Clinical trial NCT03325439: 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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Electroencephalographic Neonatal Seizures
Keywords: Electroencephalographic neonatal seizures
Brivaracetam
Epilepsy
ENS
Newborns
Pharmacokinetic
Lead sponsor: UCB Pharma
Sponsor class: INDUSTRY
First posted: 2017-10-30
Enrollment: 9
Sex: ALL
Minimum age (years): 1
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1
timeFrame: 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:
measure: Percentage of Responders to BRV Treatment From Baseline to 3 Hours After the Initial BRV Treatment
timeFrame: From Baseline to 3 hours after the initial BRV treatment
measure: Percentage of Participants With at Least 80% Reduction in Nonsevere Seizure Burden From Baseline to 3 Hours After the Initial BRV Treatment
timeFrame: From Baseline to 3 hours after the initial BRV treatment
measure: Percentage of Participants With at Least 50% Reduction in Severe Seizure Burden From Baseline to 3 Hours After the Initial BRV Treatment
timeFrame: From Baseline to 3 hours after the initial BRV treatment
measure: Absolute Change in Average Seizure Burden Measured by Continuous Video-electroencephalography (VEEG) From Baseline to the End of the 96-hour Evaluation Period
timeFrame: From Baseline to the end of the 96-hour Evaluation Period
measure: Percentage Change in Average Seizure Burden Measured by Continuous VEEG From Baseline to the End of the 96-hour Evaluation Period
timeFrame: From Baseline to the end of the 96-hour Evaluation Period
measure: Percentage of BRV Responders at the End of the 96-hour Evaluation Period
timeFrame: From Baseline to the end of the 96-hour Evaluation Period
measure: 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
timeFrame: From Baseline to 24 hours after the initial BRV treatment
measure: Time to Reduction in Seizure Burden for BRV Responders
timeFrame: From Baseline to the first timepoint when BRV responder criteria are met (up to 96-hour Evaluation Period)
measure: Percentage of Participants With Seizure Freedom at the End of the Down-Titration Period
timeFrame: From Baseline to the end of the Down-Titration Period (up to 97 days)
measure: 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
timeFrame: From Baseline to the end of the 96-hour Evaluation Period
measure: Percentage of Participants Who Are Seizure-free by Time Interval Over the 96-hour Evaluation Period Following the Start of the Initial BRV Treatment
timeFrame: From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation Period
measure: 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
timeFrame: From Baseline to the end of the 24-hour Evaluation Period
measure: 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
timeFrame: From Baseline to the end of the 24-hour Evaluation Period
measure: Percentage of Participants With Adverse Events (AEs) as Reported by the Investigator
timeFrame: Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: N01349 204
city: Praha
country: Czechia
facility: N01349 205
city: Lille
country: France
facility: N01349 207
city: Paris
country: France
facility: N01349 206
city: Erlangen
country: Germany
facility: N01349 218
city: Freiburg
country: Germany
facility: N01349 209
city: Cork
country: Ireland
facility: N01349 211
city: Messina
country: Italy
facility: N01349 212
city: Parma
country: Italy
facility: N01349 213
city: Roma
country: Italy
facility: N01349 256
city: Cambridge
country: United Kingdom
facility: N01349 251
city: London
country: United Kingdom
facility: N01349 216
Study officials:
affiliation: UCB (+1 844 599 2273)
name: UCB Cares
role: STUDY_DIRECTOR
References:
citation: 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.