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

Phase 3TerminatedNCT03325439

UCB Biopharma SRL9 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Electroencephalographic Neonatal Seizures

Interventions

Brivaracetam (BRV) intravenous (iv)DRUG

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.

Brivaracetam (BRV) oralDRUG

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

Eligibility

Sex: ALLMin age: 1 DayMax age: 28 Days

Medical Language ↔ Plain English

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

Locations (12)

N01349 204

Leuven, Belgium

N01349 205

Prague, Czechia

N01349 207

Lille, France

N01349 206

Paris, France

Outcomes

Primary Outcomes

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.

Time frame: 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 Outcomes

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.

Time frame: 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.

Time frame: From Baseline to 3 hours after the initial BRV treatment

Data from ClinicalTrials.gov

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N01349 218

Erlangen, Germany

N01349 209

Freiburg im Breisgau, Germany

N01349 211

Cork, Ireland

N01349 212

Messina, Italy

N01349 213

Parma, Italy

N01349 256

Roma, Italy

...and 2 more locations

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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: From Baseline to 24 hours after the initial BRV treatment

Time to Reduction in Seizure Burden for BRV Responders

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)