(558) Use of a Second Dose of Diazepam Nasal Spray Within 4 Hours and Effect on the Safety Profile in Patients with Seizure Clusters: Interim Results from a Phase 3, Open-label, 12-Month Repeat Dose Safety Study

Rationale: The need for a second dose of a benzodiazepine to treat a seizure cluster episode varies by agent and route of administration. Timing of a second dose (historically, 4–12 hours after the initial dose for diazepam rescue therapy) and the effect that dose has on the safety profile may be important factors in assessing a rescue medication. Diazepam nasal spray (Valtoco^®), a proprietary formulation with Intravail^® A3 that is indicated for acute treatment of seizure clusters in patients with epilepsy aged six years and older, provides a rapid, noninvasive, and socially acceptable route of administration. The safety profile associated with a second dose of diazepam nasal spray given within four hours of the initial dose was explored ad hoc.

Methods: This Phase 3 safety study of diazepam nasal spray included epilepsy patients aged six to 65 years with seizure clusters; results from an interim analysis are reported. Age- and weight-based doses of 5, 10, 15, or 20 mg were administered; patients and caregivers were instructed that a second dose may be given four to 12 hours later, if needed. In this real-world setting, safety was assessed for patients with second doses administered within 4 hours of the initial dose, to determine if the safety profile of those patients differed from patients given second doses between four and 24 hours after the initial dose.

Results: As of the October 31, 2019, interim cutoff, 177 patients had been enrolled, and 158 patients were evaluated in the safety population (mean [SD] age, 23.5 [15.1] years; 53.8% female; 82.3% white) who had 3370 seizure-cluster episodes treated with diazepam nasal spray. Of that population, 77 patients (48.7%) received a second dose of diazepam nasal spray for 439 seizure cluster episodes (< 4 hours, 35 patients/142 episodes; 4–24 hours, 42 patients/297 episodes). Demographics in both second-dose groups were similar to the overall population. In both groups, most patients had a duration of exposure of ≥12 months (< 4 hours, 77.1%; 4–24 hours, 81.0%). The rates and types of treatment-emergent adverse events (TEAEs) deemed at least possibly related to treatment were similar between the two groups (< 4 hours, 31.4%; 4–24 hours, 26.2%; Table); none of the treatment-related TEAEs were reported as serious. Overall rates of TEAEs (i.e., including those unrelated to treatment) were also similar between groups (Table). The single sedation event was in the 4 to 24 hour second-dose group.

Conclusions: In this Phase 3 safety study, 13.0% of seizure-cluster episodes were treated with a second dose of diazepam nasal spray. Although diazepam rescue therapies for seizure clusters have traditionally provided for second doses between four and 12 hours after the initial dose, these real-world data did not show a clinically different safety profile for patients receiving a second dose within four hours compared with patients treated four to 24 hours after the initial dose.

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