Overview

Status:Not yet recruiting
Keywords:Brivaracetam , Seizures , Neurology
IRB Number:00063920
Specialty:Neurology
Sub Specialty:Seizures

Brief Summary

This is a randomized, double-blind, placebo (PBO)-controlled, multicenter, therapeutic

confirmatory study evaluating 2 active doses of brivaracetam (BRV). The primary objective

is 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 (POS) not

fully controlled despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs).

Secondary objectives are to assess the safety and tolerability of BRV. Exploratory objectives

are to assess the effects of BRV on subjects’ Health-Related Quality of Life (HRQoL), to

obtain a description of the patients’ self-reported health status, and to explore direct medical

resource use.

This study will enroll adults (≥16 years to 80 years) with refractory POS whether or not

secondarily generalized. Subjects under 18 years may only be included 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

levetiracetam (LEV) are excluded from this study. Subjects may be eligible for conversion to

a long-term follow-up (LTFU) study (N01379) upon completion of the Treatment Period. For

subjects not entering the LTFU study, there is a 4-week Down-Titration Period followed by a

2-week Study Drug Free Period.

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.

The primary efficacy variable is the POS (Type I) frequency over the Treatment Period

standardized to a 28-day duration. The primary efficacy outcome for the United States of

America (USA) will be the percent reduction in POS (Type I) frequency over PBO based on

analysis of covariance (ANCOVA). The primary efficacy outcome for European authorities

will be the 50% responder rate based on percent reduction in weekly POS (Type I) frequency

from Baseline to the Treatment Period.

Secondary efficacy variables include the percent reduction in POS (Type I) frequency from

the Baseline to the Treatment Period, categorized percent reduction from Baseline in seizure

frequency for POS (Type I) over the Treatment Period, seizure freedom rate (all seizure

types), all seizure frequency (Type I+II+III) over the Treatment Period, and time to nth (n=1,

5, 10) Type I seizure during the Treatment Period.

Other variables include Patient’s Global Evaluation Scale (P-GES), Investigator’s GES

(I-GES), Patient Weighted Quality of Life in Epilepsy Inventory (QOLIE-31-P) scores,

Hospital Anxiety and Depression Scale (HADS) scores, medical resource use, and

socio-professional data (driver’s license, employment status, etc).

Pharmacokinetic (PK) variables include BRV (parent compound only) plasma levels and

concomitant AED (and/or relevant metabolites) plasma levels.

Safety variables include adverse events (AEs), laboratory tests (blood chemistry, hematology,

urinalysis, and pregnancy test), electrocardiogram (ECG), vital signs, and body weight.

In order to randomize 720 subjects (240 randomized subjects per treatment group),

approximately 900 subjects will be screened assuming a screen failure rate of 20%. It is

planned to have those subjects recruited in about 120 sites.

Principle Investigator: Matthew Sweney
Principle Department: Pediatric Administration
Co Investigator:

Contact Information

Name:Fumiko Alger
Phone:801-213-4180
Email:fumiko.alger@hsc.utah.edu

Inclusion Criteria

  • An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approvedwritten 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.
  • 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.
  • Subjects (male or female) from 16 to 80 years, both inclusive. Subjects under 18 years may only be included where legally permitted and ethically accepted.
  • Subjects with a body weight ≥40kg.
  • 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.

 

  • Well-characterized focal epilepsy/epileptic syndrome according to the 1989 International
  • League Against Epilepsy (ILAE) classification.
  • Presence of an EEG reading compatible with the clinical diagnosis of focal epilepsy within the last 5 years.
  • Presence of a brain MRI/computed tomography (CT) scan performed within the last 2 years.
  • 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.
  • Subjects having at least 2 partial onset seizures whether or not secondarily generalized per month during the 3 months preceding V1.
  • 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.
  • 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

  • Subject previously randomized within this study or any other prior study with BRV as adosing arm.
  • Seizure type IA (1981 ILAE classification) nonmotor as only seizure type.
  • 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).
  • Subject is currently treated with LEV.
  • Subject has taken LEV within 90 days prior to V1.
  • 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.
  • Subject has a known hypersensitivity to any components of the investigational medicinal product or comparative drugs as stated in this protocol.
  • Subject not able to read and understand the informed consent form, assent form, or seizure diary card instructions.
  • Subject has obvious cognitive impairment or mental retardation as per Investigator assessment.
  • Subjects whose seizures could not be reliably counted on a regular basis due to their fast and repetitive occurrence (clusters or flurries).
  • Subject has history or presence of status epilepticus during the year preceding V1 or during Baseline.
  • Subject has history or presence of known psychogenic nonepileptic seizures.
  • Subject on felbamate with less than 18 months exposure before V1.
  • 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.
  • 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.
  • 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.
  • Subject has history of cerebrovascular accident, including transient ischemic attack, in the last 6 months.
  • Subject is suffering from severe cardiovascular disease or peripheral vascular disease
  • 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.
  • 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.
  • Subject has presence of a terminal illness.
  • Subject has presence of a serious infection.
  • Subject has history of severe adverse hematologic reaction to any drug.
  • Subject is suffering from severe disturbance of hemostasis.
  • 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.
  • 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.
  • 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.
  • Subject has clinically significant ECG abnormalities according to the Investigator.
  • Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 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 Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening.
  • Subject has ongoing psychiatric disease other than mild controlled disorder.
  • Subject has known allergic reaction or intolerance to pyrrolidine derivatives and/or investigational product excipients.
  • Subject has known multiple drug allergies or severe drug allergy.
  • Subject is pregnant or lactating woman.
  • Subject has known alcohol or drug addiction or abuse within the last 2 years.
  • 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.