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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03325439
Recruitment Status : Suspended (Study recruitment temporarily halted as a precautionary measure due to the COVID-19 pandemic)
First Posted : October 30, 2017
Last Update Posted : April 17, 2020
Sponsor:
Information provided by (Responsible Party):
UCB Pharma ( UCB Biopharma S.P.R.L. )

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 previous antiepileptic drug (AED) treatment, and to identify the optimal BRV dose (Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts of this study.

Condition or disease Intervention/treatment Phase
Electroencephalographic Neonatal Seizures Drug: Brivaracetam (BRV) intravenous (iv) Drug: Brivaracetam (BRV) oral Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open-label, Single-arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Neonates With Repeated Electroencephalographic Seizures
Actual Study Start Date : May 7, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Seizures

Arm Intervention/treatment
Experimental: Brivaracetam (BRV)
Exploratory Cohort and Confirmatory Cohorts
Drug: Brivaracetam (BRV) intravenous (iv)

Exploratory Cohort:

Subjects will be dosed with BRV (0.5 mg/kg twice daily (bid)) according to the sites standard procedures. Treatment with antiepileptic drugs (AEDs) per standard of care (first-line, second-line, or subsequent treatment) will continue in parallel with BRV treatment.

Confirmatory Cohort:

For subjects who enter the Confirmatory Cohorts, the dosing of BRV will be determined based on the Pharmacokinetic findings of the Exploratory Cohort. Administration of BRV is proposed as approximately 15-minute intravenous (iv) infusions. Treatment with previous antiepileptic drugs is permitted to continue if the subject is on a stable dose from 1 hour prior to initiation of the BRV treatment.

Other Name: Briviact

Drug: Brivaracetam (BRV) oral
Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period.
Other Name: Briviact




Primary Outcome Measures :
  1. Plasma concentration of Brivaracetam (BRV) following first dose on Day 1 [ Time Frame: 30-60 minutes, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 ]
    Pharmacokinetic blood samples will be taken 30-60 minutes, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 to determine the BRV plasma concentration.


Secondary Outcome Measures :
  1. Percentage of responders to BRV treatment from Baseline to 3 hours after the initial BRV treatment [ Time Frame: From Baseline to 3 hours after the initial BRV treatment ]

    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 need for rescue medication, compared to the seizure burden measured during the 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 video-electroencephalography (VEEG) in all 30-minute timespans) 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 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.

  2. 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 all 30-minute timespans. Timespans of 30 minutes 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.

  3. 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 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.

  4. 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 video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total electroencephalographic neonatal seizures (ENS) in minutes per hour) during a period of up to 1 hour immediately prior to the first administration of study drug.

  5. 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 video-electroencephalography (VEEG). Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total electroencephalographic neonatal seizures (ENS) in minutes per hour) during a period of up to 1 hour immediately prior to the first administration of study drug.

  6. 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 need for rescue medication, compared to the seizure burden measured during the 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 all 30-minute timespans) 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)

  7. Percentage of subjects who are seizure-free 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.

  8. Time to reduction in seizure burden for BRV responders [ Time Frame: From Baseline to the first timepoint when BRV responder criteria are 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 need for rescue medication, compared to the seizure burden measured during the 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 all 30-minute timespans) 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)

  9. 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 (up to 39 days) ]
    Seizure freedom is defined as 100 % reduction in seizure burden from Baseline.

  10. 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 up to 1 hour immediately prior to the first administration of study drug.

  11. Percentage of subjects who are seizure-free by time interval over the 96-hour Evaluation Period following the start of the initial BRV treatment [ 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.

  12. 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 video-electroencephalography (VEEG).

  13. 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 video-electroencephalography (VEEG).

  14. Adverse Events (AEs) as reported by the Investigator [ Time Frame: Adverse Events were collected from Screening Period until the Safety Follow-Up Period (up to 75 days) ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 28 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmation on video-electroencephalography (VEEG) of >= 2 minutes of cumulative electroencephalographic neonatal seizures (ENS), or >=3 identifiable ENS prior to entering the Evaluation Period, despite receiving previous antiepileptic drug treatment for the treatment of electroencephalographic seizures. The occurrence of ENS during an up to 1-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
  • Subject is male or female and must be at least 34 weeks of corrected gestational age (CGA). In addition, term neonates up to 27 days of postnatal age (PNA) and preterm neonates up to 40 weeks of postmenstrual age (PMA) and 27 days of PNA can be enrolled
  • Subject weighs at least 2.3 kg at the time of enrollment
  • Subjects with or without concomitant hypothermia treatment

Exclusion Criteria:

Subjects are not permitted to be enrolled in the study if any of the following criteria are met:

  • Subject receiving antiepileptic drug (AED) treatment other than phenobarbital, midazolam, phenytoin, levetiracetam (≤60 mg/kg/day), or lidocaine for the treatment of seizures prior to or at the time of enrollment (Confirmatory Cohorts only)
  • Subject with seizures responding to previous AED treatment immediately prior to BRV treatment, pyridoxine treatment, or correction of metabolic disturbances (hypoglycemia, hypomagnesemia, or hypocalcemia)
  • 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
  • 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 AST, ALT or ALP <5x ULN is acceptable, if initial and peak elevation of liver function tests (LFTs) occurs within 5 days after birth, and the time course of LFT elevation is compatible with hepatic injury due to perinatal asphyxia. The determination of ULN will be based on the subject's gestational age (GA) and the site's normal range values for the respective GA
  • Subject has direct (conjugated) bilirubin levels >2 mg/dL
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03325439


Locations
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Belgium
N01349 203
Brussels, Belgium
N01349 204
Leuven, Belgium
Czechia
N01349 205
Praha, Czechia
France
N01349 207
Lille, France
N01349 206
Paris, France
N01349 249
Rouen, France
N01349 208
Tours, France
Germany
N01349 218
Erlangen, Germany
N01349 209
Freiburg, Germany
Ireland
N01349 211
Cork, Ireland
Italy
N01349 212
Messina, Italy
N01349 213
Parma, Italy
Netherlands
N01349 214
Rotterdam, Netherlands
United Kingdom
N01349 251
Cambridge, United Kingdom
N01349 216
London, United Kingdom
Sponsors and Collaborators
UCB Biopharma S.P.R.L.
Investigators
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Study Director: UCB Cares UCB (+1 844 599 2273)
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Responsible Party: UCB Biopharma S.P.R.L.
ClinicalTrials.gov Identifier: NCT03325439    
Other Study ID Numbers: N01349
2015-002756-27 ( EudraCT Number )
First Posted: October 30, 2017    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data from this study may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.clinicalstudydatarequest.com and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal. This plan may change if a determination is made that the data cannot be adequately anonymized.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data from this study may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.clinicalstudydatarequest.com and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
URL: http://www.clinicalstudydatarequest.com

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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
Keywords provided by UCB Pharma ( UCB Biopharma S.P.R.L. ):
Electroencephalographic neonatal seizures
Brivaracetam
Epilepsy
ENS
Newborns
Pharmacokinetic
Additional relevant MeSH terms:
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Seizures
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Brivaracetam
Anticonvulsants