title: Adjunctive levetiracetam in patients aged 1 month to <4 years with partial-onset seizures: subpopulation analysis of a prospective, open-label extension study of up to 48 weeks.
abstract: BACKGROUND
  In a recent double-blind, placebo-controlled study, adjunctive levetiracetam (LEV) was reported to be effective and well tolerated during 5-day treatment in patients aged 1 month to <4 years with partial-onset seizures. A study was planned to fulfill the regulatory requirement to evaluate the long-term safety of LEV as adjunctive therapy for partial-onset seizures in pediatric patients.
  
  
  OBJECTIVE
  This study evaluated the long-term effectiveness and tolerability of adjunctive LEV in infants and young children with partial-onset seizures.
  
  
  METHODS
  This was a prospective, open-label, outpatient, multicenter study (N01148; ClinicalTrials.gov identifier NCT00152516) conducted as an extension of a previously published study (N01009; NCT00175890). Patients were enrolled from 3 sources, as follows: (1) patients who had completed study N01009; (2) patients who had failed screening for entry into study N01009 but fulfilled the eligibility criteria for entry into this study; and (3) patients who were directly enrolled. The study consisted of a 2- to 4-week retrospective baseline period (and a 3- to 10-day prospective baseline period for directly enrolled patients), a 2- to 8-week uptitration/conversion period, and a maintenance period. Eligible patients were required to have epilepsy with partial-onset seizures, treated with a stable regimen of 1 or 2 antiepileptic drugs. Patients received adjunctive LEV, 20 to 80 mg/kg/d, for up to 48 weeks (total study duration). The primary variable for effectiveness was the percentage reduction from baseline in the weekly frequency of partial-onset seizures, as recorded in patients' diaries. Data for effectiveness were also analyzed by age strata (1 month to <1 year, 1 to <2 years, and 2 to <4 years). Neuropsychological assessment was conducted with the Bayley Scales of Infant Development, Second Edition (BSID-II). All analyses were performed on observed data, and the last-observation-carried-forward approach was not used. The intent-to-treat (ITT) population was defined as all patients who took at least one dose of LEV during the study. Treatment-emergent adverse events (TEAEs) were assessed by observation, spontaneous reporting, standard questions, review of diary cards, and neuropsychologists' clinical reports. Additional measures included physical and neurologic examinations, vital signs, ECGs, routine blood chemistry, and routine hematology assessments.
  
  
  RESULTS
  The study included 152 patients in the ITT population. In total, 51.3% (78/152) of the patients were male, and mean (SD) age was 23.5 (12.4) months. The mean LEV maintenance dose was 56.1 (16.2) mg/kg/d, and the median (Q1-Q3) treatment duration was 287.8 (209.0-295.5) days. Ninety-seven patients (63.8%) completed the study. The BSID-II subpopulation included 51 patients. During maintenance, the overall median (Q1-Q3) percentage reduction from baseline in the weekly frequency of partial-onset seizures was 56.0% (-10.9% to 92.8%), which was sustained over time and appeared comparable across the age strata (1 month to <1 year, n = 25, 50.9%; 1 to <2 years, n = 48, 58.0%; and 2 to <4 years, n = 59, 55.0%). The overall responder rate (ie, ≥50% reduction from baseline in weekly partial-onset seizures) was 53.8% (71/132), was maintained over time, and was consistent across the age strata (1 month to <1 year, 52.0%; 1 to <2 years, 56.3%; and 2 to <4 years, 52.5%). Mean BSID-II raw scores for psychomotor development and behavioral functioning remained static, whereas mental development appeared to improve over time, although this was not tested statistically. At least one TEAE was reported in 143 patients (94.1%). The most frequently reported TEAEs were pyrexia (60/152; 39.5%), upper respiratory tract infection (42/152; 27.6%), and vomiting (28/152; 18.4%). The most common TEAEs affecting the central nervous system were convulsion (25/152; 16.4%), irritability (19/152; 12.5%), and somnolence (16/152; 10.5%). Most TEAEs (77.0%) were mild or moderate in intensity.
  
  
  CONCLUSIONS
  Adjunctive LEV treatment for up to 48 weeks was associated with effective and sustained seizure control and had an acceptable tolerability profile in this small, selected population of infants and young children aged 1 month to <4 years with partial-onset seizures.
authors.affiliation: Department of Neurology and Pediatrics, Children's Hospital at Vanderbilt, Nashville, Tennessee 37232, USA. eric.pina-garza@vanderbilt.edu
authors.forename: Jesus Eric
authors.initials: JE
authors.lastname: Piña-Garza
authors.forename: Jimmy
authors.initials: J
authors.lastname: Schiemann-Delgado
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Duncan
authors.forename: Jan
authors.initials: J
authors.lastname: Hadac
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hunter
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam