This study has the purpose to assess the pharmacokinetic (the science determining the fate of substances administered to the human body), safety and efficacy of brivaracetam (the study drug) in neonates who have seizures that are not adequately…
ID
Source
Brief title
Condition
- Encephalopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 concentrations of BRV on other occasions
5. Plasma concentration of the BRV metabolite ucb-42145 (acid) 30-60 min after
the BRV infusion on day 1
6. Plasma concentration of the BRV metabolite ucb-42145 (acid) 2-4 hours after
the BRV infusion on day 1
7. Plasma concentration of the BRV metabolite ucb-42145 (acid) 8-12 hours after
the BRV infusion on day 1
8. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 30-60 min
after the BRV infusion on day 1
9. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 2-4 hours
after the BRV infusion on day 1
10. Plasma concentration of the BRV metabolite ucb-100406-1 (hydroxy) 8-12
hours after the BRV infusion on day 1
11. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 30-60
min after the BRV infusion on day 1
12. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 2-4
hours after the BRV infusion on day 1
13. Plasma concentration of the BRV metabolite ucb-107092-1 (hydroxyacid) 8-12
hours after the BRV infusion on day 1
14. Area under the BRV plasma concentration time curve
15. Distribution volume of BRV
16. Plasma clearance of BRV
17. Plasma concentration of the concomitant antiepileptic drug phenobarbital
AEDs if administered
Secondary outcome
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. Percent reduction 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
Background summary
The PETITE study is about the drug brivaracetam (study drug). Brivaracetam is
approved in Europe for oral and intravenous use as add-on therapy to other
medication to treat focal seizuresin patients 4 years of age and older. In the
US brivaracetam is approvd as stand-alone and add-on therapy to treat focal
epilepsy, for oral use in patients 4 years of age and older and for oral and
intravenous use in patients 16 years of age and older.
Brivaracetam is not approved for the treatment of newborn children with
electroencephalo-graphic seizures. The purpose of the current study is to
investigate this indication in this population.
An electroencephalographic seizure is an uncontrolled neuronal discharge in any
part of the brain and may be caused by encephalopathy (different syndromes of
bad functioning of the brain). An electroencephalogram (EEG), also called brain
movie, is a test that detects electrical activity in the brain using small,
flat metal discs (electrodes) attached to the scalp. This activity shows up as
wavy lines on an EEG recording. In this study the EEG is coupled in parallel
with a video recorder to align seizures and brain electrical activity.
Study objective
This study has the purpose to assess the pharmacokinetic (the science
determining the fate of substances administered to the human body), safety and
efficacy of brivaracetam (the study drug) in neonates who have seizures that
are not adequately controlled with other treatments, and to identify the best
dose of the study drug.
This study aims to determine the fate of the study drug administered to the
child and to identify the optimal dose of the study drug.
The primary objective of this study is to evaluate the PK of BRV in neonates
who have seizures that are not adequately controlled with previous AED
treatment, and to identify the optimal BRV dose (Exploratory Cohort) for the
treatment of subjects enrolled into the Confirmatory Cohorts
of this study. Secondary objectives include the evaluation of the short-term
safety and tolerability of BRV in neonates and the evaluation of the efficacy
of BRV in severe and nonsevere seizure burden (defined as total minutes of ENS
per hour) in neonates with seizures that are not adequately controlled with
previous AED treatment.
Study design
Screening
The study starts with a Screening Period to see whether the child may
participate in this study. This study is designed with a 2-step approach: to
confirm or adjust the expected dosing in the first step (Exploratory Group),
and to evaluate the efficacy of the study drug in the second step (Confirmatory
Group).
The study drug brivaracetam will be given intravenously (directly into the
vein).
Exploratory group:
In this Exploratory group (first step), the child will be treated with AEDs per
standard of care. Should the standard medication not help controlling seizures,
the child will enter the 48-hour Evaluation Period and receive up to 4 doses of
the study drug. The study drug will be given intravenously (directly into the
vein). The study drug will be dosed at the lower range of the dose used in
children and adult patients. Therefore, treatment effects cannot be guaranteed.
To ensure the child*s seizures are effectively treated during the Evaluation
Period, the administration of AEDs per standard of care will continue.
Confirmatory group:
The child will participate in the Confirmatory Group. This means the child will
be treated in the Screening Period with one or more of the following
anti-epileptic drugs (AEDs) per standard of care for the treatment of neonatal
seizures: phenobarbital (PB), midazolam (MDZ), phenytoin (PHT), levetiracetam
(LEV; at a dose of *60mg/kg/day), or lidocaine (LDC). .
In this Confirmatory group (second, the child will be treated with AEDs per
standard of care. Should the standard medication not help controlling seizures,
the child will enter the 96-hour Evaluation Period and receive the study drug
in intervals of 12 hours at a dose based on the results of the Exploratory
Group.
During the Evaluation Period a continuous video-EEG will be recorded. In case
the child does not need or not benefit from study drug treatment, the study
doctor will propose not to continue the treatment after completion of the
Evaluation Period. An extra safety assessment will be performed 30 days after
final study drug administration then. Depending on the age of the newborn child
at the time of enrollment, and whether or not the child would benefit from
continued study treatment, the individual study duration may be longer.
In case the child does not need or not benefit from study drug treatment, the
study doctor will propose not to continue the treatment after completion of the
Evaluation Period. An extra safety assessment will be performed 30 days after
final study drug administration then. Depending on the age of the newborn child
at the time of enrollment, and whether or not the child would benefit from
continued study treatment, the individual study duration may be longer.
Extension Period
Newborns who benefit from study drug treatment may enter the Extension Period.
Newborns participating in the Extension Period need to stay at the study site
if the study drug is administered intravenously. Newborns able to swallow oral
study drug are allowed to be treated at home.
If the child enters the Extension Period, the route of administration of the
study drug could be replaced by administration of oral solution, if this is
appropriate for the child.
If your study doctor considers at any time that the study drug is not working
for the child, another drug will be used right away, as considered appropriate
by the study doctor.
30 days after final study drug administration an extra safety assessment will
also be performed in this phase. In this case the total study duration could
last up to 75 days.
Follow-up Study
At the end of the current study, all newborns who benefit from study drug
treatment will be offered entry into a Follow-up study, if they meet the
eligibility criteria for that study.
Intervention
brivaracetam 10mg/ml - 5ml vial (sterile solution for intravenous infusion)
brivaracetam 10mg/ml - 300ml oral solution for use
Study burden and risks
Participation in the study could last up to a maximum of 75 days in total.
During that time, the patient will stay at the hospital NICU in first instance.
During the extension period, newborns able to swallow oral study drug are
allowed to be treated at home. Newborns participating in the extension period
need to stay at the study site if the study drug is administered intravenously
or via the enteral route.
For an overview of the risks and benefits associated with participation in this
study, see also the informed consent form.
Allée de la Recherche 60
Brussel 1070
BE
Allée de la Recherche 60
Brussel 1070
BE
Listed location countries
Age
Inclusion criteria
1. An Independent Ethics Committee (IEC)-approved written ICF is signed and
dated by the parent(s) or legal representative(s).
2a. Confirmation on VEEG of *2 minutes of cumulative ENS or *3 identifiable ENS
prior to entering the Evaluation Period (ENS is defined as a seizure lasting
for at least 10 seconds on VEEG), despite receiving previous AED 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.
3. Subject is male or female and must be at least 34 weeks of CGA. In addition,
term neonates up to 27 days of PNA and preterm neonates up to 40 weeks of PMA
and 27 days of PNA can be enrolled.
4. Subject weighs at least 2.3kg at the time of enrollment.
5. Subjects with or without concomitant hypothermia treatment.
Exclusion criteria
1a. Subject receiving AED treatment other than PB, MDZ, PHT, LEV (*60mg/
kg/day), or LDC for the treatment of seizures prior to or at the time of
enrollment (Confirmatory Cohorts only).
2. Subject with seizures responding to previous AED treatment immediately prior
to BRV treatment, pyridoxine treatment, or correction of metabolic disturbances
(hypoglycemia, hypomagnesemia, or hypocalcemia).
3. Subject requires extra corporeal membrane oxygenation.
4. Subject has seizures related to prenatal maternal drug use or drug
withdrawal.
5. Subject has known severe disturbance of hemostasis, as assessed by the
Investigator.
6. Subject has a poor prognosis for survival, as judged by the Investigator.
7a. 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.
8a. Subject has direct (conjugated) bilirubin levels >2mg/dL.
9. Subject requiring or expected to require phototherapy or exchange
transfusion due to elevated bilirubin.
10. Subject with rapidly increasing bilirubin that may preclude the subject
from inclusion in the study at the discretion of the Investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002756-27-NL |
| CCMO | NL60876.078.17 |