PDF: VALOR
(2020)Objective
Lacosamide - To evaluate the efficacy and safety of adjunctive lacosamide in patients ≥4 years old with idiopathic generalized epilepsy and primary generalized tonic-clonic seizures (PGTCS).
Study Summary
Intervention
Adjunctive oral lacosamide (up to 400 mg/day or 12 mg/kg/day) vs placebo added to stable background AEDs.
Inclusion Criteria
Patients ≥4 years old with idiopathic generalized epilepsy and ≥3 PGTCS in the 16-week baseline (with at least 2 historical and 1 prospective event).
Study Design
Arms: Lacosamide vs Placebo
Patients per Arm: Lacosamide: 121; Placebo: 121
Outcome
Bottom Line
Adjunctive lacosamide was efficacious and generally safe for uncontrolled PGTCS in patients with IGE. Treatment with lacosamide resulted in a significantly lower risk of developing a second PGTCS (HR 0.540; p<0.001) and a significantly higher rate of 166-day freedom from PGTCS (31.3% vs 17.2%; difference 14.1%; p=0.011) than placebo. Lacosamide did not appear to worsen absence or myoclonic seizures. These results support the use of adjunctive oral lacosamide for treatment of uncontrolled PGTCS in patients ≥4 years of age with IGE.
Major Points
- First trial to use 'time to second seizure' as primary endpoint for an AED efficacy trial
- Lacosamide significantly reduced risk of second PGTCS (HR 0.540, 95% CI 0.377-0.774, p<0.001)
- Kaplan-Meier survival estimates at 24 weeks: 55.27% lacosamide vs 33.37% placebo
- PGTCS freedom at day 166: 31.3% vs 17.2% (difference 14.1%, p=0.011)
- 50% responder rate: 68.1% vs 46.3%; 75% responder rate: 57.1% vs 36.4%
- Observed freedom from PGTCS: 27.5% vs 13.2%
- Median percent reduction in PGTCS frequency: -77.92% vs -43.24%
- No evidence of increased risk of absence or myoclonic seizure worsening
- Freedom from all generalised seizures at 24 weeks: 21.1% vs 13.2%
- Efficacy consistent across subgroups including pediatric patients, SCB users, and valproate users
- Generally well tolerated with predictable CNS adverse events (dizziness, somnolence, headache)
- No deaths during the trial
Study Design
- Study Type
- Phase 3, double-blind, randomised, placebo-controlled, multicentre trial
- Randomization
- Yes
- Blinding
- Double-blind. Patients randomised 1:1 to lacosamide or matching placebo and stratified by baseline PGTCS frequency (≤2 or >2 per 28 days) and age at informed consent (≥4 to <12 years, ≥12 to <18 years, and ≥18 years).
- Sample Size
- 242
- Follow-up
- 4-week prospective baseline plus 6- to 24-week treatment period (6-week titration and up to 18-week maintenance). Minimum 6 weeks treatment required for safety evaluation.
- Centers
- 115
- Countries
- USA, Canada, multiple Latin American countries, multiple European countries, Australia, Japan, other Asia-Pacific countries
Primary Outcome
Definition: Time to second PGTCS during the 24-week (166-day) treatment period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: 76 events, K-M survival estimate 33.37%, median time to second PGTCS 77.0 days (95% CI 49.0-128.0) | Lacosamide: 49 events, K-M survival estimate 55.27%, median time to second PGTCS could not be estimated (>50% did not have second PGTCS) | 0.54 (0.377 to 0.774) | <0.001 |
Limitations & Criticisms
- Novel 'time to second seizure' endpoint not yet widely validated for regulatory or clinical decision-making
- Relatively short treatment period (up to 24 weeks) limits long-term efficacy and safety conclusions
- High placebo response rate (46.3% 50% responders, 13.2% seizure-free) may reduce apparent treatment effect
- Trial discontinued enrollment once 125th event occurred, potentially affecting power for subgroup analyses
- Pediatric subgroup analysis limited by small numbers (n=49) and not powered for significance
- Open-label extension available, which may have influenced patient reporting during the blinded phase
- Limited data on effect on absence and myoclonic seizures - sample sizes small for these analyses
- Some concern about myoclonic seizure worsening (8.5% vs 4.1% had ≥50% increase), though numbers small
- Trial sponsored by UCB Pharma (manufacturer of lacosamide) with industry employees as authors
- Exclusion criteria not fully detailed in publication
- Treatment duration was significantly longer for lacosamide group (median 143 days vs 65 days) due to trial design
Citation
J Neurol Neurosurg Psychiatry 2020;0:1–9. doi:10.1136/jnnp-2020-323524