title: Adjunctive zonisamide therapy in the long-term treatment of children with partial epilepsy: results of an open-label extension study of a phase III, randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  To investigate the safety/tolerability and efficacy of long-term adjunctive zonisamide and its impact on growth and development in children (6-18 years) with partial epilepsy.
  
  
  METHODS
  Open-label extension of a phase III, placebo-controlled trial. Started with double-blind transition period (2-11 weeks), during which patients on zonisamide continued at the same dose and those on placebo switched to zonisamide 1 mg/kg/day, up-titrated to 8 mg/kg/day (maximum 500 mg/day). During the subsequent open-label period (45-57 weeks), zonisamide dosing could be adjusted according to tolerability/response. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, and vital signs. Efficacy assessments included responder rate (primary assessment) and seizure freedom rate during the open-label period. Growth and development assessments comprised Tanner stages, hand x-rays, Child Behavior Checklist (CBCL 6/18), School Performance questionnaire, Physician and Parent/Guardian Global Impression of Change, and Controlled Oral Word Association Test (COWAT).
  
  
  RESULTS
  One hundred forty-four children entered the study; 99 (68.8%) of 144 children completed it, and 108 (75.0%) of 144 received zonisamide for ≥1 year. TEAEs occurred in 39 (27.1%) of 144 patients. There were low incidences of serious TEAEs (2.1%) and TEAEs leading to discontinuation (2.8%). Bicarbonate level decreases >3.5 mm occurred in 64 patients (44.4%), and 24 patients (16.7%) had a weight decrease of ≥10% from baseline. During the open-label period, 81 (56.3%) of 144 patients were responders and 16 (11.1%) of 144 achieved seizure freedom. Tanner staging and skeletal development were as expected for the study population. Changes were minimal for CBCL 6/18 and School Performance scores. Most patients were "much improved"/"very much improved" on Physician (73.8%) and Parent/Guardian (75.4%) Global Impressions of Change. Median changes in COWAT Category and Letter Fluency scores were 2.0 and 0.5, respectively.
  
  
  CONCLUSIONS
  Adjunctive zonisamide was well tolerated and efficacious over a period of at least 1 year in children with partial epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
authors.affiliation: Pediatric Neurology Unit and Laboratories, Department of Neuroscience, Pharmacology and Child Health, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Anna
authors.initials: A
authors.lastname: Rosati
authors.forename: Kate
authors.initials: K
authors.lastname: Bradshaw
authors.forename: Luigi
authors.initials: L
authors.lastname: Giorgi
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000008:administration & dosage*; D002648:Child; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D013997:Time Factors; D016896:Treatment Outcome; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D000078305:Zonisamide
keywords: Development; Growth; Partial seizures; Pediatric epilepsy; Safety/tolerability; Zonisamide