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

Authors


Address correspondence to Wim Van Paesschen, Department of Neurology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: wim.vanpaesschen@uz.kuleuven.ac.be

Summary

Purpose:  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, placebo-controlled, 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 up-titration 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 statistical significance; however, statistically significant differences compared with placebo were observed on several secondary efficacy outcomes. BRV was well tolerated.

Although a substantial proportion of the estimated 50 million patients with epilepsy worldwide have a good prognosis, up to 30% still fail to achieve seizure freedom despite optimized antiepileptic drug (AED) therapy (Kwan & Brodie, 2010). There remains, therefore, a clear need for newer AEDs with improved efficacy and a better tolerability profile.

Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels (Kenda et al., 2004; Zona et al., 2010; Gillard et al., 2011). BRV is effective in a wide range of animal epilepsy models and has the potential to be a broad-spectrum AED (Matagne et al., 2008). In preclinical experimental models of focal and generalized epilepsy, BRV demonstrated a higher potency and efficacy as an antiseizure and antiepileptogenic agent when compared with levetiracetam (LEV) (Tai & Truong, 2007; Matagne et al., 2008). In healthy subjects, BRV exhibits linear pharmacokinetics over a wide dose range (10–600 mg, single oral dose), is rapidly and completely absorbed after oral administration, has an elimination half-life of 7–8 h, and has plasma protein binding of ≤20% (Sargentini-Maier et al., 2007, 2008; Rolan et al., 2008). BRV is extensively metabolized (>90%), primarily via hydrolysis of the acetamide group, and secondarily through hydroxylation mediated by cytochrome P450 (CYP) 2C19 (Bialer et al., 2010; Nicolas et al., 2012). The three major metabolites (hydroxy, acid, and hydroxyacid) are pharmacologically inactive (Sargentini-Maier et al., 2008; von Rosenstiel & Perucca, 2009). BRV is eliminated as urinary metabolites with >95% of a radioactive dose recovered in the urine within 72 h, including only 8.6% as unchanged BRV (Sargentini-Maier et al., 2008). BRV (single dose; range 10–80 mg) has shown efficacy in the proof-of-concept photoparoxysmal response model in patients with photosensitive epilepsy (Kasteleijn-Nolst Trenite et al., 2007). Seventeen (94%) of 18 patients had a response to BRV, whereas eight of 18 patients (44%) responded to placebo. Complete abolishment of the photoparoxysmal response was achieved in 14 (78%) of 18 BRV-treated patients but was not seen in any patients post placebo.

To explore the efficacy, safety, and tolerability of BRV in patients with focal epilepsy, two phase IIb, double-blind, placebo-controlled studies of twice-daily BRV as adjunctive treatment in adults with uncontrolled partial-onset seizures were conducted. BRV at doses of 50 and 150 mg/day (N01114; NCT00175929), and at doses of 5, 20, and 50 mg/day (N01193; NCT00175825) (French et al., 2010) was evaluated. This report describes the methodology and findings of study N01114.

Methods

Study design

This was a randomized, double-blind, placebo-controlled, multicenter, parallel group, dose-ranging study of BRV as adjunctive treatment for uncontrolled partial-onset seizures in adults (N01114; NCT00175929). The study consisted of a 4-week prospective baseline; a double-blinded 10-week treatment period, which included a 3-week up-titration followed by a 7-week maintenance period; and a 2-week double-blinded conversion period before entry into an optional open-label long-term follow-up study at a dose of 100 mg/day (N01125; NCT00175916). Patients who did not enter the long-term follow-up study entered a 2-week double-blinded down-titration period and returned for a safety visit after a 2-week drug-free period (Fig. 1).

Figure 1.


Study design.
*Patients randomized to placebo during the double-blind phase were titrated to BRV 100 mg/day over a 2-week period. BRV, brivaracetam; LTFU, long-term follow-up.

Patients were randomized in a 1:1:1 ratio to receive BRV 50 mg/day or 150 mg/day administered twice daily in equally divided doses, or matching placebo. Treatment was assigned using a central randomization method (random permuted blocks) that stratified for LEV (concomitant use of LEV at study entry, previous use of LEV, never used LEV) and carbamazepine (CBZ) (concomitant use of CBZ at study entry, no concomitant use of CBZ), to ensure balance of these stratification factors across treatment groups.

Patients randomized to BRV 50 mg/day started at a dose of 25 mg/day, and were up-titrated to 50 mg/day after 1 week. Patients randomized to BRV 150 mg/day started at a dose of 50 mg/day and were up-titrated to 100 mg/day after 1 week and 150 mg/day after 2 weeks. Patients randomized to placebo received placebo during the up-titration and maintenance periods. The maintenance period started 3 weeks after the start of up-titration. At the discretion of the investigator, one fallback to the next lower dose was allowed after the patient entered the maintenance period, with patients taking BRV 50 and 150 mg/day decreasing their dose to 25 and 100 mg/day, respectively. After fallback, patients stayed on this dose for the remainder of the maintenance period.

The study was conducted in accordance with the International Conference on Harmonisation notes for Guidance on Good Clinical Practice (ICH/CPMP/135/95) and the Declaration of Helsinki. All study sites had ethics committee approval of the study protocol. Written informed consent was obtained from all patients before enrollment in any study-specific procedure.

Study population

Patients aged 16–65 years with partial-onset seizures, with or without secondary generalization were enrolled in the study. All study participants were required to have well-characterized focal epilepsy or epileptic syndrome (International League Against Epilepsy [ILAE] classification) (International League Against Epilepsy, 1989), two or more partial-onset seizures per month during the 3 months prior to study entry, four or more partial-onset seizures during the 4-week prospective baseline period, and a stable regimen of one to two concomitant AEDs. The same doses and AEDs were required to have been maintained for ≥1 month before screening (visit 1) and throughout study participation. Vagus nerve stimulation (VNS) was allowed but was not counted as a concomitant AED. Benzodiazepines taken more than once per week for any indication were considered to be a concomitant AED.

The main exclusion criteria were simple partial (type IA) nonmotor seizures as the only seizure type; a history or presence of seizures occurring only in clustered patterns within the previous 5 years; a history or presence of either status epilepticus (during the previous 5 years or during baseline) or pseudo-seizures (nonepileptic seizures); treatment with any drug that may significantly influence the metabolism of BRV, or any drug with possible central nervous system effects (unless the dose was stable for at least 1 month before screening and was expected to remain stable during the study); history of suicide attempt, current suicidal ideation, or other serious psychiatric disorders requiring or having required hospitalization or medication during the previous 5 years; any clinically significant medical condition that may contraindicate the use of BRV, impair reliable participation in the trial, or necessitate the use of medication not allowed per protocol; and any clinically significant abnormal laboratory value (e.g., creatinine clearance <50 ml/min, platelet count <100,000/μl, neutrophil count <1,800/μl).

Assessments

Efficacy

Efficacy assessments were made using data recorded by the patients on daily record cards and assessed by the investigator at each study visit. The primary efficacy outcome was the percent reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week maintenance period. Secondary efficacy outcomes included the reduction in partial-onset seizure frequency/week over placebo during the 10-week treatment period; percent reduction from baseline in partial-onset seizure frequency/week (maintenance and treatment periods); 50% responder rate (the percentage of patients with a ≥50% reduction in partial-onset seizure frequency/week from baseline during the maintenance and treatment periods); and freedom from partial-onset seizures (defined as the percentage of patients who completed the 10-week treatment period and were free of partial-onset seizures, and had no missing seizure diary data during the treatment period).

Safety and tolerability

Treatment-emergent adverse events (TEAEs), their severity, seriousness, outcome, and any relationship to study medication were recorded by the investigator. A TEAE was an AE with onset on or after the day of randomization. AEs were considered to be related to study medication if they were classified by the investigator as possibly, probably, or highly probably related to study medication. Additional safety variables included physical and neurologic examinations, vital signs, clinical laboratory tests, and electrocardiograms (ECGs).

Statistical analysis

All statistical analyses were performed on the intent-to-treat (ITT) population, defined as all randomized patients who received one or more doses dose of study medication. Descriptive statistics were used to summarize efficacy and safety outcomes.

Determination of sample size

There was no control for multiplicity, since this was an exploratory dose-finding study; this study was to be considered positive if the comparison of either BRV group with placebo was statistically significant at the 0.05 level for the primary outcome. A sample size of 48 patients per treatment group would provide 80% power to detect a treatment effect of −0.261 between BRV and placebo for log-transformed seizure frequency/week, based on a standard deviation of 0.45 and two-sided testing at the 0.05 significance level, where the difference of −0.261 corresponds to a 23% reduction over placebo for seizure frequency/week. To account for a 5% expected dropout rate, a total of 51 patients were to be randomized within each treatment group for a total planned sample size of 153 randomized patients.

Primary efficacy analysis

Seizure frequencies within each study period were standardized to a 7-day duration. The primary analysis was based on a mixed-model repeated-measures analysis with effects for treatment, study period (up-titration and maintenance), treatment by study period interaction, stratification effects, and log-transformed baseline seizure frequency/week as a continuous covariate. An unstructured covariance structure was assumed. A log-transformation [log(x + 1)] was applied to the 7-day adjusted seizure frequencies to obtain data that could be appropriately analyzed with the above parametric statistical methodology. Appropriate statistical contrasts were constructed to obtain treatment group comparisons for the maintenance period, which was the primary analysis period for this study. Treatment effects were expressed as percent reduction over placebo after backtransformation of the least squares means from this model.

Secondary efficacy analyses

Analysis of covariance (ANCOVA) with effects for treatment, stratification effects, and log-transformed baseline seizure frequency as a continuous covariate was used to analyze loge-transformed seizure frequency/week for the 10-week treatment period. Treatment group comparisons for median percent change from baseline for partial-onset seizure frequency/week were carried out using a Wilcoxon rank-sum test. Responder rates were analyzed using logistic regression with effects for treatment, stratification effects, and log-transformed baseline seizure frequency as a continuous covariate. Odds ratios (ORs) and corresponding two-sided 95% confidence intervals (CIs) [Wald method] were also derived from this model.

Results

Patients

The study started on 11 May 2005 and was completed on 28 March 2006. Forty-two centers in nine European countries (Belgium, Czech Republic, Finland, France, Germany, The Netherlands, Poland, Spain and the United Kingdom) enrolled patients in the study. The majority of patients were recruited from specialist epilepsy centers.

Of 194 patients screened, 37 patients were screen failures. The remaining 157 patients were randomized (53 BRV 50 mg/day; 52 BRV 150 mg/day; 52 placebo) and comprised the ITT population. Overall, 148/157 (94.3%) (51 BRV 50 mg/day, 96.2%; 49 BRV 150 mg/day, 94.2%; 48 placebo, 92.3%) completed the study, with 7 patients (4.5%) withdrawing due to an AE (2 BRV 50 mg/day, 3.8%; 3 BRV 150 mg/day, 5.8%; 2 placebo, 3.8%), and an additional 2 patients (1.3%) withdrawing due to lack of efficacy (both in the placebo group) (Fig. 2). Seventeen patients (10.8%) had major protocol deviations, the most common of which was the use of prohibited medication/therapy during the treatment period (nine patients, 5.7%: four BRV 50 mg/day; three BRV 150 mg/day; two placebo). Notably, six patients (11.3%) in the BRV 50 mg/day group had fewer than the required four partial-onset seizures during the 4-week baseline period, compared with one patient (1.9%) in the placebo group and none in the BRV 150 mg/day group. Three patients (5.8%) in the BRV 150 mg/day group had their dose reduced to 50 mg/day during the maintenance period; no subjects in the BRV 50 mg/day or placebo groups were identified to require fallback. The majority of patients (135/157, 86.0%) subsequently entered the long-term, open-label, follow-up study (46 BRV 50 mg/day, 86.8%; 48 BRV 150 mg/day, 92.3%; 41 placebo, 78.8%).

Figure 2.


Patient disposition.
*One patient discontinued during the up-titration period due to pregnancy that was not reported as an AE. One patient discontinued due to dizziness that was not reported as an AE. AE, adverse event.

Baseline demographic and epilepsy characteristics were well balanced across treatment groups. All patients in the study were Caucasian, apart from one patient (Asian/Pacific Islander) in the placebo group (Table 1). All patients presented with partial-onset seizures, and the majority (142/157 patients, 90.4%) experienced complex partial seizures before study entry (lifetime history), with 126 patients (80.3%) reporting complex partial seizures during the 4-week baseline period. Overall, 113 patients (72.0%) had previously experienced partial seizures with secondary generalization and 39 patients (24.8%) experienced this seizure type during the baseline period.

Table 1.   Patient demographics and epilepsy characteristics at baseline (ITT population)
ParameterPlacebo (n = 52)BRV 50 mg/day (n = 53)BRV 150 mg/day (n = 52)
  1. AED, antiepileptic drug; BMI, body mass index; BRV, brivaracetam; ITT, intent-to-treat; SD, standard deviation.

  2. aSeizure types reported as occurring at any time prior to study entry.

  3. bTaken within the past 5 years and discontinued prior to study entry.

  4. cPatients receiving ≥3 concomitant AEDs generally used benzodiazepines as needed.

  5. dUsed by ≥10% patients in any treatment group.

Gender, male, n (%)25 (48.1)24 (45.3)21 (40.4)
Age, years, mean (SD)
Range (min–max)
40.0 (11.7)
16.7–65.6
38.2 (12.1)
20.2–62.0
34.4 (10.1)
16.5–58.9
Race, n (%)   
 Caucasian51 (98.1)53 (100.0)52 (100.0)
 Asian/Pacific Islander 1 (1.9) 0 0
BMI, kg/m², mean (SD)
Range (min–max)
24.8 (4.9)
16.9–41.6
25.1 (5.0)
16.3–37.3
24.2 (4.4)
16.7–37.0
Duration of epilepsy, years, mean (SD)
Range (min–max)
21.0 (12.9)
 2–54
25.1 (14.8)
 3–55
19.8 (11.6)
 3–58
Baseline partial-onset seizure frequency/week, median (Q1–Q3) 2.27 (1.37–5.18) 1.75 (1.08–4.00) 2.94 (1.91–4.34)
Seizure typea, n (%)   
 Partial52 (100.0)53 (100.0)52 (100.0)
  Simple partial22 (42.3)27 (50.9)24 (46.2)
  Complex partial43 (82.7)51 (96.2)48 (92.3)
  Secondarily generalized36 (69.2)40 (75.5)37 (71.2)
 Generalized 0 1 (1.9) 2 (3.8)
 Clusters 3 (5.8) 1 (1.9) 4 (7.7)
Number of patients having previously taken ≥1 AEDb, n (%)51 (98.1)52 (98.1)49 (94.2)
Number of prior AEDsb, n (%)   
 0–1 8 (15.4)10 (18.9) 9 (17.3)
 2–426 (50.0)19 (35.8)24 (46.2)
 ≥518 (34.6)24 (45.3)19 (36.5)
Number of concomitant AEDs, n (%)   
 1 7 (13.5)13 (24.5) 9 (17.3)
 243 (82.7)35 (66.0)39 (75.0)
 ≥3c 1 (1.9) 5 (9.4) 4 (7.7)
Concomitant AEDsd, n (%)   
 Carbamazepine16 (30.8)18 (34.0)21 (40.4)
 Lamotrigine14 (26.9)21 (39.6)18 (34.6)
 Valproic acid12 (23.1) 9 (17.0)15 (28.8)
 Levetiracetam11 (21.2)11 (20.8)12 (23.1)
 Oxcarbazepine13 (25.0)11 (20.8)10 (19.2)
 Topiramate 8 (15.4) 9 (17.0)11 (21.2)

Most patients (74.5%) were taking two AEDs at study entry, the most common of which were CBZ (35.0%), lamotrigine (33.8%), valproic acid (22.9%), LEV (21.7%), oxcarbazepine (21.7%), and topiramate (17.8%). In the 5 years before study entry, 152 patients (96.8%) had taken and discontinued at least one AED, the most common of which were CBZ (43.3%), LEV (42.0%), topiramate (40.8%), and benzodiazepine derivatives (37.6%).

The median baseline partial-onset seizure frequency/week was higher in the BRV 150 mg/day (2.94) and placebo (2.27) groups than in the BRV 50 mg/day group (1.75) [Table 1]. However, adjustment for baseline seizure frequency was applied for subsequent efficacy analyses.

Efficacy

Primary efficacy analysis

During the 7-week maintenance period, the median (Q1–Q3) partial-onset seizure frequency/week was 1.00 (0.71–2.38), 1.96 (1.14–3.07), and 1.86 (0.94–4.69) in the BRV 50 mg/day, BRV 150 mg/day, and placebo groups, respectively. The percent reduction (95% confidence interval [CI]) in baseline-adjusted partial-onset seizure frequency/week over placebo during the maintenance period was 14.7% (−2.7, 29.2; p = 0.093) in the BRV 50 mg/day group and 13.6% (−4.1, 28.3; p = 0.124) in the BRV 150 mg/day group.

Secondary efficacy analyses

During the 10-week treatment period, the median (Q1–Q3) partial-onset seizure frequency/week was 1.10 (0.70–2.00), 2.05 (1.01–3.32) and 1.95 (1.05–5.12) in the BRV 50 mg/day, BRV 150 mg/day, and placebo groups, respectively. Statistically significant percent reductions over placebo in the partial-onset seizure frequency/week were observed in the BRV 50 mg/day (17.7%; 95% CI 2.3, 30.7; p = 0.026) and BRV 150 mg/day (16.3%; 95% CI 0.6, 29.5; p = 0.043) groups.

Over the maintenance period, the median percent reduction from baseline in partial-onset seizure frequency/week was 38.2% (p = 0.017) in the BRV 50 mg/day group and 30.0% (p = 0.113) in the BRV 150 mg/day group, compared with 18.9% in the placebo group (Fig. 3A). Over the treatment period, the median percent reduction from baseline in partial-onset seizure frequency/week was 34.9% (p = 0.004) for BRV 50 mg/day and 28.3% (p = 0.070) for BRV 150 mg/day, compared with 16.3% for placebo.

Figure 3.


Median percent reduction from baseline in partial-onset seizure frequency/week (A) and 50% responder rate (B) over the treatment and maintenance periods (ITT population). *Significant difference versus placebo.

Over the maintenance period, 50% responder rates were 39.6% (OR 2.17, p = 0.077) in the BRV 50 mg/day group and 33.3% (OR 1.66, p = 0.261) in the BRV 150 mg/day group, compared with 23.1% in the placebo group (Fig. 3B). Over the treatment period, 50% responder rates were 35.8% (OR 2.69, p = 0.038) and 30.8% (OR 2.15, p = 0.114) for BRV 50 and 150 mg/day, respectively, and 17.3% for placebo. Among patients who were receiving concomitant LEV, the numbers who achieved a 50% or greater reduction in partial-onset seizure frequency from baseline to the maintenance period were 5/11 for BRV 50 mg/day, 1/12 for BRV 150 mg/day, and 3/11 in the placebo group. Among patients with prior LEV use, 5/20, 7/18, and 4/18 in the BRV 50 mg/day, BRV 150 mg/day, and placebo groups, respectively, were 50% responders. Among the LEV-naive patients, there were 11/22, 9/21, and 5/23 50% responders in the BRV 50 mg/day, BRV 150 mg/day, and placebo groups, respectively. The numbers of patients who received concomitant LEV or who were LEV naive were too small to draw any conclusions based on these results.

Freedom from partial-onset seizures during the entire 10-week treatment period was achieved in a total of nine patients (five BRV 50 mg/day, 9.4%; three BRV 150 mg/day, 5.8%; one placebo, 1.9%).

Safety and tolerability

During the treatment period, at least one TEAE was reported by 36/53 (67.9%) patients on BRV 50 mg/day, 35/52 (67.3%) on BRV 150 mg/day, and 37/52 (71.2%) on placebo (Table 2). TEAEs that were reported by at least 5% of patients treated with BRV, and at a higher incidence than in the placebo group, were headache (BRV vs. placebo: 11.4% vs. 7.7%), fatigue (9.5% vs. 7.7%), nasopharyngitis (8.6% vs. 5.8%), somnolence (7.6% vs. 5.8%), dizziness (6.7% vs. 5.8%), and urinary tract infection (5.7% vs. 1.9%) (Table 2). Nausea was reported by 7.6% and 11.5% of patients who received BRV and placebo, respectively. Psychiatric TEAEs occurred with a higher incidence in placebo-treated patients (21.2%) than in BRV-treated patients (BRV 50 mg/day: 13.2%; BRV 150 mg/day: 11.5%). The majority of TEAEs were of mild or moderate intensity. Treatment-emergent serious AEs (SAEs) were reported by seven patients during the treatment period (Table S1): one (1.9%) on BRV 50 mg/day (cystitis), two (3.8%) on BRV 150 mg/day (convulsion, patella fracture), and four (7.7%) on placebo (postictal state, sympathetic posterior cervical syndrome, convulsion, joint dislocation). Of these SAEs, two (3.8%) in the placebo group were considered to be related to study medication (postictal state, joint dislocation). No SAE was considered to be related to study medication in either BRV group. Two additional patients reported SAEs after discontinuation of study medication (placebo: bronchopneumonia; BRV 150 mg/day: spontaneous abortion). TEAEs associated with fallback (three patients in the BRV 150 mg/day group) were dizziness (one patient), irritability (one patient), loss of consciousness, and a fall (one patient).

Table 2.   Overall summary of TEAEs and incidence of TEAEs reported during the treatment period by at least 5% of the subjects in any treatment groupa (ITT population)
MedDRA
Preferred term
Placebo (n = 52)BRV 50 mg/day (n = 53)BRV 150 mg/day (n = 52)
 Number (%) of patients
  1. MedDRA, Medical Dictionary for Regulatory Activities.

  2. aTEAEs ordered by decreasing percentage in the BRV 150 mg/day group.

At least one TEAE37 (71.2)36 (67.9)35 (67.3)
Drug-related TEAEs22 (42.3)22 (41.5)19 (36.5)
Dizziness3 (5.8)2 (3.8)5 (9.6)
Headache4 (7.7)8 (15.1)4 (7.7)
Nasopharyngitis3 (5.8)5 (9.4)4 (7.7)
Nausea6 (11.5)4 (7.5)4 (7.7)
Fatigue4 (7.7)7 (13.2)3 (5.8)
Somnolence3 (5.8)5 (9.4)3 (5.8)
Insomnia1 (1.9)1 (1.9)3 (5.8)
Anorexia1 (1.9)1 (1.9)3 (5.8)
Vomiting1 (1.9)03 (5.8)
Urinary tract infection1 (1.9)4 (7.5)2 (3.8)
Irritability2 (3.8)3 (5.7)1 (1.9)
Back pain4 (7.7)2 (3.8)1 (1.9)
Convulsion5 (9.6)1 (1.9)1 (1.9)
Disturbance in attention3 (5.8)2 (3.8)0

During the treatment period, TEAEs led to permanent discontinuation of study medication in five patients: two (3.8%) in the BRV 50 mg/day group (neutropenia and memory impairment), two (3.8%) in the BRV 150 mg/day group (neutrophil count decreased, psychomotor hyperactivity), and one (1.9%) in the placebo group (postictal state).

No deaths occurred during the study. Changes from baseline in clinical laboratory parameters, body weight, and physical and neurologic examinations deemed possibly clinically relevant were reported as TEAEs. No clinically relevant changes from baseline were observed in vital signs or ECG parameters (data not shown).

Discussion

In this study, the results of the primary efficacy analysis (percent reduction over placebo in baseline-adjusted partial-onset seizure frequency/week during the 7-week maintenance period) did not reach statistical significance for either BRV doses, 50 mg/day (p = 0.093) or 150 mg/day (p = 0.124). However, notably, during the 10-week treatment period (combined up-titration and maintenance period) statistical significance was achieved with BRV 50 and 150 mg/day for percent reduction over placebo in partial-onset seizure frequency/week (p = 0.026 and p = 0.043, respectively).

In addition, BRV 50 mg/day demonstrated a statistically significant difference versus placebo for median percent reduction from baseline in the partial-onset seizure frequency/week for both the maintenance and treatment periods. The probability of achieving 50% reduction in seizure frequency was also statistically significantly higher (p = 0.038) in the BRV 50 mg/day group than the placebo group for the treatment period. The relatively short duration of the treatment period (3-week up-titration and 7-week maintenance periods) compared with the typical 12-week maintenance period used in regulatory studies of adjunctive therapy for partial-onset seizures is a limitation of this study.

Despite the failure to reach statistical significance for the primary variable, the efficacy results for BRV 50 mg/day in this study are consistent with those in a previously reported phase IIb study of BRV as adjunctive treatment for adults with refractory partial-onset seizures (N01193) (French et al., 2010). Efficacy results in the French et al. (2010) study showed a strong dose–response effect for BRV in the dose range of 5–50 mg/day; and the study met its primary endpoint at the 50 mg/day dose (reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week treatment period). Secondary efficacy variables (median percent reduction from baseline in weekly partial-onset seizure frequency; 50% responder rate) also showed statistically significant effects for BRV at both 20 and 50 mg/day doses.

In the present study, BRV 150 mg/day did not demonstrate a statistically significant benefit over placebo for the primary efficacy analysis based on the maintenance period. For the secondary outcomes, however, a statistically significant difference was observed over the treatment period for percent reduction over placebo in partial-onset seizure frequency/week (p = 0.043). Median percent reduction from baseline in partial-onset seizure frequency/week over the treatment period was 28.3% for the 150 mg/day dose of BRV compared with 16.3% for placebo (p = 0.070). Based on the results observed in this study, the data do not suggest that BRV 150 mg/day offers additional benefit over 50 mg/day.

Freedom from partial-onset seizures during the 10-week treatment period was achieved for five of 53 patients (9.4%) receiving BRV 50 mg/day and three of 52 patients (5.8%) receiving BRV 150 mg/day compared with one of 52 patients (1.9%) on placebo. These seizure freedom rates are encouraging, given the strict definition used in the assessment of this parameter (whereby patients who discontinued from the study or had missing data were not counted as seizure free), in accordance with recommendations from previous analyses (Leppik et al., 2006; Gazzola et al., 2007), but it should be noted that the treatment period was relatively short (10 weeks). When considered together with the results of the other efficacy assessments, these data broadly support the potential of BRV (both 50 and 150 mg/day) in the treatment of partial-onset seizures in adults.

Some differences have been identified in the number of AEDs used by patients recruited to study N01114 compared with those included in study N01193 (French et al., 2010). In study N01193, 49.0% of patients had taken and discontinued ≥2 AEDs during the past 5 years (UCB, data on file) compared with 82.8% of patients in study N01114. Previous research has demonstrated that the rates of seizure freedom and patients with a >50% seizure frequency reduction after administration of a new AED decrease as a function of the number of previously failed AEDs (Schiller & Najjar, 2008). Concomitant AED use also differed between the two studies; in study N01193, 35.1% and 58.7% of patients were receiving one or two concomitant AEDs, respectively, compared with 18.5% and 75.8% in study N01114. Evaluation of the efficacy and tolerability of BRV relative to concomitant and previous LEV use was not appropriate based on the small number of patients in this single study.

Adjunctive BRV demonstrated a favorable safety and tolerability profile at doses of 50 and 150 mg/day in this study, as shown by the high completion rate across both BRV groups (95.2%) which was similar to placebo (92.3%). More BRV- than placebo-treated patients continued into the long-term follow-up study (89.5% vs. 78.8%). The incidence of TEAEs with both doses of BRV was similar to placebo. The most frequently reported TEAEs in the BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. Psychiatric TEAEs occurred less frequently in BRV-treated than in placebo-treated patients. The tolerability results in this study are consistent with study N01193, where BRV 5–50 mg/day was well tolerated despite the absence of titration (French et al., 2010).

In conclusion, in this 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 statistical significance; however, statistically significant differences compared with placebo were observed on several secondary efficacy outcomes. Both doses of BRV were well tolerated. The results of further studies will provide additional insight into the efficacy and safety of adjunctive BRV in adults with inadequately controlled focal epilepsy, and help to establish the optimal therapeutic dose range.

Acknowledgments

The N01114 study was sponsored by UCB. UCB Pharma was responsible for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. UCB Pharma was involved in the preparation and review of this report, along with the listed authors, and covered all related costs. The authors would like to acknowledge the members of the N01114 Brivaracetam Study Group and patients involved in this trial and the members of the Independent Safety Data Monitoring Committee who were Emilio Perucca, Greg Bergey, and Nancy Temkin. The authors thank Antoinette Brodsky, MD (study physician) and Cecilia Dubois (study statistician) who were employees of UCB Pharma, Brussels, Belgium, at the time the study was conducted; John Logan, MSc (consultant working for UCB Pharma) for statistical analysis support; Isabelle Schelstraete, PhD (clinical trial manager; UCB Pharma, Brussels, Belgium); Sarah Lu, MD, PhD (UCB Pharma, Raleigh, U.S.A.) and Martin Merschhemke, MD, PhD (formerly an employee of UCB Pharma, Monheim, Germany) for their critical review; Svetlana Dimova, MD, PhD and Laurent Turet, PhD (UCB Pharma, Brussels, Belgium) for their critical review and coordination of the manuscript preparation; and Helen Attisha, MSc, PhD (formerly QXV Communications, Macclesfield, United Kingdom) and Jennifer Stewart, MSc (QXV Communications, Macclesfield, United Kingdom) for their assistance with the manuscript preparation, which was funded by UCB Pharma.

Disclosure

Wim Van Paesschen has received honorarium as a consultant from UCB Pharma, GlaxoSmithKline, Pfizer, Johnson & Johnson, Valeant, and Janssen-Cilag. Edouard Hirsch has received honorarium as a consultant from UCB Pharma, GlaxoSmithKline, and Johnson & Johnson. Martin Johnson is an employee of UCB Pharma, Raleigh, U.S.A. Ursula Falter and Philipp von Rosenstiel were employees of UCB Pharma, at the time when this research was conducted and the preparation of this report was initiated. We confirm that we have read the Journal’s position on issues involved in ethical publication and confirm that this report is consistent with those guidelines.

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