Brivaracetam was found to be a safe and tolerable add-on treatment for uncontrolled epilepsy in adults, in a phase III, randomized, double-blind placebo-controlled trial.
This confirms findings from previous phase II trials of the investigational antiepileptic drug.
The current industry-sponsored study found similar rates of adverse events in the placebo and treatment groups. Efficacy endpoints were secondary in this trial; however, most of these did not reach statistical significance (Epilepsia 2013 Oct. 3 [doi:10.1111/epi.12391]).
Dr. Patrick Kwan, chair of neurology at the University of Melbourne, and his colleagues, recruited 480 adults with focal epilepsy (n = 431) subjects) or generalized epilepsy (n = 49) who were already taking one to three antiepileptic drugs, and randomized them (3:1) to brivaracetam or placebo. A total of 74 outpatient centers in 15 countries enrolled the patients between October 2007 and December 2008.
Doses of brivaracetam could begin at 20 mg/day, with titration up to 150 mg/day during an initial 8-week dose-finding period, after which fixed-dose treatment was continued for another 8 weeks. More than 70% of patients in the treatment group ended up on a dose of 100 mg or higher.
The 16-week study was completed by 90% of patients in the treatment group and 92% in the placebo group. Similar percentages of patients in the treatment (66%) and placebo groups (65%) reported adverse events, most frequently headache, somnolence, and dizziness, mostly in the dose-finding period. Patients with generalized seizures, a group for which treatment options are more limited, tolerated brivaracetam as well as did patients with focal seizures.
In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency per week in the brivaracetam group (n = 323) over the placebo group (n = 108) was 7.3% (P = .125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency per week was 26.9% for brivaracetam, compared with 18.9% for placebo (P = .070).
In the smaller group of patients with generalized seizures, seizure days per week decreased from 1.42 at baseline to 0.63 during the treatment period in the brivaracetam group and from 1.47 at baseline to 1.26 during the treatment period in placebo-treated patients.
One efficacy endpoint that did meet statistical significance was the 50% or higher responder rate in patients with focal seizures, which was 30.3% for the treatment group, compared with 16.7% for the placebo group (P = .006).
Dr. Kwan and his colleagues wrote in their analysis that both the 50% or higher responder rate and median percent reduction from baseline in the treatment group were comparable with findings from a study that evaluated brivaracetam at 50 mg/day and 150 mg/day (Epilepsia 2013;54:89-97), but lower than those reported in another study that investigated dosing up to 50 mg/day (Neurology 2010;75:519-25). The optimal dose "remains to be defined," they wrote.
Brivaracetam is an analogue of the antiepileptic drug levetiracetam, and was shown in preclinical studies to be a far more powerful inhibitor of seizures than levetiracetam. However, Dr. Kwan and his colleagues wrote, "the expected corresponding efficacy benefit was not observed in this study." Another phase III trial is currently in progress to determine the most efficacious dose of brivaracetam.
The investigators acknowledged the flexible dosing design as a limitation of their study, "which may hinder conclusions regarding efficacy." They also noted that the numbers of patients with generalized epilepsy included were small, meaning that any results from that group should be considered exploratory and approached with caution.
The study was funded by UCB Pharma, the manufacturer of brivaracetam. Dr. Kwan disclosed financial relationships with UCB and GlaxoSmithKline and having served on scientific advisory boards for Eisai. Dr. Kwan’s coauthors disclosed consulting, honoraria, or advisory relationships with UCB and many other companies marketing antiepileptic drugs. Two coauthors are employees of UCB.