PDF: Lacosamide for Focal Seizures
(2019)Objective
Lacosamide - To evaluate the long-term safety and efficacy of lacosamide monotherapy compared to controlled-release carbamazepine in patients with newly diagnosed focal epilepsy.
Study Summary
Intervention
Double-blind monotherapy with lacosamide (200–600 mg/day) or carbamazepine-CR (400–1200 mg/day), dose-escalated based on seizure control.
Inclusion Criteria
Patients ≥16 years with newly diagnosed epilepsy and ≥2 unprovoked focal seizures in the previous 12 months.
Study Design
Arms: Lacosamide vs carbamazepine-CR
Patients per Arm: Lacosamide: 444; Carbamazepine-CR: 442
Outcome
Bottom Line
Long-term lacosamide monotherapy was efficacious and generally well tolerated over median ~2 years in adults with newly diagnosed epilepsy, with similar seizure freedom rates to carbamazepine-CR but lower rates of drug-related adverse events and discontinuations due to adverse events.
Major Points
- This reports combined data from initial noninferiority trial (SP0993) and double-blind extension (SP0994)
- 886 patients treated in initial trial; 548 continued in extension
- 75.6% of lacosamide patients vs 66.9% of carbamazepine-CR patients completed the extension trial
- Kaplan-Meier estimated 12-month seizure freedom: 50.8% lacosamide vs 54.9% carbamazepine-CR
- Kaplan-Meier estimated 24-month seizure freedom: 47.0% lacosamide vs 50.9% carbamazepine-CR
- Drug-related TEAEs were lower with lacosamide (40.8% vs 50.2%)
- Discontinuations due to TEAEs were lower with lacosamide (13.1% vs 19.0%)
- Most patients remained on lowest dose level throughout both trials (64.2% lacosamide, 66.5% carbamazepine-CR)
- Patients with more comorbid conditions had higher rates of TEAEs, but lacosamide showed consistent tolerability advantage across subgroups
Study Design
- Study Type
- Phase 3, randomized, double-blind, double-dummy, noninferiority trial with long-term extension
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy; patients, investigators, and outcome assessors blinded
- Sample Size
- 886
- Follow-up
- Median exposure: lacosamide 630 days, carbamazepine-CR 589 days
- Centers
- 149
- Countries
- Europe, North America, Asia Pacific
Primary Outcome
Definition: Treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs (extension trial primary endpoints); long-term seizure freedom assessed as post hoc efficacy outcomes
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 83.3% any TEAEs; 50.2% drug-related TEAEs; 19.0% discontinued due to TEAEs (combined trials) | 80.0% any TEAEs; 40.8% drug-related TEAEs; 13.1% discontinued due to TEAEs (combined trials) | - |
Limitations & Criticisms
- Post hoc nature of pooled efficacy analyses limits strength of conclusions
- MedDRA coding classified age-related physiologic conditions (menopause) as comorbidities, potentially inflating comorbidity counts
- Patients with medical/psychiatric conditions that could jeopardize health were excluded, so enrolled population may have had relatively mild comorbidities
- No formal statistical comparison between treatment groups for most efficacy outcomes
- Patients who discontinued during initial trial due to lack of efficacy at highest dose or adverse events were excluded from extension, creating selection bias
- Open-label follow-up after unblinding limits long-term assessment
- Kaplan-Meier seizure freedom estimates from first dose differ methodologically from initial trial's estimates following stabilization
Citation
Epilepsia. 2019;60:2437-2447