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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of RWJ-333369 as Adjunctive Therapy in Subjects with Partial Onset Seizures Followed by an Open-Label Extension Study

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2006-003839-68
    Trial protocol
    		 FI   SE   DE   CZ  
    Global end of trial date
    05 Oct 2010

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Jun 2016
    First version publication date
    03 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    333369-EPY-3001/3004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00425282
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, 2340 Beerse, Belgium,
    Public contact
    Janssen-Cilag International N.V., Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International N.V., Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.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
    05 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the efficacy, safety, and tolerability of carisbamate (CRS) 200 and 400 milligram per day (mg/d) as adjunctive treatment of partial onset seizures (POS).
    Protection of trial subjects
    Safety was monitored by means of Data Safety Monitoring Board (DSMB). Safety was evaluated by examining the incidence and severity of adverse events, evaluation of clinical laboratory tests (hematology, serum chemistry, serum lipid profile and urinalysis), vital signs, 12-lead electrocardiogram (ECGs), physical and neurological examination, and assessment of physician withdrawal checklist.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2007
    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
    Argentina: 39
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    China: 53
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    India: 75
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 64
    Country: Number of subjects enrolled
    Russian Federation: 105
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United States: 85
    Worldwide total number of subjects
    565
    EEA total number of subjects
    114
    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)
    23
    Adults (18-64 years)
    532
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who successfully completed the 8-week prospective baseline period and experienced at least 6 simple partial motor, complex partial, or secondarily generalized seizures per 56 days, with no seizure-free period of more than 3 weeks during the baseline period, were allowed to enter into the double blind treatment phase.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo orally from Day 1 and remained on placebo for the next 12 weeks.
    Arm type
    		 other

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo orally for 12 weeks.

    Arm title
    		 CRS 200 mg/day
    Arm description
    		 Subjects received their randomly assigned dosage, CRS 200 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carisbamate
    Investigational medicinal product code
    Other name
    (S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received CRS 200 mg/day orally for 12 weeks.

    Arm title
    		 CRS 400 mg/day
    Arm description
    		 Subjects received their randomly assigned dosage, CRS 400 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carisbamate
    Investigational medicinal product code
    Other name
    (S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received CRS 400 mg/day orally for 12 weeks.

    Number of subjects in period 1
    		Placebo CRS 200 mg/day CRS 400 mg/day
    Started
    186
    187
    192
    Completed
    171
    176
    180
    Not completed
    15
    11
    12
         Consent withdrawn by subject
    3
    5
    2
         Adverse event, non-fatal
    7
    1
    7
         Other
    2
    1
    -
         Pregnancy
    1
    -
    1
         Adverse event, serious non-fatal
    -
    1
    2
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    2
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo orally from Day 1 and remained on placebo for the next 12 weeks.

    Reporting group title
    CRS 200 mg/day
    Reporting group description
    		 Subjects received their randomly assigned dosage, CRS 200 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.

    Reporting group title
    CRS 400 mg/day
    Reporting group description
    		 Subjects received their randomly assigned dosage, CRS 400 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.

    Reporting group values
    		 Placebo CRS 200 mg/day CRS 400 mg/day Total
    Number of subjects
    		 186 187 192 565
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 7 6 10 23
        Adults (18-64 years)
    		 175 177 180 532
        From 65 to 84 years
    		 4 4 2 10
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 36 ( 13.06 ) 35.1 ( 12.11 ) 34.8 ( 12.89 ) -
    Title for Gender
    Units: subjects
        Female
    		 99 95 86 280
        Male
    		 87 92 106 285

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo orally from Day 1 and remained on placebo for the next 12 weeks.

    Reporting group title
    CRS 200 mg/day
    Reporting group description
    		 Subjects received their randomly assigned dosage, CRS 200 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.

    Reporting group title
    CRS 400 mg/day
    Reporting group description
    		 Subjects received their randomly assigned dosage, CRS 400 mg/day orally beginning on Day 1, and remained on that dosage for the next 12 weeks.

    Primary: Percent Reduction From Baseline to Double Blind Phase in Partial Onset Seizure Frequency

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    End point title
    		 Percent Reduction From Baseline to Double Blind Phase in Partial Onset Seizure Frequency
    End point description
    The intent-to-treat (ITT) population included all randomized subjects who had completed the seizure diary during both the baseline period and the double-blind phase.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 85
    End point values
    		 Placebo CRS 200 mg/day CRS 400 mg/day
    Number of subjects analysed
    183 [1]
    187
    191 [2]
    Units: percent reduction
        median (full range (min-max))
    15.21 (-1300 to 100)
    16.44 (-190 to 100)
    27.27 (-262 to 100)
    Notes
    [1] - Here 'N' signifies number of subjects analysed for this endpoint.
    [2] - Here 'N' signifies number of subjects analysed for this endpoint.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v CRS 200 mg/day
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.678
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v CRS 400 mg/day
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Change from Baseline to the End of Double Blind Treatment Phase in the Seizure Severity Questionnaire (SSQ) Recovery Phase Composite Score (RPCS)

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    End point title
    		 Change from Baseline to the End of Double Blind Treatment Phase in the Seizure Severity Questionnaire (SSQ) Recovery Phase Composite Score (RPCS)
    End point description
    The SSQ is a 10-item questionnaire designed to track seizure severity signs and is formatted as a structured interview. It is organized into 3 components: the Warning, Activity-movement, and Recovery (cognitive, emotional, and physical) aspects of seizures. Questions review duration, severity, bothersomeness, and overall ratings, and the most bothersome aspect of seizures. Lower scores represent better function. The ITT population included all randomized subjects who had completed the seizure diary during both the baseline period and the double-blind phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 85
    End point values
    		 Placebo CRS 200 mg/day CRS 400 mg/day
    Number of subjects analysed
    182 [3]
    185 [4]
    189 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 43 (n= 172, 177, 181)
    -0.6 ( 1.73 )
    -0.5 ( 1.76 )
    -0.6 ( 1.81 )
        Day 85 (n= 170, 173, 178)
    -0.7 ( 1.86 )
    -0.6 ( 1.62 )
    -0.5 ( 1.81 )
        Endpoint (n= 182, 184, 189)
    -0.7 ( 1.83 )
    -0.5 ( 1.59 )
    -0.4 ( 1.84 )
    Notes
    [3] - Here 'N' signifies number of subjects analysed for this endpoint.
    [4] - Here 'N' signifies number of subjects analysed for this endpoint.
    [5] - Here 'N' signifies number of subjects analysed for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline to Double Blind End Point in SSQ Scores

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    End point title
    		 Change From Baseline to Double Blind End Point in SSQ Scores
    End point description
    The SSQ is a 10-item questionnaire designed to track seizure severity signs and is formatted as a structured interview. It is organized into 3 components: the Warning, Activity-movement, and Recovery (cognitive, emotional, and physical) aspects of seizures. Questions review duration, severity, bothersomeness, and overall ratings, and the most bothersome aspect of seizures. Lower scores represent better function. The intent-to-treat (ITT) population included all randomized subjects who had completed the seizure diary during both the baseline period and the double-blind phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 85
    End point values
    		 Placebo CRS 200 mg/day CRS 400 mg/day
    Number of subjects analysed
    175 [6]
    174 [7]
    180 [8]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.7 ( 1.26 )
    3.7 ( 1.21 )
    3.8 ( 1.26 )
        End Point
    -0.6 ( 1.5 )
    -0.6 ( 1.28 )
    -0.5 ( 1.38 )
    Notes
    [6] - Here 'N' signifies number of subjects analysed for this endpoint.
    [7] - Here 'N' signifies number of subjects analysed for this endpoint.
    [8] - Here 'N' signifies number of subjects analysed for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to End of study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    PLACEBO
    Reporting group description
    		 Placebo

    Reporting group title
    CRS 400mg
    Reporting group description
    		 CARISBAMATE 400 mg per day

    Reporting group title
    CRS 200mg
    Reporting group description
    		 CARISBAMATE 200 mg per day

    Serious adverse events
    		 PLACEBO CRS 400mg CRS 200mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 186 (4.30%)
    5 / 192 (2.60%)
    10 / 187 (5.35%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Injury
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic Brain Injury
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    3 / 187 (1.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand Mal Convulsion
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Generalised
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic Disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary Retention
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Necrotising
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 PLACEBO CRS 400mg CRS 200mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 186 (43.55%)
    101 / 192 (52.60%)
    81 / 187 (43.32%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    2 / 187 (1.07%)
         occurrences all number
    2
    6
    2
    Chest Pain
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    2
    0
    3
    Fatigue
         subjects affected / exposed
    12 / 186 (6.45%)
    13 / 192 (6.77%)
    7 / 187 (3.74%)
         occurrences all number
    13
    13
    8
    Pyrexia
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    2 / 187 (1.07%)
         occurrences all number
    1
    4
    2
    Irritability
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 192 (2.08%)
    4 / 187 (2.14%)
         occurrences all number
    2
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    3
    Dyspnoea
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 192 (1.04%)
    2 / 187 (1.07%)
         occurrences all number
    2
    2
    2
    Nasal Congestion
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    2
    0
    3
    Pharyngolaryngeal Pain
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 192 (2.08%)
    1 / 187 (0.53%)
         occurrences all number
    2
    4
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 192 (1.04%)
    3 / 187 (1.60%)
         occurrences all number
    2
    2
    3
    Bradyphrenia
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Confusional State
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 192 (1.04%)
    1 / 187 (0.53%)
         occurrences all number
    1
    2
    1
    Depressed Mood
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Depression
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    2
    2
    0
    Insomnia
         subjects affected / exposed
    4 / 186 (2.15%)
    6 / 192 (3.13%)
    4 / 187 (2.14%)
         occurrences all number
    5
    6
    6
    Nervousness
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences all number
    2
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 192 (1.56%)
    7 / 187 (3.74%)
         occurrences all number
    2
    3
    8
    Excoriation
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    3
    Head Injury
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences all number
    3
    1
    0
    Skin Laceration
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    3
    Thermal Burn
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    2
    0
    1
    Tongue Injury
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    3
    0
    0
    Nervous system disorders
    Coordination Abnormal
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    1 / 187 (0.53%)
         occurrences all number
    2
    3
    1
    Disturbance in Attention
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    2 / 187 (1.07%)
         occurrences all number
    3
    3
    2
    Dizziness
         subjects affected / exposed
    13 / 186 (6.99%)
    23 / 192 (11.98%)
    7 / 187 (3.74%)
         occurrences all number
    19
    35
    8
    Epilepsy
         subjects affected / exposed
    4 / 186 (2.15%)
    2 / 192 (1.04%)
    1 / 187 (0.53%)
         occurrences all number
    5
    2
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 186 (0.00%)
    4 / 192 (2.08%)
    1 / 187 (0.53%)
         occurrences all number
    0
    4
    1
    Headache
         subjects affected / exposed
    27 / 186 (14.52%)
    27 / 192 (14.06%)
    25 / 187 (13.37%)
         occurrences all number
    58
    53
    50
    Memory Impairment
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    1 / 187 (0.53%)
         occurrences all number
    2
    1
    0
    Migraine
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    7 / 186 (3.76%)
    3 / 192 (1.56%)
    2 / 187 (1.07%)
         occurrences all number
    9
    3
    2
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Somnolence
         subjects affected / exposed
    2 / 186 (1.08%)
    10 / 192 (5.21%)
    8 / 187 (4.28%)
         occurrences all number
    2
    11
    8
    Tremor
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    2
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    2
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences all number
    2
    1
    0
    Vertigo
         subjects affected / exposed
    3 / 186 (1.61%)
    3 / 192 (1.56%)
    0 / 187 (0.00%)
         occurrences all number
    5
    3
    0
    Eye disorders
    Conjunctival Haemorrhage
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    2
    Vision Blurred
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 192 (2.08%)
    2 / 187 (1.07%)
         occurrences all number
    1
    5
    5
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 186 (2.15%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    4
    1
    2
    Constipation
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    3 / 187 (1.60%)
         occurrences all number
    1
    3
    3
    Dry Mouth
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    4 / 186 (2.15%)
    5 / 192 (2.60%)
    7 / 187 (3.74%)
         occurrences all number
    9
    5
    8
    Dyspepsia
         subjects affected / exposed
    3 / 186 (1.61%)
    3 / 192 (1.56%)
    0 / 187 (0.00%)
         occurrences all number
    4
    4
    0
    Gastritis
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    2
    6
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 192 (1.04%)
    1 / 187 (0.53%)
         occurrences all number
    1
    4
    1
    Nausea
         subjects affected / exposed
    11 / 186 (5.91%)
    6 / 192 (3.13%)
    10 / 187 (5.35%)
         occurrences all number
    15
    8
    12
    Toothache
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 192 (0.52%)
    3 / 187 (1.60%)
         occurrences all number
    0
    1
    3
    Vomiting
         subjects affected / exposed
    7 / 186 (3.76%)
    2 / 192 (1.04%)
    3 / 187 (1.60%)
         occurrences all number
    9
    2
    3
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Eczema
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Rash
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 192 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    1
    0
    3
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 192 (1.04%)
    1 / 187 (0.53%)
         occurrences all number
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 192 (1.56%)
    0 / 187 (0.00%)
         occurrences all number
    1
    3
    0
    Back Pain
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 192 (1.04%)
    1 / 187 (0.53%)
         occurrences all number
    3
    2
    1
    Myalgia
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 192 (0.52%)
    3 / 187 (1.60%)
         occurrences all number
    3
    1
    3
    Musculoskeletal Pain
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    1 / 187 (0.53%)
         occurrences all number
    2
    1
    1
    Pain in Extremity
         subjects affected / exposed
    4 / 186 (2.15%)
    3 / 192 (1.56%)
    2 / 187 (1.07%)
         occurrences all number
    4
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 192 (0.52%)
    0 / 187 (0.00%)
         occurrences all number
    2
    3
    0
    Influenza
         subjects affected / exposed
    3 / 186 (1.61%)
    4 / 192 (2.08%)
    4 / 187 (2.14%)
         occurrences all number
    5
    5
    4
    Nasopharyngitis
         subjects affected / exposed
    9 / 186 (4.84%)
    6 / 192 (3.13%)
    6 / 187 (3.21%)
         occurrences all number
    9
    7
    6
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 192 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    0
    0
    3
    Sinusitis
         subjects affected / exposed
    0 / 186 (0.00%)
    3 / 192 (1.56%)
    0 / 187 (0.00%)
         occurrences all number
    0
    3
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 186 (2.69%)
    8 / 192 (4.17%)
    9 / 187 (4.81%)
         occurrences all number
    7
    10
    10
    Viral Infection
         subjects affected / exposed
    0 / 186 (0.00%)
    3 / 192 (1.56%)
    0 / 187 (0.00%)
         occurrences all number
    0
    3
    0
    Urinary Tract Infection
         subjects affected / exposed
    3 / 186 (1.61%)
    2 / 192 (1.04%)
    2 / 187 (1.07%)
         occurrences all number
    3
    2
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 192 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    2
    0
    1
    Anorexia
         subjects affected / exposed
    1 / 186 (0.54%)
    5 / 192 (2.60%)
    1 / 187 (0.53%)
         occurrences all number
    3
    6
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2007
    Amendment INT-1 included the following changes - Updated information on cases of elevated liver enzymes, reduction of the lower limit for body weight from 40 kg to 35 kg, extension of baseline platelet count and haemoglobin test value ranges, and requirement of the dosage of concomitant anti-epileptic drugs (AEDs) to be stable for at least 1 month (changed from 2 months) with no new AEDs to be added for the previous 2 months before screening. In addition, subjects with congenital short QT syndrome were now excluded and periodic use of acetaminophen up to 2,500 mg/d was now allowed throughout the study. For the efficacy analyses, the statistical method for the step-down procedure performed as the primary analysis for the United States was revised to exclude the responder rate as an end point to be analysed sequentially. Clarification to the analysis of EuroQol 5D scores was also made. For the safety analyses, the categories for analysis of subjects with elevated liver enzyme tests were changed from 5 to 8 times the upper limit of normal (ULN) to 5 to 10 x ULN, and from >8 x ULN to >10 x ULN.
    04 Sep 2007
    The study objectives, hypotheses, statistical methods, and efficacy analyses were revised to present the primary and secondary efficacy end points by group for registration in the United States and the ROW and in the countries of Europe, Australia, New Zealand, and South Africa, to meet United States and Committee for Human Medicinal Products (CHMP) guideline requirements. Additional cardiovascular assessment procedures were added to further establish cardiac risk factors, including the collection of smoking history and family history of coronary artery disease and sudden death at the screening visit and evaluation and measurement of the QTc interval using Fridericia’s correction (QTcF). Analysis of additional SSQ domains, vital signs, physical and neurologic examinations, and Physician Withdrawal Check-list scores were also made.
    02 Nov 2007
    Changes were made to correct minor errors in Amendment INT-2; there were no changes made to study conduct or statistical analyses.

    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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