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Randomized dose‐controlled study of topiramate as first‐line therapy in epilepsy
Author(s) -
Arroyo S.,
Dodson W. E.,
Privitera M. D.,
Glauser T. A.,
Naritoku D. K.,
Dlugos D. J.,
Wang S.,
Schwabe S. K.,
Twyman R. E.
Publication year - 2005
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/j.1600-0404.2005.00485.x
Subject(s) - tolerability , randomized controlled trial , medicine , topiramate , epilepsy , dose , randomization , anesthesia , clinical endpoint , pediatrics , adverse effect , anticonvulsant , psychiatry
Objectives – To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose‐controlled study design. Materials and methods – We conducted a multinational, randomized, double‐blind trial in adults and children (≥6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to ≥2 lifetime unprovoked seizures, patients had to have one or two partial‐onset seizures or generalized‐onset tonic‐clonic seizures in the 3‐month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure‐free rate at 6 months and 1 year. Double‐blind treatment continued until 6 months after the last patient was randomized. Results – Kaplan–Meier survival analyses for time to first seizure (intent‐to‐treat, n = 470) favored 400 mg/day over 50 mg/day ( P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference ( P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure‐free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day ( P = 0.005). Seizure‐free rates at 12 months were 76% and 59%, respectively ( P = 0.001). Differences favoring the higher dose were significant in patients with partial‐onset seizures ( P = 0.009) and in those with generalized‐onset tonic‐clonic seizures ( P = 0.005). The most common dose‐related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive‐related adverse events were 2% in the 50‐mg group and 7% in the 400‐mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. Conclusion – Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step‐wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.