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    Clinical Trial Results:
    A Multicenter, Open-Label, Single-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Neonates with Repeated Electroencephalographic Seizures

    Summary
    EudraCT number
    2015-002756-27
    Trial protocol
    IE   DE   GB   BE   CZ   HU   NL   FR   IT  
    Global end of trial date
    29 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jul 2022
    First version publication date
    08 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01349
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03325439
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SRL
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, 1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000332-PIP02-17
    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
    09 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate the pharmacokinetics (PK) of brivaracetam (BRV) in neonates who have seizures that are not adequately controlled with previous antiepileptic drug (AED) treatment and to identify the optimum BRV dose (Exploratory Cohort) for the treatment of participants enrolled into the Confirmatory Cohorts of this study.
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    07 May 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Ethical reason
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Ireland: 5
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    2
    Newborns (0-27 days)
    7
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    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
    The study started to enroll participants in May 2019 and concluded in May 2021.

    Pre-assignment
    Screening details
    No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues. The Participant Flow refers to the All Subjects Screened.

    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
    Exploratory Cohort
    Arm description
    Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    Other name
    BRV
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eligible participants in this arm received BRV 0.5 mg/kg administered as iv solution for injection twice daily (bid) during the 48-hour Evaluation Period.

    Number of subjects in period 1
    Exploratory Cohort
    Started
    9
    Treated
    6
    Completed
    6
    Not completed
    3
         Ineligibility
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exploratory Cohort
    Reporting group description
    Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.

    Reporting group values
    Exploratory Cohort Total
    Number of subjects
    9 9
    Age Categorical
    Units: participants
        Gestational Age <37 weeks
    2 2
        Gestational Age >=37 weeks
    7 7
    Age Continuous
    Corrected gestational age at time of enrollment is reported.
    Units: weeks
        arithmetic mean (standard deviation)
    39.2 ( 1.9 ) -
    Sex: Female, Male
    Units: participants
        Female
    6 6
        Male
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Exploratory Cohort
    Reporting group description
    Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.

    Primary: Plasma concentration of Brivaracetam (BRV) following first dose on Day 1

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    End point title
    Plasma concentration of Brivaracetam (BRV) following first dose on Day 1 [1]
    End point description
    Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 to determine the BRV plasma concentration. The Pharmacokinetic Per-Protocol Set (PK-PPS) consisted of all study participants who provided at least 1 measurable post-Baseline plasma sample (with recorded sampling time) on at least 1 post-Baseline Visit with documented study drug intake times. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. Here, 'n' signifies participants who were evaluable at specified time points.
    End point type
    Primary
    End point timeframe
    Pharmacokinetic blood samples were taken 0.5 to 1 hour, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1
    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
    Exploratory Cohort
    Number of subjects analysed
    6
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        0.5-1 hour (n=5)
    534.2 ( 15.4 )
        2-4 hours (n=6)
    500.1 ( 28.2 )
        8-12 hours (n=5)
    342.7 ( 13.2 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with Adverse Events (AEs) as reported by the Investigator

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    End point title
    Percentage of participants with Adverse Events (AEs) as reported by the Investigator
    End point description
    An adverse event (AE) was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. The All Study Participants Screened Set consisted of all study participants who had signed the Informed Consent form (ICF) and underwent the study inclusion and exclusion criteria of the current protocol.
    End point type
    Secondary
    End point timeframe
    Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
    End point values
    Exploratory Cohort
    Number of subjects analysed
    9
    Units: percentage of participants
        number (not applicable)
    55.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
    Adverse event reporting additional description
    Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Exploratory Cohort
    Reporting group description
    Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment.

    Serious adverse events
    Exploratory Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Exploratory Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 9 (55.56%)
    Investigations
    Ammonia increased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         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
    10 Oct 2019
    Global Protocol Amendment 5.0, dated 10 Oct 2019, was a substantial protocol amendment created after 1 eligible study participant had been enrolled in the study. Protocol Amendment 5.0 was implemented through Global Protocol Amendment 6.0. The primary purpose of this substantial protocol amendment was to implement the changes from the agreed Pediatric Investigation Plan for BRV in order to improve the enrollment rate. The primary change was to remove restrictions in terms of concomitant medication and to simplify electroencephalogram (EEG) requirements; as a result, the primary and secondary objectives were revised. In addition, the age range at enrollment was modified. A brief list of important modifications and changes to this protocol amendment included the following: • Phenobarbital was no longer required as first line treatment prior to BRV and replaced by treatment of electroencephalographic neonatal seizures (ENS) allowed per SToC for the Exploratory Cohort, and 1 or more of the following AEDs: phenobarbital (PB), midazolam (MDZ), phenytoin (PHT), levetiracetam (LEV) (≤60mg/kg/day), or lidocaine (LDC) for the Confirmatory Cohorts. • Two hour Baseline EEG and 48-hour VEEG were removed from the Exploratory Cohort; required ENS to be confirmed by the Investigator via local EEG. • Duration of the 2-hour Baseline Period was shortened to up to 1 hour for the Confirmatory Cohorts and was separated by seizure activity: “at least 1 hour” for study participants with intermittent ENS and “up to 30 minutes” for study participants in status epilepticus. • Treatment with “MDZ only” during the first 3 hours of the Evaluation Period was removed from the Confirmatory Cohort; duration of the Evaluation Period hence shortened from 51 hours to 48 hours. • The initiation of LEV treatment after the first time BRV was introduced was prohibited throughout the study for the Confirmatory Cohorts.
    24 May 2021
    Global Protocol Amendment 7.0, dated 24 May 2021, was a substantial protocol amendment implemented after 6 eligible study participants had been enrolled in the study. The primary purposes of this substantial protocol amendment were as follows: • Specified the BRV dose recommended by the Data Monitoring Committee (DMC) for the Confirmatory Cohorts. • Incorporated the measures described in UCB’s coronavirus disease 2019 (COVID-19) Contingency Plan for N01349. • Prolonged the BRV Extension Period for up to 90 days postnatal age (PNA) for sites that may not have been ready to transition study participants to EP0156 at the time that N01266 was closed.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Mar 2020
    The study was interrupted due to COVID-19.
    15 Jul 2020

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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