Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design

Purpose: A double-blind, randomized, placebo-controlled clinical trial to e xamine the safety, tolerability, and antiepileptic activity of ganaxolone i n patients after withdrawal from other antiepileptic drugs during presurgic al evaluations was performed. Methods: Fifty-two eligible patients were withdrawn from antiepileptic drug s and randomized to receive ganaxolone (24 patients) or placebo (28 patient s) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: im mediately after breakfast, lunch, and dinner. Results: The primary measure of antiepileptic activity was duration of trea tment before withdrawal from the trial. Kaplan-Meier curves depicted a clea r separation between treatment groups, with 50% of the ganaxolone-treated p atients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward eff icacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revea led a significant treatment effect on survival time in men (p = 0.03). Post -hoc X-2 probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse ev ents being reported by 79% of patients in the ganaxolone group and 68% of p atients in the placebo group. Conclusions: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that gana xolone does have antiepileptic activity.