Progabide Treatment in Severe Epilepsy: A Double-Blind Cross-over Trial Versus Placebo

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Abstract
Twenty therapy-resistant epileptic patients entered a double-blind, randomized, 2-period, cross-over trial comparing progabide (19.3-36 mg/kg per day) and placebo as add-on drugs to standard therapy. Each period lasted 6 wk with a gradual crossover during 4 days. Five patients were dropped because of reasons unrelated to treatment. Among the 15 patients who completed the study, 7 had partial, 6 primary generalized and 2 secondary generalized epilepsies. Preexisting antiepileptic drugs (AED) ranging from 1-3 per patient (mean 2.2 AED/patient) were maintained unchanged during the trial. Efficacy was assessed biweekly by means of total seizure counts, counts of each seizure type and global clinical judgment. At the same time intervals, safety was assessed by means of reports of adverse events, clinical and neurological examination, laboratory tests and measurement of plasma concentrations of progabide and associated AED. According to the clinical global judgment 8 patients were considered improved during progabide treatment. Seizures were reduced in 14 of 15 patients during the progabide as compared with the placebo period. During the progabide period the reduction of the total seizure count was 45 and 58% in 2 patients and 88-97% in 6 patients. A significant reduction of the total seizure number was observed in the progabide period as compared with the placebo period both in the whole patient group (P < 0.01) and in the 2 subgroups of patients with generalized (P < 0.01) and partial (P < 0.05) epilepsies. Absences, major generalized and partial seizures (including partial seizures with secondary generalization) were significantly reduced on progabide as compared with placebo (P < 0.05). No dropouts owing to adverse effects were observed. In 1 case somnolence required a reduction of the progabide dose. Somnolence (3 cases), nausea or vomiting (2 cases) and dysarthria (1 case) were observed in 6 other patients on progabide but were judged to be mild. Laboratory tests did not show any treatment-related alterations. Plasma concentrations of progabide measured before the morning dose ranged from < 50 to 1474 ng/ml. No correlation was found between plasma concentrations and the clinical outcome. Progabide is well tolerated and possesses a promising antiepileptic activity in both partial and generalized epilepsies.

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