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    Clinical Trial Results:
    An open label, multicenter, parallel-group, two-arm study comparing the pharmacokinetics of Keppra XR in children (aged 12-16 years old) with epilepsy and in adults (aged 18-55 years old) with epilepsy

    Summary
    EudraCT number
    		 2014-004376-39
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 Mar 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01340
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00961441
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES, Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, 27617
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 May 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the PK of Keppra XR in children (12 to 16 years old) and adults (18 to 55 years old) with epilepsy.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 Concomitant antiepileptic drugs/ vagus nerve stimulation
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    01 Sep 2009
    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
    United States: 25
    Worldwide total number of subjects
    25
    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)
    0
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Intent-to-treat (ITT) population includes all enrolled patients who received at least one dose of study medication. Pharmacokinetic Per-Protocol (PK-PP) population is a subset of the ITT population, consisting of those patients who had no major protocol deviations affecting the pharmacokinetic parameters.

    Pre-assignment
    Screening details
    		 Participant Flow and Baseline characteristics refer to the Intention-to-treat (ITT) population. Two subjects were excluded from the PK-PP due to study medication noncompliance, one due to wrong dosing regimen.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Keppra XR in Children (12-16 years old)
    Arm description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Levetiracetam (LEV)
    Other name
    Keppra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Keppra XR 500 mg tablets and Keppra XR 750 mg tablets. Dosage: Keppra XR 1000-3000 mg/day taken once daily.

    Arm title
    		 Keppra XR in Adults (18-55 years old)
    Arm description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Levetiracetam (LEV)
    Other name
    Keppra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Keppra XR 500 mg tablets and Keppra XR 750 mg tablets. Dosage: Keppra XR 1000-3000 mg/day taken once daily.

    Number of subjects in period 1
    		Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Started
    12
    13
    Pharmacokinetic (PK-PP) population
    12
    10 [1]
    Completed
    12
    13
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Two subjects were excluded due to study medication noncompliance, one due to wrong dosing Regimen.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Keppra XR in Children (12-16 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Reporting group title
    Keppra XR in Adults (18-55 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Reporting group values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old) Total
    Number of subjects
    		 12 13 25
    Age categorical
    Units: Subjects
        12-17 years
    		 12 0 12
        18-64 years
    		 0 13 13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.88 ( 1.37 ) 41.78 ( 9.21 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 6 8 14
        Male
    		 6 5 11
    Race
    Units: Subjects
        Black
    		 4 3 7
        Caucasian
    		 8 9 17
        Other / mixed
    		 0 1 1
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 77.2 ( 24.1 ) 82.5 ( 23 ) -
    Height
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    		 165.9 ( 8.8 ) 169.3 ( 10.3 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.62 ( 7.01 ) 28.63 ( 7.14 ) -
    Body Surface Area (BSA)
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.87 ( 0.34 ) 1.95 ( 0.32 ) -

    End points

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    End points reporting groups
    Reporting group title
    Keppra XR in Children (12-16 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Reporting group title
    Keppra XR in Adults (18-55 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Primary: Maximum Concentration at Steady State (Cmax) of Keppra XR normalized by dose, and by body weight and dose during up to 7 days of administration

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    End point title
    		 Maximum Concentration at Steady State (Cmax) of Keppra XR normalized by dose, and by body weight and dose during up to 7 days of administration
    End point description
    The Cmax is the maximum plasma concentration normalized by dose and by body weight and dose. Cmax normalized by 1000 mg dose was calculated as: Cmax/(mg dose taken/ 1000 mg Keppra XR). Cmax normalized by body weight and dose (1 mg Keppra XR/kg) was calculated as: Cmax/(bodyweight (kg)/ mg dose Keppra XR taken). Pharmacokinetic (PK) samples were taken predose and 1h, 2.5h, 4h, 6h and 10h after study medication at day 4, 5, 6 or 7 of Keppra XR administration.
    End point type
    Primary
    End point timeframe
    6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    End point values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Number of subjects analysed
    12
    10
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Dose norm. ( Keppra XR 1000mg)
    17.3 (14.3 to 21)
    14.9 (12.1 to 18.5)
        Dose and weight norm. ( Keppra XR 1 mg/kg)
    1.27 (1.12 to 1.44)
    1.24 (1.08 to 1.42)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    An ANOVA for log-transformed values has been used as the basis for calculation of point estimates and Confidence Intervals (CIs). Point estimates for the geometric means ratios children/adults for Cmax normalized by dose and Body weight and 90% CIs have been calculated.
    Comparison groups
    Keppra XR in Children (12-16 years old) v Keppra XR in Adults (18-55 years old)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Point estimate for ratio
    Point estimate
    1.0271
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8817
         upper limit
    		 1.1964

    Primary: Area Under the Plasma Concentration Curve over a dosing interval of 24 hours (AUCtau) of Keppra XR normalized by dose, and by body weight and dose during up to 7 days of administration

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    End point title
    		 Area Under the Plasma Concentration Curve over a dosing interval of 24 hours (AUCtau) of Keppra XR normalized by dose, and by body weight and dose during up to 7 days of administration
    End point description
    AUCtau normalized by 1000 mg dose was calculated as: AUCtau/(mg dose taken/ 1000 mg Keppra XR). AUCtau normalized by body weight and dose (1 mg Keppra XR/kg) was calculated as: AUCtau/(bodyweight (kg)/ mg dose Keppra XR taken). 6 PK samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration. At steady state, reached after 2 days of administration of Keppra XR, the concentrations at 24h postdose is equal to the predose concentration. The predose concentration was used as the 24h concentration to calculate AUCτau.
    End point type
    Primary
    End point timeframe
    6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    End point values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Number of subjects analysed
    12
    10
    Units: µg*h/mL
    geometric mean (confidence interval 95%)
        Dose norm. (Keppra XR 1000mg)
    265 (214 to 327)
    236 (187 to 298)
        Dose and weight norm. (Keppra XR 1 mg/kg)
    19.4 (16.5 to 22.9)
    19.6 (16.4 to 23.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    An ANOVA for log-transformed values has been used as the basis for calculation of point estimates and Confidence Intervals (CIs). Point estimates for the geometric means ratios children/adults for AUCtau normalized by dose and body weight and 90% CIs have been calculated.
    Comparison groups
    Keppra XR in Children (12-16 years old) v Keppra XR in Adults (18-55 years old)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Point estimate for ratio
    Point estimate
    0.9914
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.811
         upper limit
    		 1.2118

    Primary: Time of Maximum Plasma Concentration (Tmax) of Keppra XR during up to 7 days of administration

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    End point title
    		 Time of Maximum Plasma Concentration (Tmax) of Keppra XR during up to 7 days of administration [1]
    End point description
    The Tmax is the time corresponding to the maximum plasma concentration of Keppra XR. It was directly obtained from the observed concentration versus time curve.6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    End point type
    Primary
    End point timeframe
    6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    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: No formal statistical hypothesis testing was planned for this primary outcome. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Number of subjects analysed
    12
    10
    Units: hours (h)
    median (full range (min-max))
        median (full range)
    5.9 (2.5 to 6.07)
    5.93 (2.45 to 6.05)
    No statistical analyses for this end point

    Primary: Apparent Total Body Clearance (CL/F) of Keppra XR during up to 7 days of administration

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    End point title
    		 Apparent Total Body Clearance (CL/F) of Keppra XR during up to 7 days of administration [2]
    End point description
    The Apparent Total Body Clearance (CL/F) was calculated as Dose/ AUCtau. 6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    End point type
    Primary
    End point timeframe
    6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
    Notes
    [2] - 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: No formal statistical hypothesis testing was planned for this primary outcome. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Number of subjects analysed
    12
    10
    Units: L/h
    geometric mean (geometric coefficient of variation)
        geometric mean (GeoCV(%))
    3.78 ( 31.4 )
    4.23 ( 41.8 )
    No statistical analyses for this end point

    Secondary: Occurrence of Treatment-Emergent Adverse Events from Starting Study Drug Treatment (Day 1) to up to 14 days

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    End point title
    		 Occurrence of Treatment-Emergent Adverse Events from Starting Study Drug Treatment (Day 1) to up to 14 days
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Treatment emergent means that an AE has begun or got worse after start of Keppra XR administration.
    End point type
    Secondary
    End point timeframe
    From Starting Study Drug Treatment (Day 1) to up to 14 days
    End point values
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Number of subjects analysed
    12
    13
    Units: Count
    number (not applicable)
        Total number of AEs
    7
    11
        Patients with at least 1 AE
    3
    3
        Patients with severe AEs
    0
    1
        Patients with serious AEs
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Starting Study Drug Treatment (Day 1) to up to 14 days.
    Adverse event reporting additional description
    Treatment-Emergent AEs were collected and refer to the Safety Set. Safety Set includes all subjects who took at least one dose of study medication. Treatment emergent means that an Adverse Event has begun or got worse after start of Keppra XR administration.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Keppra XR in Children (12-16 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Reporting group title
    Keppra XR in Adults (18-55 years old)
    Reporting group description
    		 Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days

    Serious adverse events
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Keppra XR in Children (12-16 years old) Keppra XR in Adults (18-55 years old)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 13 (23.08%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Hypoaesthesia facial
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Infections and infestations
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2009
    Protocol Amendment 1 (dated 19 May 2009) was primarily issued to update the Minimum amount of blood to be taken for PK sampling from 1mL to 4mL to ensure that there was enough plasma volume to perform accurate PK analyses. Furthermore, it was clarified that the Final Visit was to take place 7(+3) days after the Evaluation Visit (ie, 7 [+3] days after the final blood sampling) or, if applicable, 7 (+3) days after the Early Discontinuation Visit (EDV) (ie, 7[+3] days after the final administration of Keppra XR). In addition, footnotes in the schedule of study assessments were updated, and clarification was provided regarding the daily record card (DRC), drug accountability, and laboratory measurements. Protocol Amendment 1 was issued prior to any subject being enrolled in N01340 (Listing 13.1).

    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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