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
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 150 sites.
Principal Investigator: Matthew Sweney
Department: Pediatric Administration