ClinicalTrials.gov Identifier: NCT00220415
Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial
Version of Record online: 22 JAN 2009
Wiley Periodicals, Inc. © 2009 International League Against Epilepsy
Volume 50, Issue 3, pages 443–453, March 2009
How to Cite
Halász, P., Kälviäinen, R., Mazurkiewicz-Beldzińska, M., Rosenow, F., Doty, P., Hebert, D., Sullivan, T. and on behalf of the SP755 Study Group (2009), Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia, 50: 443–453. doi: 10.1111/j.1528-1167.2008.01951.x
- Issue online: 4 MAR 2009
- Version of Record online: 22 JAN 2009
- Accepted October 7, 2008; Early View publication January 22, 2009.
- Partial-onset seizures;
- Antiepileptic drugs;
- Randomized controlled trial
Purpose: To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.
Methods: This multicenter, double-blind, placebo-controlled trial randomized patients (age 16–70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period.
Results: Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p = 0.02), and 36.4% for 400 mg/day (p = 0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p = 0.04) and 44.9% for 400 mg/day (p = 0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p = 0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p < 0.01) compared with the placebo responder rate (27.5%). Dose-related adverse events (AEs) included dizziness, nausea, and vomiting. Clinically relevant changes in the mean plasma concentrations of commonly used AEDs were not observed.
Discussion: Results of this trial demonstrated the efficacy and tolerability of adjunctive lacosamide 200 and 400 mg/day and support that lacosamide may be an advantageous option for the treatment of partial-onset seizures in patients with epilepsy.
The goal of pharmacologic therapy with antiepileptic drugs (AEDs) is to reduce the frequency of seizures and achieve a seizure-free state with minimal side effects (Shneker & Fountain, 2003). However, only half of patients achieve seizure freedom with the first administered AED, and about 60–70% of patients become seizure-free with the first or second AED tried (Brodie & Kwan, 2002). Approximately 30% of patients treated with available AEDs continue to experience uncontrolled seizures (Kwan & Brodie, 2000). Despite the availability of a new generation of AEDs, many patients are unable to achieve seizure control, whereas others experience intolerable side effects; therefore, the need remains for the development of effective and well-tolerated new AEDs (Bialer, 2002).
Lacosamide, the R-enantiomer of 2-acetamido-N-benzyl-3-methoxypropionamide, is a novel functionalized amino acid that was synthesized as a potential anticonvulsant compound (Andurkar et al., 1999; Hovinga, 2003). Lacosamide was effective in a range of animal models of epilepsy (Brandt et al., 2006; Beyreuther et al., 2007; Stöhr et al., 2007). Based on in vitro studies, lacosamide appears to have a dual mode of action. It selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation (Errington et al., 2006, 2008; Sheets et al., 2008). In addition, lacosamide binds to collapsin-response mediator protein 2 (CRMP-2), a protein that is involved in neuroplastic processes such as neuronal outgrowth or the modulation of N-methyl-d-aspartate (NMDA) receptor subunit NR2B (Beyreuther et al., 2007; Beyreuther et al., 2006).
Oral lacosamide is absorbed completely and rapidly from the gastrointestinal tract with negligible first-pass metabolism (Thomas et al., 2007). Administration with food does not alter the rate or extent of lacosamide absorption (Cawello et al., 2004; Doty et al., 2007). Lacosamide plasma concentrations have shown a proportional relationship for oral doses ranging from 100–800 mg/day (Horstmann et al., 2002). Peak plasma levels occur within 1–4 h of an oral lacosamide dose with a 13-h elimination half-life that is independent of dose or duration of administration (Horstmann et al., 2002; Hovinga, 2003; Bialer et al., 2007). Lacosamide is eliminated primarily by renal excretion and biotransformation. Approximately 40% of the drug is eliminated unchanged in the urine. Lacosamide has demonstrated low plasma protein binding (≤15%) as well as a low potential for pharmacokinetic drug–drug interactions (Thomas et al., 2007). No pharmacokinetic interactions were evident between lacosamide and carbamazepine, valproic acid, metformin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), or omeprazole in dedicated studies (Horstmann et al., 2003; Kropeit et al., 2006; Doty et al., 2007). Lacosamide has shown no or low potential to inhibit or to induce CYP isoforms (Kropeit et al., 2006).
A recent multicenter, randomized, double-blind, placebo-controlled trial evaluated lacosamide 200 mg/day, 400 mg/day, and 600 mg/day when added to one or two AEDs in 418 adult patients with uncontrolled partial-onset seizures (SP667; Ben-Menachem et al., 2007). Reductions in seizure frequency and the proportion of patients with at least a 50% reduction in seizure frequency (50% responder rate) with lacosamide 400 and 600 mg/day were statistically significant compared with placebo in the primary intent-to-treat (ITT) population. However, in the per protocol population, reductions in seizure frequency and in the 50% responder rate were significant compared with placebo with all three doses of lacosamide (200, 400, and 600 mg/day). Adverse events (AEs) that appeared dose-related included dizziness, nausea, fatigue, ataxia, abnormal vision, diplopia, and nystagmus. In addition, lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs.
The primary objective of this trial (SP755) was to evaluate the efficacy and safety of lacosamide doses of 200 mg/day and 400 mg/day when added to one to three marketed concomitant AEDs in patients with uncontrolled partial-onset seizures, with or without additional vagus nerve stimulation (VNS). Dose proportionality of lacosamide and the stability of concomitant AED concentrations were assessed by determination of steady-state plasma concentrations of these drugs. This trial was designed to complement the previous trial (SP667; Ben-Menachem et al., 2007) in order to establish the efficacy of adjunctive lacosamide.
Materials and Methods
This international, multicenter, double-blind, randomized, placebo-controlled, parallel group trial (SP755; NCT00220415) was conducted between June 2004 and January 2006 at 75 enrolling sites in Australia, Croatia, Czech Republic, Finland, France, Germany, Hungary, Lithuania, Poland, Russia, Spain, Sweden, and the United Kingdom. The trial was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, and the local laws of the countries involved, as well as the ICH Tripartite Guideline, Guideline for GCP, January 1997. The trial protocol, amendments, and informed consents were reviewed by the applicable national regulatory authority in each country and relevant ethics committees for each site. All patients or their legal representatives gave written informed consent before trial participation.
The study included patients between the ages of 16 and 70 years with a diagnosis of partial-onset seizures with or without secondary generalizations (ILAE, 1981). Patients must have had an electroencephalography (EEG) study 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.
Enrollment criteria required patients to have had partial-onset seizures for at least the preceding 2 years despite prior therapy with at least two AEDs. Patients were to have had at least four partial-onset seizures per 28 days on average, with no seizure-free period longer than 21 days during the 8-week period before enrollment as well as during the 8-week baseline period. In addition, patients were to have been taking a stable dosage regimen of one to three AEDs, with or without VNS, in the 4 weeks before enrollment and during the baseline period.
Female patients were excluded from participation if they were pregnant, breast-feeding, or of childbearing potential and not using approved methods of contraception. Patients were excluded if they had previously received lacosamide or had participated in any other investigational trial within the last 2 months. Patients were also excluded if they had a history of chronic alcohol or drug abuse; any medical condition that might jeopardize the patient’s health or compromise the patient’s ability to participate in this trial; liver function test results of at least two times the upper limit of normal; creatinine clearance <50 ml/min; diastolic blood pressure <50 mm Hg or >105 mm Hg or pulse <50 or >110 beats per minute after 3 min in a sitting position; heart rate by electrocardiography (ECG) <50 or >110 beats per minute; confirmed clinically significant ECG abnormality; history of severe anaphylactic reaction or serious blood dyscrasias; nonepileptic events, including psychogenic seizures; seizure clustering (i.e., episodes lasting ≤30 min in which seizures occur with such frequency that the initiation and completion of each seizure cannot be distinguished) 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 or vigabatrin therapy within the last 6 months; any other clinically significant condition, or recent chronic consumption of non-AED medications that might interfere with drug absorption, distribution, metabolism, or excretion; or treatment on a regular basis with one of the following medications influencing the CNS—neuroleptics, monoamine oxidase (MAO) inhibitors, barbiturates (except when taken as concomitant anticonvulsant treatment), or narcotic analgesics within 4 weeks before enrollment.
This trial consisted of baseline, titration, maintenance, and transition or taper periods (Fig. 1). Enrolled patients entered an 8-week baseline period to obtain baseline seizure frequency data and to determine eligibility for the double-blind period of the trial. Patients meeting the eligibility criteria were randomized in a 1:1:1 ratio to one of three treatment arms: placebo, lacosamide 200 mg/day (100 mg twice daily), or lacosamide 400 mg/day (200 mg twice daily). An interactive voice response system (IVRS) was used to randomly assign treatment to patients based on a predetermined computer-generated (pseudo-random number generator) schedule.
At the beginning of the 4-week forced titration period, patients were started on either placebo or lacosamide 100 mg/day. In the case of patients randomized to lacosamide 400 mg/day, the dose was increased by 100 mg/day each week until the 400 mg/day dose was reached at the beginning of week 4. Patients randomized to 200 mg/day received placebo during the first 2 weeks of titration, were started on lacosamide 100 mg/day at week 3, and the dose was increased to 200 mg/day at the beginning of week 4. One-step dose reduction of 100 mg/day was allowed at the end of the titration period at the fourth week for patients experiencing intolerable AEs. If the dose was reduced, it could not be increased again during this trial. Patients who required a second dose reduction were discontinued from the trial.
After completing the titration period, patients entered a 12-week maintenance period. Patients completing the maintenance period were eligible to enter an open-label lacosamide extension trial (SP774; NCT00515619). Patients who chose to enroll in the open-label extension trial were transitioned in a double-blind manner from their maintenance dose to lacosamide 200 mg/day over a 2-week period. For patients who discontinued during the titration or maintenance period or who elected not to enroll in the open-label extension trial, trial medication was tapered by 200 mg/day each week over a 2-week period in a double-blind fashion. For this trial, lacosamide was supplied as white, film-coated tablets in strengths of 50 and 100 mg. Placebo was supplied as white, film-coated tablets that were identical to the lacosamide tablets in size and color. Trial medication was supplied in blister packs that contained four tablets for the morning dose and four tablets for the evening dose, comprising the appropriate combination of placebo and active tablets.
The primary assessment of efficacy, based on the change in seizure frequency, was evaluated in two ways: (1) the change in seizure frequency per 28 days from baseline to the maintenance period; and (2) the 50% responder rate, defined as the proportion of patients experiencing a 50% or greater reduction in partial seizure frequency per 28 days from the baseline to the maintenance period.
Secondary efficacy variables included the percent change in seizure frequency per 28 days from baseline to the maintenance period, number and proportion of patients achieving seizure-free status throughout the maintenance period for patients completing the maintenance period, and proportion of seizure-free days during the maintenance period for patients entering the maintenance period. Patients or their caregiver kept daily diaries, which documented seizure types and seizure frequency from the beginning of baseline until the last visit.
Safety evaluation included assessment of AEs reported by the patient or their caregiver, recorded in the patient diary, or observed by the investigator; patient withdrawals due to AEs; and changes in laboratory values (hematology, clinical chemistry, or urinalysis), 12-lead ECG readings, vital sign and body weight measurements, and physical and neurologic examination findings.
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. A validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method was used to perform the quantification of lacosamide in the concentration range of 0.01–12 μg/ml. The HPLC-MS/MS method was also used to assay the plasma concentrations of carbamazepine and its epoxide metabolite, lamotrigine, levetiracetam, the monohydroxy derivative of oxcarbazepine (MHD), and clonazepam. Valproic acid and topiramate concentrations were analyzed using fluorescence polarization immunoassays, and phenytoin concentrations were analyzed using an enzyme-multiplied immunoassay technique. A central laboratory analyzed the plasma samples for AED concentrations.
Results from an earlier trial (SP667; Ben-Menachem et al., 2007) were used to make the basic assumptions in calculating sample size. For the primary assessment of change in seizure frequency per 28 days from baseline to maintenance period, an effect size of 0.371 was assumed. The effect size was calculated using a placebo-subtracted difference of −0.286 and a common standard deviation of 0.77 on the log-transformed data; the difference of −0.286 on the log-transformed data was equivalent to approximately 25% reduction over placebo after exponentiation. Based on this effect size and a two-sided test at the 5% level of significance, a sample size of 154 patients in placebo and 154 in the lacosamide 400 mg/day groups was needed to obtain 90% power. For the primary assessment of 50% responder rate, assuming a responder rate of 24% and 39.5% for placebo and lacosamide 400 mg/day groups, respectively, a two-sided continuity corrected chi-square test at a significance level of 5% provided approximately 80% power with 154 patients in placebo and 154 patients in lacosamide 400 mg/day groups.
To adjust for any site or country variability, data were pooled for sites and countries by geographic region. Countries enrolling a small number of patients were pooled 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.
For the primary efficacy variable of change in seizure frequency per 28 days from baseline to the maintenance period, the inferential statistical analysis was based on analysis of covariance (ANCOVA) with terms for treatment group and pooled site, and 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 the active treatment groups and placebo was compared using least squares means.
The other primary efficacy variable was the percentage of patients with a seizure frequency reduction of at least 50% from baseline to the maintenance period (50% responder rate). The 50% responder rate between each active treatment and placebo was analyzed using a logistic regression model with treatment group and pooled site as factors.
In the case of patients who discontinued during the titration period, efficacy data were carried forward from the titration period for inclusion in the maintenance period analyses. For patients who discontinued during the maintenance period, seizure frequency was calculated using all available data in the maintenance period.
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 ITT basis that included all randomized patients who had received at least one dose of trial medication and had at least one post-baseline efficacy assessment. Analysis was also undertaken in the per protocol population, which included all patients in the ITT group who had at least one efficacy assessment during the maintenance period and who did not have any major protocol violation.
Safety variables including AEs, clinical laboratory evaluations, 12-lead ECG readings, vital sign measurements, and physical and neurologic examination findings were assessed in the safety set population, which included all randomized patients who received at least one dose of trial medication. Plasma concentrations for lacosamide and AEDs were summarized using descriptive statistics.
Statistical analyses were performed using the SAS software version 9.1 or higher (SAS Institute, Inc., Cary, NC, U.S.A.). Unless otherwise stated, the mean values are expressed with the standard deviation (SD).
This trial screened 584 patients (Fig. 2) with partial-onset seizures. A total of 485 patients were randomly assigned (1:1:1) to one of three treatment groups—placebo, lacosamide 200 mg/day, and lacosamide 400 mg/day—and received at least one dose of trial medication. Of the 485 randomized patients, 435 (89.7%) completed the titration phase, 403 (83.1%) completed the maintenance phase, and 399 (82.3%) completed the trial. Eighty-six patients (17.7%) discontinued prematurely (Fig. 2); of these, 44 (9.1%) discontinued the trial because of AEs. Overall, 477 patients (n = 159 placebo; n = 160 lacosamide 200 mg/day; n = 158 lacosamide 400 mg/day) received at least one dose of trial medication, had at least one postbaseline efficacy assessment, and were included for the ITT analysis. The per protocol population comprised 399 patients (n = 138 placebo, n = 140 lacosamide 200 mg/day, and n = 121 lacosamide 400 mg/day).
Baseline characteristics and demographics were comparable among the treatment groups (Table 1). Patients ranged in age from 16–70 years with a mean (SD) age of 37.8 (11.88) years. Patients were primarily Caucasian (>99%) and approximately one-half were female. Across all treatment groups, the mean number of years since diagnosis of epilepsy was 22.3 ± 12.56 years. In the ITT population, 69% of patients had tried at least four AEDs in their lifetimes, with 37% having tried at least seven (Table 2). A total of 87% of patients were taking at least two AEDs, with 37% of these taking three AEDs in addition to their assigned trial medication (Table 2). Despite treatment with one to three concomitant AEDs, the median seizure frequency across all treatment groups ranged from 9.9–11.5 seizures per 28 days during the 8-week baseline period (Table 2). The five concomitant AEDs taken most commonly by patients enrolled in this trial were carbamazepine (47.8%), valproate (32.8%), lamotrigine (30.5%), topiramate (28.2%), and levetiracetam (19.8%).
|Characteristic||Placebo (n = 163)||Lacosamide|
|200 mg/day (n = 163)||400 mg/day (n = 159)||Total (n = 485)|
|Mean ± SD||38.5 ± 10.93||36.9 ± 11.70||37.9 ± 12.96||37.8 ± 11.88|
|Sex, n (%)|
|Male||91 (55.8)||90 (55.2)||69 (43.4)||250 (51.5)|
|Female||72 (44.2)||73 (44.8)||90 (56.6)||235 (48.5)|
|Race, n (%)|
|Caucasian||162 (99.4)||162 (99.4)||157 (98.7)||481 (99.2)|
|Black||0 (0)||1 (0.6)||0 (0)||1 (0.2)|
|Asian||1 (0.6)||0 (0)||2 (1.3)||3 (0.6)|
|Weight, kg (mean ± SD)||74.7 ± 17.06||74.9 ± 16.93||72.2 ± 16.90||74.0 ± 16.97|
|BMI, kg/m2 (mean ± SD)||25.9 ± 5.01||25.2 ± 4.79||25.3 ± 5.09||25.4 ± 4.96|
|Mean time since diagnosis, year (mean ± SD)||21.1 ± 12.23||22.9 ± 12.30||22.8 ± 13.15||22.3 ± 12.56|
|Seizure classification, n (%)|
|Simple partial-onset seizures||61 (37.4)||67 (41.1)||58 (36.5)||186 (38.4)|
|Complex partial-onset seizures||138 (84.7)||142 (87.1)||146 (91.8)||426 (87.8)|
|Partial-onset seizures with secondary generalization||130 (79.8)||125 (76.7)||127 (79.9)||382 (78.8)|
|Characteristic||Placebo (n = 159)||Lacosamide|
|200 mg/day (n = 160)||400 mg/day (n = 158)||Total (n = 477)|
|Lifetime AEDs, n (%)|
|1–3 AEDs||49 (30.8)||46 (28.8)||47 (29.7)||142 (29.8)|
|4–6 AEDs||53 (33.3)||54 (33.8)||49 (31.0)||156 (32.7)|
|≥7 AEDs||56 (35.2)||56 (35.0)||62 (39.2)||174 (36.5)|
|Missing data||1 (0.6)||4 (2.5)||0||5 (1.0)|
|Concomitant AEDs, n (%)|
|1 AED||21 (13.2)||17 (10.6)||25 (15.8)||63 (13.2)|
|2 AEDs||82 (51.6)||77 (48.1)||79 (50.0)||238 (49.9)|
|3 AEDs||56 (35.2)||66 (41.3)||54 (34.2)||176 (36.9)|
|VNS use n (%)||14 (8.8)||12 (7.5)||11 (7.0)||37 (7.8)|
|Median baseline partial-onset seizure frequency per 28 days||9.9||11.5||10.3||–|
The median percent reduction in seizure frequency per 28 days from baseline to the maintenance period was 20.5% for placebo, 35.3% for lacosamide 200 mg/day, and 36.4% for lacosamide 400 mg/day (ITT; Fig. 3). Based on the ANCOVA model used, statistically significant percent reductions over placebo in seizure frequency were observed for both the lacosamide 200 mg/day group [14.4%; 95% confidence interval (CI), 2.2–25.1; p = 0.02] and the 400 mg/day group (15.0%; CI, 1.4–26.8; p = 0.03). In the per protocol population, the median percent reductions in seizure frequency per 28 days from baseline to the maintenance period in comparison with placebo (25.4%) were 35.3% for lacosamide 200 mg/day (p = 0.04) and 44.9% for lacosamide 400 mg/day (p = 0.01).
The 50% responder rate for lacosamide 400 mg/day (40.5%) was statistically significant (p = 0.01) over placebo (25.8%). Although not statistically significant (p = 0.07), the 50% responder rate for lacosamide 200 mg/day (35.0%) was numerically higher than placebo (ITT; Fig. 4). In the per protocol population, compared with placebo (27.5%), the 50% responder rates were 35.0% for lacosamide 200 mg/day (p = 0.19) and 46.3% for lacosamide 400 mg/day (p < 0.01).
Among patients completing the maintenance period, 5 (3.6%) of 137 patients in the lacosamide 200 mg/day group and 3 (2.4%) of 123 patients in the lacosamide 400 mg/day group were seizure-free throughout the 12-week maintenance period compared with 3 (2.1%) of 143 in the placebo group. A statistically significant increase of 5% in the percentage of seizure-free days over placebo during the maintenance period was observed for lacosamide 400 mg/day (p = 0.01; 95% CI 1.5, 8.5).
Safety and tolerability
The most common treatment-emergent AEs (TEAEs; ≥5% in any lacosamide treatment group) were dizziness, headache, diplopia, nausea, vertigo, fatigue, nasopharyngitis, coordination abnormal, and vomiting (Table 3). Most events were reported as being mild or moderate in intensity. The most clearly dose-related TEAEs included dizziness, nausea, and vomiting. Of note, the incidence of somnolence was low for patients randomized to lacosamide, at 4.3% in the lacosamide 200 mg/day group and 3.8% in the lacosamide 400 mg/day group, and similar to the occurrence among patients randomized to placebo (3.7%).
|Adverse event||Placebo (n = 163) n (%)||Lacosamide|
|200 mg/day (n = 163) n (%)||400 mg/day (n = 159) n (%)||Total (n = 322) n (%)|
|Dizziness||8 (4.9)||17 (10.4)||25 (15.7)||42 (13.0)|
|Headache||12 (7.4)||18 (11.0)||13 (8.2)||31 (9.6)|
|Diplopia||2 (1.2)||13 (8.0)||16 (10.1)||29 (9.0)|
|Nausea||2 (1.2)||9 (5.5)||13 (8.2)||22 (6.8)|
|Vertigo||3 (1.8)||11 (6.7)||10 (6.3)||21 (6.5)|
|Fatigue||6 (3.7)||8 (4.9)||10 (6.3)||18 (5.6)|
|Nasopharyngitis||6 (3.7)||8 (4.9)||10 (6.3)||18 (5.6)|
|Coordination abnormal||1 (0.6)||7 (4.3)||10 (6.3)||17 (5.3)|
|Vomiting||3 (1.8)||5 (3.1)||9 (5.7)||14 (4.3)|
Overall, 42 patients (8.7%) discontinued participation in the trial during the treatment period because of AEs: 8 patients (4.9%) randomized to placebo, 10 (6.1%) to lacosamide 200 mg/day, and 24 (15.1%) to 400 mg/day. Four patients randomized to receive lacosamide 200 mg/day experienced AEs leading to withdrawal during the titration phase prior to receiving lacosamide (i.e., while still taking placebo). AEs leading to discontinuation from the trial in at least 1% of patients across lacosamide treatment groups were diplopia (2.2%), vertigo (1.6%), vomiting (1.2%), and convulsion (1.2%).
The overall percentage of patients experiencing serious AEs (SAEs) during the treatment period was greater in the lacosamide treatment groups compared to placebo (3.7%, 8.0%, and 9.4% of patients in the placebo, lacosamide 200 mg/day, and 400 mg/day treatment groups, respectively). Across all treatment groups, the most frequently reported SAEs were convulsion (one patient in each treatment group), epilepsy (reported term epileptic seizure; one patient in the placebo group and two in the lacosamide 200 mg/day treatment group), grand mal convulsion (two patients in the lacosamide 400 mg/day group), and psychotic disorder (two patients in the lacosamide 400 mg/day group). All other treatment-emergent SAEs occurred in only one patient each. There were no deaths among patients participating in the trial.
Comparison of on-treatment versus baseline ECG results did not demonstrate any tendency for lacosamide to prolong the QT/QTc interval or QRS duration. Lacosamide was associated with a dose-related increase in mean PR interval (4.6 ms at the end of maintenance for the 400 mg/day dose). This increase in PR interval did not affect the AE profile, as only one lacosamide patient had ECG PR prolongation reported as an AE.
Comprehensive chemistry, hematology, and urinalysis laboratory evaluations as well as periodic physical and neurologic examinations and assessments of vital signs did not reveal any abnormalities that appeared to be associated with administration of lacosamide. No patient was reported to have an alanine aminotransferase (ALT) level of at least three times the upper limit of normal and a bilirubin value of at least 2 mg/dl concurrently.
Lacosamide did not affect the body weight. The mean change from baseline to the end of the 12-week maintenance period was 0.0 kg for placebo, 0.2 kg for lacosamide 200 mg/day, and −0.2 kg for 400 mg/day.
Plasma concentrations of lacosamide showed dose proportionality. At the end of the 12-week maintenance period, the mean lacosamide plasma concentration for the lacosamide 400 mg/day dose group at 7.4 μg/ml was approximately twice the mean plasma concentrations for the 200 mg/day group at 3.8 μg/ml. Mean plasma concentrations of lacosamide remained stable during the maintenance period.
Mean plasma concentrations for the common concomitant AEDs generally were not affected by concomitant intake of 200 mg/day and 400 mg/day lacosamide, other than a decrease (4.2 ± 7.53 μg/ml) in the mean concentration of MHD in the lacosamide 400 mg/day group (Table 4).
|Antiepileptic drug||Placebo (n)||Lacosamide (n)|
|200 mg/day||400 mg/day|
|Baseline||8.0 ± 2.82 (71)||8.0 ± 2.47 (85)||8.0 ± 3.05 (72)|
|Change at end of maintenance||0.5 ± 2.08 (61)||0.1 ± 2.31 (72)||0.5 ± 1.91 (52)|
|Carbamazepine epoxide, μg/ml|
|Baseline||1.7 ± 1.12 (71)||1.7 ± 0.97 (85)||1.6 ± 0.77 (72)|
|Change at end of maintenance||0.1 ± 0.92 (61)||0.1 ± 0.93 (72)||0.2 ± 0.53 (52)|
|Valproic acid, μg/ml|
|Baseline||58.0 ± 21.19 (58)||64.4 ± 30.73 (50)||71.1 ± 28.97 (50)|
|Change at end of maintenance||2.8 ± 26.41 (53)||−2.2 ± 19.54 (43)||−4.5 ± 20.45 (41)|
|Baseline||6.7 ± 3.79 (51)||6.7 ± 4.38 (44)||6.6 ± 4.22 (51)|
|Change at end of maintenance||−0.1 ± 1.48 (43)||−0.1 ± 1.68 (34)||0.0 ± 1.57 (35)|
|Baseline||7.0 ± 5.15 (43)||6.3 ± 3.85 (48)||7.2 ± 4.81 (43)|
|Change at end of maintenance||−0.6 ± 3.09 (39)||0.0 ± 3.78 (42)||0.1 ± 1.74 (34)|
|Baseline||33.8 ± 21.70 (29)||41.0 ± 21.74 (29)||33.7 ± 17.34 (37)|
|Change at end of maintenance||3.6 ± 12.95 (24)||−0.3 ± 17.31 (26)||0.2 ± 10.32 (28)|
|Baseline||25.4 ± 11.99 (26)||26.4 ± 12.71 (26)||28.3 ± 16.56 (23)|
|Change at end of maintenance||−0.8 ± 8.22 (24)||−0.4 ± 6.48 (20)||−4.2 ± 7.53 (19)|
|Baseline||20.8 ± 20.16 (19)||23.0 ± 17.45 (19)||25.1 ± 24.21 (15)|
|Change at end of maintenance||2.3 ± 21.92 (16)||1.2 ± 3.93 (13)||−1.0 ± 4.41 (13)|
|Baseline||11.5 ± 8.30 (15)||8.5 ± 5.88 (13)||11.9 ± 9.92 (11)|
|Change at end of maintenance||2.4 ± 4.17 (14)||1.6 ± 1.61 (11)||−0.5 ± 3.37 (11)|
Lacosamide 200 mg/day and 400 mg/day significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures when added to one to three concomitant AEDs. These results are encouraging given the characteristics of the population studied in this trial. Trial patients had been experiencing a median of 9.9–11.5 seizures per 28 days at baseline, with 87% taking two to three other AEDs, including newer AEDs such as lamotrigine, topiramate, and levetiracetam. These patients had a mean duration of epilepsy of over 22 years, and more than one-third of these patients had tried at least seven AEDs in their lifetime. The secondary efficacy analyses in the per protocol population were consistent with the primary ITT analyses and showed a greater seizure reduction with the lacosamide 400 mg/day dose compared with placebo.
Compared to placebo, lacosamide was generally well tolerated, and it did not produce clinically meaningful changes in plasma concentrations of commonly used concomitant AEDs. The apparent small decrease in the MHD of oxcarbazepine concentration in this trial was not observed in two other clinical trials with lacosamide in patients with partial-onset seizures (Ben-Menachem et al., 2007; Thomas et al., 2007).
Results from this trial confirm and extend those from a previously completed randomized, placebo-controlled trial (SP667; Ben-Menachem et al., 2007) that evaluated the efficacy and safety of lacosamide as adjunctive therapy for patients with uncontrolled partial-onset seizures. In the earlier trial (Ben-Menachem et al., 2007) as well as in the present trial, lacosamide 400 mg/day produced a significant reduction in seizure frequency and achieved a significantly higher 50% responder rate compared with placebo. The 50% responder rate for lacosamide 200 mg/day (35.0%) was numerically greater than placebo, similar to the 200 mg/day responder rate (33%) in the SP667 trial, and was within the range reported for marketed AEDs (14–45 %; Cramer et al., 2001).
Comparative trials between old and new AEDs have suggested that newer AEDs might be better tolerated than older ones, with a lower incidence of side effects (Sander, 1998; Sander & Bell, 2004). In the present trial, the incidence of TEAEs was generally low and most events were considered mild or moderate in intensity. The most commonly reported TEAEs were associated with the nervous and gastrointestinal systems. Adverse events that appeared to be dose related included dizziness, nausea, and vomiting. The incidence of somnolence in patients on lacosamide was low and similar to that in the placebo group. Discontinuations because of treatment-emergent adverse events were relatively low and were similar between placebo and lacosamide 200 mg/day. The higher rate of discontinuation among patients who received lacosamide 400 mg/day was primarily because of nervous system and gastrointestinal-related adverse events. The overall AE profile was comparable in quality and frequency to that reported earlier with lacosamide (SP667; Ben-Menachem et al., 2007). Based on the findings in this trial, the tolerability profile of lacosamide compares favorably with marketed AEDs (Marson et al., 1996, 1997; Bialer et al., 2002).
Lacosamide generally had no clinically important effects on laboratory values, vital sign measurements, body weight, or ECG variables. Lacosamide produced a small, dose-related increase in PR interval that was not of clinical consequence.
Several characteristics of lacosamide contribute to its ease of use. Lacosamide dose escalation of 100 mg/day per week resulted in an effective dose (200 mg/day) being achieved after 1 week of treatment. Oral lacosamide is administered twice daily and has a low potential for pharmacokinetic drug interactions. Clinical pharmacokinetic studies in healthy patients have demonstrated that lacosamide does not affect the plasma concentrations of concomitant AEDs (valproic acid and carbamazepine) or other medications, including metformin, oral contraceptive agents (ethinyl estradiol and levonorgestrel), and digoxin (Kropeit et al., 2006; Bialer et al., 2007; Thomas et al., 2007). The development of an intravenous formulation of lacosamide as short-term replacement for oral lacosamide further contributes to the ease of use of lacosamide (Krauss et al., 2007; Biton et al., 2008).
For new AEDs currently under development, important characteristics include demonstrated fewer side effects, improved ease of use, lack of drug interactions, and ability to prevent epileptogenesis or potential for disease modification, as well as broad use in other CNS disorders (Bialer, 2002). Results of the current trial and other trials indicate that lacosamide demonstrates most of these characteristics. Although results from preclinical studies indicate that lacosamide may have the potential to retard kindling-induced epileptogenesis, further research is needed to evaluate whether lacosamide possesses antiepileptogenic or disease-modifying effects (Brandt et al., 2006).
Results from this trial confirm the efficacy of lacosamide 200 mg/day or 400 mg/day, as adjunctive treatment for partial-onset seizures in patients with epilepsy. A high proportion of patients with uncontrolled partial-onset seizures responded well to treatment with adjunctive lacosamide. Lacosamide was generally well tolerated. With twice-daily dosing, low potential for drug–drug interactions, demonstrated efficacy, a favorable tolerability profile, and the potential availability of an intravenous formulation, adjunctive lacosamide may provide an advantageous treatment option for patients with partial-onset seizures.
The authors wish to acknowledge the contribution made by all of the members of the SP755 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.
Australia: S. Berkovic, D. Reutens (Victoria); M. Kiley (Adelaide); T. O’Brien (Parkville); M. Robinson (Woodville); G. Schapel (Maroochydore); E. Somerville (Randwick) Croatia: T. Babic, V. Demarin, S. Hajnsek, Z. Poljakovic (Zagreb). Czech Republic: M. Bar (Ostrava); J. Buresova (Olomouc); H. Hojdikova (Hradec Kralove); P. Marusic (Prague); E. Nespor, J. Zarubova (Prague); I. Rektor (Brno); H. Vacovska (Plzen). Finland: T. Keränen (Tampere); J. Korpelainen (Oulu); R. Kälviäinen (Kuopio); S. Lamusuo, T. Nylund (Helsinki). France: A. Crespel (Montpellier); P. Derambure (Lille); E. Hirsch (Strasbourg); P. Ryvlin (Bron); F. Semah (Paris); L. Valton (Toulouse). Germany: S. Arnold (Munich); H. Lerche (Ulm); H. Meencke, B. Schmitz (Berlin); F. Rosenow (Marburg); C. Siebold (Starnberg); H. Stefan (Erlangen); H. Straub (Bernau); F. Tergau (Göttingen); K. Werhahn (Mainz). Hungary: A. Balogh, P. Halász, A. Solyom (Budapest); A. Horvath (Szombathely Markusovsky); I. Kondakor (Ret); L. Vecsei (Szeged). Lithuania: M. Endziniene, V. Liesiene (Kaunas); R. Mameniskiene, A. Skaringa (Vilnius). Poland: A. Czlonkowska (Warsaw); W. Fryze, M. Mazurkiewicz-Beldzińska (Gdansk); J. Kochanowicz (Bialystok); R. Motyl (Krakow). Russia: A. Fedin, A. Guekht, V. Karlov, S. Kotov, A. Petrukhin, (Moscow); V. Guzeva, A. Skoromets (St. Petersburg). Spain: A. Gil-Nagel, M. Moro, J. Serratosa (Madrid); J. Llerda (Zaragoza); A. Molins (Girona); J. Sanchez (Granada). Sweden: E. Ben-Menachem (Göteborg); P. Lindström (Stockholm); B. Söderfeldt (Linkoping). United Kingdom: O. Cockerell (Essex); P. Cooper (Salford); R. Roberts (Dundee); J. Sander (London); M. Brodie (Glasgow); I. Sawhney (Swansea); P. Smith (Cardiff).
UCB Group Monheim, Germany, provided the trial supplies and UCB Group, Research Triangle Park, NC, USA, sponsored and funded the trial.
Central laboratory facilities were provided by Quintiles Laboratories, Europe (West Lothian, Scotland, U.K.), for the European sites and their affiliate in Singapore, Malaysia, for the Australian sites. Plasma samples were analyzed by UCB, 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.).
The authors would like to express their appreciation to Bengt Hoepken, PhD, and Maria Hackenson, clinical trial managers, UCB, and Jyoti Nandi MD, PhD, for writing and Allison Coppola, both of UCB for editorial support.
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 of conflicts of interest: P. Halász and M. Mazurkiewicz-Beldzińska have no conflict of interest to disclose. R. Kälviäinen has acted as a paid consultant or received speakers honoraria from Algol Pharma, Cephalon, Eisai, GlaxoSmithKline, Johnson & Johnson, Janssen Cilag, Orion, Pfizer, Schwarz Pharma GmbH and UCB, Inc. F. Rosenow has received research grants, educational grants, and honoraria from UCB, Inc. and Schwarz Pharma GmbH. P. Doty and D. Hebert are employees and T. Sullivan is a former employee of Schwarz Biosciences, Inc., a member of the UCB group.
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