To evaluate the efficacy of BRV at doses of 100 and 200mg/day compared to PBO as adjunctive treatment in adult focal epilepsy subjects with partial onset seizures not fully controlled despite current treatment with 1 or 2 concomitant AEDsTo assess…
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Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable is the POS (Type I) frequency per 28 days during
the 12-week Treatment Period.
The primary efficacy outcome for the USA will be the percent reduction in POS
(Type I) frequency over PBO based on ANCOVA.
The primary efficacy outcome for European authorities will be the 50% responder
rate based on percent reduction in POS (Type 1) frequency from Baseline to the
12-week Treatment Period.
Secondary outcome
• Percent reduction in POS (Type I) frequency from Baseline to the 12-week
Treatment Period
• Categorized percent reduction in POS (Type 1) frequency from Baseline to the
12-week Treatment Period
• Seizure freedom rate (all seizure types) during the 12-week Treatment Period
• All seizure frequency (Type I + II + III) during the 12-week Treatment Period
• Time to nth (n=1, 5, 10) Type I seizure during the 12-week Treatment Period
Background summary
Epilepsy is one of the most common and challenging neurological disorders. It
has been estimated that over 50 million people are affected worldwide (Engel
and Pedley, 1998; Sander and Shorvon, 1996; Hauser et al, 1993; Loiseau et al,
1990). The prevalence of epilepsy is around 1%. The annual incidence in
developed countries is approximately 50 to 70 cases per 100,000. In developing
countries, the figure is higher due to more limited obstetric services and the
greater likelihood of cerebral infection and trauma. The incidence varies
greatly with age, with high rates occurring in childhood, falling to low levels
in early adult life, but with a second peak in those aged over 65 years. In
many people, particularly children, the condition may remit, although a
significant proportion will have epilepsy lifelong. The disease duration is
often determined by the underlying cause. Sudden unexpected death, a
complication of great concern, occurs in 1 to 5 per 1000 patient years,
particularly if the seizure disorder remains uncontrolled. The treatment for
epilepsy remains difficult, and there is an ongoing medical need for new AEDs.
For a considerable proportion of patients, seizure freedom can still not be
reached with currently available AEDs (Nasreddine et al, 2010; Kwan and Brodie,
2001).
Diagnosis of epilepsy is based on the recurrence of seizures. Seizures may be
caused by an underlying brain disorder or lesion or due to genetic conditions.
Characterization of the epileptic syndrome has profound implications for
treatment and prognosis. The major dichotomy for the diagnosis of epilepsy
being the differentiation between focal epilepsies (ie, related to a focal
brain dysfunction) which are the most frequent and account for approximately 60
to 70% of all cases, and generalized epilepsy syndromes which represent
approximately 25 to 30% of all epilepsy syndromes. In about 10% of cases, other
specific syndromes are classified or the classification remains uncertain.
The classification of epileptic syndromes and seizure types is - and always was
- a matter of ongoing debate. First published in 1960 and last updated
officially in 1981 for seizures and 1989 for epilepsies (Commission on
Classification and Terminology of the International League Against Epilepsy
(ILAE, 1981 and 1989), these ILAE classifications were based on concepts that,
for the most part, predate modern technologies and concepts (Engel, 2006;
International League Against Epilepsy [http://www.ilae-epilepsy.org]). The
availability of these modern techniques, like long-term video
electroencephalograms (EEG) and high-resolution magnetic resonance imaging
(MRI), providing much more precise knowledge in regard to seizure type
classifications and epileptic syndromes, led some epilepsy groups and
scientists towards introducing competing classification systems (like the
Cleveland Clinic Epilepsy Classification) and even debating how useful the
currently used ILAE classification system is at all (Lüders et al, 2006).
This ongoing debate regarding the classification systems for epilepsies and
seizures is also reflected within the latest Report of the Commission on
Classification and Terminology (Classification Task Force) which proposes a
thoroughly revised terminology and concept for the diagnosis of epilepsy
syndromes and also to some extent seizure types (Berg et al, 2010). Despite
this ongoing debate, for the purpose of this study the seizure type
classification will follow the 1981 ILAE classification of epileptic seizures
which speaks of partial seizures, classified as simple partial seizures (no
alteration of consciousness), complex partial seizures (with alteration of
consciousness), and secondarily generalized seizures and on the other hand
defines generalized seizure types, referred to as absence seizures (typical and
atypical), myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic
seizures, and atonic seizures. Apart from myoclonic seizures, consciousness is
almost invariably impaired from the onset of the seizure (Commission on
Classification and Terminology of the ILAE, 1981). Likewise, the classification
of epilepsy syndromes will be used according to the 1989 ILAEpublication
(Commission on Classification and Terminology of the ILAE,1989).
Study objective
To evaluate the efficacy of BRV at doses of 100 and 200mg/day compared to PBO
as adjunctive treatment in adult focal epilepsy subjects with partial onset
seizures not fully controlled despite current treatment with 1 or 2 concomitant
AEDs
To assess the safety and tolerability of BRV.
Study design
This is a randomized, double-blind, PBO-controlled, multicenter, therapeutic
confirmatory study evaluating 2 active doses of BRV. The subject population
will be adults (>=16 years to 80 years) with refractory POS whether or not
secondarily generalized. Subjects under 18 years may be included only where
legally permitted and ethically accepted. Subjects will complete an 8-week
prospective Baseline Period, followed by a 12-week Treatment Period. Subjects
receiving concomitant LEV are excluded from this study. Subjects may be
eligible for conversion to a LTFU study (N01379) upon completion of the
Treatment Period. There is a 4-week Down-Titration Period followed by a 2-week
Study Drug Free Period for subjects not entering the LTFU study.
A 1:1:1 central randomization (random permuted blocks) stratified for country,
LEV use (LEV naïve versus prior LEV use only), and number of AEDs previously
used but discontinued prior to study entry (<=2 versus >2 AEDs) will be used to
ensure the balance across treatment groups (PBO, BRV 100mg/day, BRV 200mg/day)
within each combination of stratification levels. Randomization will not be
stratified by study center due to the expected small number of randomized
subjects per study center.
No restrictions are placed on the proportion of randomized subjects within each
stratification level, either overall or on a regional basis.
At UCB Clinical Trial Supply, kit numbers will be allocated according to the
package list generated by a validated program by UCB. This list will be
provided to the Interactive Voice Response System (IVRS).
Concomitant LEV is exclusionary. Furthermore, LEV use within 90 days prior to
study entry
(Visit 1) is not allowed.
Intervention
Oral film-coated tablets of BRV 10mg, BRV 25mg, BRV 50mg, and matching PBO
tablets to oral film-coated 10mg, 25mg, and 50mg BRV tablets will be used in
this study. The tablets of BRV (10mg, 25mg, 50mg) or matching PBO will be
packaged in blister cards that are cross-designed in such a way as to keep the
blind.
After an 8-week Baseline Period and once the subject has fulfilled the
eligibility criteria, he/she will be randomized to enter the double-blind
Treatment Period (V3 to V7), which will last 12 weeks.
During the Treatment Period, subjects will be treated with BRV 100mg/day, BRV
200mg/day, or matching PBO, in a double-blinded manner. Study medication should
be given as 2 equally divided doses administered twice daily. The first intake
of newly dispensed study medication should occur in the evening of the day of
the visit. Subjects should take tablets according to instructions provided by
Investigator.
At the end of the Treatment Period (V7), the subject will either enter the LTFU
study N01379 or down-titrate. Subjects who continue treatment will enter the
LTFU study at a dose of BRV 150mg/day.
The Down-Titration Period (4 weeks) will consist of the following:
• For subjects randomized to 100mg/day, the Down-Titration Period will consist
of the following: 1 week at 50mg/day, 1 week at 20mg/day, followed by 2 weeks
of PBO.
• For subjects randomized to 200mg/day, the Down-Titration Period will consist
of the following: 1 week at 150mg/day, 1 week at 100mg/day, 1 week at 50mg/day,
followed by 1 week at 20mg/day.
The down-titration procedure needs to be applied in case of early
discontinuation.
Study burden and risks
After taking the medication, you might experience one or more side effects or
discomforts. The most common side effects from taking brivaracetam include:
somnolence (sleepiness), dizziness, insomnia (difficulty and/or lack of sleep),
constipation, and blurred vision. Also you may experience vertigo (dizziness
characterized by a sensation of whirling motion), headache, nausea (stomach
upset), vomiting, abdominal pain (stomach pain), diarrhea, dry mouth,
toothache, asthenia (lack or loss of strength and energy), fatigue (feeling
tired), feeling drunk, gait disturbance (balance or walk disorder), infections
(e.g. nasopharyngitis , upper respiratory and/or urinary), anorexia ( decreased
appetite), back pain, muscle pain, pain in extremities, balance disorder,
abnormal coordination, diplopia (double vision), postural dizziness (related to
changes in position), nystagmus (uncontrollable and rapid movement of the
eyeball in any direction) paraesthesia (numbness), tremor (shakiness),
depression (feelings of sadness/low mood), euphoric (excessively
happy/elevated) mood, nervousness, irritability, dysmenorrhoea (abnormally
difficult or painful menstruation ) , cough, nasal congestion,
pharyngolaryngeal pain, throat irritation, pruritus (itching ), hypotension
(low blood pressure), orthostatic hypotension ( low blood pressure related with
changes in position) , neutropenia / neutrophil count decreased( decrease of
white blood cell number). Some of the side effects may be more frequent when
first starting the medicine. Some of the side effects may bother you when
operating a machine. Harm to an unborn child.
An increased risk of suicide and suicidal thoughts has been seen in people who
take these types of medications.
If you decide to participate, you will be asked to come back to see your study
doctor for at least 7 visits and a maximum of about 9 visits. The total
duration of the study is approximately 26 weeks.
At each visit, your study doctor will make sure that you meet all study
requirements and decide if you may continue in the study. After a first visit
(Screening visit) at which all the necessary information about your health is
collected and scheduling of the different examinations arranged, you will be
asked to return once a month for Visits 2 and 3. You will start the study
medicine on the evening of Visit 3.
Your study doctor will supply you with the study medicine in the form of
tablets to take by mouth. You will have to take 2 tablets in the morning and 2
tablets in the evening. At each visit, your study doctor will give you enough
tablets to last to the next visit and he/she will give you clear instructions
about how to take them. The study medication must be taken ONLY by the person
for whom it was prescribed.
You will be contacted by phone 1 week after starting study medicine. You will
be asked to return 1 week later for Visit 4 and then 2 weeks later for Visit
5. You will be asked to return once a month for Visits 6 and 7.
After Visit 7, your study doctor may suggest that you enter a long-term
follow-up study (all patients in this long-term follow-up study will receive
brivaracetam) and continue with regular visits, but you may decide together
with your study doctor to stop the study medicine. For your own safety and
comfort, stopping the medicine will be done gradually over 4 weeks if you
choose not to enter the long-term follow-up study. You should never stop the
medicine abruptly (quickly). During the 4 week period, you will take 3 tablets
in the morning and 3 tablets in the evening. You will be asked to return at
the end of the 4 week period of gradually coming off the study medicine.
Finally, you will be asked to return 2 weeks after taking the last tablets for
a final check on your health.
During this study, you will have physical and neurological examinations
conducted at Visit 1 and 3 and at the end of the study. Your blood pressure and
pulse rate will be measured at each visit. Your height will be measured as
Visit 1. You will be weighed at all visits.
An electrocardiogram (ECG), which is a recording of the heart activity, will be
done at Visit 1, Visit 4, Visit 5, and at Visit 7 or when you decide to stop
the study medicine, and possibly at the end of the study.
Urine samples will be obtained a maximum of eight times during the study for
standard safety tests. Additional urine samples may be required if any repeat
tests need to be performed.
Blood samples (maximum 21ml per blood sampling) will be taken a maximum of 8
times during the study for standard safety tests, to measure the amount of
brivaracetam and to measure the amount of other antiepileptic drugs in your
body. Additional blood samples may be required if any repeat tests need to be
performed for standard safety tests. The total amount of blood that will be
taken for the entire study is about 170ml.
If you have not had one within the last 5 years, a routine electroencephalogram
(EEG, which is a tracing of brain activity) will be done between Visit 1 and 3,
to check the electrical activity of your brain. A brain scan (either Computed
Tomography (CT) or Magnetic Resonance Image (MRI) which are both tests that
produce pictures of the brain) will also be done between Visits 1 and 3, if you
have not had one within the last 2 years.
You will be asked to keep a daily diary to record all the seizures that you
have and other information about your health during the study. Your study
doctor will ask you how you are feeling and whether you are having any
problems, at each of your visits. At 2 visits, you will be asked to complete 2
health-related questionnaires and at 1 of those visits you are also asked to
complete an evaluation scale.
Arco Corporate Drive, Suite 100 8010
Raleigh NC 27617
US
Arco Corporate Drive, Suite 100 8010
Raleigh NC 27617
US
Listed location countries
Age
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved
written informed consent form is signed and dated by the subject or by the parent(s) or
legal representative. The consent form or a specific assent form, where required, will be
signed and dated by minors.
2. Subject/legal representative is considered reliable and capable of adhering to the protocol
(eg, able to understand and complete diaries), visit schedule, or medication intake
according to the judgment of the Investigator.
3. Subjects (male or female) from 18 to 80 years, both inclusive.
4. Subjects with a body weight >=40kg.
5. Female subjects without childbearing potential (premenarcheal, postmenopausal for at
least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are
eligible. Female subjects with childbearing potential are eligible if they use a medically
accepted contraceptive method. Oral or depot contraceptive treatment with at least 30µg
ethinylestradiol per intake [or 50µg ethinylestradiol per intake if associated with any
strong enzyme inducer (eg carbamazepine, phenobarbital, primidone, phenytoin,
oxcarbazepine, St. John*s Wort, rifampicin)], monogamous relationship with
vasectomized partner, or double-barrier contraception are acceptable methods. The
subject must understand the consequences and potential risks of inadequately protected
sexual activity, be educated about and understand the proper use of contraceptive
methods, and undertake to inform the Investigator of any potential change in status.
Abstinence will be considered as an acceptable method of contraception if the
Investigator can document that the subject agrees to be compliant.
6. Well-characterized focal epilepsy/epileptic syndrome according to the 1989 International
League Against Epilepsy (ILAE) classification.
7. Presence of an EEG reading compatible with the clinical diagnosis of focal epilepsy
within the last 5 years.
8. Presence of a brain MRI/computed tomography (CT) scan performed within the last
2 years.
9. Subjects having at least 8 Type I seizures [POS; focal seizures (according to the 1981
ILAE classification)] during the 8-week Baseline Period with at least 2 Type I seizures
during each 4-week interval of the Baseline Period.
10. Subjects having at least 2 partial onset seizures whether or not secondarily generalized
per month during the 3 months preceding V1.
11. Subjects being uncontrolled while treated by 1 or 2 permitted concomitant AED(s). Vagal
Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED.
12. Permitted concomitant AED(s) and VNS being stable and at optimal dosage for the
subject from at least 1 month (3 months for phenobarbital, phenytoin, and primidone)
before V1 and expected to be kept stable during the Baseline and Treatment Period.
Benzodiazepine taken more than once a week (for any indication) will be considered as a
concomitant AED.
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject previously randomized within this study or any other prior study with BRV as
a dosing arm.
2. Seizure type IA (1981 ILAE classification) nonmotor as only seizure type.
3. Subject has participated in another study of an investigational medication (or a
medical device) within the last 30 days or is currently participating in another study of
an investigational medication (or a medical device).
4. Subject is currently treated with LEV.
5. Subject has taken LEV within 90 days prior to V1.
6. Subject has any medical or psychiatric condition that, in the opinion of the
Investigator, could jeopardize or would compromise the subject*s ability to participate
in this study.
7. Subject has a known hypersensitivity to any components of the investigational
medicinal product or comparative drugs as stated in this protocol.
8. Subject not able to read and understand the informed consent form, or
seizure diary card instructions.
9. Subject has obvious cognitive impairment or mental retardation as per Investigator
assessment.
10. Subjects whose seizures could not be reliably counted on a regular basis due to their
fast and repetitive occurrence (clusters or flurries).
11. Subject has history or presence of status epilepticus during the year preceding V1 or
during Baseline.
12. Subject has history or presence of known psychogenic nonepileptic seizures.
13. Subject on felbamate with less than 18 months exposure before V1.
14. Subject currently on vigabatrin. Subject with history of vigabatrin use but either no
visual fields examination report available including standard static (Humphrey or
Octopus) or kinetic perimetry (Goldman) or results of these examinations are
abnormal.
15. Subject taking any drug with possible central nervous system (CNS) effects except if
stable from at least 1 month before V1 and expected to be kept stable during the
Treatment Period.
16. Subject taking any drug that may significantly influence the metabolism of BRV
cytochrome P450 (potent inducers) except if the dose has been kept stable at least
1 month before V1, and is expected to be kept stable during the Treatment Period.
17. Subject has history of cerebrovascular accident, including transient ischemic attack, in
the last 6 months.
18. Subject is suffering from severe cardiovascular disease or peripheral vascular disease
19. Subject has presence of any sign (clinical or imaging techniques) suggesting rapidly
progressing (ie, not expected to stay stable during study participation) brain disorder
or brain tumor. Stable arteriovenous malformations, meningiomas, or other benign
tumors may be acceptable.
20. Subject has any clinical conditions (eg, bone marrow depression, chronic hepatic
disease, and/or severe renal impairment) which impair reliable participation in the
study or necessitate the use of medication not allowed by protocol.
21. Subject has presence of a terminal illness.
22. Subject has presence of a serious infection.
23. Subject has history of severe adverse hematologic reaction to any drug.
24. Subject is suffering from severe disturbance of hemostasis.
25. Subject has impaired hepatic function: ALT/SGPT (alanine aminotransferase/serum
glutamic pyruvate transaminase), AST/SGOT (aspartate aminotransferase/serum
glutamic oxaloacetic transaminase), alkaline phosphatase of more than 2 times the
upper limit of the reference range.
26. Gamma-glutamyltransferase (GGT) values of more than 3 times the upper limit of the
reference range. A result of GGT exceeding 3 times the upper limit can only be
accepted if attributable to hepatic enzyme induction caused by concomitant
antiepileptic treatment and other hepatic enzymes are below 2 times the upper limit of
the reference range.
27. Subject has clinically significant deviations from reference range values for laboratory
parameters: creatinine clearance calculated <30mL/min, platelets <100,000/µL, or
neutrophil cells <1,800/µL.
28. Subject has clinically significant ECG abnormalities according to the Investigator.
29. Subject has a lifetime history of suicide attempt (including an active attempt, interrupeted attempt or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (yes") to either Question 4 or 5 of the Columbia-Suicide Severity Rating Scale at screening
30. Subject has ongoing psychiatric disease other than mild controlled disorder.
31. Subject has known allergic reaction or intolerance to pyrrolidine derivatives and/or
investigational product excipients.
32. Subject has known multiple drug allergies or severe drug allergy.
33. Subject is pregnant or lactating woman.
34. Subject has known alcohol or drug addiction or abuse within the last 2 years.
35. Investigators, co-Investigators, their spouses or children, or any study collaborators. If
the Investigator has any other doubts concerning the eligibility, he/she should consult
UCB Study Physician or representative for clarification.
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 | EUCTR2010-019361-28-NL |
| ClinicalTrials.gov | NCT01261325 |
| CCMO | NL34940.068.11 |