FULL-LENGTH ORIGINAL RESEARCH SUMMARY. * Patrick Kwan, Eugen Trinka, Wim Van Paesschen, Ivan Rektor, #Martin E. Johnson, and **Sarah Lu

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1 FULL-LENGTH ORIGINAL RESEARCH Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial * Patrick Kwan, Eugen Trinka, Wim Van Paesschen, Ivan Rektor, #Martin E. Johnson, and **Sarah Lu SUMMARY Dr Patrick Kwan is Professor of Neurology at the University of Melbourne, Australia. Purpose: To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. Methods: This was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT ) in adults (16 70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). Key Findings: A total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/ week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the 50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the 50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. Significance: Adjunctive BRV given at individualized tailored doses ( mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures. KEY WORDS: Brivaracetam, Epilepsy, Seizures, Antiepileptic drug, Synaptic vesicle protein 2A. 38

2 39 Brivaracetam Flexible-Dose Trial Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A (SV2A) ligand (Kenda et al., 2004). BRV has shown efficacy in a wide range of animal models of focal and generalized seizures (Matagne et al., 2008). The safety, tolerability, and efficacy of adjunctive BRV in patients with uncontrolled focal epilepsy were investigated in two placebo (PBO) controlled phase IIb studies. In both studies, BRV was well tolerated, and >90% of patients randomized to BRV completed treatment (Brodsky et al., 2007; French et al., 2010; van Paesschen et al., 2013). In the N01193 study, which investigated BRV at 5, 20, and 50 mg/day, the highest dose group demonstrated a statistically significant reduction in seizure frequency/week over PBO. Higher responder rates (patients with 50% seizure reduction) were observed for all dose groups versus PBO, with a clear dose-response relationship (French et al., 2010). The N01114 study investigated BRV at 50 and 150 mg/day doses. Both doses showed numerically greater reductions in baseline-adjusted focal seizure frequency over PBO; however, the primary efficacy end point did not reach statistical significance for either BRV dose (van Paesschen et al., 2013). To further evaluate BRV as an adjunctive therapy for epilepsy, three phase III studies have been completed, two of which (N01253 and N01252) used a fixed-dose design and included patients with focal epilepsy only (Werhahn et al., 2010). The primary objective of this study (N01254) was to confirm the safety and tolerability of adjunctive BRV in patients with a broad range of epilepsies. Individualized tailored doses of BRV were used to more closely reflect reallife clinical practice, and the study also enrolled a small group of patients with generalized epilepsy in addition to those with focal epilepsy. Efficacy against focal seizures was investigated as a secondary objective, and efficacy against generalized seizures was investigated as an exploratory objective. As results of the prior phase IIb studies demonstrated good tolerability for BRV even at the highest doses evaluated, but no clear efficacy difference between 50 and 150 mg/day (French et al., 2010; van Paesschen et al., Accepted August 22, 2013; Early View publication October 3, *Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Departments of Medicine and Neurology, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Neurology, Christian-Doppler-Klinik, Paracelsus Medical University, Salzburg, Austria; Department of Neurology, University Hospital Gasthuisberg, Leuven, Belgium; First Department of Neurology, St. Anne s University Hospital, School of Medicine, and Central European Centre for Technology (CEITEC), Masaryk University, Brno, Czech Republic; #UCB Pharma, Biostatistics US Group, Raleigh, North Carolina, U.S.A.; and **UCB Pharma, CNS, Raleigh, North Carolina, U.S.A. Address correspondence to Patrick Kwan, Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. patrickkwan@cuhk.edu.hk Wiley Periodicals, Inc International League Against Epilepsy 2013), the present study was designed to gather further data on the higher doses used in the phase IIb studies. Methods Study design This was a phase III, prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial (N01254; clinicaltrials.gov identifier NCT ) performed between October 2007 and December 2008 in outpatient settings. Patients were recruited from 74 centers in 15 countries (Austria, Belgium, Czech Republic, Germany, Hong Kong, India, Italy, Norway, Republic of South Africa, Russian Federation, Singapore, South Korea, Sweden, Taiwan, and Ukraine). The study comprised a 4-week prospective baseline period and 16-week treatment period (8-week dose-finding and 8-week maintenance), followed by down-titration or entry into long-term follow-up (Fig. 1). Patients were randomized 3:1 in random permuted blocks to BRV or PBO at the end of the baseline period. Randomization was stratified by epilepsy type (focal or generalized) (International League Against Epilepsy, 1989), concomitant levetiracetam (LEV) use (yes or no), and geographic region. Similar to a previous doubleblind study involving patients with both types of epilepsy (Brodie et al., 2007), the number of patients with generalized epilepsy was limited to 20% of the patients randomized to allow exploratory assessment of BRV in this population, while it studied a sufficient number of patients with focal seizures at the same time. The number of patients receiving LEV, another SV2A ligand, was also limited to 20%. The study drug was administered twice daily in equal doses (b.i.d.). During the dose-finding period, BRV was initiated at 20 mg/day and uptitrated in a stepwise manner to 50, 100, or 150 mg/day, at 2-week intervals based on the investigator s assessment of efficacy and tolerability. Patients randomized to the PBO group received matching PBO tablets. Reduction to the next lowest dose level was allowed once during the dose-finding period for patients receiving BRV >20 mg/day or matching PBO. Patients remained on the dose received at the end of the dose-finding period during the maintenance period. Patients who completed the maintenance period and were judged by the investigator to be benefiting from study treatment were given the option of entering one of the long-term open-label follow-up studies (N01125 [NCT ] or N01199 [NCT ]). If a patient chose not to enter one of these studies, or in case of early withdrawal because of lack of seizure control or adverse events (AEs), the study drug was withdrawn over 1 3 weeks. Patient population Adults aged years with focal or generalized epilepsy uncontrolled on 1 3 antiepileptic drugs (AEDs)

3 40 P. Kwan et al. Figure 1. Study design. *Dose escalation to the next higher dose at investigator s discretion during the dose-finding period up to visit 6 included. One fallback to the immediate lower dose level allowed during the dose-finding period for patients taking doses above 20 mg/day BRV or matching PBO. Once the fallback option had been used, it was not possible to resume the previous dose. BRV, brivaracetam; DL, dose level; PBO, placebo. Epilepsia ILAE were enrolled in this study. Doses of concomitant AEDs remained unchanged for the duration of the study. Patients were included if they experienced 2 focal seizures/month (with or without secondary generalization) or 2 days with primary generalized seizures/month in the 3 months prior to screening, and 4 focal seizures or generalized seizure (any type) days during the 4-week baseline period. Patients treated with stable vagus nerve stimulation were allowed to participate. Patients with nonmotor seizures as the only seizure type or psychogenic nonepileptic seizures were excluded. Other main exclusion criteria are provided in Table S1. Standard protocol approvals, registrations, and patient consents This study was conducted in accordance with the International Conference on Harmonization notes for guidance on good clinical practice and the principles that have their origin in the Declaration of Helsinki. The study was approved by institutional review boards, and written informed consent was obtained from all patients before screening. Safety and tolerability assessments The predefined primary objective of the study was to confirm the safety and tolerability of adjunctive BRV. AEs and serious adverse events (SAEs), their severity and relationship to the treatment, discontinuations due to AEs, and any deaths were recorded by the investigators. Vital signs, physical and neurologic examinations, blood chemistry, hematology, urinalysis, and electroencephalography (ECG) findings were also recorded. Efficacy assessments The secondary objective of the study was to assess the efficacy of BRV against focal seizures. The date and number of seizures were recorded using a daily record card and were used to calculate the percent reduction in baselineadjusted focal seizure frequency/week for BRV over PBO (main efficacy end point). Other efficacy end points were the median percent reduction from baseline in focal seizure frequency/week, 50% responder rate in focal seizure frequency/week, seizure freedom rate (defined as the proportion of patients who completed the treatment period and had a complete seizure diary without reporting any seizures), and time to nth focal seizure (predefined as the time to first, fifth, and 10th focal seizure). Given the small number of patients with generalized epilepsy to be enrolled, efficacy of BRV against generalized seizures was explored descriptively. The exploratory outcomes included number of days with generalized seizures/week, median percent reduction from baseline in days with generalized seizures/week, and 50% responder rate in days with generalized seizures/ week. Statistical methods The intent-to-treat (ITT) population comprised all randomized patients who took 1 dose of study drug. This population was used for reporting all safety and tolerability end points. A subset of the ITT population, ITT focal, comprising all subjects in the ITT population with focal seizures, was used for reporting efficacy end points for focal epilepsy. Likewise, the subset ITT generalized comprised all subjects in the ITT population with generalized seizures and was used for reporting efficacy end points for generalized epilepsy. To allow for valid statistical assessments of efficacy data for focal seizures, the sample size calculation was based on the end point of reduction in focal seizure frequency/week. The sample size calculation was informed from a previous phase IIb trial, which tested BRV at a similar dose range and reported a 16.3% reduction over PBO in

4 41 Brivaracetam Flexible-Dose Trial baseline-adjusted focal seizure frequency/week for BRV 150 mg/day (van Paesschen et al., 2013). In this study, at a significance level of 0.05 with 80% power, it was estimated that a sample size of 376 (randomized 3:1 BRV:PBO) was required to detect a statistically significant difference of on the natural log-transformed scale, which corresponds to a 16% reduction over PBO in baseline-adjusted focal seizure frequency/week. It was planned to include 20% patients with generalized epilepsy; therefore, a total of 470 patients were to be randomized. No inferential statistical analysis was planned for the safety and tolerability results. The main efficacy analysis was based on parametric analysis of covariance (ANCOVA) with log-transformed treatment period focal seizure frequency adjusted over 7 days as the outcome, and included terms for treatment and stratification factors (concomitant LEV use and geographic region). The log-transformed baseline focal seizure frequency was used as a continuous covariate. Treatment effects were characterized using percent reduction over PBO after back-transformation of least squares means (LSMs) from the ANCOVA. Statistical comparisons for percent reduction from baseline in focal seizure frequency/week were based on the Wilcoxon-Mann-Whitney test. Statistical comparisons for 50% responder rate were based on a logistic regression model, with an effect for treatment and log-transformed baseline focal seizure frequency/week as a continuous covariate. Statistical comparisons for seizure freedom rates were performed using the Fisher s exact test. Time to nth seizure was analyzed by Cox-proportional-hazards model, adjusting for log-transformed baseline focal seizure frequency and stratification variables. A nonparametric ANCOVA was carried out to assess the robustness of the results of the parametric analysis. For each individual treatment group comparison, a regression of focal seizure frequency during the treatment period versus the baseline period was performed. A Mantel-Haenszel test was then used to assess the difference in raw-mean scores. Results Patients Of 543 patients who were screened, 480 were randomized to BRV (n = 359) and PBO (n = 121) and were included in the ITT population. In this population, 431 (89.8%) patients had focal epilepsy and 49 (10.2%) patients had generalized epilepsy. In total, 434 patients (BRV n = 323/359, 90.0%; PBO n = 111/121, 91.7%) in the ITT population completed the study (Fig. 2). Similar proportions of patients in the ITT focal and ITT generalized populations completed the study (Fig. 2). Eighty two patients (17.1%) were taking one concomitant AED, 218 (45.4%) two concomitant AEDs, and 179 (37.3%) three or more concomitant AEDs, whereas a total of 170 patients (35.4%) had been treated previously (i.e., AED withdrawn prior to enrollment) in the last 5 years with 0 1 AEDs, 256 (53.3%) with 2 4 AEDs, and 54 (11.3%) with 5 AEDs. Baseline demographic and epilepsy characteristics were well balanced between the BRV and PBO groups in the ITT and ITT focal populations (Table S2). In comparison, baseline demographic and epilepsy characteristics in the small number of patients in the ITT generalized population were less well balanced, particularly in generalized seizure type (Table S2). However, median (Q1 Q3) baseline seizure frequency was similar in the BRV and PBO groups of the ITT generalized population (BRV 1.42 [ ]; PBO 1.47 [ ]). The majority of the patients in the ITT population (BRV 71.6%; PBO 85.1%) entered the maintenance period at the higher dose levels (100 and 150 mg/day). The percentage of patients who received the different dosages during the maintenance period is provided in Table S3. Safety and tolerability Adverse events The proportion of patients in the ITT population reporting 1 AEs during the treatment period (8-week dose-finding + 8-week maintenance period) was similar in the BRV (66.0%) and PBO (65.3%) groups (Table 1). The majority of AEs were mild (BRV 53.5%, PBO 57.9%) to moderate (BRV 30.9%, PBO 28.1%). The incidence of AEs was higher during the dose-finding period (BRV 56.0%, PBO 55.4%) than during the maintenance period (BRV 36.8%, PBO 40.9%). The discontinuation rate due to AEs was similar in both groups (BRV 6.1%, PBO 5.0%), and was higher in the dose-finding period (BRV 4.5%, PBO 3.3%) than the maintenance period (BRV 0.3%, PBO 0%). During the treatment period, the most frequently reported AEs (>8% in the BRV group) were headache (BRV 14.2%, PBO 19.8%), somnolence (BRV 11.1%, PBO 4.1%), and dizziness (BRV 8.6%, PBO 5.8%; Table 1). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). Irritability was reported in 7 (1.9%) of 359 patients in the BRV group and 0 (0%) of 121 patients in the PBO group. Aggression was reported in 5 (1.4%) of 359 patients in the BRV group versus 1 (0.8%) of the 121 in the PBO group. The incidence of psychiatric AEs reported in 1% of patients is shown Table S4. Serious adverse events During the treatment period, the incidence of SAEs was 5.3% in BRV-treated patients and 7.4% in PBO-treated patients. The most frequently reported SAEs were convulsions (10 occurrences; BRV 9/359, 2.8%; PBO 1/121, 0.8%) and status epilepticus (three occurrences, all in one patient randomized to BRV who had discontinued BRV at time of SAEs). One death occurred during the maintenance period (patient receiving BRV 50 mg/day). The death was

5 42 P. Kwan et al. Figure 2. Patient disposition. *All randomized patients received at least one dose of study medication and comprised the ITT population. AE, adverse event; BRV, brivaracetam; ITT, intent-to-treat; PBO, placebo. Epilepsia ILAE Table 1. Adverse events in 5% of patients in either treatment group during the 16-week treatment period (ITT population) No. patients (%) BRV (n = 359) PBO (n = 121) Patients reporting 1 AE 237 (66.0) 79 (65.3) Discontinuations due to AEs 22 (6.1) a 6 (5.0) b Patients reporting 1 SAE 19 (5.3) 9 (7.4) Individual AEs by MedDRA-preferred term Headache 51 (14.2) 24 (19.8) Somnolence 40 (11.1) 5 (4.1) Dizziness 31 (8.6) 7 (5.8) Fatigue 28 (7.8) 5 (4.1) Nausea 20 (5.6) 10 (8.3) Convulsion 18 (5.0) 4 (3.3) Nasopharyngitis 14 (3.9) 8 (6.6) Back pain 11 (3.1) 8 (6.6) AE, adverse event; BRV, brivaracetam; ITT, intent-to-treat; MedDRA, Medical Dictionary for Regulatory Activities; PBO, placebo; SAE, serious adverse event. Ordered by decreasing percentage in the BRV group. a In addition to the patients who discontinued because of AEs during the treatment period, one patient discontinued because of AEs during the downtitration period. b In addition to the patients who discontinued because of AEs, one patient discontinued with reduced dose because of facial injury and is not counted here. attributed to drowning while the patient was swimming and was considered likely to be caused by a seizure while in the water and unlikely to be related to study treatment. Clinical and laboratory assessments There were no clinically meaningful changes in hematology, blood chemistry, urinalysis, vital signs, physical, or neurologic examinations. Three patients receiving BRV had clinically significant electrocardiography abnormalities of sinus bradycardia. Of these, one patient had sinus bradycardia at baseline and one patient had abnormal ECG (although not sinus bradycardia) at baseline. Sinus bradycardia was considered possibly related to study drug (BRV 150 mg/ day) by the investigator, and the AE resolved in 1 day (no changes in BRV dose were made). The third patient had a normal ECG at baseline and BRV was discontinued due to chronic pancreatitis. Efficacy ITT focal population Efficacy results for the ITT focal population for the entire treatment period, and separately for the dose-finding period and maintenance period are provided in Fig. 3A C. Treatment period For the main efficacy end point, the baseline-adjusted percent reduction in focal seizure frequency/week in the

6 43 Brivaracetam Flexible-Dose Trial A B Figure 3. Efficacy analyses. Efficacy analyses presented for over the entire treatment period and, separately, during the dose-finding and maintenance periods. A C refer to the ITT focal population, D E refer to the ITT generalized population. (A) Main efficacy end point: percent reduction in baseline-adjusted focal seizure frequency/week over placebo (95% CI). (B) Percent reduction from baseline in focal seizures/week. (C) 50% responder rate. (D) Percent reduction from baseline in days with generalized seizure/week. (E) 50% responder rate for generalized epilepsy. BRV, brivaracetam; ITT, intent-to-treat; PBO, placebo. Epilepsia ILAE D C E BRV group over PBO was not statistically significant during the 16-week treatment period (7.3%; p = 0.125; Fig. 3A). For the other efficacy end points, median percent reduction from baseline in focal seizures/week was not statistically significant in the BRV group compared with PBO (BRV 26.9% vs. PBO 18.9%; p = 0.070; Fig. 3B), although the 50% responder rate was significantly greater in the BRV group compared with PBO (BRV 30.3% vs. PBO 16.7%; p = 0.006; Fig. 3C). There was a greater baselineadjusted percent reduction in focal seizure frequency/week during the treatment period among patients in the BRV group without concomitant LEV use, compared with patients using LEV concomitantly (Table S5). Results of the other efficacy end points were generally consistent with the main efficacy analysis (Table S4). In the BRV group, 5 (1.5%) of 323 patients were seizurefree (all seizure types) throughout the 16-week treatment period compared with 0 (0%) of 108 in the PBO group (p = 0.337). Of the five patients, the last prescribed dose was 20 mg/day for two patients, 50 mg/day for two patients, and 150 mg/day for one patient. Median time (95% confidence interval [CI]) to the first focal seizure was 4(4 5) days in the BRV group versus 3 (2 4) days in the PBO group. The median time to the fifth focal seizure was 18 (16 21) days (BRV) versus 14 (11 19) days (PBO), and to the 10th focal seizure was 38 (31 43) days (BRV) versus 36 (23 44) days (PBO). Dose-finding period and maintenance period During the dose-finding period, statistically significant differences were seen in the baseline-adjusted percent reduction in focal seizure frequency/week over PBO, the median percent reduction from baseline in focal seizures/ week, and the 50% responder rate. During the maintenance

7 44 P. Kwan et al. period, a statistically significant difference between BRV and PBO was observed for seizure freedom (p = 0.003), and near statistical significance (p = 0.056) was obtained for the 50% responder rate (Fig. 3A C). Efficacy ITT generalized population Efficacy results for the ITT generalized population for the entire treatment period, and separately for the dosefinding period and maintenance period, are provided in Fig. 3D, E. During the treatment period, median (Q1 Q3) number of days with generalized seizures/week decreased to 0.63 ( ) in the BRV group and remained relatively stable in the PBO group (1.26 [ ]). Median (Q1 Q3) percent reduction from baseline in number of days with generalized seizures/week was higher in the BRV group compared with PBO (Fig. 3D), as was the 50% responder rate (Fig. 3E). Two of 36 patients in the BRV group were seizure free during the entire treatment period compared with none in the PBO group. Discussion The primary objective of this phase III trial was to assess the safety and tolerability of flexible doses of mg/ day adjunctive BRV in patients whose epilepsy was uncontrolled on 1 3 AEDs. As such, the trial was designed to resemble clinical practice more closely than standard, fixed-dose, regulatory trials with flexible dosing allowing doses of BRV to be individualized for each patient according to tolerability and efficacy during the 8-week dose-finding period. This was followed by an 8-week maintenance period of stable BRV dosing. For the first time, the clinical evaluation of BRV included patients with generalized epilepsy, although this population comprised only approximately 10% of the patients enrolled (BRV n = 36, PBO n = 13). The study achieved its primary objectives. The results confirmed the good tolerability and safety profile of adjunctive BRV. In >70% of the patients, BRV was uptitrated to higher doses ( mg/day). In total, 90% of patients completed the 16-week treatment period. The incidence of AEs reported by those randomized to BRV was similar to PBO, and only 6.1% in the BRV group withdrew from the study due to AEs compared with 5.0% in PBO group. Of note, both the incidence of AEs and discontinuations due to AEs were higher in the dose-finding period compared with the maintenance period. This was consistent with previous findings that some AEs, such as drowsiness, fatigue, dizziness, blurry vision, and poor coordination, are more common during AED treatment initiation (St Louis, 2009). The most frequently reported AEs were headache, somnolence, and dizziness, consistent with the AEs reported in the phase IIb BRV studies (French et al., 2010; van Paesschen et al., 2013). The incidence of psychiatric AEs was similar in both groups (BRV 12.3% vs. PBO 11.6%) and incidence of specific behavioral AEs such as irritability and aggression were low in the BRV group, and similar to PBO. For the secondary objective, the main efficacy end point in this trial, percent reduction over PBO in baseline-adjusted focal seizure frequency/week, was not statistically significant over the treatment period. However, BRV demonstrated statistically significant efficacy during the dosefinding period (Fig. 3A C). In the BRV group, improvements in percent reduction from baseline in focal seizures/ week and 50% responder rate were observed soon after initiation of treatment and remained stable during the maintenance period. Such an improvement in response in the active treatment group could be reflective of patients being titrated to their optimal dose in a flexible dosing design. However, a marked continual increase in response was seen in the PBO group during the entire treatment period. This resulted in smaller treatment differences between BRV and PBO during the maintenance period that did not reach statistical significance. A recent meta-analysis of randomized controlled trials of AEDs also noted significantly higher responder rates in PBO-treated patients (but not in those receiving active treatment) in the maintenance period than in the overall treatment period (Rheims et al., 2011). The percent reduction over PBO in baseline-adjusted focal seizure frequency/week, the main efficacy end point in this trial, is particularly dependent on the PBO response. The 50% responder rate in the present study was significantly higher in the BRV group compared with the PBO group. Numerically, both the 50% responder rate and median percent reduction from baseline in the BRV group and rates were comparable with those in the phase IIb study reported by van Paesschen et al. (2013), which evaluated BRV at 50 and 150 mg/day, but lower than those in that reported by French et al. (2010), which only investigated dosing up to 50 mg/day. The optimal dose of BRV remains to be defined. The stratified analysis suggested that BRV had greater efficacy in patients without concomitant LEV use. However, this observation should be treated with caution, due to the small number of patients included in the subanalysis, and would need to be explored robustly in a pooled analysis of several BRV studies. Compared with focal seizures, fewer pharmacologic options exist for controlling generalized seizures, which can even be exacerbated by some AEDs (Somerville, 2009). In addition, there have been some concerns regarding teratogenicity with certain AEDs (e.g., valproate) widely used for treating generalized seizures (Morrow et al., 2006; Shallcross et al., 2011), which can further reduce treatment options for some patients. Additional effective treatment options for generalized seizures would therefore be useful. The efficacy of BRV in this population was explored for the first time in the present study. The rationale for investigating BRV in patients with generalized seizures is supported

8 45 Brivaracetam Flexible-Dose Trial by the broad spectrum of activity that BRV has previously demonstrated in preclinical studies (Matagne et al., 2008), the established efficacy of LEV in patients with generalized seizures (Berkovic et al., 2007; Noachtar et al., 2008; Delanty et al., 2012), and the apparently low risk of teratogenicity of LEV observed in pregnancy registries (Shallcross et al., 2011; Hernandez-Diaz et al., 2012; Vajda et al., 2012). Our results show that the tolerability of BRV in this population did not appear different from that of patients with focal seizures. There was a suggestion that BRV may be efficacious in this population: percentage reduction from baseline in the number of days with generalized seizures/week, 50% responder rate and seizure freedom rate were numerically higher in the BRV-treated group compared with PBO. Of note, efficacy in the BRV-treated group appeared to be greater than in the BRV-treated group in the ITT focal population. Because this was an exploratory end point in a small population, no statistical analysis was prespecified; however, the results suggest that further study of BRV in patients with generalized epilepsy may be worthwhile. Although BRV is a more potent SV2A inhibitor than LEV, the expected corresponding efficacy benefit was not observed in this study. Therefore a further phase III trial (NCT ) is currently under investigation to determine the optimum efficacious dose of BRV in adults. Limitations of this study include the flexible dosing design, which may hinder conclusions regarding efficacy. Patients were not assigned to specific fixed-dose groups; therefore, it was not possible to describe the dose-response relationship of BRV. Patients who responded well to treatment tended to remain on lower doses. In addition, in a flexible dosing trial, time to first seizure is likely to occur when patients are still in the dose-finding period. It is also possible that a 4-week long baseline period may have led to increased variability of responses and a greater apparent placebo response, although the same duration was employed in the phase IIb studies. Finally, the numbers of patients with generalized epilepsy included were small, and therefore caution should be used when interpreting these results. In conclusion, this study has confirmed the good tolerability profile of adjunctive BRV in individualized tailored doses up to 150 mg/day for patients with epilepsy. BRV demonstrated statistically significant efficacy against focal seizures across some outcome measures, and the exploratory results among patients with generalized seizures suggest that BRV may also be efficacious in this population. Our study results provide support for further evaluation of the efficacy of adjunctive BRV for reducing both focal and generalized seizures. Acknowledgments The authors thank the patients and members of the N01254 Study Group for their participation and contributions to the study, and Laurent Turet PhD (UCB Pharma, Brussels, Belgium) for critical review of this manuscript and coordination of manuscript preparation. Sally Cotterill PhD (QXV Communications, Macclesfield, United Kingdom) provided editorial support, which was funded by UCB Pharma. Disclosure P. Kwan has received speaker s honoraria from GlaxoSmithKline and UCB Pharma, has served on scientific advisory boards for Glaxo- SmithKline and Eisai, and is an editorial board member for CNS Drugs, Epilepsy & Behavior, Epilepsy Research, Epileptic Disorders, and Seizure. His institution has received research funding from Eisai, Glaxo- SmithKline, Johnson & Johnson, Pfizer, and UCB Pharma, and the National Institutes of Health. E. Trinka has served on scientific advisory boards for UCB Pharma, Eisai, Ever Neuropharma, Bial, B ohringer Ingelheim, GlaxoSmithKline, Biogen-Idec, and Medtronics and has received speaker s honoraria from UCB Pharma, Eisai, Gerot, Cyberonics, Desitin, Bial, GlaxoSmithKline, and Actavis. His institution has received research funding from UCB Pharma, Biogen-Idec, and Merck Serono. W. Van Paesschen has served on scientific advisory boards for UCB Pharma, GlaxoSmithKline, Pfizer, and Janssen-Cilag and has received funding to attend American Epilepsy Society and European Congress of Epilepsy meetings from UCB Pharma, Johnson & Johnson, Janssen-Cilag, and Pfizer. I. Rektor has received honoraria as a speaker for UCB Pharma. M. Johnson and S. Lu are employees of UCB Pharma. We confirm that we have read the Journal s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Study Funding This study was sponsored by UCB Pharma. 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