By Chris Berrie
GLASGOW, UK -- September 5, 2006 -- At optimal dosing levels and in a setting mimicking clinical practice, the novel antiepileptic drug levetiracetam is noninferior to the controlled-release formulation of the carbamazepine in adults with newly diagnosed epilepsy, according to research presented here at the European Federation of Neurological Societies (EFNS).
Principal investigator Martin J. Brodie, MD, FRCP, professor and director, epilepsy unit, Western Infirmary, Glasgow, United Kingdom, presented the double-blind, randomised European regulatory trial with a noninferiority design on September 3rd.
This is the first study to follow the European regulatory guidelines recommending demonstration of noninferiority of the test product (levetiracetam) with an acknowledged standard (carbamazepine) at individually optimized doses using clinically relevant endpoints.
The primary endpoint was the percentage of patients achieving 6 months of seizure freedom at the last evaluated dose, with the noninferiority margin set at -15% and based on the per-protocol (PP) population. The secondary objectives were time to discontinuation and comparative tolerability in the intention-to-treat (ITT) patient population, and the 1-year seizure freedom in the PP population.
After 1 month of patient screening, levetiracetam and carbamazepine were given in identical encapsulated capsules that were taken twice daily, with an initial up-titration to the starting doses (level 1) of 1,000 mg/day and 400 mg/day, respectively.
These doses were maintained for 6 months for evaluation or until the next seizure, when patients could be further up-titrated to 2,000 mg/day and 800 mg/day, respectively (level 2). If needed, this up-titration could be extended to 3,000 mg/day and 1,200 mg/day, respectively (level 3). Then following 6 months without seizures, there were 6 months of dose maintenance, after which the patients switched to the follow-up treatment.
The inclusion criteria included age >/= 16 years and at least 2 unprovoked seizures over the previous year (> 48 hours apart; 1 in prior 3 months); these could be partial seizures (with or without secondary generalisation) or generalised tonic-clonic seizures without a clear focal origin.
The exclusion criteria were for pseudoseizures, seizures occurring only in clusters, or history, clinical, or electroencephalogram findings suggestive of idiopathic generalised epilepsy.
The study populations under consideration were the ITT population (levetiracetam, 285 patients; carbamazepine, 291 patients) and the PP population (LEV, 237; carbamazepine, 235).
In the ITT population, there were no significant differences in the clinical characteristics at baseline for levetiracetam (mean age, 39.8 years; male, 51.2%) and carbamazepine (mean age, 39.0 years; male, 58.8%), with (respectively): median number of seizures in previous year (4.0 vs 3.0); median number of seizures in prior 3 months (2.0 vs 2.0); median epilepsy duration (0.8 vs 0.8 years); and median age at onset (34.7 vs 31.9 years).
For the primary endpoint, there was no significant difference between levetiracetam and carbamazepine (PP population: 73.0% vs 72.8%). Similarly, the adjusted treatment differences with 2-sided confidence intervals at both 6 months and 1 year seizure-free all lay within the noninferiority limit of the trial design (both ITT and PP).
When analysed according to dose level (PP population), Dr. Brodie said there were no significant differences in 1-year seizure freedom between levetiracetam and carbamazepine (48.7% vs 52.2% at level 1; 5.7% vs 5.8% at level 2; and 2.2% vs 0.4% at level 3).
Similarly, the discontinuations (PP: 40.5% vs 40.0%, respectively) and adverse events (PP: 13.9% vs 16.2%) showed no significant differences. For the latter, while most of the numerous common ones showed no differences across treatments, levetiracetam showed significantly greater depression and insomnia levels over carbamazepine (ITT: 6.3% vs 2.1%; 6.0% vs 2.4%; respectively; P <.05). Conversely, levetiracetam showed significantly less back pain (ITT: 2.8% vs 6.9% for carbamazepine; P <.05) and weight gain (ITT: 7.8% vs 13.4%; P =.038).
Thus, noninferiority was proven for levetiracetam and carbamazepine, which produced similar seizure freedom rates and tolerability in adults with newly diagnosed epilepsy. This trial also confirmed that most patients with newly diagnosed epilepsy will respond to their first antiepileptic drug at low dosage, Dr. Brodie indicated.
This study was sponsored by UCB Pharma.
[Presentation title: Randomised, Double-Blind Comparison of Levetiracetam and Controlled-Release Carbamazepine in Adults With Newly Diagnosed Epilepsy. Abstract SC110]
E-Mail this DGDispatch to a colleague
