E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Electroencephalographic neonatal seizures |
|
E.1.1.1 | Medical condition in easily understood language |
Electroencephalographic neonatal seizures |
|
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 phenobarbital (PB) treatment and to identify the optimum BRV dose
(Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts of this study |
|
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 phenobarbital (PB) treatment
- To evaluate the short-term safety and tolerability of BRV in neonates |
|
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 within the 2 hours prior to
entering the Evaluation Period, despite receiving phenobarbital (PB) for
the treatment of repeated seizures
- Subject is male or female with an age at birth of at 34 weeks to less
than 42 of gestational age (GA) and up to 28 days of postnatal age at the
time of enrollment
- Subject weighs at least 2.3 kg at the time of enrollment
- Subjects with or without concomitant hypothermia treatment |
|
E.4 | Principal exclusion criteria |
Subject received antiepileptic drug (AED) treatment (other than the required 1 or 2 doses of
phenobarbital (PB) [total therapeutic administered dose of 20 to 40mg/kg] for the treatment of repeated
seizures) prior to entering the Evaluation Period.
- Subject with seizures responding to PB (total therapeutic administered dose of 20 to 40mg/kg),
pyridoxine treatment, or correction of metabolic disturbances (hypoglycemia, hypomagnesemia or
hypocalcemia)
- 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), according to the subject’s gestational
age (GA) and the site’s normal range values for the respective GA
- Subject has conjugated bilirubin levels >2mg/dL
- 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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Plasma concentration of brivaracetam (BRV) 30-60 min after the BRV infusion on day 1
2. Plasma concentration of brivaracetam (BRV) 2-4 hours after the BRV infusion on day 1
3. Plasma concentration of brivaracetam (BRV) 8-12 hours after the BRV infusion on day 1
4. Plasma concentration of the BRV metabolite ucb-42145 (acid) 30-60 min after the BRV infusion on
day 1
5. Plasma concentration of the BRV metabolite ucb-42145 (acid) 2-4 hours after the BRV infusion on
day 1
6. Plasma concentration of the BRV metabolite ucb-42145 (acid) 8-12 hours after the BRV infusion on
day 1
7. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 30-60 min after the BRV
infusion on day 1
8. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 2-4 hours after the BRV
infusion on day 1
9. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 8-12 hours after the BRV
infusion on day 1
10. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 30-60 min after the BRV
infusion on day 1
11. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 2-4 hours after the BRV
infusion on day 1
12. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 8-12 hours after the BRV
infusion on day 1
13. Area under the BRV plasma concentration time curve
14. Distribution volume of BRV
15. Plasma clearance of BRV
16. Plasma concentration of the concomitant antiepileptic drug phenobarbital (PB)
17. Plasma concentration of the concomitant antiepileptic drug phenytoin (PHT) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1, 4, 7, 10: 30-60 min after the BRV infusion on day 1
2, 5, 8, 11: 2-4 hours after the BRV infusion on day 1
3, 6, 9, 12: 8-12 hours after the BRV infusion on day 1
13, 14, 15: Samples will be collected 30-60 min, 2-4 hours, and 8-12 hours after the BRV infusion on
day 1 and potentially on day 2 for the exploratory cohort and on day 1 and day 2, or on day 1 and day 3,
or on day 1 and day 4 for the confirmatory cohorts.
16, 17: Samples will be collected 3 hours after the initial dose of BRV |
|
E.5.2 | Secondary end point(s) |
1. Percentage of responders to brivaracetam (BRV) treatment from Baseline to 3 hours after the initial
BRV dose
2. Percentage of subjects with at least 80% reduction in nonsevere seizure burden from Baseline to 3
hours after the initial BRV treatment
3. Percentage of subjects with at least 50% reduction in severe seizure burden 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
5. Percentage change in average seizure burden measured by continuous VEEG 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
7. Percentage of subjects who are seizure-free (100% reduction in seizure burden from Baseline) 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. Percentage of Subjects with 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. Percentage of subjects who are seizure-free by time interval over the 96-hour evaluation period
12. Absolute change of clinical seizures correlated with continuous VEEG from Baseline to the end of
the 96-hour Evaluation Period
13. Absolute change of clinical seizures correlated with continuous VEEG by time interval over the 96-
hour evaluation period
14. Percentage of Subjects with clinical seizures correlated with continuous VEEG from Baseline to the
end of the 96-hour Evaluation Period
15. Percentage of Subjects with clinical seizures correlated with continuous VEEG by time interval over
the 96-hour evaluation period
16. Absolute change from Baseline in clinical seizure burden by time interval over the 96-hour
evaluation period
17. Percentage change from Baseline in clinical seizure burden by time interval over the 96-hour
evaluation period
18. Categorized percentage change from Baseline to the end of the 96-hour Evaluation Period in seizure
burden
19. Percentage of responders to BRV treatment by time interval over the 96-hour evaluation period
20. Percentage of subjects who switch over from BRV to another antiepileptic drug (AED) during the 96-
hour Evaluation Period
21. Percentage of responders to other treatment from Baseline to the end of the 96-hour Evaluation
Period
22. Percentage of responders to other treatment by time interval over the 96-hour evaluation period |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3: From Baseline to 3 hours after the initial BRV dose
4, 5, 6, 10, 12, 14, 16, 17, 18, 19, 21, 22: From Baseline to the end of the 96-hour Evaluation Period
13, 15: At each 3-hour interval from Baseline to the end of the 96-hour Evaluation Period
8: From Baseline to the first timepoint when BRV responder criteria is met
7: From Baseline to 24 hours after the initial BRV treatment
9: From Baseline to the end of the end of the Down-Titration Period
11: From 3 hours following the start of the initial BRV treatment to the end of the 96-hour Evaluation
Period
20: During the 96-hour Evaluation Period |
|
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
|
Last Subject Last Visit (LSLV) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 24 |