Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb, randomized, controlled trial

Abstract

SUMMARYPurpose: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV), a novel high-affinity synaptic vesicle protein 2A ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels, in adult epilepsy patients with uncontrolled partial-onset seizures. Methods: A phase IIb, double-blind, randomized, placebocontrolled, parallel-group, dose-ranging study (N01114; NCT00175929) was conducted in patients aged 16-65 years. To be included in the study, patients were required to have experienced four or more partial-onset seizures during a 4-week prospective baseline, despite treatment with 1-2 concomitant antiepileptic drugs. Patients were randomized in a ratio of 1:1:1 to receive BRV 50 mg/day (BRV50), 150 mg/day (BRV150), or placebo. A 3-week uptitration period was followed by a 7-week maintenance period (total treatment period of 10 weeks). Key Findings: A total of 157 patients were randomized (intent-to-treat [ITT] population; BRV50 n = 53, BRV150 n = 52, placebo n = 52) and overall 148 (94.3%) completed the study. The percent reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week maintenance period (primary efficacy outcome) did not reach statistical significance (14.7% for BRV50 [p = 0.093] and 13.6% for BRV150 [p = 0.124]). However, during the entire 10-week treatment period a statistically significant difference was observed for both BRV groups (17.7% for BRV50 [p = 0.026] and 16.3% for BRV150 [p = 0.043]). The median percent reduction from baseline in partial-onset seizure frequency/week during the maintenance period was 38.2% for BRV50 (p = 0.017) and 30.0% for BRV150 (p = 0.113) versus 18.9% in the placebo group. During the treatment period, this was 34.9% for BRV50 (p = 0.004) and 28.3% for BRV150 (p = 0.070) compared with 16.3% for placebo. Fifty percent responder rates during the maintenance period were 23.1% for placebo compared with 39.6% for BRV50 (odds ratio [OR] 2.17, p = 0.077) and 33.3% for BRV150 (OR 1.66, p = 0.261). During the treatment period, 50% responder rates were 17.3% for placebo compared with 35.8% for BRV50 (OR 2.69, p = 0.038) and 30.8% for BRV150 (OR 2.15, p = 0.114). Nine patients were free from partial-onset seizures during the 10-week treatment period (five patients [9.4%] in the BRV50 group and three [5.8%] in the BRV150 group compared with one patient [1.9%] in the placebo group). Treatment-emergent adverse events (TEAEs) reported during the treatment period were mostly mild-to-moderate with similar incidence across treatment groups (BRV50 36/53, 67.9%; BRV150 35/52, 67.3%; placebo 37/52, 71.2%). The most frequently reported TEAEs in BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. Significance: In this double-blind, placebo-controlled, phase IIb study of adjunctive BRV (50 and 150 mg/day) in adults with uncontrolled partial-onset seizures, the primary efficacy analysis did not reach stat...

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial

“…Although there was only a limited group receiving concomitant levetiracetam (<20%), this finding has been reported in other studies (2,3,10,11). These results suggest that using levetiracetam in combination with brivaracetam decreases the effect of brivaracetam.…”

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

“…In patients with photosensitive epilepsy, BRV showed a dose-dependent effect in suppressing or attenuating the photoparoxysmal response (Kasteleijn-Nolst Trenite et al, 2007). Both phase II (French et al, 2010;Van Paesschen et al, 2013) and phase III (Biton et al, 2014;Ryvlin et al, 2014;Klein et al, 2015) placebocontrolled trials have provided evidence for the efficacy, safety, and tolerability of adjunctive BRV for adult patients with partial-onset seizures. BRV was recently approved as adjunctive therapy in the treatment of partial-onset (focal) seizures in patients 16 years of age and older with epilepsy.…”

Adjunctive brivaracetam for patients with refractory partial seizures: A meta-analysis of randomized placebo-controlled trials

“…After the initial title and abstract screen, 23 articles met the criteria for full-text review, of which 18 were excluded. After full-text screening, five completed RCTs satisfied all inclusion criteria for final analysis and included a total of 1639 patients (Biton et al, 2014;Ryvlin et al, 2014;Kwan et al, 2014;Van Paesschen et al, 2013;French et al, 2010). The details of included studies were summarized in Table 1.…”

“…Four trials adapted a fixed-dose procedure, assigning patients to receive BRV in a daily dose of 5 mg, 20 mg, 50 mg, 100 mg, and 150 mg (Biton et al, 2014;Ryvlin et al, 2014;Van Paesschen et al, 2013;French et al, 2010). One trials administered flexible-dose of BRV, ranging from 20 mg/d to 150 mg/d (Kwan et al, 2014) (Table 1).…”