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

Study Overview
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Brief Summary
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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.

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

Conditions
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Electroencephalographic Neonatal Seizures

Intervention / Treatment
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* Drug: Brivaracetam (BRV) intravenous (iv)
* Drug: Brivaracetam (BRV) oral


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 28 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brivaracetam (BRV)<br>Exploratory Cohort and Confirmatory Cohorts | Drug: Brivaracetam (BRV) intravenous (iv)<br>* 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.<br>* Other names: Briviact;Drug: Brivaracetam (BRV) oral<br>* Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period<br>* Other names: Briviact;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 30-60 minutes, 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 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. | From Baseline to 3 hours after the initial BRV treatment | 
| 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. | From Baseline to 3 hours after the initial BRV treatment | 
| 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. | From Baseline to 3 hours after the initial BRV treatment | 
| 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. | 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 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. | 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) | From Baseline to the end of the 96-hour Evaluation Period | 
| 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. | From Baseline to 24 hours after the initial BRV treatment | 
| 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) | From Baseline to the first timepoint when BRV responder criteria are met | 
| 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. | From Baseline to the end of the Down-Titration Period (up to 97 days) | 
| 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. | From Baseline to the end of the 96-hour Evaluation Period | 
| 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. | 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 will be 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 will be measured by continuous video-electroencephalography (VEEG). | From Baseline to the end of the 24-hour Evaluation Period | 
| 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. | Adverse Events were collected from Screening Period until the Safety Follow-Up Period (up to 130 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Electroencephalographic neonatal seizures, Brivaracetam, Epilepsy, ENS, Newborns, Pharmacokinetic