Abstracts

Rationale: Study 303 is a Phase III, open-label, 2-year study of adjunctive rufinamide (RFM) (oral suspension) in pediatric subjects aged ≥1 to < 4 years with inadequately controlled LGS. This analysis reports the final 2-year safety, tolerability, and cognitive data. Methods: Subjects were randomized 2:1 to either RFM or an approved, investigator-chosen antiepileptic drug (AED) as add-on to their existing regimen of 1–3 AEDs. RFM was administered at 10-mg/kg/day (2 equally divided doses), increased by 10-mg/kg/day every 3 days to 40-mg/kg/day, and then increased by 5-mg/kg/day to 45-mg/kg/day (target dose). Other AEDs were administered according to the investigator’s usual practice. Study phases consisted of pre-randomization (screening period + baseline visit=1–8 wks) and randomization (titration period + maintenance period=106 wks; taper period=2 wks). Safety assessments included treatment-emergent adverse events (TEAEs) using Medical Dictionary for Regulatory Activities (MedDRA) standardized terms, clinical laboratory parameters, vital signs, and 12-lead ECG. Cognitive development and behavioral effects were assessed via the Child Behavior Checklist (CBCL) Total Problems Score and change from baseline in CBCL Total Problems Score at the end of 2 years (106 wks). Results: 37 subjects were randomized into the study, 25 in the RFM group and 12 in the any-other-AED group. 67.6% of subjects were 1to  < 3 years old and 32.4% were 3–4 years old. TEAE incidence was similar between the RFM (88.0%) and the any-other-AED group (83.3%) (Table 1), with most events considered mild or moderate. TEAEs leading to study drug withdrawal occurred in 2 (8.0%) and 1 (8.3%) subjects in the RFM and any-other-AED groups, respectively. Treatment-related TEAEs occurred in 13 (52.0%) RFM and 6 (50.0%) any-other-AED subjects. Vomiting (5 [20.0%]) and somnolence (4 [16.0%]) were the only treatment-related TEAEs reported in >2 RFM subjects. Pyrexia and upper respiratory tract infection (2 [16.7%] each) were the only treatment-related TEAEs reported in >1 any-other-AED subject. There were no clinically important mean changes in laboratory values, vital signs, or ECGs. LS mean differences in CBCL Total Problems Score in the RFM and any-other-AED groups at the end of 2 years were comparable, with no statistically significant difference between the 2 treatment groups (LS mean difference [95% CI] +2.60 [-10.5,15.7]; p=0.6928). Some subjects were in the borderline/clinical range in problem area scales, suggesting high cognitive impairment at baseline that persisted throughout the study. Limitations of these analyses include the small sample sizes and greater baseline disease severity of many subjects. Conclusions: Results from Study 303 showed that RFM was well tolerated in pediatric subjects ≥1 to < 4 years of age. Cognitive development and behavior of subjects treated with RFM was comparable to that of subjects in the any-other-AED treatment group. Funding: Eisai Inc.