Abstracts

Rationale: About one third of pediatric patients with epilepsy develop refractory epilepsy that can be associated with medically resistant seizures (with or without clustering) and impaired development. Diazepam nasal spray is approved by the US Food and Drug Administration for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. This analysis assessed the safety and effectiveness of diazepam nasal spray in pediatric patients with epileptic encephalopathy from a long-term, phase 3, open-label, repeat-dose, safety study.

Methods: The study enrolled patients aged 6–65 years with frequent seizure clusters. Care partners and patients were trained to administer doses of 5, 10, 15, or 20 mg of diazepam nasal spray based on age (≤11 or ≥12 years) and weight, with instructions to administer second doses 4–12 hours later if needed. Investigators could adjust doses for effectiveness or safety reasons. Seizures, drug administration, and treatment-emergent adverse events (TEAEs) were recorded in seizure diaries. Use of a second dose within 24 hours for a seizure cluster was a proxy measure for effectiveness. The epileptic encephalopathy subgroup was determined based on the patients’ medical histories.

Results: The study enrolled 175 adult and pediatric patients, with a safety population of 163 treated patients that included 78 patients aged 6–17 years. A total of 64 (39.3%) of these patients were included in the pediatric epileptic encephalopathy subgroup (54.7% female; mean age [SD], 10.1 [3.2]; age range 6–17 years; Table 1). Duration of exposure to diazepam nasal spray in this subgroup was ≥12 months in 52 (81.3%) patients. Mean (SD) number of doses of diazepam nasal spray per month were 2.3 (1.4). There were 1402 treated seizure clusters in this subgroup; 149 (10.6%) were treated with a second dose.

TEAEs were reported in 57 (89.1%) patients in this pediatric epileptic encephalopathy subgroup, including 25 (39.1%) with serious TEAEs and 10 (15.6%) with treatment-related TEAEs (Table 2). The most common TEAEs (≥10 patients) were seizure, 17 (26.6%); nasopharyngitis, 14 (21.9%); pyrexia, 13 (20.3%); and upper respiratory tract infection, 10 (15.6%). The only treatment-related TEAE in ≥1 patient was epistaxis (n=2). In this subanalysis, there were no treatment-related serious TEAEs and no discontinuations due to TEAEs or deaths. Forty-three patients completed the study, and 7 discontinued due to study closure, for a retention rate in this subgroup up to study closure of 78.1%.

Conclusions: In an analysis of the subgroup of pediatric patients with epileptic encephalopathy from the long-term, phase 3, safety study of diazepam nasal spray, the high percentage of seizure clusters not using a second dose suggests initial-dose effectiveness in this highly intractable subgroup. There were no new safety signals compared with previous diazepam formulations for treatment of seizure clusters, with a high retention rate of 78.1% in this long-term study.

Funding: Please list any funding that was received in support of this abstract.: Neurelis, Inc.