Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures

Authors


Address correspondence and reprint requests to Elinor Ben-Menachem, Institute of Clinical Neurosciences, Division of Neurology, Sahlgrenska Academy at Göteborg University, Göteborg 413 45, Sweden. E-mail: elinor.ben-menachem@neuro.gu.se

Abstract

Summary: Purpose: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions.

Methods: During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis.

Results: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p = 0.0023) and 600 mg/day (p = 0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p = 0.0038) and 600 mg/day (p = 0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs.

Conclusions: In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.

Lacosamide (SPM 927, formerly harkoseride), the R-enantiomer of 2-acetamido-N-benzyl-3-methoxypro-pionamide, is a new chemical entity being developed as an oral formulation (Bialer et al., 2004) for the treatment of epilepsy and neuropathic pain. In addition, an intravenous formulation is being developed for short-term replacement of oral lacosamide in patients with partial-onset seizures.

Based on recent experimental studies, lacosamide appears to have a dual mode of action—enhancement of sodium-channel slow inactivation and modulation of collapsin response mediator protein-2 (CRMP-2) (Stoehr et al., 2006)—both of which are novel mechanisms for an antiepileptic drug (AED). Without affecting fast inactivation, lacosamide appears to selectively enhance sodium-channel slow inactivation, which may help normalize activation thresholds and decrease pathophysiological neuronal activity, thus controlling neuronal hyperexcitability (Errington et al., 2006). Because CRMP-2 is part of the signal transduction cascade of neurotrophic factors and can convey neuroprotective effects, the ability of lacosamide to modulate CRMP-2 may contribute to the decreased neuronal loss observed in status epilepticus animal models and its potential antiepileptogenic effects as seen in animal models (Brandt et al., 2006, Beyreuther et al., 2007).

Preclinical studies have demonstrated that lacosamide protects against seizures in various anticonvulsant animal models (Bialer et al., 2002). In animal studies of lacosamide, there was no evidence of teratogenicity or adverse effects on male or female reproductive function (Krebsfaenger, unpublished data). Studies in healthy adult volunteers have shown that oral lacosamide is rapidly and almost completely absorbed from the gastrointestinal tract and has a high oral bioavailability of approximately 100% (Hovinga, 2003). Administration with food does not alter the rate or extent of lacosamide absorption (Cawello et al., 2004). Lacosamide has demonstrated minimal binding to human plasma proteins (<15%) and has a plasma elimination half-life of approximately 13 h (Bialer et al., 2004). Pharmacokinetic studies of lacosamide have shown a linear relationship for oral doses ranging from 100 mg/day to 800 mg/day (Horstmann et al., 2002). In healthy volunteers, lacosamide did not affect the plasma concentration of the cytochrome P-450 (CYP-450) enzyme inducer carbamazepine or the CYP-450 enzyme inhibitor valproic acid; moreover, the plasma concentrations of lacosamide were not affected by carbamazepine or valproic acid (Bialer et al., 2004).

The primary objective of this multicenter, multinational, double-blind, placebo-controlled, randomized trial was to evaluate the efficacy and safety of lacosamide 200 mg/day, 400 mg/day, and 600 mg/day in two equally divided doses when added to 1 or 2 marketed concomitant AEDs in patients with uncontrolled partial-onset seizures, with or without additional vagus nerve stimulation (VNS). The secondary objectives were to evaluate the dose–response relationship of lacosamide with regard to efficacy and safety, and to examine the steady-state plasma concentrations of lacosamide and concomitant AEDs to investigate the potential for any drug–drug pharmacokinetic interactions.

METHODS

This trial was conducted between February 2002 and May 2004 at 68 centers in Germany, Hungary, Lithuania, Poland, Sweden, Switzerland, U.K., and the U.S.A. The trial was performed in accordance with the Declaration of Helsinki, European Directive 2001/83/EC, and the US Code of Federal Regulations Part 21. The trial protocol, amendments, and informed consent were reviewed by national regulatory authorities in each country and relevant ethics committees or Institutional Review Boards for each site. Before trial participation, all patients gave written informed consent.

Patients

Men and women, between the ages of 18 and 65 years, diagnosed with simple or complex partial-onset seizures, with or without secondary generalization, were enrolled in the trial. Diagnosis of partial-onset seizures was based on the 1981 Classification of Epileptic Seizures from the International League Against Epilepsy (ILAE). Patients must have had an electroencephalogram (EEG) and magnetic resonance imaging (MRI) or computed tomography (CT) scan exhibiting results consistent with this diagnosis and without evidence of progressive structural lesion in the central nervous system (CNS) or progressive encephalopathy.

To meet enrollment criteria, patients must have had partial-onset seizures for at least the last 2 years despite prior therapy with at least 2 AEDs. During the 8-week baseline period, patients must have had at least 4 partial-onset seizures per 28 days on average, with no seizure-free period longer than 21 days. In the 4 weeks before enrollment and during the baseline period, patients must have been on a stable dosage regimen of 1 or 2 AEDs, with or without VNS.

Female patients were excluded from participating in the trial if they were pregnant, breast-feeding, or of childbearing potential and not using approved methods of contraception. Patients were excluded if they had received lacosamide in a previous trial or had participated in any other investigational drug or experimental device trial within the last 2 months. Patients were also excluded if they had a history of chronic alcohol or drug abuse within the previous 2 years; any medical or psychiatric condition that might jeopardize the patient's health or compromise the patient's ability to participate in this trial; liver function test (LFT) results or a serum creatinine level of at least two times the upper limit of normal (ULN); sitting diastolic blood pressure less than 60 mm Hg or greater than 105 mm Hg, or resting pulse less than 45 beats per minute (bpm) or greater than 110 bpm; confirmed clinically significant abnormality in electrocardiogram (ECG) including prolonged corrected QT (QTc) interval, defined as at least 450 msec in males and at least 470 msec in females; history of severe anaphylactic reaction or serious blood dyscrasias; nonepileptic or psychogenic seizures; seizure clusters during the 8-week period before trial entry or during the baseline period; history of primary generalized seizures; history of status epilepticus in the last 12 months; concomitant or previous felbamate therapy within the last 6 months; concomitant treatment with vigabatrin; any other clinically significant disease or surgical condition; recent chronic consumption of nonanticonvulsant medications that might interfere with drug absorption, distribution, metabolism, or excretion; and treatment within 4 weeks before enrollment with medications influencing the CNS, except for medication taken as antiepileptic treatment.

Trial design

This was a multicenter, multinational, double-blind, placebo-controlled, randomized, dose–response trial consisting of four periods: baseline, titration, maintenance, and transition or taper.

Enrolled patients entered an 8-week monitoring period to obtain baseline data and determine their eligibility for the double-blind period of the trial. Seizure frequency data were captured in a daily diary maintained by the patient or their caregiver. Patients who met the eligibility criteria were randomized in a 1:1:1:1 ratio to one of four treatment arms: placebo or lacosamide 200 mg/day (100 mg twice daily [bid]), 400 mg/day (200 mg bid), or 600 mg/day (300 mg bid).

The 6-week dose titration period began with either placebo or lacosamide 100 mg/day. For patients randomized to 600 mg/day, the dose was increased by 100 mg/day each week until the 600 mg/day dose was reached at week 6. Patients randomized to 400 mg/day or 200 mg/day received placebo during the first 2 or 4 weeks of titration, respectively, were started on lacosamide 100 mg/day at week 3 or 5, respectively, and the dose was increased by 100 mg/day increments each week until the randomized dose was reached in week 6. One down-titration of 100 mg/day was allowed at the end of the titration period, after achieving the randomized dose, if the patient experienced an intolerable adverse event (AE). Once the dose was reduced, it could not be increased. Patients who required a second down-titration were discontinued from the trial.

After the titration period, patients entered a 12-week maintenance period. Patients who completed the maintenance period had the option to enter a long-term, open-label, extension trial of lacosamide. Those patients enrolling in the extension trial were transitioned in a double-blind fashion from their maintenance dose to lacosamide 200 mg/day over a 2-week period. Patients who discontinued during the titration or maintenance period or who chose not to participate in the open-label extension trial were tapered off the trial medication by 200 mg/day each week over a three-week period in a double-blind fashion.

Measurement of efficacy

The primary assessment of efficacy was based on the change in seizure frequency. Seizure counts were analyzed in two ways: (1) reduction in seizure frequency per 28 days from baseline to maintenance, and (2) responder rate, defined as a reduction of at least 50% in seizure frequency from baseline to maintenance. For patients who discontinued before the maintenance period, efficacy data were carried forward from the titration period for the inclusion in the maintenance period analyses.

Secondary efficacy parameters included percent change in seizure frequency, achievement of seizure-free status, proportion of seizure-free days, Clinical Global Impression of Change (CGIC) score, and Quality of Life in Epilepsy (QOLIE-31) questionnaire score. Each patient or their caregiver kept a daily diary from the beginning of the baseline period until the patient's last visit, which included seizure type and seizure frequency, as well as any AEs that occurred, and any concomitant treatment that was used. The CGIC was completed by the same investigator for each patient throughout the trial and was used to assess change in clinical status, seizure frequency and intensity, occurrence of AEs, and overall functional status. The QOLIE-31 was used to assess the patient's perception of their quality of life and the change that resulted from treatment compared to the baseline QOLIE-31 score. Because the validated questionnaire was available only in English when this trial was conducted, this assessment was only completed by patients in U.K. and the U.S.A.

Measurement of safety

Safety evaluation included the assessment of AEs, vital signs, physical and neurological examinations, clinical laboratory assessments, and 12-lead ECGs for all patients who received at least one dose of trial medication.

Pharmacokinetics

Plasma samples were drawn periodically during the trial to investigate the plasma concentration of lacosamide associated with each dose and to determine whether lacosamide had any effect on the steady-state plasma concentrations of selected concomitant AEDs. Steady-state AED plasma concentrations were obtained during the baseline period and during treatment. In order to document the approximate peak plasma concentrations for the three target lacosamide doses and to also relate individual concentrations to simultaneously recorded ECG variables, plasma samples were obtained approximately 2 to 4 h after trial medication dosing (the expected Cmax for lacosamide). These samples were analyzed for lacosamide and concomitant AED plasma concentrations. The quantification of lacosamide was performed using a validated liquid chromatography/mass spectrometry (LC/MS) method in the concentration range of 0.02 to 12 μg/mL.

Statistical analysis

A sample size of 100 patients in each treatment group was considered necessary to detect a significant difference from baseline to maintenance between lacosamide and placebo in seizure frequency and 50% responder rate with a power of 90% and a two-sided test at a significance level of 5%. The trial was powered to detect an effect size of 19% reduction in seizure frequency over placebo and a standard deviation (SD) of 0.45. For the 50% responder rate, the trial was powered assuming responder rates of 12% for placebo and 32% for lacosamide.

Change in seizure frequency per 28 days, one of the two primary efficacy variables, was calculated for the baseline and maintenance periods. For patients who discontinued before the maintenance period, efficacy data were carried forward from the titration period for inclusion in the maintenance period analysis. For patients who discontinued during the maintenance period, seizure frequency was calculated using all available data in the maintenance period. The inferential statistical analysis, based on analysis of covariance (ANCOVA) with terms for treatment and region, was performed on log-transformed seizure frequency. Log-transformed average seizure frequency during the baseline period was used as the covariate. The seizure frequency between each treatment group and placebo was compared using least squares means.

The second primary efficacy variable was the 50% responder rate, defined as the number of patients with a seizure frequency reduction of at least 50% from baseline to maintenance. The responder rate between each active treatment and placebo was analyzed using a logistic regression model with treatment and region as factors.

The testing procedure used for each primary efficacy endpoint was considered a closed testing procedure and no adjustment of the significance level was necessary. Efficacy assessment was conducted on an intent-to-treat (ITT) basis and included all randomized patients who received at least one dose of trial medication and had at least one postbaseline seizure diary entry. The per protocol population included the patients with seizure frequency data from the maintenance period who had no major protocol deviations.

Safety analyses included all randomized patients who received at least one dose of trial medication. The safety analyses covered the entire time course of the trial, including the time during the titration period when patients randomized to lacosamide 200 mg/day and 400 mg/day were receiving placebo.

Plasma concentrations for lacosamide and concomitant AEDs were summarized using descriptive statistics for all patients who received at least one dose of trial medication. Health outcome measurements were summarized for the ITT population. The QOLIE-31 overall score was summarized using descriptive statistics at the last postbaseline measurement by randomized dose.

RESULTS

Demographics

Of the 542 patients screened, 45 were screen failures (Fig. 1). Of the 497 patients who entered the baseline period, 421 were randomized to one of four treatment groups and received at least one dose of trial medication. Data for 3 patients were not included in the analyses because of site audit findings suggesting site protocol noncompliance. Of the 418 patients analyzed for safety, 3 did not have any postbaseline efficacy assessments, thus 415 patients were included in the efficacy analyses. Among the 418 patients in the safety analyses, 312 (75%) completed the trial and 106 (25%) discontinued prematurely. Of the 418 patients in the safety analyses, 73 (17%) discontinued because of AEs.

Figure 1.

Patient disposition. aMore than one primary reason for discontinuation may have been recorded by the investigator.bIn the lacosamide 200 mg/day treatment group, 6 patients were still receiving placebo when the adverse event occurred, and 3 patients in the 400 mg/day treatment group were on placebo when the adverse event occurred.

Baseline demographic characteristics were comparable between treatment groups (Table 1). The mean (SD) age of patients in the trial was 39.9 years (11.25) with an age range of 18 to 68 years. Most of the patients were Caucasian (93%) and 54% of the patients were female. Across all treatment groups, the mean number of years since diagnosis of epilepsy was 24.5 years. Approximately 84% of the patients in this trial were taking 2 AEDs, and the rest were taking 1 AED when trial medication was added to their treatment regimen. Approximately 50% of patients had tried 7 or more AEDs in their lifetime. Despite treatment with 1 or 2 concomitant AEDs, the median seizure frequency per 28 days across all treatment groups was 11–13 seizures during the 8-week baseline period.

Table 1. Demographic and baseline characteristics of patients analyzed for safety
CharacteristicPlacebo (n = 97)Lacosamide 200 mg/day (n = 107)Lacosamide 400 mg/day (n = 108)Lacosamide 600 mg/day (n = 106)
  1. SD, Standard deviation.

Age, yr 
 Mean ± SD38.9 ± 11.1139.9 ± 11.7141.2 ± 11.6139.4 ± 10.53
 Range19 – 6618 – 6518 – 6818 – 64
Sex, n (%) 
 Male47 (48)46 (43)53 (49)45 (42)
 Female50 (52)61 (57)55 (51)61 (58)
Race, n (%) 
 Caucasian88 (91)98 (92)100 (93) 101 (95) 
 Black6 (6)4 (4)5 (5)2 (2)
 Asian0 (0)2 (2)0 (0)0 (0)
 Other3 (3)3 (3)3 (3)3 (3)
Weight, Kg (mean ± SD)79.5 ± 20.9074.5 ± 17.1677.5 ± 18.6375.7 ± 19.40
Mean time since diagnosis (year)24.6 ± 11.7725.1 ± 12.8924.7 ± 13.0823.6 ± 12.74
Seizure type at baseline, n (%) 
 Simple partial-onset seizures33 (34)48 (45)41 (38)50 (47)
 Complex partial-onset seizures83 (86)101 (94) 94 (87)96 (91)
 Partial-onset seizures with secondary generalization73 (75)79 (74)77 (71)70 (66)

Efficacy

The median percent reduction in seizure frequency from baseline to maintenance was 10% in the placebo, 26% in the lacosamide 200 mg/day, 39% in the 400 mg/day, and 40% in the 600 mg/day treatment groups (Fig. 2). Based on the ANCOVA model used, statistically significant reductions in seizure frequency over placebo were observed in the lacosamide 400 mg/day (28.4%; p = 0.0023) and 600 mg/day (21.3%; p = 0.0084) treatment groups. For the lacosamide 200 mg/day treatment group, the reduction in seizure frequency over placebo was 14.6% (p = 0.1010), indicating a difference that did not reach statistical significance. The per protocol population showed an even greater treatment difference between placebo and all lacosamide treatment groups with a statistically significant reduction in seizure frequency over placebo for lacosamide 200 mg/day (21.5%; p = 0.0112), 400 mg/day (39.3%; p < 0.0001), and 600 mg/day (31.6%; p = 0.0002).

Figure 2.

Median percent reduction in seizure frequency per 28 days for maintenance. p-values are based on log-transformed data from pairwise treatment analysis of covariance (ANCOVA) models, performed on the intent-to-treat population.

Based on the logistic regression model used, the proportion of patients with at least a 50% reduction in seizure frequency during maintenance for lacosamide 400 mg/day (41.1%; p = 0.0038) and 600 mg/day (38.1% p = 0.0141) was statistically significant when compared to placebo (21.9%) (Fig. 3). For the lacosamide 200 mg/day treatment group, the 50% responder rate was 32.7% (p = 0.0899), indicating a difference that did not reach statistical significance. The per protocol analysis showed an even greater treatment difference between placebo and all lacosamide treatment groups. The 50% responder rate was 21.2% for placebo, 38.1% (p = 0.0214) for lacosamide 200 mg/day, 49.4% (p = 0.0002) for 400 mg/day, and 49.2% (p = 0.0004) for 600 mg/day.

Figure 3.

Fifty percent responder rate over placebo for maintenance. p-values are based on pairwise treatment logistic regression models performed on the intent-to-treat population.

The results of the statistical analysis of the proportion of patients with at least a 75% reduction in seizure frequency for maintenance were 6.3% for placebo, 11.2% for lacosamide 200 mg/day (p = 0.2356), 22.4% for 400 mg/day (p = 0.0020), and 16.2% for 600 mg/day (p = 0.0334). In assessing response to treatment, it was noted that some patients experienced an increase in seizure frequency during the trial; however, lacosamide did not appear to increase seizure frequency (defined as ≥ 25%) as compared to placebo (20% for placebo, 15% for lacosamide 200 mg/day, 21% for 400 mg/day, and 20% for 600 mg/day).

Seven patients were seizure-free throughout the 12-week maintenance period, all were randomized to lacosamide; 1 patient in the lacosamide 200 mg/day group, 5 in the 400 mg/day group, and 1 in the 600 mg/day group. At the end of the maintenance period, the median change from baseline in the percentage of seizure-free days was 3% for patients randomized to placebo, 6% for patients randomized to lacosamide 200 mg/day, 12% for 400 mg/day, and 12% for 600 mg/day. Statistically significant differences in the percentage of seizure-free days over placebo were observed in the lacosamide 400 mg/day (p = 0.0036) and 600 mg/day (p = 0.0004) groups.

Patients in the lacosamide 400 mg/day group experienced more improvement in quality of life than patients in the other treatment groups, as assessed by median changes in QOLIE-31 overall score from baseline, with an improvement of 2.7 points compared to an overall score of −1.3 points in the placebo group. The CGIC analysis showed an improvement (“very much improved” or “much improved”) from baseline to maintenance in a greater percentage of patients in the lacosamide 200 mg/day (35%), 400 mg/day (40%), and 600 mg/day (38%) treatment groups compared to the placebo group (25%).

Safety

Of the 321 patients treated with lacosamide, 270 (84%) experienced at least one treatment-emergent adverse event (TEAE) compared to 68 of 97 patients (70%) in the placebo group during the treatment period (titration and maintenance periods) of this trial. Most events were considered to be mild or moderate in intensity. The most commonly reported TEAEs, which occurred in at least 10% of patients in any randomized treatment group, were in the CNS and gastrointestinal system (dizziness, headache, nausea, fatigue, ataxia, vision abnormal, vomiting, diplopia, somnolence, and nystagmus) (Table 2). The number of patients reporting these TEAEs was highest in those randomized to the 600 mg/day treatment group. Events that appeared to be related to lacosamide dose included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, vertigo, and nystagmus; however, for some events, the small number of patients experiencing them makes it difficult to clearly establish a dose relationship. At 55%, the incidence of dizziness in the lacosamide 600 mg/day group was high compared to 26% in the 400 mg/day group, 24% in the 200 mg/day group, and 10% in the placebo group. There was no clinically important difference in the rate of psychiatric AEs between patients receiving lacosamide or placebo.

Table 2. Treatment-emergent adverse events (%) occurring in at least 10% of patients in any treatment group
Adverse eventaPlacebo (n = 97)Lacosamide 200 mg/day (n = 107)Lacosamide 400 mg/day (n = 108)Lacosamide 600 mg/day (n = 106)Lacosamide Total (n = 321)
  1. aPatients reporting the same adverse event more than once are counted once per adverse event and randomized dose.

  2. NOS, not otherwise specified; URI, upper respiratory infection.

Any event68 (70)85 (79)87 (81)98 (92)270 (84)
Dizziness10 (10)26 (24)28 (26)58 (55)112 (35)
Headache9 (9)12 (11)26 (24)14 (13)52 (16)
Nausea9 (9)11 (10)16 (15)19 (18)46 (14)
Fatigue5 (5)11 (10)13 (12)21 (20)45 (14)
Ataxia3 (3)4 (4)14 (13)24 (23)42 (13)
Vision abnormal5 (5)4 (4)12 (11)21 (20)37 (12)
Vomiting3 (3)11 (10)13 (12)13 (12)37 (12)
Diplopia2 (2)4 (4)12 (11)15 (14)31 (10)
Somnolence6 (6)8 (7)13 (12)10 (9) 31 (10)
URI11 (11)12 (11)13 (12)6 (6)31 (10)
Accident NOS12 (12)15 (14)6 (6)5 (5)26 (8) 
Nystagmus5 (5)3 (3)5 (5)11 (10)19 (6) 

Of the 347 patients who completed the titration period, 285 patients (82%) achieved their target dose of trial medication without the need for dose reduction at the end of the titration period; 85 in the placebo group, 79 in the lacosamide 200 mg/day group, 73 in the 400 mg/day group, and 48 in the 600 mg/day group. A total of 62 patients (18%) had dose reductions of 100 mg/day because of AEs; 7 in the placebo group, 16 in the lacosamide 200 mg/day group, 16 in the 400 mg/day group, and 23 in the 600 mg/day group.

Of the 418 patients who received at least one dose of trial medication, 69 (17%) discontinued from the trial during the treatment period because of TEAEs; 5 patients randomized to placebo, and 12, 20, and 32 patients randomized to lacosamide 200, 400, and 600 mg/day, respectively (Table 3). AEs generally had an onset during the titration period, which was also when patients were more likely to discontinue because of TEAEs. The number of patients who discontinued because of TEAEs tended to increase with higher doses of lacosamide. The TEAEs leading to discontinuation in at least 5% of patients in any lacosamide treatment group were dizziness, nausea, ataxia, vomiting, and nystagmus (Table 3). Nine patients randomized to lacosamide, 6 in the 200 mg/day group and 3 in the 400 mg/day group, experienced TEAEs leading to discontinuation while they were still receiving placebo during the titration period.

Table 3. Treatment-emergent adverse events (%) leading to discontinuation in at least 5% of patients in any treatment group
Adverse eventaPlacebo (n = 97)Lacosamide 200 mg/day (n = 107)Lacosamide 400 mg/day (n = 108)Lacosamide 600 mg/day (n = 106)Lacosamide Total (n = 321)
  1. aPercentages are based on the number of patients in the randomized dose group who received at least one dose of trial medication.

Any event that led to discontinuation5 (5)12 (11)20 (19)32 (30) 64 (20)
Dizziness0 (0) 1 (<1)5 (5)20 (19)26 (8)
Nausea0 (0) 1 (<1)5 (5)7 (7)13 (4)
Ataxia0 (0)0 (0)3 (3)9 (8)12 (4)
Vomiting0 (0) 1 (<1)5 (5)3 (3) 9 (3)
Nystagmus0 (0)0 (0)0 (0)5 (5) 5 (2)

During the treatment period, no individual serious adverse event (SAE) occurred at a frequency of greater than 1% across all patients. The most frequently reported SAEs were dizziness and convulsions (3 patients each), as well as vomiting, accident not otherwise specified, nystagmus, nausea, and aggravated convulsions (2 patients each). All other SAEs that occurred during the treatment period were experienced by only 1 patient each. The frequency of SAEs was similar across all randomized dose groups: placebo, 5% of patients; lacosamide 200 mg/day, 9%; 400 mg/day, 6%; and 600 mg/day, 3%.

Evaluation of ECG data from this trial did not show any tendency for lacosamide to prolong the QT/QTc interval. Laco-samide produced a small, dose-related increase in mean PR interval (4.2 msec at the end of maintenance visit for the 400 mg/day dose). First-degree atrioventricular (AV) block was reported as an AE for 3 patients (at lacosamide doses of 100, 200, and 500 mg/day); all 3 patients continued treatment with lacosamide. These 3 patients did not report any other AEs at the same time as the AV block.

Overall results of laboratory evaluations as well as periodic physical examinations, neurological examinations, and assessments of vital signs generally did not identify any effects associated with lacosamide treatment that were of clinical concern. Two patients experienced elevations in alanine aminotransferase (ALT) values (≥ 3 × ULN). One patient, a 36-year-old female taking lorazepam and oxcarbazepine, had been on lacosamide 100 mg/day for 65 days when she was observed to have an elevation in aspartate aminotransferase (AST) values (178 U/L, 4.9 × ULN) and ALT values (203 U/L, 5.5 × ULN) that was reported as an AE resulting in discontinuation. The patient was also taking bucindolol hydrochloride, sumatriptan, propranolol hydrochloride, lidocaine, cetirizine, and valdecoxib. While taking placebo, the patient had experienced mild elevations in AST (46 U/L) and ALT (80 U/L) values. One week after discontinuation of lacosamide, the LFT values had normalized. The other patient was a 46-year-old female who had abnormal ALT elevations before treatment, as high as 74 U/L (2 × ULN), and a subsequent level of 62 U/L during 12 weeks of treatment at a maintenance dose of lacosamide 600 mg/day. Upon reduction of this dose to 400 mg/day during transition to the extension trial, the patient was observed to have an ALT value of 124 U/L (3.4 × ULN), which decreased to 59 U/L 6 days after the transition dose of lacosamide 200 mg/day was begun. This patient was already taking phenobarbital and phenytoin sodium when she was enrolled in the trial and continued on these AEDs throughout the trial. Neither patient had an elevation in bilirubin.

Overall, the results from this trial showed that lacosamide and placebo had similar effects on body weight. The mean change from baseline to the end of the maintenance period was 0.6 kg for placebo, 0.2 kg for lacosamide 200 mg/day, 0.1 kg for 400 mg/day, and 0.3 kg for 600 mg/day.

Pharmacokinetics

Dose proportionality was observed for plasma concentrations of lacosamide. Mean ± SD plasma concentrations of lacosamide at the end of the maintenance period were 4.99 ± 2.51 μg/mL for 200 mg/day (n = 85), 9.35 ± 4.22 μg/mL for 400 mg/day (n = 83), and 12.46 ± 5.80 μg/mL for 600 mg/day (n = 61).

Mean plasma concentrations of the concomitant AEDs carbamazepine and its epoxide metabolite, lamotrigine, levetiracetam, oxcarbazepine MHD (10-monohydroxy metabolite of oxcarbazepine), phenytoin, topiramate, and valproate were not affected by concomitant intake of lacosamide (Table 4).

Table 4. Mean change from baseline in plasma concentration (μg/mL) of antiepileptic drugs taken concomitantly with lacosamide
Antiepileptic drugPlaceboLacosamide 200 mg/dayLacosamide 400 mg/dayLacosamide 600 mg/day
  1. MHD, 10-monohydroxy metabolite of oxcarbazepine; SD, standard deviation. Mean Δ, mean change from baseline value.

Carbamazepine
 Baseline (mean ± SD)8.2 ± 2.318.1 ± 2.118.0 ± 2.578.2 ± 2.90
(n = 33)(n = 28)(n = 22)(n = 42)
 End of maintenance (mean Δ± SD)0.4 ± 1.980.5 ± 1.600.2 ± 2.120.6 ± 1.81
(n = 28)(n = 22)(n = 17)(n = 21)
Carbamazepine Epoxide
 Baseline (mean ± SD)1.5 ± 0.601.5 ± 0.681.4 ± 0.541.6 ± 0.84
(n = 33)(n = 28)(n = 22)(n = 41)
 End of maintenance (mean Δ± SD)0.1 ± 0.420.0 ± 0.270.0 ± 0.400.1 ± 0.38
(n = 28)(n = 22)(n = 17)(n = 21)
Lamotrigine
 Baseline (mean ± SD)7.6 ± 5.239.1 ± 6.088.8 ± 4.729.0 ± 5.92
(n = 23)(n = 23)(n = 32)(n = 23)
 End of maintenance (mean Δ± SD)0.4 ± 2.51−0.1 ± 1.90 −0.5 ± 1.93 −0.7 ± 1.68 
(n = 21)(n = 19)(n = 24)(n = 10)
Levetiracetam
 Baseline (mean ± SD)32.4 ± 18.8337.7 ± 20.4738.0 ± 22.55 36.8 ± 22.42
(n = 24)(n = 39)(n = 30)(n = 29)
 End of maintenance (mean Δ± SD) 1.0 ± 13.14−0.5 ± 14.37  3.6 ± 12.43−1.4 ± 14.36 
(n = 22)(n = 34)(n = 25)(n = 22)
Oxcarbazepine MHD
 Baseline (mean ± SD)25.6 ± 10.6822.2 ± 10.8526.8 ± 15.9527.3 ± 7.38
(n = 15)(n = 22)(n = 16)(n = 16)
 End of maintenance (mean Δ± SD)−1.4 ± 7.05 0.9 ± 7.88−0.1 ± 6.99 −2.9 ± 5.66 
(n = 14)(n = 18)(n = 7)(n = 7)
Phenytoin
 Baseline (mean ± SD)15.1 ± 6.4612.4 ± 6.50 15.3 ± 4.5715.9 ± 7.26
(n = 11)(n = 17)(n = 22)(n = 18)
 End of maintenance (mean Δ± SD)0.1 ± 7.000.6 ± 5.800.9 ± 5.06−1.5 ± 4.24 
(n = 11)(n = 16)(n = 22)(n = 14)
Topiramate
 Baseline (mean ± SD)9.6 ± 4.5911.3 ± 6.7510.1 ± 5.888.0 ± 3.75
(n = 15)(n = 19)(n = 27)(n = 19)
 End of maintenance (mean Δ± SD)−2.0 ± 7.68 0.2 ± 3.79−1.7 ± 3.11 0.0 ± 1.69
(n = 13)(n = 13)(n = 18)(n = 12)
Valproate
 Baseline (mean ± SD)54.0 ± 20.9871.1 ± 27.2367.8 ± 21.4768.1 ± 28.25
(n = 14)(n = 22)(n = 14)(n = 21)
 End of maintenance (mean Δ± SD)9.6 ± 28.285.1 ± 26.98−6.8 ± 28.45 13.0 ± 25.10
(n = 12)(n = 15)(n = 12)(n = 9)

DISCUSSION

In this trial, lacosamide, at doses of 400 mg/day and 600 mg/day, produced a statistically significant reduction in seizure frequency for patients with partial-onset seizures, with or without secondary generalization, when added to 1 or 2 concomitant AEDs. These patients had refractory epilepsy and over half had already tried at least seven AEDs. Twice-daily lacosamide was also generally well tolerated when given as adjunctive treatment and did not affect the plasma concentrations of commonly used concomitant AEDs.

Two primary efficacy variables were defined for this trial: change in seizure frequency per 28 days from baseline to maintenance, and proportion of patients with at least a 50% reduction in seizure frequency from baseline to maintenance. Statistically significant improvement was achieved for both primary efficacy variables with lacosamide 400 mg/day and 600 mg/day in both the ITT and per protocol analyses. For lacosamide 200 mg/day, statistical significance was achieved for both primary efficacy variables in the per protocol analyses.

In this trial, the responder rates for patients on lacosamide were 33% for 200 mg/day, 41% for 400 mg/day, and 38% for 600 mg/day. Responder rates for other AEDs, such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide, range from 14% to 45%, as reported in the literature (Cramer et al., 2001; Bialer et al., 2004).

The most commonly reported AEs occurred in the CNS and gastrointestinal system and were dose related. The nature and frequency of these AEs were comparable to those reported for other AEDs used as adjunctive therapy for partial-onset seizures (Marson et al., 1996; Bialer et al., 2002). Discontinuations because of AEs occurred mostly during the titration period. Lacosamide generally had no clinically important effects on laboratory or vital sign variables, and the mean body weight changes for patients on lacosamide were comparable to those seen for patients on placebo. Lacosamide produced a small, dose-related increase in PR interval.

The 600 mg/day and 400 mg/day doses of lacosamide showed similar efficacy; however, the 400 mg/day dose appeared to be better tolerated in this trial. Further investigation is needed to clarify the effectiveness of the 200 mg/day lacosamide dose.

Although approximately 84% of patients were already taking 2 AEDs, the median seizure frequency per 28 days during the baseline period was 11–13 seizures. More than 50% of patients had previously tried 7 or more AEDs. Given the nature of the uncontrolled seizures in these patients before enrollment in the trial, the efficacy results from this trial are encouraging and suggest that lacosamide may be efficacious in a wide range of patients with partial-onset seizures.

Properties of an ideal AED include high oral efficacy, good tolerability, once- or twice-daily dosing, minimal drug interactions, and no seizure aggravation or teratogenicity (Sander, 2004). Clinical trials to date have demonstrated that lacosamide might meet these clinical criteria. In preclinical trials lacosamide was not teratogenic, however, this can only be confirmed with experience in humans. This trial demonstrated that twice-daily dosing of lacosamide produced statistically significant reductions in seizure frequency at doses of 400 and 600 mg/day in patients with uncontrolled partial-onset seizures; however, the 400 mg/day dose of lacosamide was better tolerated than the 600 mg/day dose. These results suggest that lacosamide has the potential to become an effective pharmacological treatment option for patients with partial-onset seizures.

Acknowledgments

Acknowledgments:  The authors wish to acknowledge the contribution made by all of the members of the SP667 Study Group who have contributed materially to the contents of this manuscript by their participation in taking care of patients according to the approved protocol and contributing to the total data generated for this trial: B. Abou-Khalil, Nashville, TN; M. Agostini, Dallas, TX; J. Asconape, Indianapolis, IN; D. Bartel, Wichita Falls, TX; C. Bazil, New York, NY; E. Ben-Menachem, Göteborg, Sweden; D. Bergen, Chicago, IL; V. Biton, Little Rock, AR; M. Brodie, Glasgow, Scotland; D. Cantrell, Irving, TX; D. Chadwick, Liverpool, UK; S. Chung, Phoenix, AZ; B. Dihenia, Lubbock, TX; F. Donati, Biel/Bienne, Switzerland; K. Edwards, Bennington, VT; C. Elger, Bonn, Germany; M. Endziniene, Kaunas, Lithuania; T. Fakhoury, Lexington, KY; R. Faught Jr., Birmingham, AL; A. Fessler III, St. Louis, MO; D. Fleming Jr., Greenville, NC; N. Fountain, Charlottesville, VA; J. French, Philadelphia, PA; P. Ginsberg, Hollywood, FL; P. Halasz, Budapest, Hungary; R. Hull, Huntsville, AL; A. Husain, Durham, NC; R. Jackel, Sellersville, PA; D. Jatuzis, Vilnius, Lithuania; J. Jedrzejczak, Warsaw, Poland; L. Kaminow, Scarborough, ME; P. Kaplan, Baltimore, MD; D. Ko, Los Angeles, CA; W. Kozubski, Poznan, Poland; G. Kraemer, Zurich, Switzerland; G. Krauss, Baltimore, MD; D. Labar, New York, NY; P. Lindström, Stockholm, Sweden; K. Liow, Wichita, KS; J. Liporace, Philadelphia, PA; G. Mayer, Schwalmstadt-Treysa, Germany; P. McCabe, Hershey, PA; G. Montouris, Boston, MA; J. Moore, Columbus, OH; G. Morris III, Milwaukee, WI; D. Naritoku, Springfield, IL; J. Nikl, Zalaegerszeg, Hungary; S. Noachtar, Munich, Germany; E. Passaro, St. Petersburg, FL; P. Penovich, St. Paul, MN; J. Perkins, Crestview Hills, KY; B. Phillips, Englewood, CO; M. Privitera, Cincinnati, OH; M. Raphaelson, Frederick, MD; W. Rosenfeld, St. Louis, MO; J. Sander, London, UK; E. Sandok, Marshfield, WI; A. Schulze-Bonhage, Freiburg, Germany; A. Solyom, Budapest, Hungary; E. St. Louis, Iowa City, IA; H. Stefan, Erlangen, Germany; B. Steinhoff, Kehl-Kork, Germany; A. Stepien, Warsaw, Poland; W. Tatum, Tampa, FL; B. Tettenborn, St. Gallen, Switzerland; J. Wendt, Tucson, AZ; M. Werz, Cleveland, OH; and G. Wieser, Zurich, Switzerland.

The authors would like to express their appreciation to Maria Hackenson, Jan Newcomer, and Maria Luise Esch, of SCHWARZ BIOSCIENCES, Inc., for serving as the clinical trial manager, senior clinical research associate for the USA, and senior clinical research associate for Europe, respectively.

SCHWARZ BIOSCIENCES, GmbH, Monheim, Germany, provided the trial supplies and SCHWARZ BIOSCIENCES, Inc., Research Triangle Park, NC, USA, sponsored and funded the trial. Central laboratory facilities were provided by Quintiles Laboratories USA (Smyrna, GA, U.S.A.) for the sites in the U.S.A. For European sites, laboratory tests were performed at Quintiles Laboratories, Europe (West Lothian, Scotland, U.K.). Plasma samples were analyzed by SCHWARZ BIOSCIENCES, GmbH (Monheim, Germany) and plasma concentrations of selected concomitant antiepileptic drugs were determined by MedTox, Inc. (St. Paul, MN, U.S.A.). Central electrocardiographic services for all sites were centrally read by Biomedical Systems (St. Louis, MO, U.S.A.).

Deana G. Betterton-Lewis provided medical writing services and Allison Coppola provided copyediting services on behalf of SCHWARZ BIOSCIENCES, Inc., Research Triangle Park, NC, U.S.A.

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