Brivaracetam (BRV) is a pyrrolidine derivative currently being investigated for the treatment of epilepsy (Bialer et al., 2010). It is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand (Kenda et al., 2004; Gillard et al., 2011). Preclinical studies demonstrated efficacy in a wide range of animal models of partial-onset (focal) and generalized seizures (Matagne et al., 2008) and a higher affinity (>30-fold) for SV2A in human cerebral cortex compared with levetiracetam (LEV) (Gillard et al., 2011). Pharmacokinetic studies have indicated a bioavailability close to 100% and plasma protein binding of <20% (Rolan et al., 2004). The drug is completely and rapidly absorbed throughout the gastrointestinal tract, an effect that is not altered by food (Sargentini-Maier et al., 2007; Rolan et al., 2008).
Two dose-ranging phase IIb studies (N01193 and N01114) showed that BRV may be efficacious and well tolerated as adjunctive treatment in patients with partial-onset seizures and supported further clinical development (French et al., 2010; van Paesschen et al., 2013). Study N01193 met its primary endpoint, with BRV 50 mg/day demonstrating a statistically significant reduction in baseline-adjusted partial-onset seizure frequency/week over placebo (PBO) (French et al., 2010). In study N01114, although BRV 50 and 150 mg/day showed a numerically greater reduction than PBO in baseline-adjusted partial-onset seizure frequency, the study failed to show statistically significant differences between BRV 50 or 150 mg/day and PBO in the primary efficacy analysis (van Paesschen et al., 2013). In these studies, the incidence of the most common adverse events (AEs) (headache, somnolence, fatigue, nausea, nasopharyngitis, and dizziness) and the proportion of patients discontinuing due to AEs were similar for BRV and PBO (Brodsky et al., 2007; von Rosenstiel & Perucca, 2009).
Development of BRV in patients with epilepsy has continued with three phase III studies. Two were confirmatory, fixed-dose studies (N01252 [NCT00490035] and N01253 [NCT00464269]) in patients with partial epilepsy, and one a flexible-dose safety study (N01254 [NCT00504881]) in patients with partial or generalized epilepsy. Herein, we report the findings of one of these studies, a placebo-controlled fixed-dose study (N01253), which was designed to further evaluate the efficacy, safety/tolerability of BRV as an adjunctive treatment for uncontrolled partial-onset seizures in adults.
- Top of page
- Supporting Information
In this randomized, double-blind, placebo-controlled phase III study, the primary efficacy analysis showed a 12.8% reduction in baseline-adjusted partial-onset seizure frequency per week for BRV 50 mg/day over PBO (p = 0.025). Results, however, were not significant for the lower doses of BRV 5 and 20 mg/day groups (−0.9% and 4.1%, respectively). These findings were mirrored in a post hoc analysis conducted to evaluate the partial-onset seizure frequency standardized to a 28-day period. Statistical significance was demonstrated for the BRV 50 mg/day group (22.0% reduction over PBO; p = 0.004), but not for BRV 5 and 20 mg/day (2.6% and 8.7%, respectively). Standardization of seizure frequency over longer (e.g., 28 days) rather than shorter (e.g., 7 days) periods has been used in several other phase III studies of AEDs in recent years (Ben-Menachem et al., 2007; Gil-Nagel et al., 2009; Halasz et al., 2009; Chung et al., 2010; French et al., 2012; Krauss et al., 2012). Standardizing seizure frequency to 28 days may better characterize treatment effect, as this can be underestimated when standardizing to a shorter duration. Furthermore, the longer time period may allow for normalization of any apparent PBO response.
Consistent with the primary efficacy analysis, the proportion of ≥50% responders was significantly higher for the 50 mg/day group compared with PBO, but not in the BRV 5 and 20 mg/day groups. Median percent reduction from baseline in partial-onset seizure frequency/week results were similar, and four patients (4.0%) in the BRV 50 mg/day group were seizure-free compared with none in the PBO group. Overall, these results demonstrate efficacy for the 50 mg/day BRV dose, and suggest a lesser effect at lower doses.
Results of an exploratory sub-analysis by seizure subtype indicated that in all three groups (simple partial, complex partial, and secondarily generalized) median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically higher for BRV 20 mg/day and BRV 50 mg/day compared with PBO. The difference between BRV and PBO was greatest for secondarily generalized seizures and smallest for complex partial seizures. However, the study was not powered to measure the efficacy of BRV in individual seizure subtypes; analysis of data from more patients is recommended before any further conclusions are drawn.
Across the efficacy variables, results of another sub-analysis by LEV use (LEV-naive, prior LEV, concomitant LEV) showed a greater numerical effect for BRV (20 and 50 mg/day) compared with PBO among patients who had previously received LEV or were LEV-naive at study entry. This observation had been noted in other studies of BRV (Biton et al., 2009; Kwan et al., 2009; French et al., 2010; van Paesschen et al., 2013), suggesting that concomitant LEV may reduce BRV efficacy. The overall incidence of TEAEs in this group did not raise any tolerability concerns (data not shown). However, patient numbers are not sufficient to allow firm conclusions to be drawn. The number of patients with concomitant LEV use at study entry was limited to 20% of the total study population per protocol; a small group of 56 patients received LEV in addition to BRV. A pooled analysis of data from all BRV phase IIb and III studies may be useful to assess this apparent effect in a more robust manner. From a study design perspective, the capacity of concomitant drugs' mechanisms of action to influence outcomes may constitute a potential pitfall.
Two dose-ranging studies (N01114 and N01193) of adjunctive BRV have been completed previously, evaluating doses of 5, 20, 50, and 150 mg/day in patients with uncontrolled partial-onset seizures (French et al., 2010; van Paesschen et al., 2013). In the N01114 study, for BRV 50 and 150 mg/day, the primary efficacy outcome (percent reduction in baseline-adjusted partial-onset seizure frequency/week over PBO during the 7-week maintenance period) had no statistically significant differences between the placebo and the active groups; however, a clear differentiation from PBO was observed at the BRV 50 mg/day dose for several other efficacy outcomes (van Paesschen et al., 2013). In the N01193 study, a clear dose–response effect was observed for BRV, with the 50 mg/day dose demonstrating statistically significant efficacy versus PBO across a range of outcome measures (French et al., 2010). In contrast with the efficacy results shown previously in study N01193 (French et al., 2010), in the current study the 20 mg/day dose did not demonstrate significant improvements in median percent reduction from baseline in partial-onset seizure frequency/week and ≥50% responder rate compared with placebo. It is not unusual in clinical trials for certain doses to demonstrate efficacy in one study but not in another; examples are studies of lacosamide (Ben-Menachem et al., 2007), gabapentin (Sivenius et al., 1991), and carisbamate (Sperling et al., 2010). The variation of results across these studies might be attributed to multiple factors including patient and site selections, accuracy of diagnosis, sample size, and variations in study design.
BRV was generally well tolerated in this study. Only 18 patients of 396 used the fallback option: three patients in the PBO group, compared with four, five, and six patients in the BRV 5, 20, and 50 mg/day groups, respectively. The majority of patients (91.2%) completed the study and entered the open-label extension study (87.6%). The most commonly reported TEAEs in the BRV 50 mg/day group were somnolence, dizziness, headache, fatigue, and insomnia. No clear dose–response effect was observed with regard to tolerability, or among all patients who discontinued from the study. The most common type of TEAEs leading to premature discontinuation was psychiatric disorders, and no dose correlation was demonstrated. Nonpsychotic behavioral AEs, a subgroup of psychiatric disorders that has been previously reported for LEV (e.g., irritability and aggression), appeared to be reported to a lesser extent in the present study of BRV. However, there are no head-to-head studies that can confirm this observation, although a post hoc analysis of nonpsychotic behavioral TEAEs in LEV and BRV trials support this (D'Souza et al., 2012). In addition, there were no clinically significant changes from baseline in laboratory measures, vital signs, and ECG studies. The tolerability results of the current study are comparable to those of the two phase II studies (French et al., 2010; van Paesschen et al., 2013), demonstrating BRV to be well tolerated.
Similar to other studies, a potential limitation of this study is the refractory nature of epilepsy among the patients studied; 16.7% of patients had used five or more AEDs in the last 5 years. It should be noted that information about previous AED use was not collected beyond the last 5 years before study entry. The generalizability of the study results in other populations is also a consideration, as none of the patients enrolled were from Europe. However, there was geographic representation from five countries, including Australia, Canada, and the United States of America. Finally, as in all studies investigating partial-onset seizures, it may be difficult to establish the occurrence of a simple partial-onset seizure; however, this is not likely to have affected the overall trial outcome.
In conclusion, BRV 50 mg/day demonstrated statistically significant improvements compared with PBO across both primary and secondary efficacy endpoints. All BRV doses assessed appeared to be well tolerated without titration, and the completion rate was high.
- Top of page
- Supporting Information
Victor Biton has been an investigator for Xenoport, Medivation, Dainippon, GSK, Genzyme, Astellas/Fujisawa, Myriad, RWJPRI, Insmed, Ortho McNeil, Jazz, Carter Wallace/MedPointe, Parke-Davis, HMR/Sanofi-Aventis, Novartis, IVAX, Abbott, AstraZeneca, Cyberonics, Schwabe, SkyePharma, NPS, Saegis, Eunoe, Genentech, Abbott, J&J, Marinus, Intranasal/Ikano, Ovation/Lundbeck, Schwarz/UCB, Valeant, XTL, Forest, Elan, Icagen, Impax, Janssen, Medivation, Depomed, Vernalis, and Daiichi Sankyo. He has received consulting/lecture fees from Merck, Pfizer, Jazz, Upsher-Smith, Lundbeck, Eisai, Avigen, GSK, Ortho-McNeil, Icagen, UCB/Schwarz, and Valeant. Sam Berkovic's institution has received funding from UCB Pharma for clinical trials and support for travel to study meetings, and from a planned patent for PCDH19 testing. He has received honoraria from UCB Pharma to participate in educational symposia and advisory boards, and unrestricted educational grants for research retreats from UCB Pharma, Novartis, Sanofi-Aventis, and Jansen Cilag. He and his institution were also involved with a patent held by Bionomics Inc for SCN1A testing. Michael Sperling's institution has received clinical trial funding from UCB Pharma; he has received consultancy fees by Upsher-Smith for trial design and payment as associate editor of Epilepsia. Bassel Abou-Khalil's institution has received clinical trial funding from UCB Pharma. Martin Johnson and Sarah Lu are employees of UCB Pharma. We confirm that we have read the Journal's position involved in ethical publication and affirm that this report is consistent with these guidelines.