Clinical Trial Results:
A Multicenter, Open-Label, Single-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Brivaracetam in Neonates with Repeated Electroencephalographic Seizures
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Summary
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EudraCT number |
2015-002756-27 |
Trial protocol |
IE DE GB BE CZ HU NL FR IT |
Global end of trial date |
29 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jul 2022
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First version publication date |
08 Jul 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
N01349
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03325439 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
UCB Biopharma SRL
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Sponsor organisation address |
Allée de la Recherche 60, Brussels, Belgium, 1070
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Public contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Scientific contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000332-PIP02-17 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Feb 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
29 May 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective was 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 optimum BRV dose (Exploratory Cohort) for the treatment of participants enrolled into the Confirmatory Cohorts of this study.
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Protection of trial subjects |
During the conduct of the study all participants were closely monitored.
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Background therapy |
Background therapy as permitted in the protocol. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
07 May 2019
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Ethical reason | ||
Long term follow-up duration |
3 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Ireland: 5
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Worldwide total number of subjects |
9
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EEA total number of subjects |
9
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
2
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Newborns (0-27 days) |
7
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study started to enroll participants in May 2019 and concluded in May 2021. | ||||||||||||
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Pre-assignment
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Screening details |
No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues. The Participant Flow refers to the All Subjects Screened. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Exploratory Cohort | ||||||||||||
Arm description |
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Brivaracetam
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Investigational medicinal product code |
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Other name |
BRV
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Eligible participants in this arm received BRV 0.5 mg/kg administered as iv solution for injection twice daily (bid) during the 48-hour Evaluation Period.
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Baseline characteristics reporting groups
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Reporting group title |
Exploratory Cohort
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Reporting group description |
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment. | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Exploratory Cohort
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Reporting group description |
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment. | ||
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End point title |
Plasma concentration of Brivaracetam (BRV) following first dose on Day 1 [1] | ||||||||||||||
End point description |
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. The Pharmacokinetic Per-Protocol Set (PK-PPS) consisted of all study participants who provided at least 1 measurable post-Baseline plasma sample (with recorded sampling time) on at least 1 post-Baseline Visit with documented study drug intake times. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. Here, 'n' signifies participants who were evaluable at specified time points.
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End point type |
Primary
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End point 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
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of participants with Adverse Events (AEs) as reported by the Investigator | ||||||||
End point description |
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. The All Study Participants Screened Set consisted of all study participants who had signed the Informed Consent form (ICF) and underwent the study inclusion and exclusion criteria of the current protocol.
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End point type |
Secondary
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End point timeframe |
Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events were collected from Screening Period until the Safety Follow-Up Visit (up to Day 75)
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Adverse event reporting additional description |
Safety analysis was done on All Study Participants Screened Set. Only 6 of 9 participants were treated with BRV. No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Exploratory Cohort
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Reporting group description |
Participants in this arm received brivaracetam (BRV) 0.5 milligram per kilogram (mg/kg) administered as an intravenous (iv) solution for injection twice daily (bid) during the 48-hour Evaluation Period. An additional 3 doses of BRV (0.5 mg/kg) could have been administered every 12 hours for 48 hours (at the discretion of the Investigator). Treatment with antiepileptic drugs (AEDs) per standard of care (SToC) (first-line, second-line, or subsequent treatment) were continued in parallel with BRV treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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10 Oct 2019 |
Global Protocol Amendment 5.0, dated 10 Oct 2019, was a substantial protocol amendment created after 1 eligible study participant had been enrolled in the study. Protocol Amendment 5.0 was implemented through Global Protocol Amendment 6.0.
The primary purpose of this substantial protocol amendment was to implement the changes from the agreed Pediatric Investigation Plan for BRV in order to improve the enrollment rate. The primary change was to remove restrictions in terms of concomitant medication and to simplify electroencephalogram (EEG) requirements; as a result, the primary and secondary objectives were revised. In addition, the age range at enrollment was modified. A brief list of important modifications and changes to this protocol amendment included the following: • Phenobarbital was no longer required as first line treatment prior to BRV and replaced by treatment of electroencephalographic neonatal seizures (ENS) allowed per SToC for the Exploratory Cohort, and 1 or more of the following AEDs: phenobarbital (PB), midazolam (MDZ), phenytoin (PHT), levetiracetam (LEV) (≤60mg/kg/day), or lidocaine (LDC) for the Confirmatory
Cohorts.
• Two hour Baseline EEG and 48-hour VEEG were removed from the Exploratory Cohort; required ENS to be confirmed by the Investigator via local EEG.
• Duration of the 2-hour Baseline Period was shortened to up to 1 hour for the Confirmatory Cohorts and was separated by seizure activity: “at least 1 hour” for study participants with
intermittent ENS and “up to 30 minutes” for study participants in status epilepticus.
• Treatment with “MDZ only” during the first 3 hours of the Evaluation Period was removed from the Confirmatory Cohort; duration of the Evaluation Period hence shortened from
51 hours to 48 hours.
• The initiation of LEV treatment after the first time BRV was introduced was prohibited throughout the study for the Confirmatory Cohorts. |
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24 May 2021 |
Global Protocol Amendment 7.0, dated 24 May 2021, was a substantial protocol amendment implemented after 6 eligible study participants had been enrolled in the study. The primary
purposes of this substantial protocol amendment were as follows: • Specified the BRV dose recommended by the Data Monitoring Committee (DMC) for the Confirmatory Cohorts.
• Incorporated the measures described in UCB’s coronavirus disease 2019 (COVID-19) Contingency Plan for N01349.
• Prolonged the BRV Extension Period for up to 90 days postnatal age (PNA) for sites that may not have been ready to transition study participants to EP0156 at the time that N01266 was closed. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| No eligible study participants were enrolled in the Confirmatory Cohorts. The study stopped prematurely due to enrolment challenges, the termination was not linked to any safety issues. | |||||||
