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    Clinical Trial Results:
    A 19-week, randomized, double-blind, multicenter, placebo-controlled safety study to evaluate the cognitive and neuropsychological effects of levetiracetam 20-60 mg/kg/day, divided in twice daily dosing, as adjunctive treatment in children 4-16 years old, inclusive, with refractory partial onset seizures

    Summary
    EudraCT number
    2014-004396-23
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    21 Mar 2007

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00105040
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma, 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 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Apr 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to characterize potential cognitive and neuropsychological effects of LEV (20-60 mg/kg/d), as adjunctive treatment in children 4-16 years old, inclusive, with partial onset seizures, as non-inferior when compared to adjunctive treatment with PBO.
    Protection of trial subjects
    None specific
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    28 Sep 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Ethical reason
    Long term follow-up duration
    30 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    United States: 80
    Worldwide total number of subjects
    98
    EEA total number of subjects
    0
    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)
    60
    Adolescents (12-17 years)
    38
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This double-blind, randomized, multicenter, placebo-controlled safety study started recruiting in September 2004.

    Pre-assignment
    Screening details
    The ITT population included all subjects randomized to treatment who received at least 1 dose of study medication.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Levetiracetam (LEV)
    Arm description
    Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    LEV Levetiracetam
    Other name
    Keppra
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Levetericatem: Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.

    Arm title
    Matching Placebo (PBO)
    Arm description
    Oral tablets and oral solution.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo: Oral tablets and oral solution.

    Number of subjects in period 1
    Levetiracetam (LEV) Matching Placebo (PBO)
    Started
    64
    34
    Completed
    50
    29
    Not completed
    14
    5
         Protocol deviation
    -
    1
         Lack of efficacy
    1
    1
         ' Increase in concomitant medication'
    1
    -
         Consent withdrawn by subject
    4
    -
         AE, non-serious non-fatal
    7
    2
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam (LEV)
    Reporting group description
    Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.

    Reporting group title
    Matching Placebo (PBO)
    Reporting group description
    Oral tablets and oral solution.

    Reporting group values
    Levetiracetam (LEV) Matching Placebo (PBO) Total
    Number of subjects
    64 34 98
    Age Categorical
    Units: Subjects
        4 - 7
    18 10 28
        8 - 12
    28 15 43
        13 - 16
    18 9 27
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    10.58 ± 3.49 10.27 ± 3.67 -
    Gender Categorical
    Units: Subjects
        Male
    39 17 56
        Female
    25 17 42
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    40 18 58
        Other/ mixed race
    6 5 11
        Black
    15 8 23
        Asian
    3 3 6
    Race (NIH/OMB)
    Units: Subjects
        Hispanic or latino
    6 4 10
        Not hispanic or not latino
    58 30 88

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam (LEV)
    Reporting group description
    Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.

    Reporting group title
    Matching Placebo (PBO)
    Reporting group description
    Oral tablets and oral solution.

    Subject analysis set title
    Per Protocol Set (Placebo Treated Subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Oral tablets and oral solution.

    Subject analysis set title
    Per Protocol Set (Levetiracetam Treated Subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.

    Primary: Change from Baseline in the Leiter International Performance Scale-Revised (Leiter-R) Attention and Memory (AM) Battery’s Memory Screen Composite Score from Baseline (Visit 2) to the end of the Evaluation Period (Week 12 or Early Discontinuation Visit)

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    End point title
    Change from Baseline in the Leiter International Performance Scale-Revised (Leiter-R) Attention and Memory (AM) Battery’s Memory Screen Composite Score from Baseline (Visit 2) to the end of the Evaluation Period (Week 12 or Early Discontinuation Visit)
    End point description
    The Leiter-R includes two groupings of sub-tests: (1) the Visualization and Reasoning (VR) Battery with 10 sub-tests of nonverbal intellectual ability related to visualization, reasoning, and spatial ability; and (2) the Attention and Memory (AM) Battery with 10 sub-tests of nonverbal attention and memory function. The Examiner Rating Scale has 49 items that describe the child's activity level, attention, impulse control, and other emotional characteristics that may interact with test performance. The focus of the items is on actions, verbalizations, moods and other behaviors of the child. The examiner rates the child using the following scale: 0 = rarely or never; 1 = sometimes; 2 = often; 3 = usually or always.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) to the end of the Evaluation Period (Week 12 or Early Discontinuation Visit)
    End point values
    Per Protocol Set (Levetiracetam Treated Subjects) Per Protocol Set (Placebo Treated Subjects)
    Number of subjects analysed
    46
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    5.37 ± 11.15
    5.24 ± 12.79
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Per Protocol Set (Levetiracetam Treated Subjects) v Per Protocol Set (Placebo Treated Subjects)
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9473
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -4.69
         upper limit
    5.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.93

    Secondary: Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) General Memory from Baseline to Week 12 or Early Discontinuation Visit (EDV)

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    End point title
    Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) General Memory from Baseline to Week 12 or Early Discontinuation Visit (EDV)
    End point description
    The WRAML-2 is comprised of 2 Verbal, 2 Visual, and 2 Attention-Concentration sub-tests, yielding a Verbal Memory Index, a Visual Memory Index and an Attention-Concentration Index. Together these sub-tests yield a General Memory Index. Scaled and standard scores allow performance comparisons based on age and 4 delayed recall sub-tests include guidelines for determining the level of recall. A composite General Memory Index score will be computed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 or EDV
    End point values
    Per Protocol Set (Levetiracetam Treated Subjects) Per Protocol Set (Placebo Treated Subjects)
    Number of subjects analysed
    43
    23
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    3.14 ± 9.93
    7.39 ± 10.4
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Per Protocol Set (Levetiracetam Treated Subjects) v Per Protocol Set (Placebo Treated Subjects)
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2022
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.75
         upper limit
    1.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.66

    Secondary: Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Visual Memory Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)

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    End point title
    Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Visual Memory Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)
    End point description
    The WRAML-2 is comprised of 2 Verbal, 2 Visual, and 2 Attention-Concentration sub-tests, yielding a Verbal Memory Index, a Visual Memory Index and an Attention-Concentration Index. Together these sub-tests yield a General Memory Index. Scaled and standard scores allow performance comparisons based on age and 4 delayed recall sub-tests include guidelines for determining the level of recall. A composite General Memory Index score will be computed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 or EDV
    End point values
    Per Protocol Set (Levetiracetam Treated Subjects) Per Protocol Set (Placebo Treated Subjects)
    Number of subjects analysed
    43
    23
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    6.16 ± 12.45
    12.91 ± 17.02
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Per Protocol Set (Levetiracetam Treated Subjects) v Per Protocol Set (Placebo Treated Subjects)
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3107
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.19
         upper limit
    3.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.37

    Secondary: Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Verbal Memory Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)

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    End point title
    Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Verbal Memory Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)
    End point description
    The WRAML-2 is comprised of 2 Verbal, 2 Visual, and 2 Attention-Concentration sub-tests, yielding a Verbal Memory Index, a Visual Memory Index and an Attention-Concentration Index. Together these sub-tests yield a General Memory Index. Scaled and standard scores allow performance comparisons based on age and 4 delayed recall sub-tests include guidelines for determining the level of recall. A composite General Memory Index score will be computed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 or EDV
    End point values
    Per Protocol Set (Levetiracetam Treated Subjects) Per Protocol Set (Placebo Treated Subjects)
    Number of subjects analysed
    46
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    2.23 ± 11.95
    2.04 ± 12.2
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Per Protocol Set (Levetiracetam Treated Subjects) v Per Protocol Set (Placebo Treated Subjects)
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6574
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.65
         upper limit
    7.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    3

    Secondary: Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Attention/Concentration Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)

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    End point title
    Change from Baseline in Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) Attention/Concentration Index from Baseline to Week 12 or Early Discontinuation Visit (EDV)
    End point description
    The WRAML-2 is comprised of 2 Verbal, 2 Visual, and 2 Attention-Concentration sub-tests, yielding a Verbal Memory Index, a Visual Memory Index and an Attention-Concentration Index. Together these sub-tests yield a General Memory Index. Scaled and standard scores allow performance comparisons based on age and 4 delayed recall sub-tests include guidelines for determining the level of recall. A composite General Memory Index score will be computed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 or EDV
    End point values
    Per Protocol Set (Levetiracetam Treated Subjects) Per Protocol Set (Placebo Treated Subjects)
    Number of subjects analysed
    44
    23
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -0.27 ± 8.62
    2.13 ± 9.72
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Per Protocol Set (Levetiracetam Treated Subjects) v Per Protocol Set (Placebo Treated Subjects)
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3544
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.73
         upper limit
    2.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent Adverse Events were collected during the study, which began on 28 September 2004 and concluded on 21 March 2007.
    Adverse event reporting additional description
    Adverse Events refer to the ITT Population, which included all subjects randomized to treatment who received at least 1 dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Matching Placebo (PBO)
    Reporting group description
    Oral tablets and oral solution.

    Reporting group title
    Levetiracetam (LEV)
    Reporting group description
    Oral tablets or oral solution at 20-60 mg/kg/d, divided into twice daily dosing.

    Serious adverse events
    Matching Placebo (PBO) Levetiracetam (LEV)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Matching Placebo (PBO) Levetiracetam (LEV)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 34 (82.35%)
    51 / 64 (79.69%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 34 (0.00%)
    6 / 64 (9.38%)
         occurrences all number
    0
    8
    Epistaxis
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 64 (4.69%)
         occurrences all number
    2
    4
    Cough
         subjects affected / exposed
    2 / 34 (5.88%)
    4 / 64 (6.25%)
         occurrences all number
    2
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 34 (14.71%)
    17 / 64 (26.56%)
         occurrences all number
    7
    26
    Somnolence
         subjects affected / exposed
    3 / 34 (8.82%)
    9 / 64 (14.06%)
         occurrences all number
    4
    11
    Psychomotor hyperactivity
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 64 (6.25%)
         occurrences all number
    5
    4
    Dizziness
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 64 (9.38%)
         occurrences all number
    4
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 34 (11.76%)
    9 / 64 (14.06%)
         occurrences all number
    4
    10
    Pyrexia
         subjects affected / exposed
    3 / 34 (8.82%)
    5 / 64 (7.81%)
         occurrences all number
    3
    7
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    3 / 34 (8.82%)
    8 / 64 (12.50%)
         occurrences all number
    4
    9
    Abnormal behaviour
         subjects affected / exposed
    0 / 34 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    5
    Anxiety
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    4
    Insomnia
         subjects affected / exposed
    1 / 34 (2.94%)
    4 / 64 (6.25%)
         occurrences all number
    1
    4
    Mood altered
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    4
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 34 (8.82%)
    9 / 64 (14.06%)
         occurrences all number
    3
    10
    Abdominal pain upper
         subjects affected / exposed
    3 / 34 (8.82%)
    11 / 64 (17.19%)
         occurrences all number
    5
    17
    Stomach discomfort
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 64 (4.69%)
         occurrences all number
    2
    3
    Acne
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Decreased appetite
         subjects affected / exposed
    1 / 34 (2.94%)
    5 / 64 (7.81%)
         occurrences all number
    1
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 34 (26.47%)
    12 / 64 (18.75%)
         occurrences all number
    11
    16
    Pharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 34 (11.76%)
    10 / 64 (15.63%)
         occurrences all number
    4
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2004
    No subjects had been enrolled when Amendment 1 was issued. This amendment included changes to the study entry criteria based on discussions at the Investigator’s Meeting. These changes were as follows: • Subjects who had received treatment with benzodiazepines on a chronic or routine Basis were allowed to enter the study if they discontinued These medications 4 weeks prior to Visit 1 • Excluded psychiatric diagnoses were specified more narrowly as serious, unstable psychiatric diagnoses that would confound the Investigator’s ability to conduct the trial or prevent the subject from completing the requirements of the protocol • Any ADHD medication intake was to remain stable during the study and had to be stable 1 month prior to Visit 1 • Subjects taking phenobarbital or primidone prior to Visit 1 were excluded • Subjects with seizures too close together to be accurately counted were excluded Other minor changes included addition or clarification of procedural details that were unlikely to significantly affect enrollment or study outcome.
    22 Aug 2005
    Amendment 2 allowed for establishment of a greater number of study sites and allowed for sites to be established in Canada and South Africa. Minor changes were made in the study safety assessments in order to satisfy requirements of the EMEA. These changes included addition of height and TSH measurements. Amendment 2 incorporated information about the FDA approval of LEV for use in children (4 years of age and above) with partial onset seizures (approval occurred in June 2005), and included information about the efficacy and safety results of other ongoing studies of LEV. Amendment 2 allowed for subjects with previous exposure to LEV to enroll in the study under limited circumstances. One impact of these changes was to allow more subjects to enroll, particularly subjects outside the US.
    06 Jan 2006
    Amendment 3 modified the Inclusion and Exclusion criteria in the following ways, to make the sample more representative of the target population: • The IQ criterion for study inclusion was reduced from 70 to 65 • The weight criterion was changed from ≤ 80 kg to ≤ 100 kg • Exclusions for subjects with current psychiatric diagnoses were relaxed from the Initial trict criteria after data from pivotal study N159 showed that LEV did not exacerbate ifficulties in children with history of psychiatric illnesses. Serious, unstable sychiatric illnesses were still excluded (such as suicide risk within the past 6 months, sychotic disorder, or acute mania) • The requirement for 2 partial onset seizures within the 4 weeks prior to Visit 1 was reduced to a requirement of only 1 partial onset seizure within the same time period. This criterion change, which is consistent with the intended population on the current LEC label, would terefore enable the collection of additional relevant safety data. There is no evidence that reducing the seizure number criterion would impair the sensitivity of the study to demonstrate potential psychiatric or neuropsychological effects of LEV Assumptions for the sample size estimation were adjusted in Amendment 3, so the sample size was recalculated and the total evaluable n was reduced by 13 subjects. Due to difficulties with enrollment, the sample size calculation was reviewed. During the review, it was determined that the Leiter-R Memory Screen un-inflated standard deviation of 6.94 that was used in the initial sample size was miscalculated. The actual un-inflated standard deviation should have been 10.19. To adjust for the younger age group in N01103, their epileptic disease state, and the unknown time between test and re-test, the estimate was inflated to 13.00 (a little more than 25%). Additionally, the type II error rate was relaxed from 15% to 20%, reducing statistical power to 80%.
    06 Jan 2006
    The increase to the type II error rate results in a smaller subject requirement, an acknowledgement of the difficulty enrolling subjects from this population while staying within generally accepted constraints for sample size determinations. Finally, the drop-out rate/major protocol deviation rate assumption was increased from 20% to 30% to more accurately reflect the actual rate occurring in the study. These changes were discussed with the FDA and accepted prior to implementing the changes. Amendment 3 also increased the number of study centers.

    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/20547106
    http://www.ncbi.nlm.nih.gov/pubmed/19702752
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