E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Electroencephalographic neonatal seizures |
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E.1.1.1 | Medical condition in easily understood language |
Electroencephalographic neonatal seizures |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- 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 subjects enrolled into the Confirmatory Cohorts of this study |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of brivaracetam (BRV) in severe and nonsevere seizure burden (defined as total minutes of electroencephalographic neonatal seizures [ENS] per hour) in neonates with seizures that are not adequately controlled with previous antiepileptic drug (AED) treatment - To evaluate the short-term safety and tolerability of BRV in neonates |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 CGA. In addition, term neonates up to 27 days of 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 |
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E.4 | Principal exclusion criteria |
- 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Plasma concentration of Brivaracetam (BRV) following first dose on Day 1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
30-60 min, 2 to 4 hours, and 8 to 12 hours after the BRV infusion on Day 1 |
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E.5.2 | Secondary end point(s) |
1. Proportion of responders to brivaracetam (BRV) treatment from Baseline to 3 hours after the initial BRV dose 2. Proportion of subjects with at least 80% reduction in nonsevere seizure burden from Baseline to 3 hours after the initial BRV treatment 3. Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 3 hours after the initial BRV treatment 4. Absolute reduction in average seizure burden measured by continuous video-electroencephalography (VEEG) from Baseline to the end of the 96-hour Evaluation Period 5. Percent reduction in average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour Evaluation Period 6. Proportion of BRV responders at the end of the 96-hour Evaluation Period 7. Proportion of subjects 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 8. Time to reduction in seizure burden for BRV responders 9. Seizure Freedom at the end of Down-Titration Period 10. Percentage of Subjects with at least 50% reduction in electroencephalographic neonatal seizures (ENS) frequency per hour from Baseline to the end of the 96-hour Evaluation Period 11. Proportion of subjects who are seizure-free by time interval over the 96-hour evaluation period following the start of the initial BRV treatment 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 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 14. Adverse Events (AEs) as reported by the Investigator |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. – 3. From Baseline to 3 hours after the initial BRV treatment 4. – 6., 10. From Baseline to the end of the 96-hour Evaluation Period 7. From Baseline to 24 hours after the initial BRV treatment 8. From Baseline to the first timepoint when BRV responder criteria are met 9. From Baseline to the end of the Down-Titration Period (up to 97 days) 11. From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation Period 12., 13. From Baseline to the end of the 24-hour Evaluation Period 14. Adverse Events were collected from Screening Period until the Safety Follow-Up Period (up to 130 days) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last Subject Last Visit (LSLV) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 28 |