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    Clinical Trial Results:
    An Open-Label Extension Phase of the Double-Blind, Placebo-Controlled, Dose-Escalation, Parallel-Group Studies to Evaluate the Efficacy and Safety of E2007 (Perampanel) Given as Adjunctive Therapy in Subjects With Refractory Partial Seizures

    Summary
    EudraCT number
    2007-006170-28
    Trial protocol
    CZ   ES   AT   BE   PT   LT   NL   HU   FR   GB   SE   EE   LV   DK   IT   DE   FI   BG   GR  
    Global end of trial date
    18 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Apr 2016
    First version publication date
    13 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2007-G000-307
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00735397
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    155 Tice Boulevard, Woodcliff Lake, New Jersey, United States, 07677
    Public contact
    Medical Information, Eisai Europe Limited, +44 0845 676 1400, LMedInfo@eisai.net
    Scientific contact
    Medical Information, Eisai Europe Limited, +44 0845 676 1400, LMedInfo@eisai.net
    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
    26 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the safety and tolerability of perampanel (up to 12 mg/day) given as adjunctive treatment in subjects with refractory partial seizures and to evaluate the maintenance of effect of perampanel for the control of refractory partial seizures.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Estonia: 26
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Lithuania: 17
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Chile: 32
    Country: Number of subjects enrolled
    China: 54
    Country: Number of subjects enrolled
    Hong Kong: 22
    Country: Number of subjects enrolled
    India: 71
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 44
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Philippines: 6
    Country: Number of subjects enrolled
    Serbia: 42
    Country: Number of subjects enrolled
    Thailand: 21
    Country: Number of subjects enrolled
    Taiwan: 16
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    United States: 241
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 58
    Country: Number of subjects enrolled
    Argentina: 80
    Country: Number of subjects enrolled
    Australia: 47
    Worldwide total number of subjects
    1218
    EEA total number of subjects
    383
    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)
    124
    Adults (18-64 years)
    1076
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was an open-label Extension (OLE) study for participants who completed one of the following double-blind (DB), placebo-controlled, Phase 3 studies: E2007-G000-304 (NCT00699972), E2007-G000-305(NCT00699582), and E2007-G000-306 (NCT00700310).

    Pre-assignment
    Screening details
    From a total of 1218 participants who provided informed consent, 2 participants were lost to follow-up and did not have any postbaseline safety data after the first OLE dose.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    During the Conversion Period, subjects and investigators remained blinded to the treatment received in the previous DB study. To achieve this, all subjects continued to take 6 tablets of study medication (2 mg perampanel or matching placebo) or fewer as they were instructed during the core DB study. During the open-label Maintenance Period, subjects were treated with the perampanel dose that provided the best combination of individual efficacy and tolerability.

    Arms
    Arm title
    Perampanel
    Arm description
    Participants previously receiving perampanel/placebo in the DB study, were titrated to receive perampanel 2 mg to 12 mg, once daily in the OLE study up to approximately 5 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Perampanel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Perampanel 2 mg to 12 mg tablet, once daily orally in the Open-Label Extension (OLE) study up to approximately 5 years.

    Number of subjects in period 1
    Perampanel
    Started
    1218
    Completed
    35
    Not completed
    1183
         Adverse events
    194
         Subject Choice
    252
         Administrative/Other
    502
         Inadequate therapeutic effect
    202
         Lost to follow-up
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    1218 1218
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    33 (12 to 76) -
    Gender categorical
    Units: Subjects
        Female
    607 607
        Male
    611 611

    End points

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    End points reporting groups
    Reporting group title
    Perampanel
    Reporting group description
    Participants previously receiving perampanel/placebo in the DB study, were titrated to receive perampanel 2 mg to 12 mg, once daily in the OLE study up to approximately 5 years.

    Subject analysis set title
    Perampanel (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) was defined as participants who provided informed consent for the OLE, received at least 1 dose of perampanel in the OLE study, and had valid seizure data during the perampanel treatment duration (DB and/or OLE studies).

    Subject analysis set title
    Perampanel (SAS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) was defined as subjects who provided informed consent for the OLE study, received at least 1 dose of perampanel in the OLE study, and had at least 1 postdose safety assessment in the OLE study.

    Primary: Number of participants with Treatment-emergent non-serious adverse events (AEs) and Treatment-emergent serious adverse events (SAEs)

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    End point title
    Number of participants with Treatment-emergent non-serious adverse events (AEs) and Treatment-emergent serious adverse events (SAEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered with an investigational product. A SAE was defined as any untoward medical occurrence that at any dose; resulted in death, was life-threatening (ie, the participant was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was as a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). In this study, treatment emergent AEs (defined as an AE (serious or non-serious) that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed.
    End point type
    Primary
    End point timeframe
    From date of first dose of perampanel up to 30 days after the last dose of perampanel or up to approximately 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study group and the study drug administered for this outcome.
    End point values
    Perampanel (SAS)
    Number of subjects analysed
    1216
    Units: Participants
        Treatment-emergent non serious AEs
    1018
        Treatment-emergent SAEs
    288
    No statistical analyses for this end point

    Secondary: Median Percent Change in Seizure Frequency Per 28 Days Relative to Pre-Perampanel Baseline

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    End point title
    Median Percent Change in Seizure Frequency Per 28 Days Relative to Pre-Perampanel Baseline
    End point description
    Seizure frequency was derived from information (seizure count and type) recorded in participant diary. The seizure frequency per 28 days was calculated as the number of seizures divided by the number of days in the interval and multiplied by 28. The percent change in 28-day seizure frequency from pre-perampanel baseline was assessed for all partial-onset seizure types. The pre-perampanel baseline was defined as: (1) for participants who had been assigned to placebo treatment in the core DB study, the pre-perampanel baseline was computed from all data during the core DB study, and (2) for participants who had been assigned to perampanel in the core DB study, the pre-perampanel baseline was computed from the pre-randomization phase of the core DB study.
    End point type
    Secondary
    End point timeframe
    Pre-perampanel Baseline and Weeks (1-13, 14-26, 27-39, 40-52, 53-65, 66-78, 79-91, 92-104, 105-117, 118-130, 131-143, 144-156, 157-169, 170-182, 183-195, 196-208, 209-221, 222-234, 235-247, and 248-260)
    End point values
    Perampanel (ITT)
    Number of subjects analysed
    1217
    Units: Percent change
    median (full range (min-max))
        Weeks 1-13
    -29.14 (-100 to 737.1)
        Weeks 14-26; N=1159
    -38.54 (-100 to 866.6)
        Weeks 27-39; N=1088
    -42.81 (-100 to 780.6)
        Weeks 40-52; N=969
    -46.22 (-100 to 685.7)
        Weeks 53-65; N=882
    -49.34 (-100 to 526.4)
        Weeks 66-78; N=822
    -51.65 (-100 to 861.5)
        Weeks 79-91; N=762
    -53.06 (-100 to 697.5)
        Weeks 92-104; N=720
    -56.59 (-100 to 660.9)
        Weeks 105-117; N=676
    -59.07 (-100 to 627.9)
        Weeks 118-130; N=642
    -60.89 (-100 to 540)
        Weeks 131-143; N=583
    -60.67 (-100 to 716)
        Weeks 144-156; N=517
    -61.45 (-100 to 570.2)
        Weeks 157-169; N=429
    -65.46 (-100 to 418.3)
        Weeks 170-182; N=323
    -64.29 (-100 to 367.4)
        Weeks 183-195; N=210
    -66.63 (-100 to 698.7)
        Weeks 196-208; N=119
    -73.3 (-100 to 671.8)
        Weeks 209-221; N=59
    -72.47 (-100 to 226.4)
        Weeks 222-234; N=37
    -81.36 (-100 to 175.3)
        Weeks 235-247; N=14
    -78.1 (-100 to 200.4)
        Weeks 248-260; N=5
    -97.16 (-100 to 250.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced a 50% or Greater Reduction in Seizure Frequency Per 28 Days Relative to the Pre-perampanel Baseline

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    End point title
    Percentage of Participants Who Experienced a 50% or Greater Reduction in Seizure Frequency Per 28 Days Relative to the Pre-perampanel Baseline
    End point description
    Seizure frequency was derived from information (seizure count and type) recorded in participant diary. The percentage of participants who experienced a 50% or greater reduction in seizure frequency per 28 days relative to the pre-perampanel Baseline (responders) was assessed. The pre-perampanel baseline was defined as: (1) for participants who had been assigned to placebo treatment in the core DB study, the Pre-perampanel baseline was computed from all data during the core DB study, and (2) for participants who had been assigned to perampanel in the core DB study, the pre-perampanel baseline was computed from the pre-randomization phase of the core DB study. The data is presented as percent responders.
    End point type
    Secondary
    End point timeframe
    Pre-perampanel Baseline and Weeks (1-13, 14-26, 27-39, 40-52, 53-65, 66-78, 79-91, 92-104, 105-117, 118-130, 131-143, 144-156, 157-169, 170-182, 183-195, 196-208, 209-221, 222-234, 235-247, and 248-260)
    End point values
    Perampanel (ITT)
    Number of subjects analysed
    1217
    Units: Percent responders
    number (not applicable)
        Weeks 1-13
    30.8
        Weeks 14-26; N=1159
    40.9
        Weeks 27-39; N=1088
    44.2
        Weeks 40-52; N=969
    45.6
        Weeks 53-65; N=882
    49.5
        Weeks 66-78; N=822
    51.5
        Weeks 79-91; N=762
    52.9
        Weeks 92-104; N=720
    57.2
        Weeks 105-117; N=676
    57.1
        Weeks 118-130; N=642
    58.9
        Weeks 131-143; N=583
    59.3
        Weeks 144-156; N=517
    60.9
        Weeks 157-169; N=429
    63.2
        Weeks 170-182; N=323
    60.1
        Weeks 183-195; N=210
    62.9
        Weeks 196-208; N=119
    64.7
        Weeks 209-221; N=59
    67.8
        Weeks 222-234; N=37
    73
        Weeks 235-247; N=14
    64.3
        Weeks 248-260; N=5
    80
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose of perampanel up to 30 days after the last dose of perampanel or up to approximately 5 years
    Adverse event reporting additional description
    Tha analysis was performed using the Safety Analysis Set (SAS), defined as subjects who provided informed consent for the OLE study, received at least 1 dose of perampanel in the OLE study, and had at least 1 postdose safety assessment in the OLE study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    -

    Serious adverse events
    Arm 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    288 / 1216 (23.68%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Medical device removal
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Benign lung neoplasm
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Abortion spontaneous incomplete
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Drug ineffective
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    14 / 1216 (1.15%)
         occurrences causally related to treatment / all
    12 / 15
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    8 / 1216 (0.66%)
         occurrences causally related to treatment / all
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Affective disorder
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    4 / 1216 (0.33%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    4 / 1216 (0.33%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Paranoia
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Abnormal behavior
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Agitation
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Adjustment disorder
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anger
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Catatonia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delusion of grandeur
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epileptic psychosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mood altered
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Negativism
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obsessive thoughts
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Personality change due to a general medical condition
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Postictal psychosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Dysfunctional uterine bleeding
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bartholinitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast enlargement
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian mass
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian rupture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Polycystic ovaries
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine cyst
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    12 / 1216 (0.99%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    Ankle fracture
         subjects affected / exposed
    7 / 1216 (0.58%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Toxicity to various agents
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    4 / 1216 (0.33%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    4 / 1216 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain contusion
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Clavicle fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fibula fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hand fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaw fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Burns second degree
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Burns third degree
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Epidural haemorrhage
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Excoriation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle strain
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck injury
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post concussion syndrome
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull fractured base
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Traumatic iritis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Clostridium test positive
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular dissociation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull malformation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nasal septum deviation
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    43 / 1216 (3.54%)
         occurrences causally related to treatment / all
    15 / 49
         deaths causally related to treatment / all
    1 / 2
    Status epilepticus
         subjects affected / exposed
    16 / 1216 (1.32%)
         occurrences causally related to treatment / all
    6 / 17
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    15 / 1216 (1.23%)
         occurrences causally related to treatment / all
    2 / 19
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Seizure cluster
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Drug withdrawal convulsions
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Carotid artery dissection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Incoherent
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Memory impairment
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multifocal motor neuropathy
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Postictal paralysis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stupor
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Temporal lobe epilepsy
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertebral artery dissection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Iritis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Conductive deafness
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    4 / 1216 (0.33%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scoliosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    3 / 1216 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    13 / 1216 (1.07%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    6 / 1216 (0.49%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    5 / 1216 (0.41%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    2 / 1216 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral infection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural pneumonia
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Typhoid fever
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 1216 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1018 / 1216 (83.72%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    116 / 1216 (9.54%)
         occurrences all number
    246
    Laceration
         subjects affected / exposed
    67 / 1216 (5.51%)
         occurrences all number
    120
    Investigations
    Weight increased
         subjects affected / exposed
    161 / 1216 (13.24%)
         occurrences all number
    204
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    591 / 1216 (48.60%)
         occurrences all number
    1401
    Ataxia
         subjects affected / exposed
    84 / 1216 (6.91%)
         occurrences all number
    136
    Balance disorder
         subjects affected / exposed
    74 / 1216 (6.09%)
         occurrences all number
    129
    Convulsion
         subjects affected / exposed
    78 / 1216 (6.41%)
         occurrences all number
    126
    Dysarthria
         subjects affected / exposed
    61 / 1216 (5.02%)
         occurrences all number
    84
    Headache
         subjects affected / exposed
    246 / 1216 (20.23%)
         occurrences all number
    506
    Somnolence
         subjects affected / exposed
    266 / 1216 (21.88%)
         occurrences all number
    449
    Eye disorders
    Diplopia
         subjects affected / exposed
    64 / 1216 (5.26%)
         occurrences all number
    92
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    182 / 1216 (14.97%)
         occurrences all number
    281
    Gait disturbance
         subjects affected / exposed
    80 / 1216 (6.58%)
         occurrences all number
    127
    Irritability_
         subjects affected / exposed
    69 / 1216 (5.67%)
         occurrences all number
    85
    Pyrexia
         subjects affected / exposed
    79 / 1216 (6.50%)
         occurrences all number
    135
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    78 / 1216 (6.41%)
         occurrences all number
    147
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    79 / 1216 (6.50%)
         occurrences all number
    101
    Depression
         subjects affected / exposed
    82 / 1216 (6.74%)
         occurrences all number
    102
    Insomnia
         subjects affected / exposed
    86 / 1216 (7.07%)
         occurrences all number
    124
    Irritability
         subjects affected / exposed
    125 / 1216 (10.28%)
         occurrences all number
    166
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    84 / 1216 (6.91%)
         occurrences all number
    121
    Nausea
         subjects affected / exposed
    115 / 1216 (9.46%)
         occurrences all number
    154
    Vomiting
         subjects affected / exposed
    95 / 1216 (7.81%)
         occurrences all number
    119
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    86 / 1216 (7.07%)
         occurrences all number
    111
    Infections and infestations
    Influenza
         subjects affected / exposed
    70 / 1216 (5.76%)
         occurrences all number
    100
    Nasopharyngitis
         subjects affected / exposed
    142 / 1216 (11.68%)
         occurrences all number
    239
    Upper respiratory tract infection
         subjects affected / exposed
    107 / 1216 (8.80%)
         occurrences all number
    188

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2008
    Amendment 01 – 17 Oct 2008 • Increased the study duration (from 14 months to 26 months) to obtain additional on-drug and off-drug safety information in subjects with longer durations of perampanel exposure. • Removed the 2-week titration designation to allow greater flexibility, thereby accommodating individual subject tolerability. • Clarified that felbamate is allowed as a concomitant medication to maintain consistency with the preceding double-blind studies. • Made minor editorial, grammatical, consistency, and formatting corrections. Note: this list is not exhaustive.
    26 Nov 2008
    Amendment A-Germany: 26 Nov 2008 • Administrative changes such as to update with the name of the current Study Director. • Added precausions to be followed while on the study drug, • Addressed the exclusion of subjects who cannot consent to participate in the study as per local regulations. • Defined the conditions under which the study may be terminated: The program is intended to continue until the investigational drug is licensed in Germany, or until it is terminated. At present, there are no other foreseeable reasons for termination of the study. However, the study could be terminated due to safety concerns or for other reasons. Note: this list is not exhaustive.
    05 Dec 2008
    Amendment B-Lithuania: 05 December 2008 • Administrative changes such as to update with the name of the current Study Director. • Corrected the hyperlink reference, etc. • Revise the inclusion criteria, concomitant therapy, etc. Note: this list is not exhaustive.
    12 Jan 2009
    Amendment C – Germany: 12 January 2009 • Increase the study duration. • Removed the 2-week titration designation. • Clarify that felbamate is allowed as a concomitant medication. • Made editorial, grammatical, consistency, and formatting corrections. • Administrative changes such as to update with the name of the current Study Director, etc. • Added precausions to be followed while on the study drug. • Addressed the exclusion of subjects who cannot consent to participate in the study as per local regulations. Note: this list is not exhaustive.
    17 Feb 2009
    Amendment D-Republic of South Africa: 17 February 2009 • Revised the version of the Declaration of Helsinki from the 1996 version to the latest 2008 version as per the request of the South African Medical Association Research Ethics Committee (SAMAREC).
    20 Mar 2009
    Amendment 02: 20 March 2009 • The exploratory objective was added to evaluate the potential withdrawal symptoms of perampanel vs. placebo in subjects with refractory partial seizures. • Update the protocol with information regarding an additional safety questionnaire on study drug withdrawal symptoms. • Administrative changes such as sponsor company's registered office address change, etc. • Correction of typographical errors. • Define database lock as end of study. • Clarified the treatment for subjects rolling over into the OLE study. • Concomitant medication section was revised. Changes in concomitant therapy are allowed (ie, they are not considered deviations); therefore, no discussion regarding changes are needed. • Amended text surrounding how subjects should handle light related skin changes that occur during the study. • Defined Bazett as the QT interval correction method to be reported by the central lab. • Included information about safety monitoring via the Data Monitoring Committee. Note: this list is not exhaustive.
    28 Sep 2009
    Amendment 03: 28 September 2009, v1.0 • Update the protocol with the Sponsor’s new legal name and address. • Included objectives related to the addition of adolescent-specific growth and development assessments (pharmacokinetic samples, height, thyroid and IGF-1 testing, and Tanner Staging) and PK/PD analysis. • Removed inconsistency, as subjects will not receive placebo in this study. • Extended the study duration for a total duration of approximately 5 years, until the marketing of perampanel, or until perampanel development is terminated. • Treatment administered section was revised as gaps between the core study and OLE are no longer allowed. • Administrative changes such as update in sponsor address, study director, clarifications, etc. Note: this list is not exhaustive.
    24 Jun 2010
    Amendment E (United Kingdom [UK] and India): 24 Jun 2010, v2.0 • Updated the protocol with the Sponsor’s new legal name and address, updated references, etc. • Included objectives related to the addition of adolescent-specific growth and development assessments (pharmacokinetic samples, height, thyroid and IGF-1 testing, and Tanner Staging). • Removed inconsistency, as subjects will not receive placebo in this study. • Corrected an inconsistency in the presentation of the number of weeks in the Conversion Period. • Extend the study duration for a total duration of approximately 5 years. • Update the protocol for consistency with the extension of the study duration. • Added analysis of additional adolescent-specific safety, PK and PK/PD analysis. • Treatment administered section was revised as gaps between the core study and OLE are no longer allowed. Note: this list is not exhaustive.
    27 Jun 2012
    Amendment F: 27 June 2012 • Closure of Study Protocol: The perampanel Phase 3 program in partial onset seizures (POS) has been completed, and Regulatory submissions to seek approval for marketing have been made to several countries and regions. Positive Opinion has been received from CHMP. Therefore, Study E2007 G000 307 will be closed • Revision to Schedule Regarding the EOT Visit: To accommodate the implementation of this protocol amendment resulting in the closure of the study protocol • Revision to Follow-up visit Procedures To provide subjects the option to continue accessing perampanel treatment if they are benefiting from the study drug • Revision to Questionnaire Procedures: These questionnaires are no longer deemed necessary for subjects who will continue to receive perampanel therapy after the conclusion of the study • Revision to Monitoring Schedule: To accurately reflect the current interim monitoring visit schedule

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Jan 2012
    The sponsor terminated the study in 2012 following receipt of a positive opinion for perampanel from the Committee for Medicinal Products for Human Use. An end-of-treatment (EOT) visit was scheduled within 2 to 6 weeks for all subjects who remained in the Maintenance Period. If it was the opinion of the treating physician that a subject would benefit significantly from further treatment with perampanel after the trial concluded, perampanel treatment was made available under Eisai’s compassionate use policy in accordance with local country legislative provisions until the time that perampanel was commercially available in the country in which the subject resided.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Results were ready but could not be released before 21 July 2015 due to EudraCT System issues.
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