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    Clinical Trial Results:
    Open-label, Single-arm, Multi-center, Pharmacokinetic, Safety and Tolerability Study of Levetiracetam Intravenous Infusion in Children (1 Month- 4 Years Old) With Epilepsy

    Summary
    EudraCT number
    2007-003517-13
    Trial protocol
    BE   DE   FR  
    Global end of trial date
    11 Mar 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01275
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00505934
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Chemin du Foriest, Braine-l’Alleud, Belgium, B-1420
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 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
    15 Jun 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 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 safety and tolerability of the LEV IV 15-minute infusion administered every 12 hours, either as adjunctive treatment or monotherapy in children (1 month to <4 years old) with epilepsy (except status epilepticus), either after switching from the equivalent LEV oral dose administration or as a new antiepileptic treatment.
    Protection of trial subjects
    Subjects were hospitalized for the duration of the levetiracetam iv treatment. For the Screening and Final Visit, blood samples were drawn by direct venipuncture using disposable needles. During the treatment period, a catheter may have been used to minimize trauma and speed up sampling. The catheter could have been fitted on the morning of the first day. If not possible, direct venipuncture was performed. EMLA (or other topical anesthetics) could have been used to minimize pain due to puncture or insertion of a catheter. Blood samples must have been taken from another vein than the vein used for the IV infusion.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    16 May 2008
    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
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Mexico: 8
    Worldwide total number of subjects
    19
    EEA total number of subjects
    2
    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)
    12
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    0
    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
    Subjects were recruited from sites in the United States, Belgium, Germany, France, Mexico, and Turkey. The study began in May 2008 and continued until March 2010, with the last subject's visit occurring in March of 2010.

    Pre-assignment
    Screening details
    Of the 23 subjects screened, 19 were enrolled into the study and received levetiracetam IV (LEV IV). Participant Flow refers to the Intent-to-treat (ITT) Population, consisting of all subjects who received at least 1 dose of study medication.

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

    Arms
    Arm title
    Levetiracetam
    Arm description
    Intravenous 100 mg/mL, twice a day, maximum of 4 days Subjects on oral levetiracetam at study entry receive the same intravenous (IV) dosage (mg-for-mg) to their oral dose within the following dose range, calculated on the basis of their age and weight: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily) to 42 mg/kg/day (21 mg/kg/day twice daily); • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily) to 60 mg/kg/day (30 mg/kg/day twice daily). For subjects not taking levetiracetam oral solution prior to entering the study, the intravenous (IV) dosage corresponded to their age and weight as follows: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily). • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily).
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    LEV
    Other name
    Keppra
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous 100 mg/mL, twice a day, maximum of 4 days. Subjects on oral levetiracetam at study entry receive the same intravenous (IV) dosage (mg-for-mg) to their oral dose, calculated on the basis of their age and weight.

    Number of subjects in period 1
    Levetiracetam
    Started
    19
    Completed
    16
    Not completed
    3
         Other: Unable to obtain IV & PK samples
    1
         AE, non-serious non-fatal
    1
         Other: IV dose needed to be changed
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Intravenous 100 mg/mL, twice a day, maximum of 4 days Subjects on oral levetiracetam at study entry receive the same intravenous (IV) dosage (mg-for-mg) to their oral dose within the following dose range, calculated on the basis of their age and weight: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily) to 42 mg/kg/day (21 mg/kg/day twice daily); • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily) to 60 mg/kg/day (30 mg/kg/day twice daily). For subjects not taking levetiracetam oral solution prior to entering the study, the intravenous (IV) dosage corresponded to their age and weight as follows: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily). • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily).

    Reporting group values
    Levetiracetam Total
    Number of subjects
    19 19
    Age Categorical
    Units: Subjects
        <=18 years
    19 19
        Between 18 and 65 years
    0 0
        >=65 years
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    1.59 ± 1.24 -
    Gender Categorical
    Units: Subjects
        Female
    7 7
        Male
    12 12
    Region of Enrollment
    Units: Subjects
        United States
    7 7
        Mexico
    8 8
        Belgium
    1 1
        Turkey
    2 2
        Germany
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Intravenous 100 mg/mL, twice a day, maximum of 4 days Subjects on oral levetiracetam at study entry receive the same intravenous (IV) dosage (mg-for-mg) to their oral dose within the following dose range, calculated on the basis of their age and weight: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily) to 42 mg/kg/day (21 mg/kg/day twice daily); • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily) to 60 mg/kg/day (30 mg/kg/day twice daily). For subjects not taking levetiracetam oral solution prior to entering the study, the intravenous (IV) dosage corresponded to their age and weight as follows: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily). • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily).

    Primary: Number of subjects reporting at least 1 Treatment-Emergent Adverse Event (TEAE) during the treatment period (up to 4 days)

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    End point title
    Number of subjects reporting at least 1 Treatment-Emergent Adverse Event (TEAE) during the treatment period (up to 4 days) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Treatment period (up to 4 days)
    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 study. Results were summarized in tables as descriptive statistics only.
    End point values
    Levetiracetam
    Number of subjects analysed
    19
    Units: Subjects
        Number of Subjects
    12
    No statistical analyses for this end point

    Secondary: Number of subjects who received high-dose levetiracetam intravenous (LEV IV) (more than 28 mg/kg/day for subjects <6 months; >40 mg/kg/day for subjects ≥6 months) during the treatment period (up to 4 days)

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    End point title
    Number of subjects who received high-dose levetiracetam intravenous (LEV IV) (more than 28 mg/kg/day for subjects <6 months; >40 mg/kg/day for subjects ≥6 months) during the treatment period (up to 4 days)
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period (up to 4 days)
    End point values
    Levetiracetam
    Number of subjects analysed
    19
    Units: Subjects
        Number of Subjects
    6
    No statistical analyses for this end point

    Secondary: Number of consecutive levetiracetam intravenous (LEV IV) doses received

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    End point title
    Number of consecutive levetiracetam intravenous (LEV IV) doses received
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period (up to 4 days)
    End point values
    Levetiracetam
    Number of subjects analysed
    19
    Units: Consecutive doses
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    2.89 ± 1.41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4 days
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Intravenous 100 mg/mL, twice a day, maximum of 4 days Subjects on oral levetiracetam at study entry receive the same intravenous (IV) dosage (mg-for-mg) to their oral dose within the following dose range, calculated on the basis of their age and weight: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily) to 42 mg/kg/day (21 mg/kg/day twice daily); • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily) to 60 mg/kg/day (30 mg/kg/day twice daily). For subjects not taking levetiracetam oral solution prior to entering the study, the intravenous (IV) dosage corresponded to their age and weight as follows: • Ages ≥ 1 month to < 6 months: 14 mg/kg/day (7 mg/kg twice daily). • Ages ≥ 6 months to < 4 years: 20 mg/kg/day (10 mg/kg twice daily).

    Serious adverse events
    Levetiracetam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 19 (21.05%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Investigations
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    CARDIAC ARREST
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    BRADYCARDIA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    CONVULSION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    METABOLIC ACIDOSIS
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Infections and infestations
    ABDOMINAL SEPSIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    PNEUMONIA
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levetiracetam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 19 (52.63%)
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    PROCEDURAL PAIN
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Investigations
    ELECTROENCEPHALOGRAM
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Cardiac disorders
    BRADYCARDIA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    RHINORRHOEA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Nervous system disorders
    SOMNOLENCE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    MYOCLONIC EPILEPSY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    DROOLING
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Eye disorders
    EYE SWELLING
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    IRRITABILITY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    PAIN
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    PUNCTURE SITE PAIN
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Psychiatric disorders
    RESTLESSNESS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    VOMITING
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    PETECHIAE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    NEURODERMATITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2008
    Changes to the protocol included revision of inclusion and exclusion criteria, the schedule of PK assessments as well as some logistical aspects of the study procedures in order to facilitate the recruitment of subjects. The minimum required number of complete sets of PK sampling per maximum 4 days in-patient hospitalization during the Evaluation Period was lowered from 2 sets to 1 set of PK sampling. Also, the sample scheduled to be taken pre-dose was replaced by a sample collected 3-10 minutes after the start of infusion to maximize the number of samples during the Evaluation Period.
    18 Sep 2008
    Changes to the protocol included updates to exclusion criteria, administrative changes, clarification of study objectives (main goal of study is safety and tolerability of levetiracetam IV in pediatrics, with a lesser emphasis on PK) and addition of FDA requests that approximately 1/2 of the subjects are exposed to at least 3 consecutive levetiracetam IV doses and at least 1/3 of the subjects should be in the high dose range [i.e. Subjects ≥ 1 month to < 6 months: ≥ 28 mg/kg/day (i.e. 14 mg/kg b.i.d.); subjects ≥ 6 months to < 4 years: ≥ 40 mg/kg/day(i.e. 20 mg/kg b.i.d.)]. Results of simulations of exposure in children from 1 month to 4 years of age performed to evaluate the necessity of a dose adjustment and to establish a nomogram (study N01288) showed that children aged 1 to 6 months would require about 70% of the dose for a 4 year old. Therefore levetiracetam IV dosage was updated.
    08 Oct 2009
    Rationale: Changes to the protocol included revision of the inclusion of the age categories to have more balanced age groups (updated categories of 6 subjects ≥1 month to <6months; 6 subjects ≥6 months to <2 years; and 6 subjects ≥2 years to <4 years), clarification of the use of local laboratory and ECG results for the evaluation of subjects’ eligibility. Study team members’information was also updated.

    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/23533164
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