title: Randomized dose-controlled study of topiramate as first-line therapy in epilepsy.
abstract: OBJECTIVE
  To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design.
  
  
  METHODS
  We conducted a multinational, randomized, double-blind trial in adults and children (> or =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 > or =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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Hospital Clinico de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Arroyo
authors.forename: W E
authors.initials: WE
authors.lastname: Dodson
authors.forename: M D
authors.initials: MD
authors.lastname: Privitera
authors.forename: T A
authors.initials: TA
authors.lastname: Glauser
authors.forename: D K
authors.initials: DK
authors.lastname: Naritoku
authors.forename: D J
authors.initials: DJ
authors.lastname: Dlugos
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: S K
authors.initials: SK
authors.lastname: Schwabe
authors.forename: R E
authors.initials: RE
authors.lastname: Twyman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077236:Topiramate; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose