Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial

Abstract

Objective: To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE).

Methods: Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1-3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment.

Results: 242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.

Conclusions: Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.

Figure 1

Trial design. *Patients were required to achieve and maintain a minimum lacosamide (or matching PBO) dose for at least the final 3 days of week 6 to be eligible for entry into the maintenance period. †The highest possible dose per body weight category is shown for each taper period week. ‡Patients on lacosamide remained on their maintenance dose at entry into the transition period (as indicated by the grey background box), whereas patients in the PBO group initiated lacosamide in a double-blind fashion. On completion of the transition period, eligible patients entered the open-label extension on a weight-based dose (<30 kg: 10 mg/kg/day; ≥30–<50 kg: 8 mg/kg/day; ≥50 kg: 400 mg/day). PBO, placebo.

Figure 2

Patient disposition. *Two of these patients were successfully rescreened and randomised into the trial; †37 patients were baseline failures because of their PGTCS frequency during the combined baseline; ‡41/44 patients on placebo and 22/25 patients on lacosamide did not continue into maintenance because they had a second PGTCS during titration, one patient on lacosamide was labelled as a completer due to a site error, and the five remaining patients did not continue into maintenance because the 125th event had occurred in the trial; §Patients who met a protocol-defined endpoint (completion of ≥6 weeks of the treatment period and occurrence of two or more PGTCS, completion of 24 weeks of the treatment period without occurrence of two PGTCS, or the 125th event occurred in the trial). FAS, full analysis set; PGTCS, primary generalised tonic-clonic seizure; SS, safety set.

Figure 3

Kaplan-Meier estimates for time to second PGTCS (125 events) (FAS). One patient in the lacosamide group was randomised after the 125th event and does not appear in this analysis. Symbols represent censored patients (patients who completed the treatment period without having a second PGTCS). FAS, full analysis set; PGTCS, primary generalised tonic-clonic seizure.

Figure 4

(A) 50% responder rates for PGTCS, (B) 75% responder rates for PGTCS and (C) freedom from PGTCS* (FAS). *Percentages are based on the number of patients who had either two PGTCS or completed the time period of interest or completed the trial due to occurrence of the 125th event; †6-week titration period + first 6 weeks of maintenance period; ‡6-week titration period +18-week maintenance period. FAS, full analysis set; PGTCS, primary generalised tonic-clonic seizure.