(761) Time of Day of Occurrence of Seizure Clusters in Patients With Epilepsy Treated With Diazepam Nasal Spray: Interim Results From a Phase 3, Open-label, Repeat Dose Safety Study

Rationale: Specific circadian patterns and sleep/wake distributions of seizures have been reported depending on seizure type and onset location. Understanding the timing of seizure patterns may provide important information for improving patient care and quality of life; however, data on patterns for patients with seizure clusters are limited. To better understand these data, a time-of-day analysis of seizure-cluster onset was conducted in patients from a Phase 3, long-term, repeat-dose study of diazepam nasal spray (Valtoco^®). This proprietary diazepam formulation with Intravail^® A3 is indicated for acute treatment of seizure clusters in patients with epilepsy aged six years and older and is designed to be a rapid, noninvasive, and socially acceptable route of administration.

Methods: The Phase 3 safety study enrolled patients aged six to 65 years with seizure clusters. Caregivers and patients were trained in the use of the intranasal sprayer to administer diazepam nasal spray 5, 10, 15, or 20 mg based on age and weight, with a second dose, if needed, administered four to 12 hours later. Seizure onset and dosing information was recorded in a diary. Clock time of onset of each cluster was assessed. Treatment-emergent adverse events (TEAEs) by dosage group were reported.

Results: Of 177 patients enrolled at the October 31, 2019, interim cutoff, 158 patients (mean age 23.5 [range: 6 to 65] years; 53.8% female; 82.3% white) were treated with diazepam nasal spray and evaluated in the safety set. Exposure to diazepam nasal spray was ≥12 months in 116 patients (73.4%), 6 to < 12 months in 31 patients (19.6%), and < 6 months in 11 patients (7.0%); 89 patients (56.3%) averaged ≥ 2 doses/month. Among the 3,646 seizures with reported start dates and times that were used in this analysis, onset was generally highest during mornings and late evenings and lowest in the afternoon, early evening, and middle of the night (Figure). The pattern was generally consistent across dosing groups with some apparent variation in the 5 mg and 10 mg groups (Table). A total of 119 patients (75.3%) had TEAEs, with six (3.8%) in the 5 mg group, 38 (24.1%) in the 10 mg group, 34 (21.5%) in the 15 mg group, and 41 (25.9%) in the 20 mg group; none of the TEAEs were unexpected. There were no discontinuations due to a TEAE.

Conclusions: These preliminary results from the Phase 3 safety study of diazepam nasal spray support the view that circadian rhythms influence time of day when monitoring patients with seizure clusters may need stressing in daily practice. Further analysis by seizure type and other variables is warranted upon study completion. The safety profile for diazepam nasal spray was consistent with what may be expected for diazepam.

Funding: Please list any funding that was received in support of this abstract.: Neurelis, Inc.
Click here to view image/table

Click here to view image/table