Introduction

A high risk of recurrent seizures (30%) and undesirable side effects are reported in epilepsy patients, despite the use of multiple concomitant antiepileptic drugs (AEDs). Lacosamide (200-600 mg/day), a novel antiepileptic drug, has shown efficacy and safety in randomized, double-blind, placebo-controlled trials when administered in addition to AEDs (one to three) in uncontrolled partial-onset seizures (POS). It significantly reduced seizure frequency and improved 50% responder rates versus placebo with mild or moderate adverse events.

Aim

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). To further assess the safety, potential dose response relationships, and steady-state plasma concentrations of lacosamide and concomitant AEDs.

Patient Profile

• 405 patients with partial-onset seizures, with or without secondary generalization and on a stable dosage regimen of one to three AEDs, with or without vagus nerve stimulation (VNS)

Method

Study Design

• Multicenter, double-blind, randomized, placebo-controlled parallel-group trial
• Patients were randomised to placebo, lacosamide 400 mg, or lacosamide 600 mg/day
• Treatment was initiated with placebo or lacosamide 100 mg/day, titrated to the target dose, followed by a 12-week maintenance period

Endpoints

• Primary endpoints: change in seizure frequency per 28 days from baseline to the maintenance period, and the proportion of individual patients who experienced a >50% reduction in seizure frequency from baseline to end of maintenance period (50% responder rate)
• Secondary endpoint: percent change in seizure frequency per 28 days from baseline to maintenance, 75% responder rate, number and proportion of patients achieving seizure-free status throughout the maintenance period, percentage of seizure-free days throughout 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)
• Pharmacokinetics of lacosamide (plasma concentrations) and any possible effects on the steady-state plasma concentrations of select concomitant AEDs
• Safety endpoints: treatment emergent adverse events (TEAEs), withdrawals due to TEAEs, changes in 12-lead ECG readings, vital sign and body weight measurements, laboratory values, and physical and neurologic examination findings

Results

Efficacy

• Adjunctive lacosamide 400 mg/day and 600 mg/day significantly reduced the seizure frequency per 28 days from baseline to maintenance as compared to placebo by 21.6% (37.3% vs. 20.8%, p = 0.008) and 24.6% (37.8% vs. 20.8%, p = 0.006), respectively, in the intention-to-treat (ITT) population (Figure 1)
• In the per-protocol set, lacosamide 400 mg/day and 600 mg/day achieved a median percent reduction from baseline to maintenance of 20.6% (39.6% vs. 21.7%; p = 0.015) and 33.0% (50.0% vs. 21.7%; p = 0.002) over placebo, resp.
• The 50% responder rates significantly improved from baseline to maintenance with lacosamide 400 and 600 mg/day versus placebo in the ITT population (38.3% and 41.2% vs. 18.3%; p < 0.001) as well as in the per-protocol set (40.0% and 50.9% vs. 18.4%; p < 0.001; Figure 1)
• Lacosamide 400 and 600 mg/day achieved a significant 75% responder rate from baseline to maintenance (20.4%, p = 0.005 and 21.6%, p = 0.007) versus placebo (7.7%)
• Lacosamide reduced secondarily generalized tonic–clonic seizures relative to baseline, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for 600 mg/day versus 14.3% for placebo, and corresponding responder rates of 56.0% and 70.2% versus placebo (33.3%)
• A dose-related reduction in seizure frequency was observed for complex partial seizures
• Lacosamide showed a significant increase over placebo in the percentage of seizure-free days during maintenance (5.3%; p = 0.013 for 400 mg/day and 8.2%; p < 0.001 for 600 mg/day)

Pharmacokinetics

• Actual daily dose of lacosamide 400 and 600 mg/day demonstrated proportionality at the end of both the titration period (7.75, 9.89 lg/ml) and the maintenance period (7.19, 9.50 lg/ml)
• Plasma concentrations of concomitant AEDs were not affected by lacosamide, except valproic acid.

Figure 1: Effect of adjunctive lacosamide on the primary endpoint in uncontrolled POS patients

Safety 

• An incidence of at least 10% was reported for treatment emergent adverse events (TEAEs) like dizziness, nausea, diplopia, vision blurred, headache, vomiting, and tremor with lacosamide; most of them were mild or moderate in intensity
• Dose-related adverse events included dizziness, nausea, and vomiting
• Total incidence of TEAE related premature withdrawals was 16.5%; most common ones 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 incidence of serious adverse events (SAEs) was 2.9%, 5.9%, and 3.1% with placebo, lacosamide 400 mg/day, and lacosamide 600 mg/day, respectively; convulsion and appendicitis were most frequent
• No effects were observed on clinical laboratory tests and vital sign measurements across treatment groups
• A small change was observed in ECG readings from baseline to the end of maintenance (heart rate, QTc interval, QRS duration) in all 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)
• Lacosamide showed minimal effect on body weight (mean changes from baseline in body weight after 18 weeks of exposure: +0.6 kg with placebo, +0.1 kg and +0.2 kg with lacosamide 400 and 600 mg/day)

Conclusion

• Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency, provided favorable pharmacokinetic profile and tolerability in patients with uncontrolled partial-onset seizures on one to three concomitant AEDs (with or without secondary generalization)
• 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. 

Epilepsia 2010; 51(6): 958–967