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    Clinical Trial Results:
    A double-blind, placebo-controlled, randomized efficacy and safety study of levetiracetam Extended release formulation (LEV XR), administered as 2 x 500 mg LEV XR tablets once daily as add-on therapy in subjects from 12 to 70 years with refractory epilepsy suffering from partial onset seizures.

    Summary
    EudraCT number
    		 2006-000987-10
    Trial protocol
    		 FI  
    Global end of trial date
    30 May 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2016
    First version publication date
    11 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01235
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00368069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB, Inc.
    Sponsor organisation address
    1950 Lake Park Drive, Smyrna, United States, 30080
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48, clinicaltrials@ucb.com
    Sponsor organisation name
    UCB Pharma, S.A.
    Sponsor organisation address
    Chemin du Foriest, Braine-l’Alleud, Belgium, 1420
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48, clinicaltrials@ucb.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jul 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of LEV XR 2 x 500 mg/day once daily, using a placebo as control, as adjunctive therapy in the treatment of refractory epilepsy patients 12 to 70 years of age with partial onset seizures.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 Standard anti-epileptic Drug (AED) therapy
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    21 Aug 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    India: 51
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Russian Federation: 38
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Ukraine: 25
    Worldwide total number of subjects
    158
    EEA total number of subjects
    4
    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)
    16
    Adults (18-64 years)
    140
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants flow presents all subjects randomized (Baseline Participants). Safety population does not include 2 patients that never took any study medication.

    Pre-assignment
    Screening details
    		 The study was conducted in subjects from 12 to 70 years of age with refractory epilepsy suffering from partial onset seizures; no more than three concomitant anti-epileptic drugs (AEDs) per subject were allowed. It was planned to randomize 130 subjects, 65 per treatment Group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Keppra®
    Arm description
    		 Keppra® extended release formulation (XR)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Keppra®
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LEV XR 2 x 500 mg oral tablet

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet

    Number of subjects in period 1
    		Keppra® Placebo
    Started
    79
    79
    Completed
    71
    72
    Not completed
    8
    7
         AE, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    1
         AE, non-serious non-fatal
    1
    1
         no blood sampling possible
    -
    1
         Lost to follow-up
    1
    -
         SAE, non-fatal
    2
    1
         SAE, non-fatal + AE, non-serious non-fatal
    1
    -
         Lack of efficacy
    -
    1
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Keppra®
    Reporting group description
    		 Keppra® extended release formulation (XR)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Keppra® Placebo Total
    Number of subjects
    		 79 79 158
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 7 9 16
        Adults (18-64 years)
    		 71 69 140
        From 65-84 years
    		 1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.97 ( 13.41 ) 32.38 ( 12.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 27 32 59
        Male
    		 52 47 99
    Region of Enrollment
    Units: Subjects
        Mexico
    		 15 16 31
        Finland
    		 2 2 4
        Ukraine
    		 13 12 25
        South Africa
    		 4 4 8
        Russian Federation
    		 19 19 38
        India
    		 25 26 51
        Brazil
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Keppra®
    Reporting group description
    		 Keppra® extended release formulation (XR)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: partial onset seizure (POS) frequency per week - Intention-To-Treat (ITT) Population

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    End point title
    		 partial onset seizure (POS) frequency per week - Intention-To-Treat (ITT) Population
    End point description
    Number of POS over the treatment period standardized to 1 week period.
    End point type
    Primary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    75
    78
    Units: seizures per week (log-transformed data)
    least squares mean (standard error)
        least squares mean (standard error)
    0.912 ( 0.053 )
    1.067 ( 0.052 )
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Treatment difference was assessed through the percent reduction in POS freq/week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data.
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Transf. of ANCOVA results on log data
    Parameter type
    		 Percent reduction over Placebo
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 26
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.301

    Primary: partial onset seizure (POS) frequency per week - Per Protocol (PP) Population

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    End point title
    		 partial onset seizure (POS) frequency per week - Per Protocol (PP) Population
    End point description
    Number of POS over the treatment period standardized to 1 week period
    End point type
    Primary
    End point timeframe
    Treatment Period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    67
    69
    Units: seizures per week (log-transformed data)
    least squares mean (standard error)
        least squares mean (standard error)
    0.914 ( 0.049 )
    1.119 ( 0.048 )
    Statistical analysis title
    		 Statistical Analyisis 2
    Statistical analysis description
    Treatment difference was assessed through the percent reduction in POS frequency per week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Transf. of ANCOVA results on log data
    Parameter type
    		 Percent reduction over Placebo
    Point estimate
    18.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.7
         upper limit
    		 28.9

    Secondary: POS seizure frequency per Week over Baseline and Treatment Period

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    End point title
    		 POS seizure frequency per Week over Baseline and Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Period (8 weeks) - Treatment Period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    79
    79
    Units: seizures per week
    median (inter-quartile range (Q1-Q3))
        Baseline POS frequency per week
    1.8 (1.13 to 4.13)
    2.11 (1.33 to 3.26)
        Treatment POS frequency per week
    0.99 (0.33 to 2.7)
    1.36 (0.92 to 2.85)
    No statistical analyses for this end point

    Secondary: All (Type I+II+III) seizures frequency per week

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    End point title
    		 All (Type I+II+III) seizures frequency per week
    End point description
    Number of All type Seizures over the treatment period standardized to 1 week period (Type I -Partial Onset Seizures, Type II - Generalized Seizures, Type III - Unclassified Epileptic Seizures)
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    75
    78
    Units: seizures per week (log-transformed data)
    least squares mean (standard error)
        least squares mean (standard error)
    0.928 ( 0.053 )
    1.086 ( 0.052 )
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Treatment difference was assessed through the percent reduction in POS frequency per week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Transf. of ANCOVA results on log data
    Parameter type
    		 Percent reduction over Placebo
    Point estimate
    14.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 26.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.158
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.012
         upper limit
    		 0.305

    Secondary: 50% response in weekly POS frequency

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    End point title
    		 50% response in weekly POS frequency
    End point description
    A subject is considered as a 50% responder in POS if he/she has a >= 50% decrease from Baseline in the POS frequency/week over Treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    79
    79
    Units: Participants
        Response
    34
    23
        Non-Response
    45
    56
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 3.55

    Secondary: Response in weekly POS frequency (categorized into 6 categories according to reduction) over the treatment period of 12 weeks

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    End point title
    		 Response in weekly POS frequency (categorized into 6 categories according to reduction) over the treatment period of 12 weeks
    End point description
    The response is classified according to the percent reduction from baseline in the POS frequency per week over the Treatment Period of 12 weeks duration.
    End point type
    Secondary
    End point timeframe
    over the treatment period (12 weeks)
    End point values
    		 Keppra® Placebo
    Number of subjects analysed
    79
    79
    Units: Participants
        < -25%
    11
    13
        -25% - <25%
    14
    23
        25% - <75%
    35
    34
        75% - <100%
    11
    7
        100%
    8
    2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Keppra® v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from Selection Visit (Week 0) until Final Visit (Week 22).
    Adverse event reporting additional description
    The Safety population comprised all subjects who were dispensed study medication. This population was used for the analysis of safety data.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 placebo

    Reporting group title
    Keppra®
    Reporting group description
    		 Keppra® extended release formulation (XR)

    Serious adverse events
    		 Placebo Keppra®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 79 (2.53%)
    6 / 77 (7.79%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stupor
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Keppra®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 79 (26.58%)
    23 / 77 (29.87%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 77 (5.19%)
         occurrences all number
    2
    4
    Headache
         subjects affected / exposed
    11 / 79 (13.92%)
    5 / 77 (6.49%)
         occurrences all number
    21
    8
    Somnolence
         subjects affected / exposed
    2 / 79 (2.53%)
    6 / 77 (7.79%)
         occurrences all number
    2
    7
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    0 / 79 (0.00%)
    5 / 77 (6.49%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 77 (5.19%)
         occurrences all number
    2
    5
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 77 (7.79%)
         occurrences all number
    3
    7
    Nasopharyngitis
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 77 (6.49%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2006
    Amendment 1: Incorporated 10-Aug-2006 The Amendment reflected the decision from FDA to use a two-sided test for the primary and secondary efficacy variables. The sample size was increased accordingly for the same power. Details regarding the population pharmacokinetic and plasma analysis were added as requested by FDA. Additionally, explorative efficacy variables were also added. LEV XR is a new formulation under development in order to provide the subjects the convenience of once daily dosing. This is a Phase III therapeutic confirmatory study to evaluate the efficacy and safety of LEV XR, administered as 2 x 500 mg XR tablets once daily as add-on therapy in refractory epilepsy subjects 12 to 70 years with partial onset seizures.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/19317886
    http://www.ncbi.nlm.nih.gov/pubmed/19699156
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