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    Clinical Trial Results:
    A Multicenter, Double Blind, Randomized, Placebo-Controlled Trial to Determine the Efficacy and Safety of Ganaxolone as Adjunctive Therapy for Adults With Drug-Resistant Partial-Onset Seizures Followed by Long-term Open-Label Treatment

    Summary
    EudraCT number
    		 2014-004363-21
    Trial protocol
    		 BG   DE   PL  
    Global end of trial date
    01 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2023
    First version publication date
    23 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1042-0603
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01963208
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Marinus Pharmaceuticals, Inc.
    Sponsor organisation address
    5 Radnor Corporate Center, 100 Matsonford Road, Suite 500, Radnor, United States, PA 19087
    Public contact
    Marinus Pharmaceuticals, Inc., Safety Department, 001 484-801-4670, clinicaltrials@marinuspharma.com
    Scientific contact
    Marinus Pharmaceuticals, Inc., Safety Department, 001 484-801-4670, clinicaltrials@marinuspharma.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
    01 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy of ganaxolone compared to placebo as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalizations.
    Protection of trial subjects
    At the first visit, prior to initiation of any study-related procedures, the parent(s) or legal guardian(s) of the subjects gave their written consent to participate in the study after having been informed about the nature and purpose of the study, participation / termination conditions, and risks and benefits. Before the informed consent document was signed, the investigator, or a person designated by the investigator, provided the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial were answered to the satisfaction of the subject or the subject's legally acceptable representative.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2013
    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
    Poland: 42
    Country: Number of subjects enrolled
    Bulgaria: 77
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Australia: 47
    Country: Number of subjects enrolled
    Russian Federation: 81
    Country: Number of subjects enrolled
    United States: 141
    Worldwide total number of subjects
    405
    EEA total number of subjects
    136
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    391
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 2-cohort study where each cohort comprised of 2 treatment phases. Phase 1 was a double-blind phase followed by Phase 2, an open-label phase. The study analyzed safety, tolerability and pharmacokinetics (PK) of Ganaxolone when compared with placebo in both the cohorts.

    Pre-assignment
    Screening details
    		 This was a 2-cohort study where each cohort comprised of 2 treatment phases. Phase 1 was a double-blind phase followed by Phase 2, an open-label phase. The study analyzed safety, tolerability and pharmacokinetics (PK) of Ganaxolone when compared with placebo in both the cohorts.

    Period 1
    Period 1 title
    Treatment Phase 1 (Up to Week 14)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double Blind: Cohort 1 - Ganaxolone
    Arm description
    		 Participants were administered ganaxolone 1200 milligrams per day (mg/day) and 1800 mg/day + Antiepileptic drug (AED). Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ganaxolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ganaxolone was administered

    Arm title
    		 Double Blind: Cohort 1 - Placebo
    Arm description
    		 Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.
    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
    Placebo was administered.

    Arm title
    		 Double Blind: Cohort 2 - Ganaxolone
    Arm description
    		 Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ganaxolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ganaxolone will be administered

    Arm title
    		 Double Blind: Cohort 2 - Placebo
    Arm description
    		 Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase
    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
    Placebo was administered.

    Number of subjects in period 1
    		Double Blind: Cohort 1 - Ganaxolone Double Blind: Cohort 1 - Placebo Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Started
    24
    22
    179
    180
    Completed
    23
    19
    135
    154
    Not completed
    1
    3
    44
    26
         Consent withdrawn by subject
    -
    2
    8
    9
         Non-Compliance
    -
    -
    4
    -
         Adverse event, non-fatal
    1
    -
    30
    11
         Protocol violation
    -
    -
    1
    3
         Insufficient Clinical Response
    -
    -
    -
    1
         Unspecified
    -
    1
    1
    1
         Lost to follow-up
    -
    -
    -
    1
    Period 2
    Period 2 title
    Treatment Phase 2 (Up to Week 68)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Open Label: Ganaxolone in Double-blind Phase
    Arm description
    		 Following the completion of the double-blind phase, participants randomized to ganaxolone remained on the drug at 1800 mg/day + AED. Participants from Double Blind: Cohort 1 - Ganaxolone and Double Blind: Cohort 2 - Ganaxolone were combined to enter in Open Label: Ganaxolone in Double-blind Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ganaxolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ganaxolone was administered.

    Arm title
    		 Open Label: Placebo in Double-blind Phase
    Arm description
    		 Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone + AED. Participants from Double Blind: Cohort 1 - Placebo and Double Blind: Cohort 2 - Placebo were combined to enter in Open Label: Placebo in Double-blind Phase
    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
    Placebo was administered

    Number of subjects in period 2
    		Open Label: Ganaxolone in Double-blind Phase Open Label: Placebo in Double-blind Phase
    Started
    158
    173
    Completed
    57
    44
    Not completed
    101
    129
         Consent withdrawn by subject
    7
    19
         Non-Compliance
    -
    1
         Adverse event, non-fatal
    16
    15
         Protocol violation
    -
    1
         Death
    -
    1
         Insufficient Clinical Response
    20
    17
         Unspecified
    58
    75

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Phase 1 (Up to Week 14)
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Phase 1 (Up to Week 14) Total
    Number of subjects
    		 405 405
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 391 391
        From 65-84 years
    		 14 14
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.99 ( 12.379 ) -
    Gender categorical
    Units: Subjects
        Female
    		 243 243
        Male
    		 162 162
    Subject analysis sets

    Subject analysis set title
    Double Blind: Cohort 1 – Ganaxolone
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered ganaxolone 1200 mg/day and 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase

    Subject analysis set title
    Double Blind: Cohort 1 - Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase. Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at

    Subject analysis set title
    Double Blind: Cohort 2 - Ganaxolone
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Subject analysis set title
    Double Blind: Cohort 2 - Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Subject analysis sets values
    		 Double Blind: Cohort 1 – Ganaxolone Double Blind: Cohort 1 - Placebo Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects
    24
    21
    178
    172
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    35.1 ( 10.25 )
    41.1 ( 11.83 )
    40.6 ( 12.48 )
    42.1 ( 12.37 )
    Gender categorical
    Units: Subjects
        Female
    13
    12
    113
    97
        Male
    11
    9
    65
    75

    End points

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    End points reporting groups
    Reporting group title
    Double Blind: Cohort 1 - Ganaxolone
    Reporting group description
    		 Participants were administered ganaxolone 1200 milligrams per day (mg/day) and 1800 mg/day + Antiepileptic drug (AED). Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Reporting group title
    Double Blind: Cohort 1 - Placebo
    Reporting group description
    		 Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Reporting group title
    Double Blind: Cohort 2 - Ganaxolone
    Reporting group description
    		 Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Reporting group title
    Double Blind: Cohort 2 - Placebo
    Reporting group description
    		 Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase
    Reporting group title
    Open Label: Ganaxolone in Double-blind Phase
    Reporting group description
    		 Following the completion of the double-blind phase, participants randomized to ganaxolone remained on the drug at 1800 mg/day + AED. Participants from Double Blind: Cohort 1 - Ganaxolone and Double Blind: Cohort 2 - Ganaxolone were combined to enter in Open Label: Ganaxolone in Double-blind Phase

    Reporting group title
    Open Label: Placebo in Double-blind Phase
    Reporting group description
    		 Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone + AED. Participants from Double Blind: Cohort 1 - Placebo and Double Blind: Cohort 2 - Placebo were combined to enter in Open Label: Placebo in Double-blind Phase

    Subject analysis set title
    Double Blind: Cohort 1 – Ganaxolone
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered ganaxolone 1200 mg/day and 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase

    Subject analysis set title
    Double Blind: Cohort 1 - Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase. Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at

    Subject analysis set title
    Double Blind: Cohort 2 - Ganaxolone
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Ganaxolone 1800 mg/day + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Subject analysis set title
    Double Blind: Cohort 2 - Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were administered Placebo + AED. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Primary: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period [1]
    End point description
    Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Primary analysis was performed using a rank analysis of covariance (ANCOVA). Modified intent to treat (mITT) population: all randomized participants who received at least 1 dose of study medication and provided any post Baseline seizure outcome data.
    End point type
    Primary
    End point timeframe
    Baseline and Week 14
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percent change
        median (confidence interval 95%)
    -21.28 (-29.60 to -14.29)
    -10.25 (-20.14 to -1.28)
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    Double Blind: Cohort 2 - Ganaxolone, Double Blind: Cohort 2 - Placebo
    Comparison groups
    Double Blind: Cohort 2 - Ganaxolone v Double Blind: Cohort 2 - Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1788 [2]
    Method
    		 Rank ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -7.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.44
         upper limit
    		 3.52
    Notes
    [2] - The null hypothesis is that there is no difference between the distributions of the two treatment groups with respect to percent change in seizure frequency.

    Secondary: Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change – Improvement (CGI-I) at Week 14

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    End point title
    		 Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change – Improvement (CGI-I) at Week 14 [3]
    End point description
    The CGI-I scale is a clinician-rated 7-point Likert scale used to assess the degree to which the participant's epilepsy symptoms have changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher scores indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    At Week 14
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    140
    159
    Units: Participants
    number (not applicable)
        Very much improved
    7
    5
        Much improved
    28
    30
        Minimally improved
    41
    47
        No change
    56
    67
        Minimally worse
    6
    8
        Much worse
    2
    2
        Very much worse
    0
    0
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Number of Participants With ≥50% Responder Rate During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Number of Participants With ≥50% Responder Rate During Titration + Maintenance Period [4]
    End point description
    A 50% responder was a participant who experienced at least a 50% decrease in 28-day seizure frequency compared to Baseline
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Participants
        number (not applicable)
    50
    39
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Titration + Maintenance Period [5]
    End point description
    Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire Baseline period (<=56 days) divided by the number of days with available seizure data in the baseline period and multiplied by 28. Post-Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Change from Baseline in number of seizure free days per 28-day period from Baseline was calculated as: Post-Baseline number of seizure free days per 28-day period minus Baseline number of seizure free days per 28-day period. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Seizure free days
        arithmetic mean (standard deviation)
    1.47 ( 4.396 )
    1.01 ( 4.223 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period [6]
    End point description
    Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Seizures per 28 days
        arithmetic mean (standard deviation)
    -1.46 ( 9.650 )
    -0.33 ( 11.040 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Maintenance Period [7]
    End point description
    Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2 to Week 14
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    166
    169
    Units: Seizures per 28 days
        arithmetic mean (standard deviation)
    -1.67 ( 11.809 )
    -0.64 ( 12.153 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Maintenance Period [8]
    End point description
    Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2 to Week 14
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    166
    169
    Units: Percent change
        median (confidence interval 95%)
    -20.56 (-31.56 to -12.69)
    -12.50 (-20.78 to -3.03)
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Maintenance Period [9]
    End point description
    Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Post-Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Change from Baseline in number of seizure free days per 28-day period from Baseline was calculated as: Post-Baseline number of seizure free days per 28-day period minus Baseline number of seizure free days per 28-day period. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2 to Week 14
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    166
    169
    Units: Seizure free days
        arithmetic mean (standard deviation)
    1.63 ( 4.824 )
    1.20 ( 4.462 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Titration + Maintenance Period [10]
    End point description
    Percentage of participants who had reductions of ≥ 80%, ≥ 60%, ≥ 40%, and ≥ 20% in 28-day seizure frequency from Baseline is presented. A responder is an individual whose reduction of percent change from Baseline in 28-day seizure frequency was ≥ 50%. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percentage of participants
    number (not applicable)
        Reduction ≥ 80%
    7.3
    2.33
        Reduction ≥ 60%
    20.79
    16.86
        Reduction ≥ 40%
    33.15
    29.65
        Reduction ≥ 20%
    51.69
    43.6
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Maintenance Period [11]
    End point description
    Percentage of participants who had reductions of ≥ 80%, ≥ 60%, ≥ 40%, and ≥ 20% in 28-day seizure frequency from Baseline is presented. A responder is an individual whose reduction of percent change from Baseline in 28-day seizure frequency was ≥ 50%. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 14
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percentage of participants
    number (not applicable)
        Reduction ≥ 80%
    8.43
    5.81
        Reduction ≥ 60%
    24.16
    18.02
        Reduction ≥ 40%
    33.71
    31.4
        Reduction ≥ 20%
    47.19
    42.44
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percentage of Seizure Free Participants During the Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percentage of Seizure Free Participants During the Maintenance Period [12]
    End point description
    Percentage of participants who completed the study without any seizures is presented
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 14
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percentage of participants
        number (not applicable)
    1.12
    0
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percentage of Participants Who Experienced at Least One 28-day Seizure Free Period During Titration + Maintenance Phase

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    End point title
    		 Double Blind: Cohort 2: Percentage of Participants Who Experienced at Least One 28-day Seizure Free Period During Titration + Maintenance Phase [13]
    End point description
    Percentage of participants who experienced at least one 28-day seizure free period is presented
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percentage of participants
        number (not applicable)
    17.98
    18.02
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency for Different Subtypes of Seizures During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency for Different Subtypes of Seizures During Titration + Maintenance Period [14]
    End point description
    Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. The analysis was conducted for Partial-Onset Seizure (POS) only which included seizure subtypes: Complex partial seizures (CPS), secondarily generalized tonic-clonic (SGTC) seizures, simple partial seizure with motor/observable component (SPS-Motor) and Simple partial seizure (SPS) without motor/observable component. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (≤ 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    150
    152
    Units: Percent change
    arithmetic mean (standard deviation)
        CPS (n= 150, 152)
    -4.70 ( 92.373 )
    -6.52 ( 59.126 )
        SGTC (n= 69, 82)
    -27.42 ( 69.394 )
    1.02 ( 118.444 )
        SPS-Motor (n= 44, 32)
    -5.52 ( 93.228 )
    -21.97 ( 52.473 )
        SPS (n= 33, 31)
    12.57 ( 129.979 )
    -3.53 ( 87.071 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Longest Percent of Time Spent Seizure-free During Titration + Maintenance Period

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    End point title
    		 Double Blind: Cohort 2: Longest Percent of Time Spent Seizure-free During Titration + Maintenance Period [15]
    End point description
    The longest period of time seizure-free was defined as the percent of the longest seizure-free period (days) divided by the days with available seizure data, and then multiplied by 100%.
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    178
    172
    Units: Percentage of time spent
        arithmetic mean (standard deviation)
    24.00 ( 22.457 )
    17.58 ( 12.743 )
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Number of Participants With Patient Global Impression of Change – Improvement (PGI-I) at Week 8 and Week 14

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    End point title
    		 Double Blind: Cohort 2: Number of Participants With Patient Global Impression of Change – Improvement (PGI-I) at Week 8 and Week 14 [16]
    End point description
    The PGI-I scale was a 7-point Likert scale completed by the Patient or Caregiver representing the degree to which the participant's epilepsy symptoms had changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher score indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    Week 8 and Week 14
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    166
    161
    Units: Participants
    number (not applicable)
        Week 8: Very Much Improved
    7
    5
        Week 8: Much Improved
    30
    21
        Week 8: Minimally Improved
    44
    51
        Week 8: No Change
    59
    65
        Week 8: Minimally Worse
    12
    11
        Week 8: Much Worse
    8
    4
        Week 8: Very Much Worse
    6
    4
        Week 14: Very Much Improved
    7
    10
        Week 14: Much Improved
    33
    29
        Week 14: Minimally Improved
    43
    43
        Week 14: No Change
    46
    60
        Week 14: Minimally Worse
    7
    12
        Week 14: Much Worse
    3
    4
        Week 14: Very Much Worse
    1
    1
    No statistical analyses for this end point

    Secondary: Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change – Improvement (CGI-I) at Week 8

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    End point title
    		 Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change – Improvement (CGI-I) at Week 8 [17]
    End point description
    The CGI-I scale is a clinician-rated 7-point Likert scale used to assess the degree to which the participant's epilepsy symptoms have changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher scores indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    		 Double Blind: Cohort 2 - Ganaxolone Double Blind: Cohort 2 - Placebo
    Number of subjects analysed
    166
    162
    Units: Participants
    number (not applicable)
        Very much improved
    3
    4
        Much improved
    27
    20
        Minimally improved
    50
    49
        No change
    68
    71
        Minimally worse
    8
    12
        Much worse
    9
    5
        Very much worse
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week -8 through Week 14 in Double blind phase and from Week 16 to Week 68 in open label phase
    Adverse event reporting additional description
    Safety Population: included all randomized participants who received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Open Label: Ganaxolone in Double-blind Phase
    Reporting group description
    		 Following the completion of the double-blind phase, participants randomized to ganaxolone remained on the drug at 1800 mg/day + AED. Participants from Double Blind: Cohort 1 - Ganaxolone and Double Blind: Cohort 2 - Ganaxolone were combined to enter in Open Label: Ganaxolone in Double-blind Phase

    Reporting group title
    Open Label: Placebo in Double-blind Phase
    Reporting group description
    		 Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone + AED. Participants from Double Blind: Cohort 1 - Placebo and Double Blind: Cohort 2 - Placebo were combined to enter in Open Label: Placebo in Double-blind Phase

    Reporting group title
    Double Blind: Cohort 1 and Cohort 2- Ganaxolone
    Reporting group description
    		 Participants were administered ganaxolone 1200 milligrams per day (mg/day) and 1800 mg/day + Antiepileptic drug (AED) in Cohort 1 and Participants were administered Ganaxolone 1800 mg/day + AED in Cohort 2. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase.

    Reporting group title
    Double Blind: Cohort 1 and Cohort 2 - Placebo
    Reporting group description
    		 Participants were administered Placebo + AED in Cohort 1 and Cohort 2. Following the completion of the double-blind phase, participants randomized to placebo were transitioned to ganaxolone while participants randomized to ganaxolone remained on the drug at 1800 mg/day in the open-label phase

    Serious adverse events
    		 Open Label: Ganaxolone in Double-blind Phase Open Label: Placebo in Double-blind Phase Double Blind: Cohort 1 and Cohort 2- Ganaxolone Double Blind: Cohort 1 and Cohort 2 - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 158 (7.59%)
    12 / 173 (6.94%)
    9 / 203 (4.43%)
    9 / 197 (4.57%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Foot fracture
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Tongue injury
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Ankle fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 158 (0.63%)
    4 / 173 (2.31%)
    2 / 203 (0.99%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
    0 / 2
    Epilepsy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Toxic encephalopathy
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Postictal psychosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Grand mal convulsion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Psychiatric disorders
    Psychogenic seizure
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Depression
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Anxiety
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (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 / 1
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         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 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (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 / 1
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Open Label: Ganaxolone in Double-blind Phase Open Label: Placebo in Double-blind Phase Double Blind: Cohort 1 and Cohort 2- Ganaxolone Double Blind: Cohort 1 and Cohort 2 - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 158 (26.58%)
    67 / 173 (38.73%)
    134 / 203 (66.01%)
    98 / 197 (49.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign hepatic neoplasm
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Cervical polyp
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Cardiovascular disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    4 / 158 (2.53%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    4
    2
    1
    1
    Aortic disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Venous thrombosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypertensive crisis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    4
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Open reduction of fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Night sweats
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    9 / 158 (5.70%)
    15 / 173 (8.67%)
    23 / 203 (11.33%)
    12 / 197 (6.09%)
         occurrences all number
    10
    19
    30
    12
    Gait disturbance
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    5 / 203 (2.46%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    5
    1
    Asthenia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cyst
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Procedural pain
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    2
    0
    1
    Immune system disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Social circumstances
    Stress at work
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Menopausal symptoms
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Breast cyst
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 158 (0.00%)
    3 / 173 (1.73%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    3
    0
    1
    Erectile dysfunction
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Menorrhagia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Metrorrhagia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Polymenorrhoea
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Amenorrhoea
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Breast tenderness
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vaginal inflammation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Uterine polyp
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Menstruation irregular
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    3 / 203 (1.48%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Asthma
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    1
    1
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    2 / 158 (1.27%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    2
    1
    0
    1
    Nasal inflammation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 158 (0.63%)
    3 / 173 (1.73%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhonchi
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Euphoric mood
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mood swings
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    2
    0
    0
    1
    Anger
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Panic attack
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Stress
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Suicidal ideation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Affective disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Nervousness
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    3
    1
    Confusional state
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    1 / 197 (0.51%)
         occurrences all number
    1
    1
    2
    1
    Irritability
         subjects affected / exposed
    0 / 158 (0.00%)
    3 / 173 (1.73%)
    2 / 203 (0.99%)
    2 / 197 (1.02%)
         occurrences all number
    0
    3
    2
    2
    Anxiety
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    3 / 203 (1.48%)
    3 / 197 (1.52%)
         occurrences all number
    2
    0
    3
    3
    Mood altered
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Mental status changes
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Libido decreased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Suicide attempt
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychotic disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Emotional distress
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Agitation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aggression
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abnormal behaviour
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood alkaline phosphatase abnormal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Biopsy skin
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 158 (0.00%)
    3 / 173 (1.73%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    3
    0
    2
    Blood potassium increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    0
    0
    1
    2
    Blood glucose abnormal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diagnostic procedure
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arthroscopy
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Neurological examination abnormal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood iron increased
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count increased
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 158 (0.00%)
    4 / 173 (2.31%)
    3 / 203 (1.48%)
    4 / 197 (2.03%)
         occurrences all number
    0
    8
    3
    4
    Fall
         subjects affected / exposed
    1 / 158 (0.63%)
    3 / 173 (1.73%)
    1 / 203 (0.49%)
    3 / 197 (1.52%)
         occurrences all number
    1
    6
    2
    3
    Head injury
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    2 / 197 (1.02%)
         occurrences all number
    1
    1
    2
    2
    Ligament sprain
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    2 / 203 (0.99%)
    1 / 197 (0.51%)
         occurrences all number
    1
    2
    2
    1
    Rib fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    3 / 197 (1.52%)
         occurrences all number
    0
    0
    0
    3
    Facial bones fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    0
    0
    2
    Laceration
         subjects affected / exposed
    3 / 158 (1.90%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    3
    5
    2
    1
    Excoriation
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Muscle contusion
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Periorbital contusion
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Foot fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye contusion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wound haemorrhage
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tibia fracture
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tendon injury
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Incision site erythema
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Burns third degree
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Concussion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Paroxysmal arrhythmia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Silent myocardial infarction
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bundle branch block left
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    12 / 158 (7.59%)
    29 / 173 (16.76%)
    46 / 203 (22.66%)
    10 / 197 (5.08%)
         occurrences all number
    13
    33
    56
    10
    Dizziness
         subjects affected / exposed
    8 / 158 (5.06%)
    27 / 173 (15.61%)
    38 / 203 (18.72%)
    9 / 197 (4.57%)
         occurrences all number
    16
    29
    50
    9
    Headache
         subjects affected / exposed
    9 / 158 (5.70%)
    11 / 173 (6.36%)
    18 / 203 (8.87%)
    15 / 197 (7.61%)
         occurrences all number
    15
    12
    19
    15
    Ataxia
         subjects affected / exposed
    2 / 158 (1.27%)
    2 / 173 (1.16%)
    6 / 203 (2.96%)
    0 / 197 (0.00%)
         occurrences all number
    2
    3
    7
    0
    Balance disorder
         subjects affected / exposed
    3 / 158 (1.90%)
    1 / 173 (0.58%)
    7 / 203 (3.45%)
    1 / 197 (0.51%)
         occurrences all number
    3
    1
    7
    1
    Aphasia
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    5 / 203 (2.46%)
    2 / 197 (1.02%)
         occurrences all number
    1
    2
    5
    2
    Convulsion
         subjects affected / exposed
    5 / 158 (3.16%)
    4 / 173 (2.31%)
    5 / 203 (2.46%)
    5 / 197 (2.54%)
         occurrences all number
    5
    5
    5
    5
    Tremor
         subjects affected / exposed
    2 / 158 (1.27%)
    2 / 173 (1.16%)
    4 / 203 (1.97%)
    1 / 197 (0.51%)
         occurrences all number
    24
    2
    4
    1
    Dysarthria
         subjects affected / exposed
    2 / 158 (1.27%)
    4 / 173 (2.31%)
    3 / 203 (1.48%)
    1 / 197 (0.51%)
         occurrences all number
    2
    4
    3
    1
    Memory impairment
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    3 / 197 (1.52%)
         occurrences all number
    1
    2
    1
    3
    Sedation
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    4 / 203 (1.97%)
    0 / 197 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Agitation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    1
    0
    2
    Slow speech
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Amnesia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    3 / 203 (1.48%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Disorientation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Dyskinesia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Essential tremor
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Grand mal convulsion
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mental impairment
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    1
    2
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychomotor skills impaired
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sleep terror
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Speech disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    0
    1
    Seizure cluste
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dementia Alzheimer''s type
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Postictal state
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Radicular pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Delayed sleep phase
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Slow response to stimuli
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Splenomegaly
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Anaemia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 158 (0.00%)
    5 / 173 (2.89%)
    4 / 203 (1.97%)
    0 / 197 (0.00%)
         occurrences all number
    0
    7
    4
    0
    Ear pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Nystagmus
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Diplopia
         subjects affected / exposed
    2 / 158 (1.27%)
    4 / 173 (2.31%)
    2 / 203 (0.99%)
    2 / 197 (1.02%)
         occurrences all number
    2
    4
    2
    2
    Vision blurred
         subjects affected / exposed
    3 / 158 (1.90%)
    1 / 173 (0.58%)
    7 / 203 (3.45%)
    2 / 197 (1.02%)
         occurrences all number
    11
    1
    14
    2
    Eye swelling
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Visual impairment
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dry eye
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Eye allergy
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blepharospasm
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ocular dysmetria
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    2 / 203 (0.99%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    2
    1
    Nausea
         subjects affected / exposed
    5 / 158 (3.16%)
    4 / 173 (2.31%)
    1 / 203 (0.49%)
    8 / 197 (4.06%)
         occurrences all number
    13
    5
    1
    8
    Diarrhoea
         subjects affected / exposed
    2 / 158 (1.27%)
    3 / 173 (1.73%)
    3 / 203 (1.48%)
    5 / 197 (2.54%)
         occurrences all number
    2
    5
    3
    5
    Vomiting
         subjects affected / exposed
    2 / 158 (1.27%)
    7 / 173 (4.05%)
    1 / 203 (0.49%)
    5 / 197 (2.54%)
         occurrences all number
    2
    7
    1
    5
    Constipation
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    3 / 203 (1.48%)
    1 / 197 (0.51%)
         occurrences all number
    1
    2
    3
    1
    Dry mouth
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    3 / 197 (1.52%)
         occurrences all number
    0
    0
    1
    3
    Abdominal pain
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    3 / 197 (1.52%)
         occurrences all number
    0
    2
    0
    3
    Oral pruritus
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 158 (0.63%)
    3 / 173 (1.73%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Dental caries
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Disbacteriosis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    1
    1
    1
    1
    Eructation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    0
    0
    2
    Abdominal discomfort
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bowel movement irregularity
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophagitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Retching
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Cholecystitis chronic
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Skin hypopigmentation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain of skin
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Acne
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 158 (1.27%)
    1 / 173 (0.58%)
    3 / 203 (1.48%)
    1 / 197 (0.51%)
         occurrences all number
    2
    1
    3
    1
    Alopecia
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    4 / 203 (1.97%)
    0 / 197 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Rash
         subjects affected / exposed
    3 / 158 (1.90%)
    2 / 173 (1.16%)
    5 / 203 (2.46%)
    2 / 197 (1.02%)
         occurrences all number
    3
    2
    5
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Swelling face
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Micturition urgency
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Menstruation irregular
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Adrenal cyst
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gynaecomastia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    2
    2
    0
    3
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Muscle fatigue
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypertonia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Exostosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    3 / 158 (1.90%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    4
    2
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    1
    2
    1
    Myalgia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    1
    0
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Muscle spasms
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    2 / 203 (0.99%)
    0 / 197 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Back pain
         subjects affected / exposed
    1 / 158 (0.63%)
    4 / 173 (2.31%)
    1 / 203 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    1
    6
    2
    2
    Sensation of heaviness
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthritis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Osteochondrosis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 158 (3.80%)
    9 / 173 (5.20%)
    5 / 203 (2.46%)
    9 / 197 (4.57%)
         occurrences all number
    6
    9
    5
    9
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 158 (2.53%)
    5 / 173 (2.89%)
    6 / 203 (2.96%)
    3 / 197 (1.52%)
         occurrences all number
    6
    5
    6
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 158 (1.90%)
    8 / 173 (4.62%)
    3 / 203 (1.48%)
    2 / 197 (1.02%)
         occurrences all number
    3
    9
    3
    2
    Sinusitis
         subjects affected / exposed
    2 / 158 (1.27%)
    3 / 173 (1.73%)
    2 / 203 (0.99%)
    2 / 197 (1.02%)
         occurrences all number
    2
    4
    2
    2
    Pharyngitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    3 / 197 (1.52%)
         occurrences all number
    0
    0
    0
    3
    Influenza
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    2
    0
    0
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    2
    Bronchitis
         subjects affected / exposed
    6 / 158 (3.80%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    6
    2
    0
    1
    Corneal infection
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    2
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    1
    2
    0
    1
    Infected bites
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Rotavirus infection
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis bacterial
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    2 / 158 (1.27%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Fungal infection
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 158 (0.63%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Laryngitis
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 173 (1.16%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Impetigo
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral diarrhoea
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 158 (1.27%)
    1 / 173 (0.58%)
    1 / 203 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    1
    1
    2
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 158 (0.00%)
    4 / 173 (2.31%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Thirst
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    1 / 197 (0.51%)
         occurrences all number
    0
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    1 / 203 (0.49%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 173 (0.58%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 173 (0.00%)
    0 / 203 (0.00%)
    0 / 197 (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
    03 Dec 2013
    Inclusion criterion 6.e was added: “Perampanel: The use of perampanel was allowed provided that the subject had been maintained on a stable dose of perampanel for ≥ 3 months and had not experienced any serious psychiatric and behavioral reactions such as hostility- or aggression related adverse reactions. Section 9.4.10 (Background antiepileptic drug [AED] Medications) was modified state that perampanel was permitted as a concomitant medication only if the subject had been on a stable dose for at least 3 months prior to screening and had not experienced any serious psychiatric and behavioral reactions, and was expected to remain on a constant dose through the double-blind phase of the study. An exclusion criterion was added (#12) and existing exclusion criteria #12 through #24 were re-numbered one number higher. The new exclusion criterion was: “Current use of ezogabine (retigabine; Potiga®; Trobalt®) was not permitted. Subjects who may have used this agent in the past were to have been off this medication for at least 3 months prior to screening and were to have had a documented normal fundoscopic examination by an ophthalmologist. Section 9.4.10 (Background AED Medications) was modified state that current use of ezogabine (retigabine) was not permitted, and that subjects who may have used this agent in the past were to have been off this medication for at least 3 months prior to screening and were to have had a documented normal fundoscopic exam by an ophthalmologist. Exclusion criterion #16 (history of drug abuse) was re-numbered to #17 and revised as follows: “The subject had a positive urine drug screen at screening or met criteria for current or historical Substance Use Disorder (Diagnostic and Statistical Manual of Mental Disorders [DSM]-V criteria) within the past 5 years. As with other AEDs, the use of alcohol was not advised.
    10 Mar 2014
    The original treatment scheme was 4 weeks of prospective baseline plus 63 weeks of treatment: 1 week of titration, 4 weeks at 1200 milligrams per day (mg/day), 4 weeks at 1800 mg/day for the double-blind phase, 1-week transition to open-label, and 51 weeks at 1800 mg/day for the open-label phase. Treatment was then de-escalated over 2 weeks. A second treatment scheme was added and called ‘Cohort 2,’ as follows: 4 weeks of prospective baseline plus 68 weeks of treatment: 2 weeks of titration, 12 weeks at 1800 mg/day for the double-blind phase, 2 weeks of transition to open-label, and 50 weeks at 1800 mg/day for the open-label phase. Treatment was then de-escalated over 2 weeks. The protocol was revised in other sections as appropriate to support the addition of the second treatment scheme (i.e., Cohort 2), as follows: A new secondary objective was added: “To evaluate serum levels of ganaxolone at 1200 mg/day and 1800 mg/day after chronic dosing.”; The planned sample size was increased from 150 subjects to 200 subjects, with approximately 50 subjects being enrolled into Cohort 1 and 150 subjects being enrolled into Cohort 2. Randomization remained at 1:1 ganaxolone or placebo in both cohorts; A schedule of events was added for Cohort 2; The primary efficacy endpoint was the change from baseline in 28-day seizure frequency during the double-blind phase for subjects in Cohort 2; A graphic illustration of the study design for Cohort 2 was added; A table showing the dosing schedule for Cohort 2 was added. Inclusion criterion #5 and exclusion criterion #9 were clarified. Randomization was modified to be stratified by country. The Per Protocol (PP) population was re-defined to require that subjects receive at least 12 weeks of treatment, rather than 9 weeks, without major protocol violations. The analysis method for the primary efficacy variable was revised from an ANCOVA with treatment and pooled countries as factors to an ANCOVA with treatment and country as factors.
    23 Sep 2014
    The planned sample size for Cohort 2 was increased from 150 subjects to 292 subjects. The time period for determination of the baseline seizure frequency was modified from a 4-week retrospective period plus a 4-week prospective period to an 8-week prospective period. The number of study sites was increased from 30 to 55 (both approximately), and the estimate of the time required for enrollment of study subjects was increased from 20 months to 26 months. Inclusion criterion #5 and exclusion criterion #6 were clarified. Section 9.4.11 (Excluded Prior and Concomitant Medications) was modified to add that treatment with the 5-α-reductase inhibitor finasteride may not be initiated during the study because it affects endogenous levels of allopregnanolone, which could affect seizure frequency.
    08 Apr 2016
    The planned sample size for Cohort 1 was decreased from 50 subjects to 46 subjects. The planned sample size for Cohort 2 was increased from 292 subjects to 359 subjects. Instead of the single primary efficacy endpoint of percent change from baseline in 28-day seizure frequency, two co-primary efficacy endpoints were defined because of the difference in registration requirements in the US and the EU. The original primary endpoint was unchanged, and was to be used to support a US submission, and a second co-primary endpoint of 50% responder rate during the Maintenance Period was added to support an EU submission. This change was made throughout the study protocol. In addition to the second co-primary efficacy endpoint, three key secondary efficacy endpoints were identified, and a fixed sequence analysis procedure was established to protect the familywise error rate at 0.05. These endpoints were: 50% responder rate during the Titration + Maintenance Period (Cohort 2), change from baseline in the number of seizure-free days per 28-day period during the Titration + Maintenance Period (Cohort 2), and CGI-I at Week 14 of the double-blind phase (Cohort 2). It was stated that all remaining secondary efficacy endpoints would be tested at an alpha of 0.05 and that those p-values would be nominal. Exploratory efficacy endpoints of weekly seizure frequency for each week after randomization during the double-blind phase in Cohort 2 and 28-day seizure frequency for each 4-week period in the open-label phase of the study were added. For inclusion criterion #6, it was added that AEDs could be adjusted during the open-label phase of the study. A criterion for withdrawal from the study (liver function test abnormalities) was added to Section 9.3.4.1 of the study protocol. Specific values of liver function test elevations had to be met to fulfill this criterion, and these were defined in the study protocol.

    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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