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

Primary Purpose

Electroencephalographic Neonatal Seizures

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Brivaracetam (BRV) intravenous (iv)

Brivaracetam (BRV) oral

About this trial

This is an interventional treatment trial for Electroencephalographic Neonatal Seizures focused on measuring Electroencephalographic neonatal seizures, Brivaracetam, Epilepsy, ENS, Newborns, Pharmacokinetic

Eligibility Criteria

1 Day - 28 Days (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

N01349 204
N01349 207
N01349 218
N01349 209
N01349 211
N01349 251

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Brivaracetam (BRV)

Arm Description

Exploratory Cohort and Confirmatory Cohorts

Outcomes

Primary Outcome Measures

Plasma concentration of Brivaracetam (BRV) following first dose 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

Percentage of responders to BRV treatment 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.

Percentage of subjects with at least 80% reduction in nonsevere seizure burden 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.

Percentage of subjects with at least 50% reduction in severe seizure burden 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.

Absolute change in average seizure burden measured by continuous VEEG 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.

Percentage change in average seizure burden measured by continuous VEEG 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 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)

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

Seizure freedom is defined as 100 % reduction in seizure burden from Baseline.

Time to reduction in seizure burden for BRV responders

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)

Percentage of Subjects with Seizure Freedom at 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

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.

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

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

Seizures will be measured by continuous 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

Seizures will be measured by continuous video-electroencephalography (VEEG).

Adverse Events (AEs) as reported by the Investigator

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.

Full Information

NCT ID

NCT03325439

First Posted

October 25, 2017

Last Updated

March 10, 2022

Sponsor

UCB Biopharma SRL

1. Study Identification

Unique Protocol Identification Number

NCT03325439

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Terminated

Why Stopped

The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues.

Study Start Date

May 7, 2019 (Actual)

Primary Completion Date

September 3, 2020 (Actual)

Study Completion Date

May 29, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

UCB Biopharma SRL

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Electroencephalographic Neonatal Seizures

Keywords

Electroencephalographic neonatal seizures, Brivaracetam, Epilepsy, ENS, Newborns, Pharmacokinetic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Brivaracetam (BRV)

Arm Type

Experimental

Arm Description

Exploratory Cohort and Confirmatory Cohorts

Intervention Type

Drug

Intervention Name(s)

Brivaracetam (BRV) intravenous (iv)

Other Intervention Name(s)

Briviact

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Brivaracetam (BRV) oral

Other Intervention Name(s)

Briviact

Intervention Description

Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period

Primary Outcome Measure Information:

Title

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

Description

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.

Time Frame

30-60 minutes, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1

Secondary Outcome Measure Information:

Title

Percentage of responders to BRV treatment from Baseline to 3 hours after the initial BRV treatment

Description

Time Frame

From Baseline to 3 hours after the initial BRV treatment

Title

Percentage of subjects with at least 80% reduction in nonsevere seizure burden from Baseline to 3 hours after the initial BRV treatment

Description

Time Frame

From Baseline to 3 hours after the initial BRV treatment

Title

Percentage of subjects with at least 50% reduction in severe seizure burden from Baseline to 3 hours after the initial BRV treatment

Description

Time Frame

From Baseline to 3 hours after the initial BRV treatment

Title

Absolute change in average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour Evaluation Period

Description

Time Frame

From Baseline to the end of the 96-hour Evaluation Period

Title

Percentage change in average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour Evaluation Period

Description

Time Frame

From Baseline to the end of the 96-hour Evaluation Period

Title

Percentage of BRV responders at the end of the 96-hour Evaluation Period

Description

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)

Time Frame

From Baseline to the end of the 96-hour Evaluation Period

Title

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

Description

Seizure freedom is defined as 100 % reduction in seizure burden from Baseline.

Time Frame

From Baseline to 24 hours after the initial BRV treatment

Title

Time to reduction in seizure burden for BRV responders

Description

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)

Time Frame

From Baseline to the first timepoint when BRV responder criteria are met

Title

Percentage of Subjects with Seizure Freedom at the end of the Down-Titration Period

Description

Seizure freedom is defined as 100% reduction in seizure burden from Baseline.

Time Frame

From Baseline to the end of the Down-Titration Period (up to 97 days)

Title

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

Description

Time Frame

From Baseline to the end of the 96-hour Evaluation Period

Title

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

Description

Seizure freedom is defined as 100% reduction in seizure burden from Baseline.

Time Frame

From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation Period

Title

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

Description

Seizures will be measured by continuous video-electroencephalography (VEEG).

Time Frame

From Baseline to the end of the 24-hour Evaluation Period

Title

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

Description

Seizures will be measured by continuous video-electroencephalography (VEEG).

Time Frame

From Baseline to the end of the 24-hour Evaluation Period

Title

Adverse Events (AEs) as reported by the Investigator

Description

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.

Time Frame

Adverse Events were collected from Screening Period until the Safety Follow-Up Period (up to 130 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Day

Maximum Age & Unit of Time

28 Days

Accepts Healthy Volunteers

Eligibility 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

UCB Cares

Organizational Affiliation

UCB (+1 844 599 2273)

Official's Role

Study Director

Facility Information:

Facility Name

N01349 204

City

Leuven

Country

Belgium

Facility Name

N01349 207

City

Lille

Country

France

Facility Name

N01349 218

City

Erlangen

Country

Germany

Facility Name

N01349 209

City

Freiburg

Country

Germany

Facility Name

N01349 211

City

Cork

Country

Ireland

Facility Name

N01349 251

City

Cambridge

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

https://vivli.org/

Learn more about this trial

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

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