SEARCH

SEARCH BY CITATION

Keywords:

  • Adjunctive therapy;
  • Adults;
  • Antiepileptic drugs;
  • Eslicarbazepine acetate;
  • Partial-onset seizures;
  • Refractory epilepsy

Summary

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

Purpose:  To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures.

Methods:  Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks.

Key Findings:  Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations.

Significance:  Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug (AED) that has been approved in 2009 by the European Medicines Agency (EMA) as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. In humans, ESL undergoes extensive first-pass hydrolysis to its major active metabolite eslicarbazepine that represents approximately 95% of circulating active moieties (Falcao et al., 2007; Almeida et al., 2008a,b; Maia et al., 2008; Almeida et al., 2009; Perucca et al., 2011). Although there is considerable variability across species, the mouse and monkey are the most relevant species in what concerns ESL human metabolism (Hainzl et al., 2001; Bialer & Soares-da-Silva, 2012). ESL and eslicarbazepine are endowed with distinctive anticonvulsant properties (Benes et al., 1999; Ambrosio et al., 2002), characterized by a wider (1.5- to 2.5-fold) protective index in the mouse maximal electroshock and the 6-Hz psychomotor tests when compared to carbamazepine (Pires et al., 2011; Torrao et al., 2011). Despite that ESL, on its own, preferentially blocks voltage-gated sodium channels (VGSCs) in rapidly firing neurons (Bonifacio et al., 2001), the in vivo effects of ESL may be limited to its extensive conversion to eslicarbazepine. Mechanistically, however, it is important to underscore that the affinity of eslicarbazepine for VGSC in the resting state is about 15- to 5-fold lower than that of carbamazepine, oxcarbazepine, and R-licarbazepine, a feature that may translate into an enhanced inhibitory selectivity of eslicarbazepine for rapidly firing “epileptic” neurons over those with normal activity (Hebeisen et al., 2011). Other distinctive properties of eslicarbazepine over carbamazepine include 10- to 60-fold higher potency for the blockade of low and high affinity hCav3.2 inward currents (Brady et al., 2011), being devoid of effects upon submaximal γ-aminobutyric acid (GABA) currents in Ltk cells stably expressing α1β2γ2, α2β2γ2, α3β2γ2, or α5β2γ2 GABAA receptors (Bonifacio et al., 2011) and lacking inhibitory effects upon KV7.2 outward currents (Soares-da-Silva et al., 2011).

Based on the results of preclinical studies and promising results from a proof-of-concept study (Elger et al., 2007), a full clinical development program was performed in patients with partial-onset seizures. The program included three pivotal, phase III, multicenter, randomized, double-blind and placebo-controlled clinical trials: Studies BIA 2093-301 (NCT00957684), 2093-302 (NCT00957047), and 2093-303 (NCT00957372). In all studies, following a 2-week titration period, the investigational products were administered at once-daily doses for 12 weeks (maintenance period). The only major differences in study designs were the number of ESL doses tested and the titration and tapering-off regimens (Fig. S1). Studies BIA 2093-301 and 2093-302 had three ESL dose groups (400, 800, or 1,200 mg once-daily), whereas study 2093-303 had only two (800 or 1,200 mg once-daily).

The main results of each individual study have been recently published (Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010). In order to describe the efficacy and safety profile of ESL in a broader population and to perform additional analyses in patient subpopulations, data from the three studies were pooled and analyzed. Because studies 301 and 302 had three ESL dose groups (400, 800, or 1,200 mg once-daily) and study 303 had only two (800 or 1,200 mg once-daily), the main results are displayed with and without study 303. The results of these analyses, which had been planned in the study protocols, are reported herein.

Patients and Methods

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

Enrolled patients were men and women age ≥18 years with simple or complex partial seizures with or without secondary generalization for at least 12 months before screening, who were receiving one or two (1–3 in study BIA 2093-302) concomitant AEDs in a stable dosage regimen for at least 2 months before screening, and had at least four partial-onset seizures in the two 4-week periods of the 8-week baseline phase with no seizure-free interval exceeding 21 consecutive days. Patients taking felbamate were excluded for safety reasons. Oxcarbazepine was not allowed as concomitant AED as it shares common metabolites with ESL. Patients with known hypersensitivity to carbamazepine or oxcarbazepine were excluded. Efficacy data were documented by means of diaries in which patients were to record all seizures by type and date and time of occurrence. The studies were approved by the appropriate independent ethics committees or institutional review boards, and were conducted according to the international and local regulations of the countries where they were performed. Patients gave their written informed consent prior to enrollment.

The predefined key efficacy end points for the pooled data analysis were seizure frequency during the 12-week maintenance phase adjusted per 4 weeks, relative reduction in seizure frequency, and responder rate (≥50% reduction in seizure frequency). Results for all three key efficacy end points are presented for the intention-to-treat (ITT) and per-protocol (PP) populations. Seizure frequency and relative reduction of seizure frequency were compared with placebo using an analysis of covariance (ANCOVA) that modeled seizure frequency adjusting for baseline seizure frequency, treatment, study, and number of concomitant AEDs. The interaction effect of ESL and concomitant AEDs taken by at least approximately 20% of patients (carbamazepine, valproic acid, and lamotrigine) was assessed with an ANCOVA that modeled seizure frequency as a function of ESL dose, study, baseline seizure frequency, concomitantly given AED, and treatment by concomitant AED interaction. The treatment differences in responder rate were evaluated using a Cochran-Mantel-Haenszel test with study as stratification factor. Additional efficacy variables performed in the ITT population included the number of days with seizures and the proportion of seizure-free patients. The analyses were performed in the full population and predefined subpopulations.

Safety data included adverse events (AEs) reporting, as well as clinical laboratory tests (hematology, coagulation, biochemistry, thyroid function, and urinalysis), records of vital signs and weight, and electrocardiography (ECG). All AEs were recorded by the investigator and assessed with regards to severity (mild, moderate, or severe), causality, and seriousness. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA, MSSO, Chantilly, VA, U.S.A.) version 10.0. Pharmacokinetic data were obtained from blood trough levels (i.e., predose) of eslicarbazepine and concomitant AEDs at the end of the baseline period and end of the 12-week maintenance period.

Data obtained from 1,049 patients enrolled by 125 centers, in 23 countries, in the three studies were pooled and analyzed. Main baseline population characteristics are presented in Table S1. The population was predominantly Caucasian, roughly 50% male, and with a mean age of approximately 37 years and mean epilepsy duration of 22 years. Most seizures at baseline were either simple partial or complex partial, and the frequency for each seizure type was similar in all treatment groups. The majority of patients were taking two AEDs, and the most common concomitant AEDs were carbamazepine (≥55% in any group), valproic acid (≥19% in any group), and lamotrigine (≥18% in any group).

Results

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

Efficacy results

The reduction in seizure frequency during the maintenance period was significantly higher (p < 0.0001) for the 800 and 1,200 mg ESL groups compared to the placebo group in both the ITT and PP populations. The ANCOVA of seizure frequency per 4 weeks is presented in Table S2. The least square (LS) means and 95% confidence intervals (CIs) of relative reduction in seizure frequency over the 12-week maintenance period are displayed in Fig. S2. The ANCOVA showed significant differences between the placebo group and the ESL 800 mg (p < 0.001) and 1,200 mg (p < 0.001) groups. The ANCOVA of seizure frequency by seizure type in the pooled data from studies BIA-2093-301, 2093-302, and 2093-303 showed that the difference compared to placebo for simple partial and complex partial seizures was statistically significant for the 800 mg once-daily (p < 0.001 and p < 0.01, respectively) and 1,200 mg once-daily (p < 0.01 and p < 0.0001, respectively) groups. Number of patients and frequency of seizures were too low to apply the ANCOVA model to the other seizure types. The results displayed in Fig. 1 showed that the efficacy of ESL was similar regardless of whether patients were taking carbamazepine, lamotrigine, or valproic acid.

image

Figure 1.  Mean and 95%CI seizure frequency per 4 weeks over the 12-week maintenance period adjusted for most commonly used concomitant antiepileptic drugs: carbamazepine, lamotrigine, and valproic acid (ITT populations).

Download figure to PowerPoint

Figure 2 presents the percentage of responders (patients with a ≥50% decrease in seizure frequency relative to baseline). The responder rate was significantly higher in the ESL 800 and 1,200 mg groups than in the placebo group. In the pooled data from ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the responder rate was 36% with ESL 800 mg and 44% with ESL 1,200 mg (placebo: 22%). Median relative reduction in seizure frequency was 15% with placebo compared to 35% with ESL 800 mg and 39% with ESL 1,200 mg.

image

Figure 2.  Responder rate (i.e., percentage of patients with ≥50% reduction in seizure frequency) over the 12-week maintenance period (ITT and PP populations).

Download figure to PowerPoint

In the pooled ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the mean ± standard deviation (SD) (median) number of days with seizures per 4 weeks at baseline was 8.0 ± 5.7 (5.9) with placebo, 8.5 ± 5.8 (6.5) with 800 mg, and 8.6 ± 6.2 (6.3) with 1,200 mg. During the maintenance period, the mean ± SD (median) number of days with seizures per 4 weeks decreased to 7.0 ± 5.8 (5.3) with placebo, 6.1 ± 5.8 (4.3) with 800 mg, and 6.1 ± 6.2 (3.8) with 1,200 mg. As compared with placebo, the decrease in the number of days with seizures was statistically significant in the 800 mg once-daily (p < 0.01) and 1,200 mg once-daily (p < 0.001) ESL groups. The proportion of subjects who were seizure-free during the maintenance period increased with increasing doses of ESL, from 2–3% of subjects in the placebo and ESL 400 mg groups to 3.8% of subjects in the 800 mg group and 7.5% of subjects in the 1,200 mg group.

Efficacy of ESL 800 and 1,200 mg was demonstrated during the maintenance period regardless of whether patients were taking any of the most commonly used concomitant AEDs. In the pooled data from ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the median relative reduction in seizure frequency in patients taking carbamazepine was 14.3%, 33.3%, and 44.3%, respectively, in the placebo, ESL 800, and 1,200 mg groups; in patients not taking carbamazepine the relative reduction was 14.8%, 38.9%, and 37.8%, respectively. The trend of the median relative reduction in seizure frequency was also relatively identical between patients taking lamotrigine (placebo: 7.4%, 800 mg: 28.9%, 1,200 mg: 28.6%) and patients not taking lamotrigine (placebo: 16.5%, 800 mg: 37.5%, 1,200 mg: 45.3%), and between patients taking valproic acid (placebo: 26.4%, 800 mg: 41.8%, 1,200 mg: 39.9%) and patients not taking valproic acid (placebo: 10.1%, 800 mg: 33.3%, 1,200 mg: 38.3%). These results are consistent with those reported for the responder rates.

No relevant differences were found between men and women, patients with longer (≥20 years) or shorter (<20 years) epilepsy duration, patients <18 years or 18–50 years of age at diagnosis, and for various geographical regions, number of concomitant AEDs (1 or 2), or types of seizures experienced during the baseline period. In the pooled data from ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the median relative reduction in seizure frequency in men (placebo: 15.8%, 800 mg: 35.6%, 1,200 mg: 32.9%) was not significantly different from that in women (placebo: 13.6%, 800 mg: 34.7%, 1,200 mg: 47.2%). Consistently, the responder rate in men (placebo: 20.4%, 800 mg: 35.3%, 1,200 mg: 38.9%) was not significantly different from that in women (placebo: 22.5%, 800 mg: 37.2%, 1,200 mg: 48.0%). The efficacy observed in each dose group was generally comparable regardless of the duration of epilepsy. The median relative reduction in seizure frequency in patients whose epilepsy duration was <20 years (placebo: 13.2%, 800 mg: 36.1%, 1,200 mg: 42.6%) was not significantly different from that in patients whose epilepsy duration was 20 years or more (placebo: 15.8%, 800 mg: 34.2%, 1,200 mg: 34.5%). Consistently, the responder rate was also identical in patients with an epileptic duration <20 years (placebo: 22.1%, 800 mg: 36.2%, 1,200 mg: 45.0%) and 20 years or more (placebo: 21.0%, 800 mg: 36.3%, 1,200 mg: 42.1%).

Despite the fact that there was no upper age limit in each study, very few (n = 14) patients ≥65 years of age were enrolled (Table S1). As a result, it was not possible to make meaningful comparisons between ESL and placebo for elderly patients.

The efficacy observed in each dose group was generally comparable regardless of the age at time of diagnosis. In the pooled data from ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the median relative reduction in seizure frequency in patients whose age at time of diagnosis was <18 years (placebo: 11.8%, 800 mg: 34.1%, 1,200 mg: 37.8%) was not significantly different from that in patients whose age at time of diagnosis was 18–50 years of age (placebo: 25.3%, 800 mg: 38.9%, 1,200 mg: 45.4%). The responder rate in patients whose age at time of diagnosis was <18 years (placebo: 17.3%, 800 mg: 34.1%, 1,200 mg: 42.8%) was not significantly different from that in patients whose age at time of diagnosis was 18–50 years of age (placebo: 32.9%, 800 mg: 38.6%, 1,200 mg: 45.0%).

The efficacy observed in each dose group was generally comparable for patients taking one AED and those taking two AEDs. Descriptive or confirmatory comparisons of patients who took more than two AEDs was not possible due to the small number of patients in this subpopulation (n = 40). In the pooled data from ITT population of studies BIA-2093-301, 2093-302, and 2093-303, the median relative reduction in seizure frequency was similar in patients taking one AED (placebo: 14.1%, 800 mg: 35.6%, 1,200 mg: 43.7%) and those taking two AEDs (placebo: 13.5%, 800 mg: 34.5%, 1,200 mg: 38.7%). The responder rate was similar in patients taking one AED (placebo: 23.1%, 800 mg: 37.7%, 1,200 mg: 45.6%) and those taking two AEDs (placebo: 22.2%, 800 mg: 35.7%, 1,200 mg: 42.6%).

Safety results

Adverse events

The overall incidence of treatment-emergent AEs (TEAEs) increased with the increase in the dose of ESL, both for all TEAEs as well as for those considered possibly related (Table S3). This was also observed for TEAEs leading to study discontinuation (mainly vertigo, diplopia, blurred vision, nausea and vomiting, fatigue, abnormal coordination, dizziness, headache, and somnolence). No dose-dependent trend was observed for serious TEAEs (SAEs), which had a similar incidence in each of the ESL treatment groups. Only one patient in the placebo group died during the studies.

Table 1 presents the incidence and severity of TEAEs reported by at least 10% of patients in any treatment group (dizziness, somnolence, and headache). The majority of TEAEs were mild or moderate in severity. The difference in the frequency of TEAEs between the ESL and the placebo groups was observed mainly during the first 6 weeks of treatment (Table S4). Thereafter, the frequency of TEAEs reported in the ESL and the placebo groups was similar. Differences in titration regimens across three studies did not allow a direct comparison of the TEAE incidence between the different titration regimens. Between 35% and 45% of patients who started at ESL 400 mg reported TEAEs, whereas those patients who began treatment at ESL 600 mg had an incidence of TEAEs of 51% and patients initially treated with ESL 800 mg had an incidence of TEAEs of 73–78%.

Table 1.   Incidence and severity of treatment-emergent adverse events (TEAEs) in at least 10% of patients in any treatment group (safety populations)
Studies 301 + 302 combined
MedDRA Preferred TermPlacebo (n = 202)ESL 400 mg (n = 196)ESL 800 mg (n = 199)ESL 1,200 mg (n = 200)
Total patients with TEAEs, n (%)100 (49.5)119 (60.7)133 (66.8)140 (70.0)
 Mild48 (23.8)56 (28.6)55 (27.6)44 (22.0)
 Moderate44 (21.8)45 (23.0)63 (31.7)72 (36.0)
 Severe8 (4.0)18 (9.2)15 (7.5)24 (12.0)
Dizziness, n (%)12 (5.9)26 (13.3)44 (22.1)57 (28.5)
 Mild11 (5.4)14 (7.1)24 (12.1)26 (13.0)
 Moderate1 (0.5)11 (5.6)18 (9.0)21 (10.5)
 Severe01 (0.5)2 (1.0)10 (5.0)
Somnolence, n (%)19 (9.4)21 (10.7)26 (13.1)31 (15.5)
 Mild16 (7.9)18 (9.2)17 (8.5)17 (8.5)
 Moderate2 (1.0)3 (1.5)9 (4.5)11 (5.5)
 Severe1 (0.5)003 (1.5)
Headache, n (%)15 (7.4)17 (8.7)24 (12.1)30 (15.0)
 Mild9 (4.5)10 (5.1)13 (6.5)15 (7.5)
 Moderate6 (3.0)5 (2.6)10 (5.0)14 (7.0)
 Severe02 (1.0)1 (0.5)1 (0.5)
Nausea, n (%)5 (2.5)10 (5.1)16 (8.0)20 (10.0)
 Mild3 (1.5)6 (3.1)7 (3.5)7 (3.5)
 Moderate2 (1.0)3 (1.5)9 (4.5)11 (5.5)
 Severe01 (0.5)02 (1.0)
Studies 301 + 302 + 303 combined
 Placebo (n = 289)ESL 800 mg (n = 284)ESL 1,200 mg (n = 280)
Total patients with TEAEs, n (%)134 (46.4)178 (62.7)189 (67.5)
 Mild56 (19.4)72 (25.4)56 (20.0)
 Moderate65 (22.5) 82 (28.9)101 (36.1)
 Severe13 (4.5)24 (8.5)32 (11.4)
Dizziness, n (%)21 (7.3)60 (21.1)81 (28.9)
 Mild13 (4.5)33 (11.6)33 (11.8)
 Moderate6 (2.1)21 (7.4)36 (12.9)
 Severe2 (0.7)6 (2.1)12 (4.3)
Somnolence, n (%)27 (9.3)37 (13.0)42 (15.0)
 Mild18 (6.2)22 (7.7)19 (6.8)
 Moderate7 (2.4)12 (4.2)19 (6.8)
 Severe2 (0.7)3 (1.1)4 (1.4)
Headache, n (%)25 (8.7)29 (10.2)38 (13.6)
 Mild12 (4.2)13 (4.6)19 (6.8)
 Moderate12 (4.2)13 (4.6)17 (6.1)
 Severe1 (0.3)3 (1.1)2 (0.7)
Nausea, n (%)6 (2.1)21 (7.4)28 (10.0)
 Mild3 (1.0)8 (2.8)9 (3.2)
 Moderate3 (1.0)11 (3.9)16 (5.7)
 Severe02 (0.7)3 (1.1)

The incidence of TEAEs in the pooled data from safety population of studies BIA-2093-301, 2093-302, and 2093-303 was higher in women (68.3%) treated with ESL than in men (59.2%), which is in contrast to the comparable incidence in placebo-treated patients (women 47.9%; men 44.8%). The difference in ESL group was accounted for mainly by the difference in the 1,200 mg group (women 75.8%; men 58.0%). The number of AEDs (one or two) appeared to have no effect on the incidence of TEAEs. Overall, the incidence of TEAEs in the ESL groups (54.1–60.3% with one AED; 63.1– 68.5% with two AEDs) relative to placebo (46.2% with one AED; 46.7% with two AEDs) was comparable in these subpopulations.

Figure 3 illustrates the TEAEs rate in the subpopulations of patients treated with or without the most frequently used concomitant AEDs, in the pooled data from safety population of studies BIA-2093-301, 2093-302, and 2093-303. Although the incidence of TEAEs was higher in patients treated with carbamazepine than in patients not treated with carbamazepine, the incidence of any TEAE in the ESL groups (no carbamazepine 50.6– 60.6%, with carbamazepine 67.8–73.2%) relative to placebo (no carbamazepine 39.8%, with carbamazepine 50.3%) was generally comparable in both subpopulations. However, concomitant treatment with carbamazepine increased the incidence of diplopia (11.4% of patients treated with carbamazepine, 2.4% of patients not treated with carbamazepine), abnormal coordination (6.7% treated with carbamazepine, 2.7% not treated with carbamazepine), and dizziness (30.0% treated with carbamazepine, 11.5% not treated with carbamazepine). The incidence of TEAEs in the ESL groups relative to placebo was also generally comparable in the lamotrigine and valproic acid subpopulations, suggesting that treatment with concomitant lamotrigine or valproic acid had no effect on the incidence of TEAEs.

image

Figure 3.  Proportion of patients reporting adverse events in the sub-populations of patients treated with or without carbamazepine, lamotrigine, or valproic acid as concomitant AEDs.

Download figure to PowerPoint

Clinical laboratory assessments

Changes in mean clinical laboratory parameters (hematology, blood chemistry, urine, and coagulation) did not yield clinically relevant findings. The review of individual data showed an incidence of clinically significant hematology abnormalities of <4% in any treatment group. None of the hematology parameters showed a dose dependency. Very few patients had clinically significant abnormalities in biochemistry parameters (<1.8% in any treatment group) or liver function tests (<1% in any treatment group).

Shift tables summarizing laboratory values that fell outside clinically significant limits showed that for most parameters there was a natural degree of fluctuation in the population around the normal ranges, with no consistent patterns. In the pooled data from safety population of studies BIA-2093-301, 2093-302, and 2093-303, a shift from baseline to the end of the maintenance treatment period in sodium levels from normal to low (<135 mm) was reported in, respectively, 3.1%, 6.1%, 7.1%, and 8.8% of patients treated with placebo and ESL 400, 800, and 1,200 mg, and a shift from normal to high (>146 mm) was reported in, respectively, 1.5%, 0.0%, 2.5%, and 0.5% of patients. Hyponatremia <125 mm was reported in four patients: 1 (0.5%) on ESL 400 mg, 2 (0.7%) on 800 mg, and 1 (0.4%) on 1,200 mg. All these patients were cotreated with ≥1,000 mg carbamazepine/day and all had sodium levels <135 mm before starting treatment with ESL. No change patterns were noticed in triglycerides or cholesterol fractions. In the placebo and ESL 400, 800, and 1,200 mg groups, low-density lipoprotein (LDL) cholesterol increased from normal to high in, respectively, 8.1%, 7.8%, 8.7%, and 9.8% of patients, and decreased from normal to low in, respectively, 2.7%, 1.7%, 2.5%, and 2.9% of patients; high-density lipoprotein (HDL) cholesterol increased from normal to high in, respectively, 2.7%, 3.3%, 5.8%, and 4.4% of patients and decreased from normal to low in, respectively, 0.4%, 1.1%, 2.5%, and 0.5% of patients.

No changes in vital signs or body weight were of clinical concern. No clinically relevant ECG abnormalities were observed in association with ESL treatment. There was no relevant trend toward changes in heart rate or prolongation of ECG intervals, and no clinically significant prolongation of the QTc interval was observed in any patient.

Pharmacokinetics

The mean (95%CI) “trough” (i.e., predose; Cmin) plasma concentrations of eslicarbazepine at the end of the maintenance period were 2.1 (1.9–2.4) μg/ml after ESL 400 mg (n = 160), 5.1 (4.5–5.6) μg/ml after 800 mg (n = 222), and 8.1 (7.3–8.9) μg/ml after 1,200 mg (n = 189).

Plasma concentrations of concomitant AEDs were determined on predose samples taken at the start and end of treatment with ESL. The end/start of treatment Cmin ratio and 95% CI values for the most common AEDs (carbamazepine, lamotrigine, and valproic acid) are displayed in Fig. S3. A mild decrease in carbamazepine (13%) and lamotrigine (25%) Cmin was observed following administration of ESL 1,200 mg. No other relevant pharmacokinetic changes were observed.

Discussion

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

The pooling of data from multiple studies with similar designs and similar patient populations can be a powerful tool to address clinical questions not readily answered in the individual studies (Reife et al., 2000). Individual studies are necessarily limited in terms of sample size and usually only powered for the main study end point(s). The pooling of data allows statistical power sufficient for the evaluation of the treatment effect in subpopulations, for example, the influence of patient characteristics on response. Therefore, a combined analysis of the pivotal studies of ESL as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization was planned in the study protocols.

The results of this integrated analysis demonstrated that adjunctive ESL once-daily doses of 800 and 1,200 mg were efficacious and well tolerated in treatment of patients with partial-onset seizures refractory to stable AED treatment. The efficacy of ESL 800 and 1,200 mg once-daily doses clearly showed consistent results across all efficacy end points and was independent of study population characteristics as well as the type and number of concomitant AEDs used. Seizure frequency was significantly reduced with ESL 800 mg once-daily (p < 0.0001) and 1,200 mg once-daily (p < 0.0001) compared to placebo.

The integrated analysis did not identify any patient characteristic that would predict a decrease or increase in ESL efficacy. ESL 800 and 1,200 mg was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant AEDs.

ESL is a novel VGSC blocker to be administered once-daily. Two of the concomitant AEDs most frequently used by the combined study population (carbamazepine and lamotrigine) were also VGSC blockers (Walker et al., 2009). Suggestion has been made that combining AEDs with different mechanisms of action should be beneficial (Brodie & Yuen, 1997). However, current knowledge on the mechanisms of action of various drugs is too limited to allow a rational application of this approach and, thus, AEDs are usually combined mainly on empirical grounds (Perucca, 2009). Hence, our rationale was not to exclude carbamazepine or other VGSC blockers (except oxcarbazepine, because it shares metabolites with ESL—Almeida et al., 2008b; Maia et al., 2008) from the add-on phase III studies with ESL. As discussed previously (Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010), the explanation for the efficacy of ESL as an adjunctive therapy in patients refractory to other VGSC blockers is certainly multifactorial, and includes pharmacokinetic/pharmacodynamic issues such as mechanisms of action that differ from VGSC blockade and the biopharmaceutical properties and pharmacokinetic profile of the ESL active entity, eslicarbazepine.

Only very few patients ≥65 years of age have been exposed to ESL in the pooled population (n = 9). The exclusion criteria for all three phase III studies did not include any upper age limit. Therefore, the age range of the population included in these studies reflects that of the target population, that is, those patients who are refractory to treatment. Although it is acknowledged that treating patients aged 65 years or older poses special problems involving age-related comorbidities and changes in pharmacokinetics, epilepsy is a secondary condition that can be reasonably well controlled. Approximately 80% of elderly patients diagnosed with epilepsy respond well to treatment with AEDs and remain free from seizures for at least 1 year (Brodie & Kwan, 2005). As a result, epilepsy in elderly patients tends to be well controlled with monotherapy without the need for adjunctive therapy.

The observed dose-dependent increase in the frequency of TEAEs was due primarily to a higher incidence of diplopia, nausea, abnormal coordination, dizziness, headache, and somnolence in the 800 and 1,200 mg ESL groups. The difference in the frequency of TEAEs between the ESL treatment groups and the placebo group was observed mainly during the first weeks of treatment. The incidence of TEAEs was higher in patients who started titration at a higher dose of ESL. Discontinuation due to TEAEs was dose-dependent, ranging from 5% in the placebo group to 19% in the ESL 1,200 mg group in the pooled data from safety population of studies BIA-2093-301, 2093-302, and 2093-303. The total discontinuation rate for ESL patients was 14%, which is low compared to rates reported in a study with oxcarbazepine (Barcs et al., 2000) where incidences of discontinuation of 12%, 36%, and 67% were found following oxcarbazepine daily doses of, respectively, 600, 1,200, and 2,400 mg, and similar to rates reported for other AEDs, such as lamotrigine, topiramate, and tiagabine (French et al., 2004).

Trough concentrations of eslicarbazepine showed to be dose-proportional. In order to expand knowledge on ESL pharmacokinetics in adults with epilepsy, a pharmacokinetic study was performed in a group of patients participating in an open-label extension trial who underwent frequent blood sampling during a dosing interval at steady-state (Perucca et al., 2011). In this particular substudy, eslicarbazepine Cmin values at all ESL dose levels were similar to those reported here. Eslicarbazepine Cmax concentrations were 9.7, 15.5, and 23.0 μg/ml, and areas under the plasma concentration-time curve over the dosing interval (AUC0–24) were 132.5, 205.4, and 336.1 μg h/ml in patients receiving ESL doses of 400, 800, and 1,200 mg once-daily, respectively (Perucca et al., 2011). These pharmacokinetic parameters (Cmax and AUC0–24) were dose-proportional and appear to represent exposure at therapeutic levels.

A mild decrease in carbamazepine and lamotrigine trough concentrations was observed following administration of ESL 1,200 mg. The plausible causal mechanism is a mild induction of CYP3A4, a cytochrome P450 (CYP) isoenzyme involved in the carbamazepine metabolism (Sillanpaa et al., 2009), and a mild induction of uridine diphosphate glucuronosyltransferases (UGTs), which are involved in lamotrigine glucuronidation (Rowland et al., 2006). Results for lamotrigine are consistent with those from a dedicated drug–drug interaction study in healthy subjects that also found a slight decrease in lamotrigine systemic exposure following ESL 1,200 mg (Almeida et al., 2010). The decrease was not significant, and it was concluded that no dosage adjustment appears to be usually required in either lamotrigine or ESL when the drugs are coadministered.

In conclusion, the efficacy of ESL 800 and 1,200 mg once-daily administered to patients with partial-onset seizures refractory to stable AED therapy showed consistent results across efficacy end points and was independent of population characteristics and concomitant AEDs. Given that ESL 800 mg caused less discontinuation due to TEAEs and presented a lower potential for pharmacokinetic interactions than ESL 1,200 mg, the combined analyses on these pooled data suggest that ESL 800 mg once-daily provides optimal balance of efficacy and tolerability as ESL target dose for adjunctive therapy of most patients with partial-onset seizures.

Disclosure

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

A. Gil-Nagel, C. Elger, E. Ben-Menachem, P. Halász, J. Lopes-Lima, and A. A. Gabbai have received research grants from BIAL, the sponsor of the studies. A. Falcão received consultancy honoraria. L. Almeida, T. Nunes and P. Soares-da-Silva were employees of BIAL at the time of the studies. 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.

References

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information
  • Almeida L, Minciu I, Nunes T, Butoianu N, Falcao A, Magureanu SA, Soares-da-Silva P. (2008a) Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol48:966977.
  • Almeida L, Potgieter JH, Maia J, Potgieter MA, Mota F, Soares-da-Silva P. (2008b) Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol64:267273.
  • Almeida L, Bialer M, Soares-da-Silva P. (2009) Eslicarbazepine acetate. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 485498.
  • Almeida L, Nunes T, Sicard E, Rocha JF, Falcao A, Brunet JS, Lefebvre M, Soares-da-Silva P. (2010) Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. Acta Neurol Scand121:257264.
  • Ambrosio AF, Soares-da-Silva P, Carvalho CM, Carvalho AP. (2002) Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res27:121130.
  • Barcs G, Walker EB, Elger CE, Scaramelli A, Stefan H, Sturm Y, Moore A, Flesch G, Kramer L, D’Souza J. (2000) Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia41:15971607.
    Direct Link:
  • Benes J, Parada A, Figueiredo AA, Alves PC, Freitas AP, Learmonth DA, Cunha RA, Garrett J, Soares-da-Silva P. (1999) Anticonvulsant and sodium channel-blocking properties of novel 10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem42:25822587.
  • Ben-Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares-da-Silva P. (2010) Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res89:278285.
  • Bialer M, Soares-da-Silva P. (2012) Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia53:935946.
  • Bonifacio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L, Soares-da-Silva P. (2001) Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia42:600608.
  • Bonifacio MJ, Bulling A, Hebeisen S, Konrad D, Soares-da-Silva P. (2011) Eslicarbazepine and R-licarbazepine do not have effects on ion transmission through alpha1, alpha2, alpha3 and alpha5 GABA channels. Epilepsia52(Suppl. 6):258.
  • Brady K, Hebeisen S, Konrad D, Soares-da-Silva P. (2011) The effects of eslicarbazepine, R-licarbazepine, oxcarbazepine and carbamazepine on ion transmission Cav3.2 channels. Epilepsia52(Suppl. 6):260.
  • Brodie MJ, Kwan P. (2005) Epilepsy in elderly people. Br Med J331:13171322.
  • Brodie MJ, Yuen AW. (1997) Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group. Epilepsy Res26:423432.
  • Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P. (2007) Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia48:497504.
  • Elger C, Halasz P, Maia J, Almeida L, Soares-da-Silva P. (2009) Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia50:454463.
  • Falcao A, Maia J, Almeida L, Mazur D, Gellert M, Soares-da-Silva P. (2007) Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel blocker. Biopharm Drug Dispos28:249256.
  • French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA. (2004) Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia45:410423.
  • Gil-Nagel A, Lopes-Lima J, Almeida L, Maia J, Soares-da-Silva P. (2009) Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand120:281287.
  • Hainzl D, Parada A, Soares-da-Silva P. (2001) Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(−)-10,11-dihydro-10-hydroxy carbamazepine. Epilepsy Res44:197206.
  • Hebeisen S, Brady K, Konrad D, Soares-da-Silva P. (2011) Inhibitory effects of eslicarbazepine acetate and its metabolites against neuronal voltage-gated sodium channels. Epilepsia52:257258.
  • Maia J, Almeida L, Falcão A, Soares E, Mota F, Potgieter JH, Potgieter MA, Soares-da-Silva P. (2008) Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther46:119130.
  • Perucca E. (2009) General principles of medical management. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 121139.
  • Perucca E, Elger C, Halasz P, Falcao A, Almeida L, Soares-da-Silva P. (2011) Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures. Epilepsy Res96:132139.
  • Pires N, Palma N, Loureiro AI, Bonifacio MJ, Wright LC, Soares-da-Silva P. (2011) Effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the maximal electroconvulsive test in the mice. Epilepsia52(Suppl. 6):118.
  • Reife R, Pledger G, Wu SC. (2000) Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia41(Suppl. 1):S66S71.
  • Rowland A, Elliot DJ, Williams JA, Mackenzie PI, Dickinson RG, Miners JO. (2006) In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos34:10551062.
  • Sillanpaa M, Haataja L, Tomson T, Johannessen SI. (2009) Carbamazepine. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 459474.
  • Soares-da-Silva P, Bulling A, Hebeisen S, Konrad D. (2011) The effects of eslicarbazepine, R-licarbazepine and carbamazepine on ion transmission through Kv7.2 channels. Epilepsia52:258259.
  • Torrao L, Machado R, Pires N, Palma N, Bonifacio MJ, Wright LC, Soares-da-Silva P. (2011) The effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the 6-Hz psychomotor seizure model in the mice. Epilepsia52:118119.
  • Walker C, Surges R, Fisher A. (2009) Mechanisms of antiepileptic drug action. In Shorvon S, Perucca E, Engel J (Eds) The treatment of epilepsy. Blackwell Publishing, Oxford, pp. 91108.

Supporting Information

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article

Figure S1. Study designs.

Figure S2. Mean and 95% CI of relative (%) reduction in seizure frequency over the 12-week maintenance period (ITT and PP populations).

Figure S3. Mean end/start of treatment ratio and 95% CI of trough (Cmin) plasma concentrations of most frequently used concomitant AEDs, carbamazepine, lamotrigine, and valproic acid.

Table S1. Main baseline characteristics of study population.

Table S2. ANCOVA of seizure frequency per 4 weeks over the 12-week maintenance period (ITT and PP populations).

Table S3. Summary of treatment-emergent adverse events (TEAEs) (safety populations).

Table S4. Time to onset of treatment-emergent adverse events (TEAEs).

Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than regarding missing material) should be directed to the corresponding author for the article.

Supporting Information

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
  10. Supporting Information

Figure S1. Study designs.

Figure S2. Mean and 95% CI of relative (%) reduction in seizure frequency over the 12-week maintenance period (ITT and PP populations).

Figure S3. Mean end/start of treatment ratio and 95% CI of trough (Cmin) plasma concentrations of most frequency used concomitant AEDs, carbamazepine, lamotrigine and valproic acid.

Table S1. Main baseline characteristics of study population.

Table S2. ANCOVA of seizure frequency per 4 weeks over the 12-week maintenance period (ITT and PP populations).

Table S3. Summary of treatment-emergent adverse events (TEAEs) (safety populations).

Table S4. Time to onset of treatment-emergent adverse events (TEAEs).

FilenameFormatSizeDescription
epi3605_sm_FigS1.tif267KSupporting info item
epi3605_sm_FigS2.tif105KSupporting info item
epi3605_sm_FigS3.tif144KSupporting info item
epi3605_sm_TableS1-S3.docx51KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.