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Keywords:

  • Antiepileptic drugs;
  • Epilepsy;
  • Partial-onset seizures;
  • Randomized controlled trial;
  • Lacosamide

Summary

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

Purpose: To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs).

Methods: This multicenter, double-blind, placebo-controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8-week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force-titrated weekly (100 mg/day increments) to the target dose, and entered a 12-week maintenance period.

Results: A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention-to-treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic–clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose-related adverse events included dizziness, nausea, and vomiting.

Discussion: Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial-onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic–clonic seizures.

Epilepsy is one of the most common neurologic disorders, affecting up to 2% of the population worldwide (CDC, 2008). Studies show that patients with refractory seizures have higher morbidity and mortality rates, as well as a poorer quality of life, than those with controlled seizures (Sperling, 2004; Forsgren et al., 2005; Wiebe, 2006; Harden et al., 2007; Tracy et al., 2007). Therefore, treatment that reduces the frequency of seizures may improve patients’ quality of life.

Treatment of epilepsy often imposes an exposure to various antiepileptic drugs (AEDs) and requires long-term commitment and compliance from the patient. Despite treatment with multiple and newer AEDs, approximately 30% of patients with epilepsy experience recurrent seizures (Kwan & Brodie, 2007; Perucca, 2007), and many experience undesirable side effects. Therefore, there remains a need to develop new agents that will reduce seizure frequency and severity as well as provide improved tolerability.

Lacosamide (VIMPAT, SPM 927, UCB-Group, Schwarz Pharma AG, Monheim am Rhein, Germany) is a novel antiepileptic drug that is the result of focused research on functionalized amino acids with anticonvulsant activity (Andurkar et al., 1999; Hovinga, 2003). Based on the efficacy and therapeutic index observed in a range of animal models of epilepsy at the National Institutes of Health (NIH) Anticonvulsant Screening Program, lacosamide warranted further evaluation and was subsequently developed as an AED for both oral and intravenous use. Lacosamide has a novel mode of action (MOA) that appears to be different from existing AEDs in that it selectively enhances the slow inactivation of voltage-gated sodium channels (Beyreuther et al., 2007; Errington et al., 2008).

Lacosamide has a linear pharmacokinetic profile with high oral bioavailability and an elimination half-life of 13 h, allowing twice-daily dosing. Lacosamide is primarily eliminated renally as unchanged drug and an inactive metabolite (Horstmann et al., 2002; Hovinga, 2003; Bialer et al., 2007). Lacosamide has low plasma protein binding (≤15%) and a low potential for pharmacokinetic drug–drug interactions (Thomas et al., 2006).

The efficacy and safety of adjunctive lacosamide for partial-onset seizures was established in three multicenter, randomized, double-blind, placebo-controlled trials. Initially, a phase IIb multinational trial (SP667) evaluated lacosamide 200, 400, and 600 mg/day compared with placebo as adjunctive treatment in 418 adults with uncontrolled partial-onset seizures (POS) taking one to two AEDs with or without additional vagus nerve stimulation (VNS) (Ben-Menachem et al., 2007). The lacosamide 400 and 600 mg/day groups showed significantly larger reductions in seizure frequency and significantly greater 50% responder rates compared with placebo. Adverse events included dizziness, headache, and diplopia and were primarily mild or moderate in intensity. Two additional phase III trials (SP755 and SP754) were conducted in parallel to confirm these results in an expanded population of patients, taking up to three AEDs with or without additional VNS. These trials differed in location and in lacosamide doses studied. Trial SP755 (Halász et al., 2009) was conducted in Europe and Australia and evaluated lacosamide 200 mg/day and 400 mg/day compared to placebo in a total of 485 randomized patients. The lacosamide 200 and 400 mg/day groups demonstrated significant reductions in seizure frequency, and the 400 mg/day group showed a significantly greater 50% responder rate compared with placebo. The 50% responder rate for lacosamide 200 mg/day was numerically higher than placebo, but did not reach statistical significance. Adverse events with lacosamide treatment included dizziness, nausea, and vomiting; most were mild or moderate in intensity.

This paper reports the results of the second phase III trial, SP754 (NCT00136019). In contrast to trial SP755, trial SP754 was conducted in the United States, with a primary objective to evaluate the efficacy of lacosamide 400 and 600 mg/day as adjunctive treatment for POS and secondary objectives to further assess the safety, potential dose-response relationships, and steady-state plasma concentrations of lacosamide and concomitant AEDs.

Methods

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

This trial was conducted between March 2004 and August 2006 at 72 enrolling sites in the United States in accordance with the International Conference on Harmonisation guidelines and the Declaration of Helsinki. Institutional review boards for each site approved the trial protocol, amendments, and informed consents. All patients or their legal representatives gave written informed consent before trial participation.

Patients

Men and women 16–70 years of age with partial-onset seizures, with or without secondary generalization, were eligible. Diagnosis was based on the Classification of Epileptic Seizures (Commission on Classification and Terminology of the International League Against Epilpesy, 1981) and supported by electroencephalography (EEG) and either magnetic resonance imaging (MRI) or computed tomography (CT) scan consistent with a diagnosis of epilepsy. Patients were to have had at least a 2-year history of partial-onset seizures despite treatment with at least two AEDs (concurrently or sequentially) and were to be currently experiencing at least four partial-onset seizures per 28 days, with no seizure-free period longer than 21 days during the 8 weeks prior to baseline and during the 8-week baseline period. Patients were to have been on a stable dosage regimen of one to three AEDs, with or without VNS (stable settings), in the 4 weeks before enrollment and during baseline.

Patients were excluded if they had previously received lacosamide or had participated in any other investigational trial within the last 2 months. Females who were pregnant, breast-feeding, or of childbearing potential and not using approved contraception methods were excluded. Patients were also excluded if they had a history of chronic alcohol or drug abuse; any medical condition that might jeopardize their health or compromise their ability to participate; liver function test results of at least two times the upper limit of normal (ULN); creatinine clearance <50 ml/min; diastolic blood pressure <50 mm Hg or >105 mm Hg; or pulse <50 or >110 beats per min after 3 min in a sitting position; heart rate by electrocardiography (ECG) <50 or >110 beats per min; confirmed clinically significant ECG abnormality; history of severe anaphylactic reaction or serious blood dyscrasias; nonepileptic events, including psychogenic seizures; seizure clustering during the 8-week period before trial entry or during baseline; history of primary generalized seizures; history of status epilepticus in the last 12 months; concomitant or previous felbamate or vigabatrin therapy within the last 6 months; any other clinically significant condition, or recent chronic consumption of non-AEDs that might interfere with drug absorption, distribution, metabolism, or excretion; or regular use of one of the following medications influencing the central nervous system (CNS)—neuroleptics, monoamine oxidase inhibitors, barbiturates (except when taken as concomitant anticonvulsant treatment), or narcotic analgesics—within 4 weeks prior to enrollment.

Trial design

This randomized, double-blind, placebo-controlled, parallel-group trial consisted of a screening visit, an 8-week baseline period (baseline), an 18-week treatment period [6-week forced titration period (titration) followed by a 12-week maintenance period (maintenance]) and either a transition or taper period (Fig. 1). An interactive voice response system (IVRS) was used to randomly assign treatment to patients based on a predetermined computer-generated (pseudorandom number generator) schedule. Patients were randomized 1:2:1 to placebo, 400 mg/day lacosamide, or 600 mg/day lacosamide administered twice daily in equally divided doses. Lacosamide was initiated at 100 mg/day and titrated in 100-mg increments per week until the target dose was met. One dose reduction (100 mg/day) was permitted at the end of titration (week 6) for patients experiencing intolerable adverse events. Patients who were unable to tolerate trial medication earlier during titration, and those unable to tolerate the reduced dose, were to discontinue treatment. Following successful completion of titration, patients entered the 12-week maintenance period during which no dose adjustments were allowed. Following maintenance, patients who chose to continue lacosamide treatment in an open-label extension trial (SP756; NCT00522275) entered a 2-week blinded transition period and were transitioned from their maintenance dose to lacosamide 200 mg/day. Patients who discontinued early or who chose not to enter the open-label extension trial were tapered off medication in a 3-week blinded taper period during which the dose was reduced by 200 mg/day each week. Lacosamide was supplied as white, film-coated 50- and 100-mg tablets. Placebo was supplied as white, film-coated tablets that were identical to the lacosamide tablets in size, taste, and color.

image

Figure 1.   Trial design. R, randomized; P, placebo; 100 = lacosamide 100 mg/day; 200 = lacosamide 200 mg/day; 300 = lacosamide 300 mg/day; 400 = lacosamide 400 mg/day; 500 = lacosamide 500 mg/day; 600 = lacosamide 600 mg/day.

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Efficacy assessments

The primary assessment of efficacy was based on the change in POS frequency and was evaluated in two ways: (1) the change in seizure frequency per 28 days from baseline to the maintenance period, and (2) the proportion of individual patients who experienced a 50% or greater reduction in seizure frequency from baseline to maintenance period (50% responder rate). Secondary efficacy variables included the percent change in seizure frequency per 28 days from baseline to maintenance, the 75% responder rate, the number and proportion of patients achieving seizure-free status throughout the maintenance period for patients completing the maintenance period and having complete efficacy data, the percentage of seizure-free days throughout maintenance for patients who entered maintenance, and the change in seizure frequency and 50% responder rate differentiated by seizure type (e.g., complex partial seizures or secondarily generalized tonic–clonic seizures for patients experiencing these seizure types at baseline). Patients or their caregivers kept a daily diary to documented seizure types and seizure frequency from the beginning of baseline until the last visit.

Safety assessments

Safety evaluation included the assessment of treatment-emergent adverse events (TEAEs), withdrawals due to TEAEs, changes in 12-lead ECG readings, vital sign and body weight measurements, laboratory values (hematology, clinical chemistry, or urinalysis), and physical and neurologic examination findings.

Pharmacokinetics

In an effort to determine lacosamide plasma concentrations associated with each dose as well as any possible effects of lacosamide on the steady-state plasma concentrations of select concomitant AEDs, plasma samples were drawn at various time points throughout the trial. Quantification of lacosamide and the concomitant AEDs levetiracetam, lamotrigine, carbamazepine and its epoxy metabolite, the monohydroxy derivative of oxcarbazepine, and gabapentin was performed using a validated high performance liquid chromatography (HPLC) with tandem mass spectrometry (HPLC-MS/MS). Fluorescence polarization immunoassay (FPIA) was used to analyze valproic acid, topiramate, and phenobarbital concentrations. Phenytoin concentrations were analyzed using enzyme-multiplied immunoassay technique (EMIT), and zonisamide concentrations were analyzed using HPLC. All plasma samples were analyzed by a central laboratory (MedTox Laboratories, Inc., St. Paul, MN, U.S.A.)

Statistical analysis

Efficacy data were analyzed using the intention-to-treat (ITT) population (primary efficacy analysis), which included all patients who received at least one dose of trial medication and had at least one postbaseline efficacy assessment. The per-protocol set included patients in the ITT population with at least one efficacy assessment from maintenance and who did not have any major protocol deviation. Safety and tolerability data were analyzed for the safety set, which included all randomized patients who received at least one dose of trial medication. Data were pooled for sites by enrollment size such that each pooled site contained at least 20 randomized patients and the largest pooled site was no more than three times larger than the smallest pooled site.

The inferential statistical analysis of the change in seizure frequency per 28 days from baseline to maintenance [based on analysis of covariance (ANCOVA) with terms for treatment and pooled site] was performed on log-transformed seizure frequency. The log-transformed average seizure frequency during baseline was used as the covariate. The change in seizure frequency between the active treatment groups and placebo was compared using least squares means. The response to treatment of at least a 50% reduction in seizure frequency from baseline to maintenance (50% responder rate) was analyzed using a logistic regression model with effects for treatment and pooled site. Efficacy assessments by seizure type were analyzed descriptively using the ITT population for patients experiencing the seizure type at baseline.

All patients with postbaseline efficacy data were included in the primary Maintenance Phase analysis (Baseline to Maintenance Phase). For subjects who prematurely discontinued the study, a last observation carried forward convention was applied in the following manner to obtain the seizure frequency estimate for the Maintenance Phase analysis:

  •  Subjects who discontinued prematurely during the Titration Phase: seizure frequency was calculated using all available data in the Titration Phase and used for the Maintenance Phase analysis.
  •  Subjects who discontinued prematurely during the Maintenance Phase: all available seizure frequency data in the Maintenance Phase was used for the Maintenance Phase analysis.
  •  Subjects who completed the Maintenance Phase: seizure frequency was calculated using all data from the Maintenance Phase.

The pairwise comparison of each lacosamide dose group versus placebo was performed at the 5% level of significance. Hypothesis testing followed predefined hierarchical order starting with 400 mg/day lacosamide versus placebo. This testing procedure was considered a closed testing procedure and no adjustment of the significance level was necessary.

Results from an earlier trial (Ben-Menachem et al., 2007) were used to make the basic assumptions in calculating sample size. Assumptions made for the 400 and 600 mg/day lacosamide groups were 28% and 21% reductions over placebo after exponentiation and responder rates of 41% and 38% versus 22% for placebo. Therefore, it was estimated that 500 enrolled patients would yield 400 randomized patients in the ratio of 1:2:1 for placebo, 400, and 600 mg/day lacosamide for analysis of efficacy to detect significant difference, with at least 90% power and a type 1 error of 5% for 400 mg/day lacosamide.

Safety analyses including adverse events, clinical laboratory evaluations, 12-lead ECG readings, vital signs, and physical and neurologic examination findings were assessed for the safety set. Data are presented for the treatment period (titration + maintenance).

Results

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

Patient disposition

Of 405 randomized patients who received trial medication (safety set; Fig. 2), 402 had at least one post-baseline efficacy assessment (ITT) and 316 (78.0%) completed the trial; 280 were included in the per-protocol set. A total of 89 patients (22.0%) discontinued the trial prematurely, with 67 (16.5%) doing so due to adverse events. Of 338 patients completing titration, 274 (81.1%) achieved their target dose of trial medication without the need for dose reduction prior to entry into maintenance [96 (98.0%) in placebo, 139 (82.7%) in lacosamide 400 mg/day, and 39 (54.2%) in lacosamide 600 mg/day].

image

Figure 2.   Patient disposition. *More than one primary reason for discontinuation may have been recorded by the investigator. **Completed trial including the transition or taper phase. TP, titration phase; MP, maintenance phase.

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Demographics and clinical characteristics

Baseline patient characteristics and demographics were comparable among the treatment groups (Table 1). A total of 82.1% of patients had been treated previously with four or more lifetime AEDs, including 48.3% who had been treated with seven or more AEDs in their lifetime (Table 2). The median seizure frequency was 15.0 (placebo), 11.5 (lacosamide 400 mg/day), and 16.5 (600 mg/day) seizures per 28 days during the 8-week baseline period despite treatment with one to three concomitant AEDs. Throughout the trial, 82.1% of patients were taking two to three concomitant AEDs, which most frequently included levetiracetam (39.1%), lamotrigine (36.1%), carbamazepine (24.9%), oxcarbazepine (21.4%), phenytoin (18.9%), topiramate (18.2%), valproate (16.9%), and zonisamide (14.7%). In addition to one to three concomitant AEDs, a total of 29.6% of patients were also using VNS.

Table 1.   Demographics and baseline characteristics (Safety Set)
 Placebo (n = 104)LacosamideTotal (n = 405)
400 mg/day (n = 204)600 mg/day (n = 97)
  1. SD, standard deviation.

Age, years
 Mean (SD)38.1 (11.96)39.1 (12.37)36.8 (11.76)38.3 (12.13)
 Range16.0–61.017.0–71.016.0–69.016.0–71.0
Sex, n (%)
 Male49 (47.1)104 (51.0)47 (48.5)200 (49.4)
 Female55 (52.9)100 (49.0)50 (51.5)205 (50.6)
Race, n (%)
 White84 (80.8)166 (81.4)80 (82.5)330 (81.5)
 Black12 (11.5)18 (8.8)8 (8.2)38 (9.4)
 Asian1 (1.0)3 (1.5)1 (1.0)5 (1.2)
 Other7 (6.7)17 (8.3)8 (8.2)32 (7.9)
Weight, kg
 Mean (SD)75.4 (18.48)83.9 (21.65)80.8 (21.26)81.0 (21.03)
 Mean time since epilepsy diagnosis, years (SD)25.4 (13.34)24.5 (13.16)23.4 (13.28)24.5 (13.22)
Table 2.   Population characteristics (ITT)
 Placebo (n = 104)LacosamideTotal (n = 402)
400 mg/day (n = 201)600 mg/day (n = 97)
  1. AED, antiepileptic drug; ITT, intention-to-treat population; VNS, vagus nerve stimulation.

Concomitant AEDs, n (%)
 1 AED18 (17.3)36 (17.9)18 (18.6)72 (17.9)
 2 AEDs54 (51.9)110 (54.7)57 (58.8)221 (55.0)
 3 AEDs32 (30.8)55 (27.4)22 (22.7)109 (27.1)
Lifetime AEDs, n (%)
 1–315 (14.4)39 (19.4)12 (12.4)66 (16.4)
 4–632 (30.8)68 (33.8)36 (37.1)136 (33.8)
 ≥755 (52.9)91 (45.3)48 (49.5)194 (48.3)
Missing data2 (1.9)3 (1.5)1 (1.0)6 (1.5)
Use of VNS, n (%)39 (37.5)51 (25.4)29 (29.9)119 (29.6)
Median baseline partial-onset seizure frequency per 28 days15.011.516.5

Efficacy

Change in seizure frequency

In the ITT population, the median percent reduction in seizure frequency per 28 days from baseline to maintenance was 20.8% for placebo, 37.3% for lacosamide 400 mg/day, and 37.8% for lacosamide 600 mg/day (Fig. 3A). These reductions in seizure frequency were significant compared with placebo in both the lacosamide 400 and 600 mg/day groups, with 21.6% (95% CI 6.3–34.5; p = 0.008) and 24.6% (95% CI 7.8–38.3; p = 0.006) reductions over placebo. For the per-protocol set, the median percent reduction from baseline to maintenance was 21.7% for placebo, 39.6% for lacosamide 400 mg/day, and 50.0% for lacosamide 600 mg/day. The 20.6% reduction over placebo with lacosamide 400 mg/day (95% CI 4.4–34.0; p = 0.015) in the per-protocol set was similar to the reduction seen in the ITT analysis, whereas a greater reduction over placebo of 33.0% (95% CI 13.6–48.1; p = 0.002) was observed with lacosamide 600 mg/day.

image

Figure 3.   Primary efficacy measures (ITT). (A) Median percent reduction in seizure frequency per 28 days from baseline period to 12-week maintenance period. P-values reflect the percent reduction over placebo and are based on log-transformed seizure frequency from pairwise treatment analysis of covariance (ANCOVA) models with terms for treatment, pooled site, and the baseline period measurement. (B) 50% response to treatment from baseline period to 12-week maintenance period. P-values are based on the pairwise treatment logistic regression model with terms for treatment and pooled site. OR, odds ratio.

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Responder rate

In the ITT population, significant differences in the 50% responder rates from baseline to maintenance were observed for each individual patient in both the 400 and 600 mg/day lacosamide treatment groups (38.3% and 41.2%; p < 0.001 for both) compared with placebo (18.3%; Fig. 3B). In the per-protocol set, significant differences also were observed in the lacosamide 400 and 600 mg/day groups (40.0% and 50.9%; p < 0.001 for both) compared with placebo (18.4%). The 75% responder rate from baseline to maintenance was also higher in the lacosamide 400 and 600 mg/day groups (20.4%, p = 0.005 and 21.6%, p = 0.007) compared with placebo (7.7%; ITT).

Efficacy by seizure type

There was a dose-related reduction in secondarily generalized tonic–clonic seizures relative to baseline in both lacosamide treatment groups, including a median percent reduction of 93.0% for lacosamide 600 mg/day and 59.4% for the lacosamide 400 mg/day group compared to 14.3% for placebo (Table 3). The corresponding responder rates were 70.2% for the lacosamide 600 mg/day group and 56.0% for the 400 mg/day group compared to placebo (33.3%; Table 3). Evidence for a dose-related reduction in seizure frequency was also observed for complex partial seizures, but not for simple partial seizures (Table 3).

Table 3.   Efficacy by partial-onset seizure type (ITT)
 NBaseline seizure frequency per 28 days median (range)Median % Reduction50% Responder rate
  1. ITT, intention-to-treat analysis.

All seizure types
 Placebo10415.0 (3.5–840.5)20.8%18.3%
 Lacosamide 400 mg/day20111.5 (3.5–1253.0)37.3%38.3%
 Lacosamide 600 mg/day9716.5 (3.5–256.7)37.8%41.2%
Secondarily generalized tonic–clonic
 Placebo454.0 (0.5–23.5)14.3%33.3%
 Lacosamide 400 mg/day843.3 (0.5–99.0)59.4%56.0%
 Lacosamide 600 mg/day475.0 (0.5–61.0)93.0%70.2%
Complex partial seizures
 Placebo8610.3 (0.5–562.5)22.2%24.4%
 Lacosamide 400 mg/day1708.0 (0.5–285.9)38.7%40.0%
 Lacosamide 600 mg/day759.5 (1.0–256.7)44.4%44.0%
Simple partial seizures
 Placebo4110.0 (1.5–833.9)47.6%43.9%
 Lacosamide 400 mg/day7312.0 (0.5–1244.5)34.9%38.4%
 Lacosamide 600 mg/day358.7 (0.5–97.7)22.6%37.1%
Seizure freedom

Of 317 patients evaluable for this analysis, 9 were seizure free throughout the 12-week maintenance period [placebo, 0 of 95 (0%); lacosamide 400 mg/day, 4 of 160 (2.5%); lacosamide 600 mg/day, 5 of 62 (8.1%)]. Baseline seizure frequencies in these nine patients ranged from 4.0–12.5 partial-onset seizures per 28 days while taking one (n = 4), two (n = 4), or three (n = 1) concomitant AEDs. When seizure freedom was calculated by the more conservative “pragmatic ITT” approach proposed by Gazzola et al. (Gazzola et al., 2007) using ITT as the denominator, the percentages were 0% (0 of 104) for placebo, 2% (4 of 201) for lacosamide 400 mg/day, and 5.2% (5 of 97) for lacosamide 600 mg/day. Both lacosamide groups showed a significant increase over placebo in the percentage of seizure-free days during maintenance [5.3%, 95% CI 1.1–9.4; p = 0.013 for lacosamide 400 mg/day (n = 168) and 8.2%, 95% CI 3.8–12.6; p < 0.001 for lacosamide 600 mg/day (n = 72); placebo, n = 98].

Safety and tolerability

Among patients randomized to lacosamide, treatment emergent adverse events (TEAEs) with an incidence of at least 10% during the treatment period (i.e., titration + maintenance) included dizziness, nausea, diplopia, vision blurred, headache, vomiting, and tremor (Table 4); all of these TEAEs were dose-related except for headache. Most of the reported TEAEs were mild or moderate in intensity. Dizziness was the most commonly reported TEAE and was reported more often during titration (placebo, 8.7%; lacosamide 400 mg/day, 37.3%; lacosamide 600 mg/day, 43.3%) rather than during maintenance (placebo, 2.0%; lacosamide 400 mg/day, 8.3%; 600 mg/day, 11.1%). Of note, the incidence of somnolence during the treatment period was 6.7% for placebo and 9.0% for the total lacosamide groups, and did not appear to be dose-related (lacosamide 400 mg/day, 10.3%; lacosamide 600 mg/day 6.2%). The incidence of rash was low for patients randomized to lacosamide 400 mg/day (4.4%) and 600 mg/day (1.0%) and similar to that reported with placebo (3.8%). No rashes were serious and all were assessed as mild to moderate in intensity. Peripheral edema was reported by 1.0% of patients in both the lacosamide 400 and 600 mg/day groups and no cases were reported in the placebo group.

Table 4.   Incidence of treatment-emergent adverse events (≥10% in any Lacosamide Treatment Group) during the treatment period (Titration + Maintenance period; Safety Set)
Adverse eventPlacebo (n = 104) n (%)Lacosamide
400 mg/day (n = 204) n (%)600 mg/day (n = 97) n (%)Total (n = 301) n (%)
Dizziness11 (10.6)86 (42.2)49 (50.5)135 (44.9)
Nausea5 (4.8)24 (11.8)16 (16.5)40 (13.3)
Diplopia3 (2.9)21 (10.3)18 (18.6)39 (13.0)
Vision blurred3 (2.9)23 (11.3)15 (15.5)38 (12.6)
Headache12 (11.5)26 (12.7)11 (11.3)37 (12.3)
Vomiting3 (2.9)18 (8.8)19 (19.6)37 (12.3)
Tremor8 (7.7)19 (9.3)14 (14.4)33 (11.0)
Coordination abnormal2 (1.9)18 (8.8)11 (11.3)29 (9.6)
Somnolence7 (6.7)21 (10.3)6 (6.2)27 (9.0)
Nystagmus5 (4.8)16 (7.8)10 (10.3)26 (8.6)

A total of 16.5% of all patients withdrew from the trial prematurely due to the occurrence of a TEAE. The incidence of TEAEs leading to withdrawal in patients randomized to lacosamide was higher during forced titration (20.3%, n = 61) than during maintenance (0.4%, n = 1). The most common TEAEs leading to discontinuation during the treatment period were dizziness (placebo, 0%; lacosamide 400 mg/day, 6.4%; lacosamide 600 mg/day, 15.5%) and abnormal coordination (placebo, 0%; lacosamide 400 mg/day, 2.0%; 600 mg/day, 2.1%).

The frequency of serious adverse events (SAEs) reported during the treatment period was 2.9%, 5.9%, and 3.1% for patients randomized to placebo, lacosamide 400 mg/day, and lacosamide 600 mg/day, respectively. The most frequently reported SAEs were convulsion (two patients in the lacosamide 400 mg/day group) and appendicitis (one patient each in the placebo and lacosamide 600 mg/day groups). No deaths occurred during the trial.

Results of clinical laboratory tests and vital sign measurements across treatment groups did not identify any changes that appeared to be associated with lacosamide. Two patients had asymptomatic increases in alanine aminotransferase (ALT) values. A 38-year-old man had a transient increase in ALT to 3.6× ULN during titration while taking lacosamide 300 mg/day in addition to oxcarbazepine and levetiracetam, which returned to baseline during continued treatment with lacosamide 600 mg/day. A 54-year-old woman had an asymptomatic increase in ALT to 8.7× ULN following 45 days of lacosamide treatment (300 mg/day for the preceding 8 days plus carbamazepine). Lacosamide was discontinued and ALT had decreased to 1.9× ULN 16 days later. Neither patient had an abnormal bilirubin value at any assessment.

Evaluation of ECG readings demonstrated little change from baseline to the end of maintenance in heart rate, QTc interval, or QRS duration for the placebo and lacosamide groups. A small increase was observed in mean PR interval at the end of maintenance (1.2, 4.4, and 6.1 ms for patients in the placebo, lacosamide 400mg/day, and lacosamide 600 mg/day groups). There were no reports of cardiac adverse events associated with PR interval prolongation.

Lacosamide showed minimal effect on body weight, with mean changes from baseline in body weight after 18 weeks of exposure (end of maintenance) of +0.6 kg for the placebo group and +0.1 kg and +0.2 kg for the lacosamide 400 and 600 mg/day groups.

Pharmacokinetics

Mean lacosamide plasma concentrations during titration increased with the actual dose administered. Dose proportionality was observed for the 400 and 600 mg/day actual daily dose groups at the end of both the titration period (7.75, 9.89 μg/ml) and the maintenance period (7.19, 9.50 μg/ml). Lacosamide mean plasma concentrations remained stable within each dose group throughout maintenance.

Plasma concentrations of selected concomitant AEDs were not affected by lacosamide, with the exception of an apparent reduction in the mean concentration of valproic acid in the lacosamide 600 mg/day group (Table S1). The reduced mean concentration of valproic acid in this group is likely due to a low concentration (0.70 μg/ml) in one patient at the last visit in the maintenance period, particularly since the valproic acid concentrations for the other patients were not notably reduced. Only a small number of patients used phenobarbital or gabapentin in this trial, making it difficult to draw conclusions from these results.

Discussion

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

The results of this double-blind, randomized, placebo-controlled trial demonstrated that adjunctive treatment with lacosamide 400 and 600 mg/day was effective in reducing the frequency of partial-onset seizures (with or without secondary generalization) in patients inadequately controlled while taking one to three concomitant AEDs. The response was most notable for secondarily generalized tonic–clonic seizures, which constitute the most disabling and potentially harmful seizure type. The efficacy results observed in this trial are notable given the epilepsy treatment history and the frequency of the seizures experienced by enrolled patients. Patients entered this study with a baseline median of 11.5–16.5 seizures per 28 days, with nearly half having previously failed to achieve adequate seizure control with seven or more AEDs and approximately one-third currently using VNS. Response to a new AED is largely affected by baseline seizure frequency and number of previous AED trials (Schiller & Najjar 2008), yet despite this difficult-to-treat study population, treatment with lacosamide 400 and 600 mg/day resulted in significant reductions from baseline in seizures, as well as significant 50% responder rates and a higher rate of seizure freedom compared with placebo— results that are comparable to established and second-generation AEDs (Cramer et al., 2001).

The lacosamide 400 and 600 mg/day groups demonstrated similar reductions in seizures for the primary efficacy analyses. The 400 mg/day dose provided a more favorable safety profile in this forced-titration design; however, numerically greater seizure reductions with the 600 mg/day group in the per-protocol analyses, the analysis of secondarily generalized tonic–clonic seizures, and the 8% seizure freedom rate suggest that the 600 mg/day dose may provide additional benefit for those able to tolerate this dose.

In the analysis by seizure type, the largest reductions were observed for secondarily generalized tonic–clonic seizures, and these reductions appeared to be dose-related. Although complete seizure control is desirable, the dramatic reduction in secondarily generalized tonic–clonic seizures seen with both the 400 and 600 mg/day lacosamide doses may ultimately contribute to a substantial improvement in morbidity and mortality rates in those patients.

Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels (Beyreuther et al., 2007; Errington et al., 2008), a mechanism of action that is distinct from those of other AEDs and which might have contributed to the seizure reductions observed in this drug-resistant population. The observed efficacy of lacosamide in patients using multiple concomitant AEDs and with a history of multiple AED use is important to consider when making adjunctive treatment decisions for patients with POS.

Despite the fixed-dose trial design and use of one to three concomitant AEDs, the safety and tolerability of lacosamide was comparable to that with many second-generation AEDs, with nervous and gastrointestinal system events being the most commonly reported TEAEs. Events such as dizziness were typically dose-related, occurring most frequently during titration. Although dose limiting for a minority of patients, nervous and gastrointestinal system side effects would be expected to occur at a lower incidence with flexible dosing and dose adjustments of concomitant AEDs. Importantly, lacosamide had a low incidence of somnolence and minimal effect on body weight; the incidences of peripheral edema and rash were notably low and similar to placebo. The small increases in mean PR interval observed in lacosamide groups were not of clinical consequence.

The tolerability of lacosamide diminished with increasing dose, indicating that the dose used in clinical practice should be individualized. Previous reports have shown that lacosamide plasma concentrations are proportional to the dose administered and that lacosamide does not affect the plasma concentrations of concomitant AEDs (Thomas et al., 2006; Ben-Menachem et al., 2007; Halász et al., 2009). Similar results were obtained in this trial in that plasma concentrations of concomitant AEDs were unaffected by lacosamide. Such an absence of interaction may allow for ease of lacosamide use as adjunctive therapy.

More than half of patients with POS will eventually require polytherapy due to lack of seizure freedom with monotherapy (Kwan & Brodie, 2007). Treatment with AEDs that demonstrate different mechanisms of action may provide broader anticonvulsant activity with greater symptom control and improved tolerability. The efficacy and safety profiles for lacosamide 400 and 600 mg/day demonstrated in this trial were comparable to those observed in two additional trials that were conducted concurrently (Ben-Menachem et al., 2007; Halász et al., 2009). These consistent results, combined with a favorable pharmacokinetic profile, indicate that lacosamide is a useful and novel therapeutic agent with potential benefit as an adjunctive treatment in patients with POS with or without secondary generalization.

Acknowledgments

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

The authors acknowledge the contribution made by members of the SP754 Study Group who contributed to the contents of this manuscript by taking care of patients according to the approved trial protocol and contributing to the total data generated for this trial: B. Abou-Khalil, Nashville, TN; M. Agostini, Dallas, TX; I. Ali, Toledo, OH; R. Armstrong, Asheville, NC; R. Ayala, Tallahassee, FL; J. Balmakund, St. Cloud, MN; G. Barkley, Detroit, MI; R. Beach, Syracuse, NY; S. Benbadis, Tampa, FL; D. Bergen, Chicago, IL; V. Biton, Little Rock, AR; A Blum, Providence, RI; M. Brown, Maitland, FL; W. Carlini, Medford, OR; S. Chung, Phoenix, AZ; J. Cohen, New York, NY; G. Connor, Tulsa, OK; J. DeCerce, Jacksonville, FL; M. Evans, Springfield, IL; T. Fakhoury, Lexington, KY; R. Faught, Birmingham, AL; A. Fessler, Rochester, NY; N. Foldvary-Schaefer, Cleveland, OH; N. Fountain, Charlottesville, VA; L. Frank, Norfolk, VA; J. French, Philadelphia, PA; S. Gazda, San Antonio, TX; J. Gibbs, Greenville, NC; J. Halford, Charleston, SC; W. Hamilton, Mobile, AL; C. Harden, New York, NY; S. Helmers, Atlanta, GA; A. Husain, Durham, NC; S. Karner, Charlotte, NC; Y. Kaydanova, Chicago, IL; D. King-Stephens, San Francisco, CA; S. Kirzinger, Louisville, KY; J. Klapper, Jr, Denver, CO; P. Klein, Bethesda, MD; D. Ko, Los Angeles, CA; G. Krauss, Baltimore, MD; K. Krishnamurthy, Boston, MA; P. Lee-Kwen, Buffalo, NY; R. Leroy, Dallas, TX; D. Leszczyszyn, Richmond, VA; K. Liow, Wichita, KS; J. Liporace, Philadelphia, PA; P. Mazzeo, Beaufort, SC; P. McAllister, Fairfield, CT; P. McCabe, Hershey, PA; W. McElveen, Bradenton, FL; J. Miller, Seattle, WA; G. Montouris, Boston, MA; J. Moore, Columbus, OH; G. Morris, III, Milwaukee, WI; W. Noland, Tucson, AZ; A. Palade, Morgantown, WV; P. Parcells, Newport News, VA; E. Passaro, St. Petersburg, FL; P. Penovich, St. Paul, MN; B. Phillips, Englewood, CO; M. Privitera, Cincinnati, OH; N. Rodgers-Neame, Tampa, FL; J. Rogin, Minneapolis, MN; W. Rosenfeld, St. Louis, MO; R. Sachdeo, New Brunswick, NJ; V. Salanova, Indianapolis, IN; M. Sam, Winston-Salem, NC; E. Sandok, Marshfield, WI; M. Sazgar, Buffalo, NY; J. Shih, Albuquerque, NM; J. Sirven, Phoenix, AZ; M. Sperling, Philadelphia, PA; E. Spokoyny, Santa Ana, CA; E. St. Louis, Iowa City, IA; W. Tatum, IV, Tampa, FL; T. Ting, Baltimore, MD; J. Tomasovic, San Antonio, TX; B. Vazquez, New York, NY; M. Werz, Cleveland, OH.

The authors express their appreciation to Margaret Beaman, Clinical Trial Manager, Cindy McShea, MPH, Senior Biostatistician, and Kimberly Doggett, Senior Clinical Research Associate, of SCHWARZ BIOSCIENCES, Inc., UCB Group (Research Triangle Park, NC, U.S.A.). Central laboratory facilities were provided by Quintiles Laboratories (Smyrna, GA, U.S.A.). Plasma concentrations of lacosamide were determined by SCHWARZ PHARMA AG, UCB Group (Monheim, Germany) and plasma concentrations of selected concomitant antiepileptic drugs were determined by MedTox Laboratories, Inc. (St. Paul, MN, U.S.A.). Electrocardiograms for all sites were centrally read by Covance Central Diagnostics, Inc. (Reno, NV, U.S.A.). SCHWARZ PHARMA GmbH, UCB Group (Monheim, Germany) provided the trial supplies and SCHWARZ BIOSCIENCES, Inc., UCB Group (Research Triangle Park, NC, U.S.A.), sponsored and funded the trial. Medical writing support was provided by Jennifer Kemp, Ph.D. on behalf of SCHWARZ BIOSCIENCES, Inc, a member of the UCB Group (Research Triangle Park, NC, U.S.A.) and by Prescott Medical Communications Group (Chicago, IL, U.S.A.). Andrea Eggert, PharmD, BCPP, UCB Inc. (Smyrna, GA, U.S.A.), provided editorial assistance.

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.

Disclosure

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

Steve Chung, M.D., is a consultant for Medtronics, Inc., GlaxoSmithKline plc. and UCB S.A., is on the speaker’s bureau of Cyberonics, Inc., GlaxoSmithKline plc., and UCB S.A., and receives grant and research support from Schwarz Pharma A.G., GlaxoSmithKline plc., UCB S.A., Valeant, Eisai Inc., Ortho-McNeil. and Medtronics, Inc. Michael Sperling, M.D., is a consultant for Dainippon Sumitomo Pharma Co., Ltd. and Valeant, is on the speaker’s bureau of Pfizer, Eisai Inc., and UCB S.A., and receives research support from UCB S.A. and Schwarz Pharma A.G., NeuroPace, Inc., Medtronics, Inc., Eisai Inc., Johnson & Johnson Inc., and Marinus Pharmaceuticals, Inc. Victor Biton, M.D., is a consultant for Avigen Inc. and GlaxoSmithKline plc., and an investigator for Dainippon Sumitomo Pharma Co., Ltd., GlaxoSmithKline plc., Genzyme Corporation, Eisai Inc., Johnson & Johnson Inc., King Pharmaceuticals Inc., Marinus Pharmaceuticals, Inc, Intranasal, Ovation Pharmaceuticals, Inc., Schwarz Pharma A.G., UCB S.A., Valeant, and XTL Biopharmaceuticals Ltd. Gregory Krauss, M.D., is an investigator for UCB S.A., Johnson & Johnson Inc., ISK-Biosciences Corporation, and Eisai Inc., and a consultant for Merck & Co., Inc., Bristol-Myers Squibb, Eisai Inc., UCB S.A., and Icagen, Inc. Pamela Doty, Ph.D., David Rudd, PharmD, M.S., and David Hebert, Ph.D., are employees of SCHWARZ BIOSCIENCES, a member of the UCB group.

References

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

Supporting Information

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

Table S1. Mean Change from Baseline in Plasma Concentrations of Concomitant AEDs (Safety Set)

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EPI_2496_sm_SupplementaryTable1.doc78KSupporting 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.