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Trial record 92 of 107 for:    PHENYTOIN

A Study to Test the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Newborns With Repeated Electroencephalographic Seizures

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ClinicalTrials.gov Identifier: NCT03325439
Recruitment Status : Recruiting
First Posted : October 30, 2017
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
UCB Pharma ( UCB Biopharma S.P.R.L. )

Tracking Information
First Submitted Date  ICMJE October 25, 2017
First Posted Date  ICMJE October 30, 2017
Last Update Posted Date May 31, 2019
Actual Study Start Date  ICMJE May 7, 2019
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Plasma concentration of brivaracetam (BRV) [ Time Frame: 30-60 min after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 30-60 min after the BRV infusion on day 1 to determine the BRV plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-42145 (acid) [ Time Frame: 30-60 min after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 30-60 min after the BRV infusion on day 1 to determine the BRV metabolite ucb-42145 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) [ Time Frame: 30-60 min after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 30-60 min after the BRV infusion on day 1 to determine the BRV metabolite ucb-100406-1 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) [ Time Frame: 30-60 min after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 30-60 min after the BRV infusion on day 1 to determine the BRV metabolite ucb-107092-1 plasma concentration.
  • Area under the BRV plasma concentration time curve (AUC) [ Time Frame: Samples will be collected 30-60 min, 2-4 hours, and 8-12 hours after the BRV infusion on day 1 and potentially on day 2 for the exploratory cohort and on day 1 and day 2, or on day 1 and day 3, or on day 1 and day 4 for the confirmatory cohorts. ]
    AUC is the area under the BRV plasma concentration time curve. Pharmacokinetic blood samples will be taken at indicated timepoints.
  • Distribution volume of BRV [ Time Frame: Samples will be collected 30-60 min, 2-4 hours, and 8-12 hours after the BRV infusion on day 1 and potentially on day 2 for the exploratory cohort and on day 1 and day 2, or on day 1 and day 3, or on day 1 and day 4 for the confirmatory cohorts. ]
    AUC is the area under the BRV plasma concentration time curve. Pharmacokinetic blood samples will be taken at indicated timepoints.
  • Plasma clearance of BRV [ Time Frame: Samples will be collected 30-60 min, 2-4 hours, and 8-12 hours after the BRV infusion on day 1 and potentially on day 2 for the exploratory cohort and on day 1 and day 2, or on day 1 and day 3, or on day 1 and day 4 for the confirmatory cohorts. ]
    AUC is the area under the BRV plasma concentration time curve. Pharmacokinetic blood samples will be taken at indicated timepoints.
  • Plasma concentration of the concomitant antiepileptic drug phenobarbital (PB) [ Time Frame: Samples will be collected 3 hours after the initial dose of BRV. ]
    Pharmacokinetic blood samples will be taken 3 hours after the initial dose of BRV to determine the phenobarbital plasma concentration.
  • Plasma concentration of the concomitant antiepileptic drug phenytoin (PHT) [ Time Frame: Samples will be collected 3 hours after the initial dose of BRV. ]
    Pharmacokinetic blood samples will be taken 3 hours after the initial dose of BRV to determine the phenytoin plasma concentration.
  • Plasma concentration of brivaracetam (BRV) [ Time Frame: 2-4 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 2-4 hours after the BRV infusion on day 1 to determine the BRV plasma concentration.
  • Plasma concentration of brivaracetam (BRV) [ Time Frame: 8-12 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 8-12 hours after the BRV infusion on day 1 to determine the BRV plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-42145 (acid) [ Time Frame: 2-4 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 2-4 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-42145 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-42145 (acid) [ Time Frame: 8-12 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 8-12 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-42145 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) [ Time Frame: 2-4 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 2-4 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-100406-1 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) [ Time Frame: 8-12 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 8-12 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-100406-1 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) [ Time Frame: 2-4 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 2-4 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-107092-1 plasma concentration.
  • Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) [ Time Frame: 8-12 hours after the BRV infusion on day 1 ]
    Pharmacokinetic blood samples will be taken 8-12 hours after the BRV infusion on day 1 to determine the BRV metabolite ucb-107092-1 plasma concentration.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03325439 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Percentage of responders to BRV treatment from Baseline to 3 hours after the initial BRV dose [ Time Frame: From Baseline to 3 hours after the initial BRV dose ]
    A BRV responder is defined as a subject who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) compared to the seizure burden measured during the 2-hour Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment:
    • At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as <=50% seizure activity on (multichannel) video-electroencephalography (VEEG) in any 30-minute timespan) OR
    • At least 50% reduction in severe seizure burden (Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute timespan). Timespans of 30 minutes can refer to the following intervals within the 2-hour period: 0 to <= 30 minutes, > 30 to <= 60 minutes, >60 to <= 90 minutes, and >90 to <= 120 minutes.
  • Percentage of subjects with at least 80% reduction in nonsevere seizure burden from Baseline to 3 hours after the initial BRV treatment [ Time Frame: From Baseline to 3 hours after the initial BRV treatment ]
    Nonsevere seizure burden is defined as <=50% seizure activity on VEEG in any 30-minute timespan. Timespans of 30 minutes can refer to the following intervals within the 2-hour period: 0 to <= 30 minutes, > 30 to <= 60 minutes, >60 to <= 90 minutes, and >90 to <= 120 minutes.
  • Percentage of subjects with at least 50% reduction in severe seizure burden from Baseline to 3 hours after the initial BRV treatment [ Time Frame: From Baseline to 3 hours after the initial BRV treatment ]
    Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute timespan. Timespans of 30 minutes can refer to the following intervals within the 2-hour period: 0 to <= 30 minutes, > 30 to <= 60 minutes, >60 to <= 90 minutes, and >90 to <= 120 minutes.
  • Absolute change in average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour Evaluation Period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    Seizure burden will be measured by continuous (multichannel) video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of 2 hours immediately prior to the first administration of study drug.
  • Percentage change in average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour Evaluation Period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    Seizure burden will be measured by continuous (multichannel) video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of 2 hours immediately prior to the first administration of study drug.
  • Percentage of BRV responders at the end of the 96-hour Evaluation Period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    A BRV responder is defined as a subject who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without the need for rescue medication, compared to the seizure burden measured during a 2-hour Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment:
    • At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as <=50% seizure activity on VEEG in any 30-minute timespan) OR
    • At least 50% reduction in severe seizure burden (Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute timespan)
  • Percentage of subjects who are seizure-free (100% reduction in seizure burden from Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects with nonsevere or severe seizure burden at Baseline [ Time Frame: From Baseline to 24 hours after the initial BRV treatment ]
    Seizure freedom is defined as 100% reduction in seizure burden from Baseline.
  • Time to reduction in seizure burden for BRV responders [ Time Frame: From Baseline to the first timepoint when BRV responder criteria is met ]
    A BRV responder is defined as a subject who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without the need for rescue medication, compared to the seizure burden measured during a 2-hour Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment:
    • At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as <=50% seizure activity on VEEG in any 30-minute timespan) OR
    • At least 50% reduction in severe seizure burden (Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute timespan)
  • Percentage of Subjects with Seizure Freedom at the end of Down-Titration Period [ Time Frame: From Baseline to the end of the Down-Titration Period ]
    Seizure freedom is defined as 100% reduction in seizure burden from Baseline.
  • Percentage of Subjects with at least 50% reduction in electroencephalographic neonatal seizures (ENS) frequency per hour from Baseline to the end of the 96-hour Evaluation Period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    For this study, an ENS is defined as an EEG seizure lasting for at least 10 seconds on VEEG. Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of 2 hours immediately prior to the first administration of study drug.
  • Percentage of subjects who are seizure-free by time interval over the 96-hour evaluation period [ Time Frame: From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation Period ]
    Seizure freedom is defined as 100% reduction in seizure burden from Baseline.
  • Absolute difference in clinical seizures at the end of the 24-hour Evaluation Period from Baseline for neonates with motor seizures at the time of inclusion [ Time Frame: From Baseline to the end of the 24-hour Evaluation Period ]
    Seizures will be measured by continuous (multichannel) video-electroencephalography (VEEG).
  • Percent difference in clinical seizures at the end of the 24-hour Evaluation Period from Baseline for neonates with motor seizures at the time of inclusion [ Time Frame: From Baseline to the end of the 24-hour Evaluation Period ]
    Seizures will be measured by continuous (multichannel) video-electroencephalography (VEEG).
  • Absolute change from Baseline in seizure burden by time interval over the 96-hour evaluation period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    Seizure burden will be measured by continuous (multichannel) video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of 2 hours immediately prior to the first administration of study drug.
  • Percentage change from Baseline in seizure burden by time interval over the 96-hour evaluation period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    Seizure burden will be measured by continuous (multichannel) video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total ENS in minutes per hour) during a period of 2 hours immediately prior to the first administration of study drug.
  • Categorized percentage change from Baseline to the end of the 96-hour Evaluation Period in seizure burden [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    Categories are as follows: <-25% (worsening), -25% to <25% (no change), 25% to <50%, 50% to <80%, and >=80%
  • Percentage of responders to BRV treatment by time interval over the 96-hour evaluation period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    A BRV responder is defined as a subject who achieves the following reduction in seizure burden (electroencephalographic neonatal seizures (ENS) in minutes per hour) without the need for rescue medication, compared to the seizure burden measured during a 2-hour Baseline Period immediately prior to BRV administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV treatment:
    • At least 80% reduction in nonsevere seizure burden (Nonsevere seizure burden is defined as <=50% seizure activity on VEEG in any 30-minute timespan) OR
    • At least 50% reduction in severe seizure burden (Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute timespan)
  • Percentage of subjects who switch over from BRV to another antiepileptic drug (AED) during the 96-hour Evaluation Period [ Time Frame: During the 96-hour Evaluation Period ]
    Subjects can switch over from BRV to another AED [eg, midazolam (MDZ) or phenytoin (PHT)], if needed.
  • Percentage of responders to other treatment from Baseline to the end of the 96-hour Evaluation Period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    A responder to other treatment is defined as at least 80% reduction in nonsevere seizure burden from start of other treatment to end of other treatment or at least 50% reduction in severe seizure burden from the initiation of other treatment to end of other treatment during the 96-hour Evaluation Period
  • Percentage of responders to other treatment by time interval over the 96-hour evaluation period [ Time Frame: From Baseline to the end of the 96-hour Evaluation Period ]
    A responder to other treatment is defined as at least 80% reduction in nonsevere seizure burden from start of other treatment to end of other treatment or at least 50% reduction in severe seizure burden from the initiation of other treatment to end of other treatment during the 96-hour Evaluation Period
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Test the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Newborns With Repeated Electroencephalographic Seizures
Official Title  ICMJE A Multicenter, Open-label, Single-arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Neonates With Repeated Electroencephalographic Seizures
Brief Summary The purpose of the study is to evaluate the pharmacokinetics (PK) of brivaracetam (BRV) in neonates who have seizures that are not adequately controlled with phenobarbital (PB) treatment and to identify the optimal BRV dose (Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts of this study
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Electroencephalographic Neonatal Seizures
Intervention  ICMJE
  • Drug: Brivaracetam (BRV) iv

    Exploratory Cohort:

    Subsequent to one or multiple therapeutic doses of midazolam ([MDZ], dose and dosing frequency of MDZ is at the discretion of the investigator), a low dose of Brivaracetam (BRV) intravenous (iv) solution for injection will be administered. At the discretion of the Investigator, 3 additional iv BRV doses, up to a total of 4 iv BRV doses (0.5mg/kg twice daily [bid]), can be administered during the 48-hour Evaluation Period.

    Confirmatory Cohort:

    During the Evaluation Period, subjects are expected to receive intravenous (iv) BRV bid. The dose and dosing frequency of BRV will be adjusted for the Confirmatory Cohorts based on the analysis of the data collected for the Exploratory Cohort.

  • Drug: Brivaracetam (BRV) oral
    Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period
Study Arms  ICMJE Experimental: Brivaracetam (BRV)
Exploratory Cohort and Confirmatory Cohorts
Interventions:
  • Drug: Brivaracetam (BRV) iv
  • Drug: Brivaracetam (BRV) oral
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 25, 2017)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmation on video-electroencephalography (VEEG) of >= 2 minutes of cumulative electroencephalographic neonatal seizures (ENS), or >=3 identifiable ENS within the 2 hours prior to entering the Evaluation Period, despite receiving phenobarbital (PB) for the treatment of repeated seizures prior to Baseline. The occurrence of ENS during the 2-hour period must be confirmed either by the local or central VEEG reader prior to drug administration. Preferably, the central VEEG reader should confirm the required ENS. If a qualified VEEG reader is available, a local VEEG reader may be used.
  • Subject is male or female with an age at birth of 34 weeks to less than 42 weeks of gestational age (GA) and up to 28 days of postnatal age at the time of enrollment
  • Subject weighs at least 2.3 kg at the time of enrollment
  • Subjects with or without concomitant hypothermia treatment

Exclusion Criteria:

  • Subject received antiepileptic drug (AED) treatment (other than the required 1 to 3 doses of phenobarbital (PB) [total therapeutic administered dose of 20 to 40mg/kg] for the treatment of repeated seizures) prior to entering the Evaluation Period.
  • Subject with seizures responding to PB (total therapeutic administered dose of 20 to 40mg/kg), pyridoxine treatment, or correction of metabolic disturbances (hypoglycemia, hypomagnesemia or hypocalcemia)
  • Subject has a poor prognosis for survival, as judged by the Investigator
  • Subject has 2x upper limit of normal (ULN) of any of the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) with the following exception: For subjects with perinatal asphyxia, elevation of ALT, AST or ALP up to 5 x ULN is acceptable, if initial and peak elevation of liver function tests (LFTs) occurs within 5 days after birth, and if the time course of LFT elevation is compatible with hepatic injury due to perinatal asphyxia. The determinations of ULN will be based on the subject's gestational age (GA) and the site's normal range values for the respective GA
  • Subject requiring or expected to require phototherapy or exchange transfusion due to elevated bilirubin
  • Subject with rapidly increasing bilirubin that may preclude the subject from inclusion in the study at the discretion of the Investigator
  • Subject requires extra corporeal membrane oxygenation
  • Subject has seizures related to prenatal maternal drug use or drug withdrawal
  • Subject has known severe disturbance of hemostasis, as assessed by the Investigator
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 28 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: UCB Cares +1844599 ext 2273 UCBCares@ucb.com
Listed Location Countries  ICMJE Belgium,   Czechia,   France,   Germany,   Ireland,   Italy,   Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03325439
Other Study ID Numbers  ICMJE N01349
2015-002756-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party UCB Pharma ( UCB Biopharma S.P.R.L. )
Study Sponsor  ICMJE UCB Biopharma S.P.R.L.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: UCB Cares UCB (+1 844 599 2273)
PRS Account UCB Pharma
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP