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Electroencephalographic Neonatal SeizuresPhase 3NCT03325439

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

A Phase 3 study testing Brivaracetam (BRV) intravenous (iv) and Brivaracetam (BRV) oral in people with Electroencephalographic Neonatal Seizures, run by UCB Biopharma SRL at 12 sites in 7 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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… Read more about this study

Who is it for?
Ages 1 day to 28 days
What is being tested?
Brivaracetam (BRV) intravenous (iv) and Brivaracetam (BRV) oral
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
12 sitesin 7 countries
Study dates
7 May 2019to 29 May 2021
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 day to 28 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 12Show fewer
  • 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

Trial locations and contacts

12 sites in 7 countries.

12 sites in 7 countries

Italy3 sites
  • N01349 212

    Messina

  • N01349 213

    Parma

  • N01349 256

    Roma

Other trials in Italy

France2 sites
  • N01349 207

    Lille

  • N01349 206

    Paris

Other trials in France

Germany2 sites
  • N01349 218

    Erlangen

  • N01349 209

    Freiburg im Breisgau

Other trials in Germany

United Kingdom2 sites
  • N01349 251

    Cambridge

  • N01349 216

    London

Other trials in United Kingdom

Belgium1 site
  • N01349 204

    Leuven

Other trials in Belgium

Czechia1 site
  • N01349 205

    Prague

Other trials in Czechia

Ireland1 site
  • N01349 211

    Cork

Other trials in Ireland

About this study

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

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.

Being tested
Brivaracetam (BRV) intravenous (iv), Brivaracetam (BRV) oral
Keywords
Electroencephalographic neonatal seizures, Brivaracetam, Epilepsy, ENS, Newborns, Pharmacokinetic
Medical subject headings
Epilepsy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Brivaracetam (BRV) intravenous (iv)Drug

    Also called Briviact

    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

    Also called Briviact

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

Study groups in NCT03325439
Study groupRoleWhat they receive
Brivaracetam (BRV)ExperimentalExploratory Cohort and Confirmatory Cohorts
Receives: Drug: Brivaracetam (BRV) intravenous (iv); Drug: Brivaracetam (BRV) oral

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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 (14)
  1. 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.

    Measured: From Baseline to 3 hours after the initial BRV treatment

  2. 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.

    Measured: From Baseline to 3 hours after the initial BRV treatment

  3. 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.

    Measured: From Baseline to 3 hours after the initial BRV treatment

  4. 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.

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

  5. 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.

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

  6. 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).

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

  7. 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.

    Measured: From Baseline to 24 hours after the initial BRV treatment

  8. 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).

    Measured: From Baseline to the first timepoint when BRV responder criteria are met (up to 96-hour Evaluation Period)

  9. 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.

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

  10. 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.

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

  11. 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.

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

  12. 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).

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

  13. 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).

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

  14. 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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Oct 2017
  2. Study start7 May 2019
  3. Primary completion3 Sep 2020
  4. Study completion29 May 2021

Why it stopped: Terminated (The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues.)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03325439
Sponsor's protocol ID
N01349
Other IDs
2015-002756-27, 2015
Status last verified
Apr 2024
First submitted
25 Oct 2017
Last updated
8 Apr 2024
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • 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.

    PubMed 38049197

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Brivaracetam (BRV) intravenous (iv) and Brivaracetam (BRV) oral in people with Electroencephalographic Neonatal Seizures, run by UCB Biopharma SRL at 12 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in Italy, France, Germany, United Kingdom, Belgium and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma Concentration of Brivaracetam (BRV) Following First Dose on Day 1 (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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03325439, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2024.

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