Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double-blind, randomized, placebo-controlled trial

Authors


  • The copyright line for this article was changed on May 4, 2015 after original online publication.

Summary

Purpose

Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16–70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage.

Methods

This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs).

Key Findings

Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue.

Significance

In this study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20–100 mg/day was well tolerated without up-titration, with a high completion rate.

Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand that is in clinical development for the treatment of epilepsy. Although the precise role of SV2A in neurotransmission remains unclear, it has been identified as an important target for antiepileptic drugs (AEDs). Early studies established that SV2A-deficient mice experience severe seizures (Crowder et al., 1999); more recently, reduced SV2A expression has been found in brain tissue obtained from animal models of epileptogenesis and patients with epilepsy (van Vliet et al., 2009). Studies in preclinical epilepsy models have indicated that SV2A-binding affinity is strongly correlated with anticonvulsant potency (Kaminski et al., 2008). BRV has a >30-fold higher affinity than levetiracetam (LEV) for SV2A in human cerebral cortex (Gillard et al., 2011) and a pharmacologic profile in animal models that supports its further development for the treatment of focal and generalized seizures (Matagne et al., 2008). Pharmacokinetic studies in healthy male subjects have shown that BRV is rapidly absorbed after oral administration (Sargentini-Maier et al., 2007; Rolan et al., 2008) and is extensively biotransformed into three major metabolites (Sargentini-Maier et al., 2008). It is weakly bound to plasma proteins (Sargentini-Maier et al., 2008) and has an elimination half-life of around 7–8 h (Sargentini-Maier et al., 2007; Rolan et al., 2008).

Two, phase IIb, double-blind, placebo-controlled, dose-ranging studies (N01193; NCT00175825, and N01114; NCT00175929) investigated the efficacy and tolerability of adjunctive BRV (5–150 mg/day) in patients aged 16–65 years with uncontrolled focal epilepsy (French et al., 2010; van Paesschen et al., 2013). These studies indicated that adjunctive BRV may be effective and well tolerated in this patient population, and supported further clinical development. Three phase III studies were subsequently conducted: two were confirmatory, fixed-dose studies in patients with uncontrolled focal epilepsy (N01252; NCT00490035 and N01253; NCT00464269; Werhahn et al., 2010), and the third was a flexible-dose, safety and tolerability study in patients with focal or generalized epilepsy (N01254; NCT00504881; Kwan et al., 2009). One further phase III fixed-dose efficacy and tolerability study in patients with uncontrolled focal epilepsy (N01358; NCT01261325) is ongoing. Herein we report the findings from study N01252. The objective was to evaluate the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients with focal seizures that were not fully controlled despite optimal treatment with one or two concomitant AEDs.

Methods

Study design

This was a phase III, double-blind, randomized, placebo-controlled, fixed-dose trial, conducted between September 2007 and February 2009. Patients were recruited from 88 sites in Poland, India, France, Germany, Spain, Italy, Switzerland, Hungary, Finland, The Netherlands, Belgium, and the United Kingdom. An 8-week prospective baseline period was followed by a 12-week treatment period with no uptitration (Fig. S1). Patients attended the study center for assessments at weeks −8 and −4 during the baseline period; at randomization (week 0); at weeks 2, 4, 8, and 12 during the treatment period; and for a final safety visit at week 16. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day, or PBO administered twice daily in equal doses. Treatment was assigned using central randomization via an interactive voice response system (IVRS), stratified by geographic region and concomitant LEV use (yes or no). Concomitant use of LEV was limited to 20% of all randomized patients. During the treatment period, the dose of study medication could be reduced once using the fallback option at the discretion of the investigator. Under the fallback option, BRV 100 mg/day was reduced to BRV 50 mg/day, BRV 50 mg/day was reduced to BRV 20 mg/day, and patients who were randomized to BRV 20 mg/day were changed to PBO. Treatment for patients randomized to PBO did not change under the fallback option. The treatment period was followed by either a 2-week down-titration and a 2-week drug-free period, or entry into one of two open-label, long-term follow-up studies (N01125; NCT00175916 or N01199; NCT00150800, depending on location) at a recommended starting dose of BRV 50 mg/day. Patients were invited to participate in a follow-up study if the investigator believed that a reasonable benefit could be expected from long-term administration of BRV.

The study was conducted in accordance with the International Conference on Harmonization notes for Guidance on Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by institutional review boards at all study sites, and written informed consent was obtained from all patients before enrollment.

Study population

Patients included were aged 16–70 years with focal epilepsy or epileptic syndrome (International League Against Epilepsy, 1989). Inclusion criteria were well-characterized focal epilepsy with a history of focal seizures with or without secondary generalization (International League Against Epilepsy, 1981), and two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline period. Patients were receiving one or two concomitant AEDs at a stable and optimal dosage from ≥1 month prior to screening and throughout the study. Vagus nerve stimulation was allowed but was not counted as a concomitant AED. A benzodiazepine taken more than once per week for any indication was considered to be a concomitant AED.

Key exclusion criteria included nonmotor simple focal seizures as the only seizure type, a history or presence of seizures occurring only in clusters before randomization, and a history or presence of status epilepticus during the 12 months prior to screening or during baseline. Patients with a history or presence of pseudo-seizures, rapidly progressing brain disorder, tumors, serious infection, or terminal illness were also excluded.

Efficacy assessments

Patients recorded the occurrence of seizures on daily record cards, which were reviewed and discussed with the investigator at each study visit. The primary efficacy variable was the focal seizure frequency/week over the treatment period.

Secondary efficacy variables were the following: the median percent reduction from baseline in focal seizure frequency/week during the treatment period; ≥50% responder rate (defined as a ≥50% reduction from baseline in focal seizure frequency/week during the treatment period) calculated for all patients and for only those who completed the study; and seizure freedom from all seizure types. Seizure freedom was defined as completion of the treatment period without experiencing seizures of any seizure type and having seizure daily record card data available for all days during the treatment period. Patients who discontinued or had missing seizure data were considered as non–seizure-free, regardless of their seizure status.

Safety and tolerability assessments

Adverse events (AEs) were recorded at each study visit, with an assessment of their severity (mild, moderate, or severe) and relationship to study medication. No specific checklist or inventory was used to assess psychiatric adverse events, including irritability or suicidality. Serious AEs were defined as those that resulted in death, were life-threatening, required hospitalization or prolonged hospitalization, resulted in persistent or significant disability or incapacity, or were congenital anomalies or birth defects. Other safety and tolerability evaluations were collection of blood and urine samples for routine laboratory investigations, and monitoring of physical and neurologic examinations, vital signs, body weight, and electrocardiograms (ECG).

Statistical methods

The safety population was defined as all randomized subjects who received at least one dose of study medication, and was used for all safety analyses. The intent-to-treat (ITT) population was defined in the same manner as the safety population, and was used for efficacy analyses. Although the safety and ITT populations were the same by definition, distinct nomenclature allowed appropriate wording to be used when reporting the study results.

The primary efficacy analysis was based on parametric analysis of covariance (ANCOVA) with log-transformed treatment period focal seizure frequency adjusted to a 7-day duration as the outcome, with effects for treatment and stratification factors (concomitant LEV use and geographic region) and log–transformed baseline focal seizure frequency/week as a continuous covariate. Treatment effects were characterized using percent reduction over PBO after back-transformation of least squares means from the ANCOVA. Comparison of each BRV arm with PBO was performed according to a predefined sequential procedure to control for multiplicity, starting with 50 mg/day, followed by 100 mg/day, and then 20 mg/day. A statistically significant outcome at the 0.050 significance level was required for BRV 50 mg/day over PBO to declare the study positive.

A post hoc analysis was produced for focal seizure frequency standardized to a 28-day duration, for comparison with the ANCOVA results based on the 7-day adjusted focal seizure frequency.

Percent reduction from baseline in focal seizure frequency/week was analyzed using the Wilcoxon-Mann-Whitney (WMW) test. Statistical analysis of ≥50% responder rates was based on a logistic regression model, with an effect for treatment and log-transformed baseline focal seizure frequency/week as a continuous covariate. Seizure freedom rates were analyzed by applying Fischer's exact test. Post hoc subgroup analyses were conducted on selected efficacy variables by LEV status (LEV-naive, only prior use of LEV, concomitant LEV use) and by focal seizure subtype (IA, IB, IC).

The sample size was based on the primary efficacy analysis. Eighty-seven patients per treatment group were required to detect a treatment difference of −0.223 between BRV and PBO (corresponding to a 20% reduction over PBO) for log-transformed focal seizure frequency/week with 90% power, at a two-sided significance level of 0.050. To compensate for some loss of power due to the sequential testing procedure, 100 patients per arm were included in this study.

Results

Patients

A total of 399 patients were randomized (Fig. 1). One patient randomized to BRV 50 mg/day died from subdural hematoma leading to respiratory failure before taking any study medication; the remaining 398 patients were included in the ITT and safety populations. Overall, 367 (92.2%) of 398 patients (BRV 20 mg/day 93/99, 93.9%; 50 mg/day 88/99, 88.9%; 100 mg/day 94/100, 94.0%; PBO: 92/100, 92.0%) completed the 12-week treatment period and 345 (86.7%) of 398 patients (BRV 20 mg/day 87/99, 87.9%; 50 mg/day 82/99, 82.8%; 100 mg/day 88/100, 88.0%; PBO: 88/100, 88.0%) subsequently entered a long-term follow-up study.

Figure 1.

Patient disposition. aPercentages are based on the ITT population. bIncludes lost to follow-up, withdrawal of consent, and other reasons. cPatients who completed the 12-week treatment period.

Mean (standard deviation, SD) BRV doses during the treatment period were 20.1 (2.0) mg/day in the 20 mg/day group, 48.9 (4.5) mg/day in the 50 mg/day group, and 97.9 (8.5) mg/day in the 100 mg/day group. Overall, the fallback option was used by <3% of patients across all treatment groups during the treatment period.

Baseline demographics and epilepsy characteristics

Baseline demographics and epilepsy characteristics were similar across all groups (Table 1). Overall, the mean (SD) duration of epilepsy was 21.8 (12.9) years, and more than two thirds of the patients (68.1%) had failed two or more AEDs in the past 5 years. Most of the patients (78.9%) were taking two concomitant AEDs at baseline, most commonly carbamazepine (46.5%). During the baseline period, all the patients experienced focal seizures. The majority of patients experienced complex focal seizures (subtype IB; 81.2% of patients), followed by secondarily generalized focal seizures (IC; 38.2%), and simple focal seizures (IA; 27.9%); 2.3% of patients experienced generalized seizures (II), 0.8% had unclassifiable seizures (III), and 3.0% had seizure clusters (IV).

Table 1. Baseline demographic and epilepsy characteristics (ITT population)
 PBO (n = 100)BRV 20 mg/day (n = 99)BRV 50 mg/day (n = 99)BRV 100 mg/day (n = 100)Total (n = 398)
  1. AED, antiepileptic drug; BRV, brivaracetam; ITT, intent-to-treat; PBO, placebo; SD, standard deviation.

  2. a

    At randomization.

  3. b

    During last 5 years.

  4. c

    Taken at baseline by ≥15% of patients overall.

  5. d

    Concomitant levetiracetam use limited to 20% of randomized patients.

Age, year, mean (SD)36.4 (13.0)35.7 (12.5)38.9 (13.6)38.0 (13.1)37.2 (13.1)
Gender     
Male, n (%)54 (54.0)61 (61.6)54 (54.5)58 (58.0)227 (57.0)
Race     
Caucasian, n (%)77 (77.0)76 (76.8)76 (76.8)76 (76.0)305 (76.6)
Weight, kg, mean (SD)70.1 (17.3)72.3 (18.5)71.1 (14.4)72.0 (18.1)71.4 (17.1)
Age at onset, year, mean (SD)16.0 (12.9)13.6 (10.8)16.5 (13.5)15.9 (12.6)15.5 (12.5)
Duration of epilepsy,a year, mean (SD)20.4 (12.3)22.1 (13.6)22.3 (13.0)22.1 (12.8)21.8 (12.9)
Baseline focal seizure frequency/week, median (Q1–Q3)2.07 (1.35–6.04)1.93 (1.28–3.59)1.80 (1.25–3.47)2.02 (1.26–3.25)1.95 (1.28–3.78)
Number of prior AEDs,b n (%)     
0–133 (33.0)31 (31.3)30 (30.3)33 (33.0)127 (31.9)
2–448 (48.0)51 (51.5)54 (54.5)50 (50.0)203 (51.0)
≥519 (19.0)17 (17.2)15 (15.2)17 (17.0)68 (17.1)
Number of concomitant AEDs, n (%)     
114 (14.0)18 (18.2)20 (20.2)16 (16.0)68 (17.1)
283 (83.0)77 (77.8)77 (77.8)77 (77.0)314 (78.9)
≥33 (3.0)4 (4.0)2 (2.0)7 (7.0)16 (4.0)
Most frequently used concomitant AEDs, c n (%)     
Carbamazepine42 (42.0)55 (55.6)48 (48.5)40 (40.0)185 (46.5)
Valproic acid17 (17.0)16 (16.2)28 (28.3)28 (28.0)89 (22.4)
Lamotrigine22 (22.0)16 (16.2)25 (25.3)20 (20.0)83 (20.9)
Oxcarbazepine22 (22.0)22 (22.2)15 (15.2)22 (22.0)81 (20.4)
Levetiracetamd18 (18.0)18 (18.2)20 (20.2)20 (20.0)76 (19.1)

Efficacy

Percent reduction over PBO in focal seizure frequency/week (primary efficacy analysis)

The percent reduction over PBO in baseline-adjusted focal seizure frequency/week was 6.8%, 6.5%, and 11.7% in the BRV 20, 50, and 100 mg/day groups, respectively (Table 2). The reduction over PBO seen in the BRV 50 mg/day group was not statistically significant (p = 0.261), and therefore this study was not considered to be positive based on the statistical testing procedure used to control for multiplicity, which required significance at BRV 50 mg/day as a first step. However, statistical significance was achieved for BRV 100 mg/day group (p = 0.037) at the 0.050 significance level.

Table 2. Median focal seizure frequency/week and percent reduction over placebo in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) and /28 days (post hoc analysis) during the 12-week treatment period (ITT population)
 PBO (n = 100)BRV 20 mg/day (n = 99)BRV 50 mg/day (n = 99)BRV 100 mg/day (n = 100)
  1. BRV, brivaracetam; CI, confidence interval; ITT, intent-to-treat; PBO, placebo; Q1, 25th percentile; Q3, 75th percentile; NA, not applicable.

  2. a

    Analysis of covariance (ANCOVA) of log-transformed focal seizure frequency.

  3. b

    Not statistically significant; therefore, based on the sequential testing procedure to control for multiplicity, the study was not considered positive.

  4. c

    Statistical significance without adjustment for multiplicity.

Focal seizure frequency/week, median (Q1–Q3)1.75 (0.76–5.12)1.34 (0.70–3.12)1.49 (0.69–2.78)1.26 (0.52–2.93)
Percent reduction over PBO in focal seizure frequency/weeka (95% CI)NA

6.8 (−4.8, 17.1)

p = 0.239

6.5 (−5.2, 16.9)

p = 0.261b

11.7 (0.7, 21.4)

p = 0.037c

Percent reduction over PBO in focal seizure frequency/28 daysa (95% CI)NA

10.2 (−6.8, 24.5)

p = 0.222

9.2 (−8.0, 23.7)

p = 0.274

20.5 (5.4, 33.1)

p = 0.010c

Results of the post hoc analysis evaluating the percent reduction in focal seizure frequency standardized to 28 days (Johnson et al., 2010) were consistent with the primary efficacy analysis (Table 2). The percent reduction over PBO in baseline-adjusted focal seizure frequency/28 days was 9.2% (p = 0.274) and 20.5% (p = 0.010) in the BRV 50 and 100 mg/day groups, respectively.

Secondary efficacy analyses

Median percent reduction from baseline in focal seizure frequency/week

Over the 12-week treatment period, median percent reduction from baseline in focal seizure frequency/week was numerically greater in the three BRV dose groups compared with the PBO group (Fig. 2A). Median percent reductions from baseline were 30.0% for BRV 20 mg/day, 26.8% for BRV 50 mg/day, and 32.5% for BRV 100 mg/day compared with 17.0% for PBO (p = 0.019, p = 0.092, and p = 0.004, respectively).

Figure 2.

(A) Median percent reduction from baseline in focal seizure frequency/week, (B) ≥50% responder rate, (C) median percent reduction from baseline in focal seizure frequency/week by seizure subtype, and (D) ≥50% responder rate by seizure subtype during the 12-week treatment period (ITT population). Note, unlike the primary variable, these analyses were not controlled for multiplicity using a predefined sequential testing procedure.

≥50% responder rate

Numerically greater ≥50% responder rates were seen in the three BRV groups compared with PBO (Fig. 2B). The ≥50% responder rates were 27.3% for BRV 20 mg/day, 27.3% for BRV 50 mg/day, and 36.0% for BRV 100 mg/day compared with 20.0% for PBO (p = 0.339, p = 0.372, and p = 0.023, respectively).

The ≥50% responder rates for patients who completed the study were similar to those for all patients: 28.0% for BRV 20 mg/day (n = 93), 27.3% for 50 mg/day (n = 88), and 37.2% for 100 mg/day (n = 94), compared with 21.7% for PBO (n = 92).

Seizure-freedom rate (all seizure types)

Complete seizure freedom over the entire treatment period was achieved by 2 of 99 patients on BRV 20 mg/day, none of the 99 patients on BRV 50 mg/day, and 4 of 100 patients on BRV 100 mg/day, compared with none of the 100 patients in the PBO arm.

Effects of LEV use

Median percent reductions from baseline in focal seizure frequency/week and ≥50% responder rates over the 12-week treatment period were generally numerically greater in the BRV groups than the PBO group among patients who were LEV naive and those who had only previous use of LEV (i.e., discontinued LEV prior to study entry; Table 3). Numerically lower treatment effects were observed for patients who were taking concomitant LEV compared with those who were LEV-naive, and those with prior use of LEV.

Table 3. Post hoc analysis of median percent reduction from baseline in focal seizure frequency/week and ≥50% responder rates during the 12-week treatment period by LEV status (ITT population)
 PBOBRV 20 mg/dayBRV 50 mg/dayBRV 100 mg/day
  1. BRV, brivaracetam; ITT, intent-to-treat; LEV, levetiracetam; PBO, placebo.

Median percent reduction from baseline in focal seizure frequency/week    
LEV-naive19.5 (n = 55)29.1 (n = 57)35.5 (n = 51)40.4 (n = 58)
Prior LEV9.6 (n = 27)35.5 (n = 24)16.8 (n = 28)32.5 (n = 22)
Concomitant LEV17.2 (n = 18)22.1 (n = 18)3.2 (n = 20)4.7 (n = 20)
≥50% responder rate    
LEV-naive18.2 (n = 55)33.3 (n = 57)33.3 (n = 51)43.1 (n = 58)
Prior LEV22.2 (n = 27)25.0 (n = 24)21.4 (n = 28)36.4 (n = 22)
Concomitant LEV22.2 (n = 18)11.1 (n = 18)20.0 (n = 20)15.0 (n = 20)

Effects of focal seizure subtype

Over the 12-week treatment period, the median percent reduction from baseline in focal seizure frequency/week was greater for BRV 100 mg/day than placebo for all focal seizure subtypes, with the greatest effect observed on secondarily generalized focal seizures (BRV 100 mg/day 46.8% vs. PBO 33.1%; Fig. 2C). Similar results were seen for ≥50% responder rate (Fig 2D).

Safety and tolerability

Overall, the incidence of treatment-emergent AEs (TEAEs) was higher in the BRV groups (combined BRV 60.7%) than the PBO group (53.0%), although there was no clear dose response (Table 4). The majority of TEAEs were considered to be mild or moderate in severity. The TEAEs most frequently reported by patients taking BRV were headache, somnolence, dizziness, and fatigue, although only headache was reported both by >10% of BRV-treated patients and with a >3% higher incidence in the combined BRV group compared with PBO (BRV 13.8%; PBO 9.0%). Across the BRV dose groups, there was a trend toward a dose response in the incidence of TEAEs that were considered by the investigator to be drug-related (Table 4).

Table 4. Overall summary of treatment-emergent adverse events and treatment-emergent adverse events reported by ≥5% patients in any treatment group during the 12-week treatment period (safety population)
Number of patients (%)PBO (n = 100)BRV 20 mg/day (n = 99)BRV 50 mg/day (n = 99)BRV 100 mg/day (n = 100)Combined BRV (n = 298)
  1. BRV, brivaracetam; PBO, placebo; TEAE, treatment-emergent adverse event.

  2. Ordered by descending frequency in BRV overall group.

  3. a

    Frequency in BRV group >3% points higher than in PBO group.

At least one TEAE53 (53.0)56 (56.6)62 (62.6)63 (63.0)181 (60.7)
TEAEs leading to permanent study drug discontinuation4 (4.0)4 (4.0)5 (5.1)5 (5.0)14 (4.7)
Drug-related TEAEs31 (31.0)23 (23.2)37 (37.4)42 (42.0)102 (34.2)
Severe TEAEs4 (4.0)4 (4.0)5 (5.1)3 (3.0)12 (4.0)
Serious AEs6 (6.0)1 (1.0)4 (4.0)2 (2.0)7 (2.3)
TEAEs reported by ≥5% patients in any treatment group     
Headache9 (9.0)14 (14.1)a18 (18.2)a9 (9.0)41 (13.8)a
Somnolence6 (6.0)8 (8.1)6 (6.1)8 (8.0)22 (7.4)
Dizziness5 (5.0)5 (5.1)7 (7.1)5 (5.0)17 (5.7)
Fatigue2 (2.0)3 (3.0)4 (4.0)8 (8.0)a15 (5.0)
Nasopharyngitis1 (1.0)8 (8.1)a1 (1.0)2 (2.0)11 (3.7)
Vertigo3 (3.0)1 (1.0)2 (2.0)8 (8.0)a11 (3.7)
Nausea4 (4.0)01 (1.0)6 (6.0)7 (2.3)
Irritability005 (5.1)a1 (1.0)6 (2.0)

During the treatment period, TEAEs led to study drug discontinuation in 14 BRV (4.0%, 5.1%, and 5.0% for BRV 20, 50, and 100 mg/day, respectively) and four PBO (4.0%) patients (Table 4). The most commonly reported TEAEs that led to discontinuation were psychiatric disorders (3.0%, 4.0%, and 3.0% for BRV 20, 50, and 100 mg/day, respectively vs. 1.0% for PBO). Psychiatric disorders that resulted in discontinuation in more than one patient were aggression (two BRV 20 mg/day; one BRV 50 mg/day), anxiety (one BRV 50 mg/day; one BRV 100 mg/day), irritability (one BRV 50 mg/day; one BRV 100 mg/day), depression (one BRV 50 mg/day; one PBO), and insomnia (one BRV 20 mg/day; one BRV 50 mg/day).

Severe TEAEs were reported by 4% of patients in both the combined BRV and PBO groups (Table 4). Serious AEs occurred in seven BRV-treated patients (2.3%: jaw fracture; convulsion/amnesia; grand mal convulsion; erosive gastritis; psychotic disorder; status epilepticus; humerus fracture) and six PBO-treated patients (6.0%: convulsion [three patients]; septicemia; angina pectoris; pregnancy). Two patients on BRV 50 mg/day reported a serious AE that was considered to be possibly or probably related to study medication (grand mal convulsion; psychotic disorder). One patient on PBO died from septicemia during the 12-week treatment period after receiving study drug.

Overall, there were no clinically significant changes from baseline for blood chemistry and urinalysis parameters, physical and neurologic examinations, vital signs, body weight, and ECG measurements. Increased body weight was reported during the treatment period as a TEAE by seven BRV-treated (2.3%; four 20 mg/day, two 50 mg/day, one 100 mg/day) and no PBO-treated patients, whereas decreased body weight was reported by four BRV-treated patients (1.3%; two 20 mg/day, one 50 mg/day, one 100 mg/day) and one PBO-treated patient (1.0%).

Discussion

In this phase III study in adults with uncontrolled focal seizures, BRV 50 mg/day did not demonstrate statistical significance on the primary analysis for percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period (6.5%, p = 0.261); therefore, the study was not considered as having met its primary end point based on the predefined sequential testing strategy. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037) at the 0.050 significance level. For the secondary efficacy variables, adjunctive BRV 100 mg/day showed a median percent reduction from baseline in focal seizure frequency/week of 32.5% compared with 17.0% for PBO (p = 0.004) and a ≥50% responder rate of 36.0% compared with 20.0% for PBO (p = 0.023).

Median percent reduction over PBO in focal seizure frequency was numerically larger in all BRV groups when seizure frequency was standardized over 28 days rather than 7 days, although the conclusions based on statistical significance were not altered. Therefore, choice of duration over which seizure frequencies are standardized prior to logarithmic transformation can impact the magnitude of the treatment effect while not having a notable impact on the statistical significance of the results. Prior work suggests that results for 7-day focal seizure frequency may underestimate the treatment effect relative to results based on a 28-day focal seizure frequency (Johnson et al., 2010).

The efficacy results of this study are inconclusive but may be useful in defining the lowest effective dose of BRV. Further information will be provided by an ongoing phase III study, which is designed to evaluate BRV at the higher dose of 200 mg/day and confirm the efficacy of 100 mg/day. Pooled evaluations of BRV studies may provide further clarification. Many factors can potentially affect the results of clinical studies in patients with epilepsy, including heterogeneity of the data across geographic regions or study centers, and baseline characteristics of the patient population. However, the number of patients included in this study of BRV was too small to conclusively evaluate these factors. The patient population had refractory epilepsy with a mean duration of 21.8 years and most had previously tried at least two other AEDs, with 17.1% having failed at least five AEDs. It has been suggested that an increase in PBO response rates over time has resulted in greater difficulty in demonstrating that a new AED is significantly more effective than PBO (Guekht et al., 2010). Indeed, a recent meta-analysis of trials of adjunctive AEDs in adults with refractory focal epilepsy found that responder rates to PBO virtually doubled between 1989 and 2009 (Rheims et al., 2011). A parallel increase in the responder rate to active medication was also observed, resulting in a nonsignificant trend toward a lower treatment effect in more recent studies (Rheims et al., 2011).

There was some evidence in the present study that patients who were taking concomitant LEV responded less well to BRV than those who had previously tried and discontinued LEV, or those who had never taken LEV. However, definitive conclusions cannot be drawn due to the small sample size: only 19% of patients were taking concomitant LEV. Another post hoc analysis by focal seizure subtype suggested that BRV may have had a greater effect on secondarily generalized focal seizures than simple or complex focal seizures; however, the study was not powered to evaluate the efficacy of BRV on focal seizure subtypes.

Several other studies in adults with uncontrolled focal seizures have investigated adjunctive BRV at a dose of 50 mg/day. Two exploratory phase IIb studies evaluated BRV doses of 5–50 mg/day (N01193; French et al., 2010) and 50–150 mg/day (N01114; van Paesschen et al., 2013), with a primary efficacy variable of percent reduction over PBO in baseline-adjusted focal seizure frequency/week. In study N01193, a clear dose response relationship was observed, and the 50 mg/day dose met the primary efficacy end point over the 7-week treatment period (22.1%; p = 0.004), although the 5 and 20 mg/day doses did not (9.8%, p = 0.24; 14.9%, p = 0.062, respectively (French et al., 2010). In study N01114, the primary efficacy analysis did not reach statistical significance for either the 50 (14.7%; p = 0.093) or 150 mg/day dose (13.6%; p = 0.124) over the 7-week stable-dose maintenance period; however, both BRV doses significantly reduced baseline-adjusted focal seizure frequency/week over PBO during the combined 3-week up-titration and the 7-week maintenance periods (van Paesschen et al., 2013). A phase III study (N01253) of a design similar to that of the current study met the primary efficacy end point with a median reduction in focal seizure frequency/week over PBO of 12.8% (p = 0.025) for BRV 50 mg/day (Werhahn et al., 2010). In each of these studies, the secondary efficacy outcomes (median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, seizure freedom) supported the primary efficacy analysis. The BRV 50 mg/day dose results for the primary efficacy end point in this study were modest in comparison with previous BRV studies. Overall, the results in previous studies and this study of BRV 50 mg/day in adults with uncontrolled focal seizures have been inconsistent.

BRV was well tolerated in the present study, as demonstrated by the high completion rate (BRV: 92.3%; PBO: 92.0%) and the high proportion of patients who continued into one of two long-term studies (BRV: 86.2%; PBO: 88.0%). The overall incidence of TEAEs and those most commonly reported by patients in the BRV groups (headache, somnolence, dizziness, fatigue) were consistent with previous studies (Kwan et al., 2009; French et al., 2010; Werhahn et al., 2010; van Paesschen et al., 2013). The most commonly reported TEAEs that led to discontinuation in BRV-treated patients were psychiatric disorders, including aggression, anxiety, irritability, depression, and insomnia, a side-effect profile reminiscent of that of the other SV2A ligand LEV. At present, no head-to-head studies have been done to confirm this observation. There was no clear evidence of a dose response in any of the safety and tolerability parameters, apart from a trend in the incidence of drug-related TEAEs (23.2%, 37.4%, and 42.0% for BRV 20, 50, and 100 mg/day, respectively).

Limitations of this study include the refractory nature of the patient population. In addition, since this study enrolled a homogenous, mostly Caucasian, population, caution should be used in extrapolating the results to other populations.

In conclusion, in this phase III study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037) at the 0.050 significance level. Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. Furthermore, BRV was well tolerated without up-titration over the dose range 20–100 mg/day, with a high completion rate.

Acknowledgments

This study was sponsored by UCB Pharma. UCB Pharma was involved in the design and conduct of the study, collection, management, and analysis of the data. The authors thank the members of the N01252 Study Group and the patients who participated in the study for their contribution to the research, and Laurent Turet, PhD (UCB Pharma), for critical review and coordination of the manuscript preparation. Jennifer Stewart, MSc (QXV Communications, United Kingdom), provided writing support, which was funded by UCB Pharma.

Disclosure

Philippe Ryvlin has received consultant or speaker fees from UCB Pharma, Eisai Inc., GlaxoSmithKline, Cyberonics, and Medtronic. Barbara Blaszczyk has declared no conflicts of interest. Konrad J. Werhahn, Martin E. Johnson, and Sarah Lu are employees of UCB Pharma. Konrad J. Werhahn was an investigator at University Medical Center of the Johannes Gutenberg University Mainz, Germany, at the time when this study was carried out. 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.

Biography

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    Philippe Ryvlin is Professor of Neurology and Chair of the Epilepsy Department, HCL, Lyon, France.

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