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

SUMMARYObjective: 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. Significance: 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.

The safety and long-term efficacy of zonisamide as adjunctive therapy for focal epilepsy

“…Similar results were found in the long-term adjunctive treatment studies with ZNS in patient cohorts with long preexisting epilepsy; accordingly seizure freedom rates were low even for short periods (28 days: 11.1% [32]) in children with focal epilepsy; for any 12-month period, 6.6%, and for the final year, only 1% of adult patients remained seizure free [30] despite the positive preselection bias of patients entering the study. This confirms earlier study results reviewed by Zaccara and Specchio [37].…”

“…Weight loss similarly occurs also in children's cohorts like reported by Guerrini et al [32], in which 16.7% of patients suffered a weight loss by >10%, some children by >20%. Again, weight loss was reported as an adverse event much less frequently (only in 6.9% of patients).…”

“…A number of studies extending over 1-6 years of ZNS treatment have been published during the recent years, providing long-term data on both children and adults with focal epilepsies, sometimes also in a wider spectrum of epilepsies [29][30][31][32][33].…”

“…Prospective open-label extension study of ZNS in adjunctive treatment in childhood A further recent study assessed long-term (1 year) results of a European extension study with adjunctive ZNS treatment in 144 children aged 6-18 years with focal onset seizures ('partial epilepsy') [32]. Patients consisted of subgroups of 72/107 patients exposed to ZNS in the preceding randomized trial and of 72/ 100 patients previously taking placebo.…”

“…Interestingly, retention tended to be better in generalized than in focal epilepsy, but even in the latter, 48% were yet on ZNS treatment 6 years after its introduction. Again, longterm data suggest that the decision to switch treatment from ZNS to another drug is only rarely due to newly emerging adverse effects during long-term treatment [31,32] but rather due to the treating physician's decision to try to improve seizure control by changing the treatment regime.…”