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

Electroencephalographic Neonatal Seizures Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03325439
• Other study ID #: N01349
• Secondary ID: 2015-002756-27
• Status: Terminated
• Phase: Phase 3
• Start date: May 7, 2019
• Est. completion date: May 29, 2021

Study information

• Verified date: April 2024
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: May 29, 2021
• Est. primary completion date: September 3, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 28 Days

Eligibility

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

Related Conditions & MeSH terms

• Electroencephalographic Neonatal Seizures
• Seizures

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
UCB Biopharma SRL

Countries where clinical trial is conducted

Belgium,  Czechia,  France,  Germany,  Ireland,  Italy,  United Kingdom, 

References & Publications (1)

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-a — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)

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