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

A Multicenter, Open-Label, Single-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Neonates With Repeated Electroencephalographic Seizures

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.

Study Overview

• Status: Terminated
• Conditions: Electroencephalographic Neonatal Seizures
• Intervention / Treatment: Drug: Brivaracetam (BRV) intravenous (iv); Drug: Brivaracetam (BRV) oral

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • N01349 204
• Czechia
  • Praha, Czechia
    • N01349 205
• France
  • Lille, France
    • N01349 207
  • Paris, France
    • N01349 206
• Germany
  • Erlangen, Germany
    • N01349 218
  • Freiburg, Germany
    • N01349 209
• Ireland
  • Cork, Ireland
    • N01349 211
• Italy
  • Messina, Italy
    • N01349 212
  • Parma, Italy
    • N01349 213
  • Roma, Italy
    • N01349 256
• United Kingdom
  • Cambridge, United Kingdom
    • N01349 251
  • London, United Kingdom
    • N01349 216

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 4 weeks (Child)
• Accepts Healthy Volunteers: No

Description

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 CGA 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 any of the following: 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 1 or more of the following antiepileptic drugs (AEDs): phenobarbital (PB), midazolam (MDZ), phenytoin (PHT), levetiracetam (LEV), or lidocaine (LDC) (first-line, second-line, or subsequent treatment) will continue in parallel with BRV treatment. Confirmatory Cohort: For subjects who enter the Confirmatory Cohorts, for the strength of BRV 1 mg/kg bid (2 mg/kg/day) has been determined based on the Pharmacokinetic (PK) findings of the Exploratory Cohort. Based on further monitoring of PK and safety findings dosing may be adjusted as new data are available. 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 Names: Briviact; Drug: Brivaracetam (BRV) oral; Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period; Other Names: Briviact

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Responders to BRV Treatment From Baseline to 3 Hours After the Initial BRV Treatment	A BRV responder was defined as a participant who achieved 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.	From Baseline to 3 hours after the initial BRV treatment
Percentage of Participants With at Least 80% Reduction in Nonsevere Seizure Burden From Baseline to 3 Hours After the Initial BRV Treatment	Nonsevere seizure burden was defined as <=50% seizure activity on VEEG in all 30-minute timespans. Seizure burden was measured during the Baseline Period immediately prior to BRV administration and evaluated for a 2-hour period starting 1 hour after the start of initial BRV. 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.	From Baseline to 3 hours after the initial BRV treatment
Percentage of Participants With at Least 50% Reduction in Severe Seizure Burden From Baseline to 3 Hours After the Initial BRV Treatment	Severe seizure burden was defined as >50% seizure activity on VEEG in any 30-minute timespan. Seizure burden was measured during the Baseline Period immediately prior to BRV administration and evaluated for a 2-hour period starting 1 hour after the start of initial BRV. 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.	From Baseline to 3 hours after the initial BRV treatment
Absolute Change in Average Seizure Burden Measured by Continuous Video-electroencephalography (VEEG) From Baseline to the End of the 96-hour Evaluation Period	Seizure burden was 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.	From Baseline to the end of the 96-hour Evaluation Period
Percentage Change in Average Seizure Burden Measured by Continuous VEEG From Baseline to the End of the 96-hour Evaluation Period	Seizure burden was measured by continuous video-electroencephalography (VEEG). Baseline seizure burden was 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.	From Baseline to the end of the 96-hour Evaluation Period
Percentage of BRV Responders at the End of the 96-hour Evaluation Period	A BRV responder was defined as a participant 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).	From Baseline to the end of the 96-hour Evaluation Period
Percentage of Participants 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	Seizure freedom is defined as 100 % reduction in seizure burden from Baseline.	From Baseline to 24 hours after the initial BRV treatment
Time to Reduction in Seizure Burden for BRV Responders	A BRV responder was defined as a participant 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).	From Baseline to the first timepoint when BRV responder criteria are met (up to 96-hour Evaluation Period)
Percentage of Participants With Seizure Freedom at the End of the Down-Titration Period	Seizure freedom was defined as 100% reduction in seizure burden from Baseline.	From Baseline to the end of the Down-Titration Period (up to 97 days)
Percentage of Participants With at Least 50% Reduction in Electroencephalographic Neonatal Seizures (ENS) Frequency Per Hour From Baseline to the End of the 96-hour Evaluation Period	For this study, an ENS was defined as an EEG seizure lasting for at least 10 seconds on VEEG. Baseline seizure burden was 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.	From Baseline to the end of the 96-hour Evaluation Period
Percentage of Participants Who Are Seizure-free by Time Interval Over the 96-hour Evaluation Period Following the Start of the Initial BRV Treatment	Seizure freedom was defined as 100% reduction in seizure burden from Baseline.	From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation Period
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	Seizures was measured by continuous video-electroencephalography (VEEG).	From Baseline to the end of the 24-hour Evaluation Period
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	Seizures was measured by continuous video-electroencephalography (VEEG).	From Baseline to the end of the 24-hour Evaluation Period
Percentage of Participants With Adverse Events (AEs) as Reported by the Investigator	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.	Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)

Collaborators and Investigators

• Sponsor: UCB Biopharma SRL
• Investigators: Study Director: UCB Cares, UCB (+1 844 599 2273)

Publications and helpful links

General Publications

• Pressler R, Boylan G, Dempsey E, Klotz KA, Krauwinkel W, Will E, Morita D, Floricel F, Elshoff JP, van den Anker J. Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study. Epilepsia Open. 2024 Apr;9(2):522-533. doi: 10.1002/epi4.12875. Epub 2024 Jan 11.

Helpful Links

• FDA Safety Alerts and Recalls
• Product Information

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2019
• Primary Completion (Actual): September 3, 2020
• Study Completion (Actual): May 29, 2021

Study Registration Dates

• First Submitted: October 25, 2017
• First Submitted That Met QC Criteria: October 25, 2017
• First Posted (Actual): October 30, 2017

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Epilepsy; Newborns; Pharmacokinetic; Electroencephalographic neonatal seizures; Brivaracetam; ENS
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Anticonvulsants; Brivaracetam
• Other Study ID Numbers: N01349; 2015-002756-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial 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 individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, 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.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial 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.
• IPD Sharing 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.Vivli.org 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• 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