Randomized dose-controlled study of topiramate as first-line therapy in epilepsy In contrast to the era in which antiepileptic drugs (AEDs) such as phenytoin, carbamazepine, and valproate first became available, double- blind, randomized controlled trials demonstra- ting an agent’s usefulness in epilepsy are now required in most countries before an AED is made available. The most widely used approach to establishing AED efficacy is the comparison of placebo and active drug as adjuncts to existing treatment in patients with inadequately controlled seizures. However, this paradigm is not relevant to untreated or newly diagnosed epilepsy. Because epilepsy is a potentially life- threatening condition, placebo as a comparator in monotherapy studies poses ethical concerns (1–3). Dose-controlled studies may be an alter- native approach to establishing that an AED is effective while minimizing the potential risks associated with placebo exposure in untreated epilepsy. Acta Neurol Scand 2005: 112: 214–222 DOI: 10.1111/j.1600-0404.2005.00485.x Copyright Ó Blackwell Munksgaard 2005 ACTA NEUROLOGICA SCANDINAVICA Arroyo S, Dodson WE, Privitera MD, Glauser TA, Naritoku DK, Dlugos DJ, Wang S, Schwabe SK, Twyman RE for the EPMN-106/ INT-28 Investigators. Randomized dose-controlled study of topiramate as first-line therapy in epilepsy. Acta Neurol Scand 2005: 112: 214–222. Ó Blackwell Munksgaard 2005. 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 ¼ 470) favored 400 mg/day over 50 mg/day (P ¼ 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P ¼ 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 ¼ 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P ¼ 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P ¼ 0.009) and in those with generalized-onset tonic-clonic seizures (P ¼ 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. S. Arroyo 1 *, W. E. Dodson 2 , M. D. Privitera 3 , T. A. Glauser 4 , D. K. Naritoku 5 , D. J. Dlugos 6 , S. Wang 6 , S. K. Schwabe 7   , R. E. Twyman 7 for the EPMN-106/INT-28 Investigators 1 Department of Neurology, Hospital Clinico de Barcelona, Barcelona, Spain; 2 St Louis Children's Hospital and Departments of Neurology and Pediatrics, Washington University School of Medicine, St Louis, MO, USA; 3 Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USA; 4 Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 5 Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA; 6 Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 7 Johnson & Johnson Pharmaceutical Research & Development L.L.C., Raritan, NJ, USA Key words: anticonvulsant; topiramate; epilepsy Roy E. Twyman, Neurology, Psychiatry and Pain Fran- chise, Johnson and Johnson Pharmaceutical Research and Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA. e-mail: rtwyman@prdus.jnj.com *Present address: Eisai Medical Research, Ridgefield Park, NJ, USA.   Present address: Novartis Pharmaceuticals, East Han- over, NJ, USA. Accepted for publication May 18, 2005 214