subjects with increase of body weight >= 7% from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    18 Week Double-blind treatment period
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    58
    114
    58
    114
    Units: percentage of participants
        number (not applicable)
    1.8
    11.7
    1.8
    11.7
    No statistical analyses for this end point

    Secondary: Proportion (%) of subjects with normal baseline sodium reaching blood sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L.

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    End point title
    		 Proportion (%) of subjects with normal baseline sodium reaching blood sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L.
    End point description
    Proportion (%) of Subjects With Normal Baseline Sodium Reaching Blood Sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    58
    114
    58
    114
    Units: percentage of participants
    number (not applicable)
        ≤ 135 and > 130 mEq/L
    8.8
    54.5
    49.1
    54.5
        ≤ 130 and > 125 mEq/L
    0
    20.9
    8.8
    20.9
        ≤ 125 mEq/L
    49.1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Proportion (%) of events in each classification of the Columbia Suicide Severity Rating Scale (C SSRS).

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    End point title
    		 Proportion (%) of events in each classification of the Columbia Suicide Severity Rating Scale (C SSRS).
    End point description
    End point type
    Secondary
    End point timeframe
    18 Week Double-blind treatment period
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    58
    114
    58
    114
    Units: Percent of particiants
    number (not applicable)
        Actual Attempt
    3.4
    0
    3.4
    0
        Non-suicidal Self-Injurious Behavior
    0
    0.9
    0
    0.9
        Interrupted Attempt
    0
    0
    0
    0
        Aborted Attempt
    0
    0
    0
    0
        Preparatory Attempts
    0
    0
    0
    0
        Suicidal Behavior
    3.4
    0
    3.4
    0
        Wish to be Dead
    1.7
    0.9
    1.7
    0.9
        Non-specific Active Suicidal Thoughts
    0
    1
    0
    1
        Act. Suicidal Idea. w/any method-no intent to act
    0
    0
    0
    0
        Act. Suicidal Idea.w/any method-some intent to act
    0
    0.9
    0
    0.9
        Act. Suicidal Idea. w/any method-Spec. Plan to act
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Standardized seizure frequency (SSF) by period

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    End point title
    		 Standardized seizure frequency (SSF) by period
    End point description
    Seizure frequency was evaluated by using a standardized frequency per 4 weeks (28 days). It was evaluated for five periods: baseline (Weeks -8 to -1), titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18).
    End point type
    Secondary
    End point timeframe
    Double-blind: week to 18; Baseline: weeks -8 to -1; titration: weeks 1 to 2; AED taper/conversion weeks 3 to 8; monotherapy: weeks 9 to 18
    End point values
    		 ESL 1200 mg ESL1600 mg ESL1200 mg ESL 1600 mg
    Number of subjects analysed
    54
    100
    54
    100
    Units: seizures in 28 days
    arithmetic mean (standard deviation)
        SSF during double-blind pd n=54,100
    5.5 ( 7.75 )
    5.2 ( 5.38 )
    5.5 ( 7.75 )
    5.2 ( 5.38 )
        SSF druing baseline pd n=54,98
    7.4 ( 5.89 )
    8.7 ( 7.2 )
    7.4 ( 5.89 )
    8.7 ( 7.2 )
        SSF during titration pd n=54,100
    6 ( 6.16 )
    6.4 ( 8.11 )
    6 ( 6.16 )
    6.4 ( 8.11 )
        SSF during AED taper/conversion pd n=54,100
    6 ( 9.68 )
    5.1 ( 5.26 )
    6 ( 9.68 )
    5.1 ( 5.26 )
        SSF during monotherapy pd n=48,88
    4.7 ( 6.1 )
    5 ( 5.62 )
    4.7 ( 6.1 )
    5 ( 5.62 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 week double-blind treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    ESL 1600 mg
    Reporting group description
    		 Titrate from 600 mg (Week 1) to 1200 mg (Week 2) to 1600 mg (Weeks 3-18) QD and taper down from 1600 mg to 800 mg QD 3 days after end of Week 18.

    Reporting group title
    ESL1200 mg
    Reporting group description
    		 Titrate from 400 mg (Week 1) to 800 mg (Week2) to 1200 mg (Weeks 3-18) QD and taper down from 1200 mg to 600 mg QD 3 days after end of Week 18.

    Serious adverse events
    		 ESL 1600 mg ESL1200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 114 (7.02%)
    1 / 58 (1.72%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    ankle fracture
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post concussion syndrome
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Complex partial seizures
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synocope
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug rash with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ESL 1600 mg ESL1200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 114 (56.14%)
    29 / 58 (50.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 114 (21.05%)
    6 / 58 (10.34%)
         occurrences all number
    37
    7
    Headache
         subjects affected / exposed
    32 / 114 (28.07%)
    11 / 58 (18.97%)
         occurrences all number
    87
    16
    Solmnolence
         subjects affected / exposed
    10 / 114 (8.77%)
    2 / 58 (3.45%)
         occurrences all number
    12
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 114 (5.26%)
    4 / 58 (6.90%)
         occurrences all number
    7
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 114 (6.14%)
    6 / 58 (10.34%)
         occurrences all number
    12
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 114 (0.88%)
    3 / 58 (5.17%)
         occurrences all number
    1
    4
    Insomnia
         subjects affected / exposed
    3 / 114 (2.63%)
    4 / 58 (6.90%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 114 (5.26%)
    3 / 58 (5.17%)
         occurrences all number
    7
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 114 (7.89%)
    4 / 58 (6.90%)
         occurrences all number
    9
    4
    Influenza
         subjects affected / exposed
    1 / 114 (0.88%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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