PDF: Lacosamide as Adjunct for Generalized Seizures
(2015)Objective
Lacosamide - To assess the safety of adjunctive lacosamide in patients with primary generalized epilepsy (PGE) experiencing uncontrolled primary generalized tonic-clonic seizures (PGTCS), with a focus on absence and myoclonic seizure frequency.
Study Summary
Intervention
Adjunctive lacosamide with flexible dosing (100–800 mg/day); initial titration to 400 mg/day over 3 weeks, followed by 6-week maintenance and optional 59-week extension.
Inclusion Criteria
Aged 16–65 with primary generalized epilepsy and PGTCS; history of absence or myoclonic seizures permitted; ≥1 AED and uncontrolled seizures during baseline.
Study Design
Arms: Open-label single-arm study of adjunctive lacosamide in PGE patients.
Patients per Arm: SP0961: 49 enrolled, 40 completed; SP0962: 39 enrolled, 29 completed.
Outcome
Bottom Line
Adjunctive lacosamide was generally well tolerated in adults with partial-onset seizures. Most TEAEs were mild or moderate in intensity and occurred predominantly during the titration phase. Common drug-associated TEAEs were dose-related and included dizziness, nausea, and diplopia. The approved dose range (200-400 mg/day) showed better tolerability than 600 mg/day, with cognition-related TEAEs similar to placebo.
Major Points
- Pooled safety analysis of 1308 patients from three phase II/III trials (SP667, SP754, SP755)
- 944 patients received lacosamide (200mg n=270; 400mg n=471; 600mg n=203) and 364 received placebo
- Most common drug-associated TEAEs: dizziness (30.6% vs 8.2%), nausea (11.4% vs 4.4%), diplopia (10.5% vs 1.9%)
- TEAEs were dose-related: any TEAE in 69.6% (200mg), 82.2% (400mg), 93.6% (600mg) vs 64.6% placebo
- Most TEAEs were mild (32.2%) or moderate (38.3%); severe TEAEs in 10.4% lacosamide vs 4.7% placebo
- TEAE incidence was notably lower during maintenance phase than titration phase
- Discontinuation due to TEAEs: 8.1% (200mg), 17.2% (400mg), 28.6% (600mg) vs 4.9% placebo
- Cognition-related TEAEs at approved doses (200-400mg combined): 6.1% vs 4.7% placebo (OR 1.3, 95% CI 0.7-2.4)
- No individual serious TEAE occurred in ≥1% of lacosamide-treated patients
- 80.6% of patients enrolled in subsequent open-label extension trials
Study Design
- Study Type
- Pooled analysis of three randomized, double-blind, placebo-controlled trials (SP667, SP754, SP755)
- Randomization
- Yes
- Blinding
- Double-blind in all three component trials
- Sample Size
- 1308
- Follow-up
- 8-week baseline + 4-6 week titration + 12-week maintenance + 2-3 week taper
- Countries
- United States, Europe, Australia
Primary Outcome
Definition: Treatment-emergent adverse events (TEAEs) during treatment phase (titration + maintenance), including overall TEAEs, serious TEAEs, and discontinuations due to TEAEs
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Any TEAE: 64.6%; Drug-related TEAE: 38.7%; Discontinuation due to TEAE: 4.9% | Any TEAE: 69.6% (200mg), 82.2% (400mg), 93.6% (600mg); Drug-related: 44.1%, 62.8%, 79.8%; Discontinuation: 8.1%, 17.2%, 28.6% | - |
Limitations & Criticisms
- Pooled analysis rather than prospective trial design
- Forced titration protocol may not reflect real-world clinical practice where flexible dosing is used
- Post hoc nature of cognition-related TEAE analysis limits conclusions
- Concomitant AED subgroup analysis limited by unbalanced sample sizes and non-mutually exclusive groups (84% on ≥2 AEDs)
- 600 mg/day dose not within approved dose range but included in analysis
- Different titration schedules across the three component trials (4-6 weeks)
- SP667 limited to ≤2 concomitant AEDs while SP754/SP755 allowed up to 3
- Safety set analysis includes patients who received at least one dose, potentially underestimating tolerability issues in those who discontinued early
- Three UCB Pharma employees among authors
- Relatively short maintenance phase (12 weeks) for long-term safety assessment
Citation
Epilepsy Behav. 2015;52:119-127