First Time May Be Charm for Anti-Epileptic Drugs

GLASGOW, Scotland, Feb. 5 -- About half of adults with newly diagnosed epilepsy will have good control of their seizures with the first medication tried, and a majority of responders will be seizure free at the lowest dose, reported European investigators.

In a double-blind trial comparing Keppra (levetiracetam) with Carbatrol (controlled-release carbamazepine) in such patients, nearly three-fourths of those randomized to either medication were seizure-free on the last evaluated dose for at least six months, reported Martin J. Brodie, M.D., of the Western Infirmary here, and colleagues, in the Feb. 6 issue of Neurology.

"Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice," the investigators wrote.

Dr. Brodie and colleagues in Italy, France, Sweden, and Germany conducted a randomized double-blind non-inferiority trial pitting the relative newcomer Keppra, currently used as adjunctive therapy for partial-onset seizures in adults and children, against Carbatrol, the controlled-release form of the old standby carbamazepine.

"This is the first study to comply with European regulations for the evaluation of new antiepileptic drugs for this indication, which recommend a non-inferiority trial showing at least a similar benefit-risk balance for the test product compared with an acknowledged standard at individually optimized dosages using clinically relevant endpoints," the authors wrote.

The guidelines call for the primary clinical outcome measure to be the proportion of patients remaining seizure-free for at least six months on either of the drugs during the evaluation period, with maintenance of efficacy for at least a year.

The investigators enrolled adults (ages 16 and older) with newly diagnosed epilepsy and two or more unprovoked partial or generalized tonic-clonic seizures, separated by at least 48 hours, in the previous year, and had had at least one seizure within the previous three months.

Patients were excluded if they had pseudoseizures, seizures occurring only in clusters, or clinical or electroencephalographic findings suggestive of idiopathic generalized epilepsy.

The patients were randomized to Keppra at 500 mg twice daily (288 patients) or Carbatrol at 200 mg twice daily (291 patients). The patients were started on a two-week titration period, followed by one week of stabilization. If a patient had a seizure within 26 weeks of stabilization, the dosage was increased incrementally to 1,500 mg twice daily of Keppra, or 600 mg twice daily of Carbatrol.

Patients who achieved the primary endpoint of being free of seizures for six months continued on treatment for an additional six-month maintenance period.

Secondary endpoints included one-year seizure-freedom rates, and six-month and one-year seizure-freedom rates by dose level. The investigators also looked at the influence of baseline seizure frequency on the six-month seizure-freedom rate. Analysis was by per-protocol and intention-to-treat.

Two-thirds of patients in each treatment group (66.7%) satisfactorily completed the study, and were included in the per-protocol analysis.

The investigators found that on the per-protocol analysis, 73.0% in the Keppra group and 72.8% in the Carbatrol group were seizure-free for at least six months at the last evaluated dose. The adjusted absolute difference between the drugs was 0.2% (95% CI, 7.8% to 8.2%). Keppra was determined to be non-inferior, because the lower limit of the confidence interval was above the non-inferiority limit set by the study protocol.

In the intention-to-treat analysis, 66.7% of patients in each drug group were seizure free for at least six months on the last evaluated dose.

There were no significant differences between treatment groups in one-year seizure freedom rates in either the per-protocol or intention-to-treat populations. In the per-protocol analysis, 56.6% of patients on Keppra, and 58.5% of patients on Carbatrol, had not had another seizure for at least one year. In the intention-to-treat analysis, one year free of seizures was obtained by 49.8% of patients taking Keppra and by 53.3% of those on Carbatrol.

Of all patients who achieved six-month remission of seizures, 80.1% of those on Keppra and 85.4% of those on Carbatrol did so at the lowest dose. Among those who had one year free of seizures, 86% in the Keppra group and 89.3% of those on Carbatrol achieved this freedom while on the lowest drug dose.

In the tolerability analysis of adverse events with a 5% or greater incidence, significantly more patients on Keppra than on Carbatrol reported depression and insomnia, while more patients on Carbatrol had back pain. There were no significant differences in the percentage of patients who discontinued their assigned drug because of adverse events.

"This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage," the authors wrote.