Abstracts

Rationale:
Usage frequency of rescue therapy for seizure clusters may vary among patients, and it is important to determine whether long-term safety is related to monthly usage frequency. Diazepam nasal spray (Valtoco®) formulated with Intravail® A3, a proprietary intranasal formulation indicated for acute treatment of seizure clusters in patients with epilepsy aged 6 years and older, provides a rapid, noninvasive, and socially acceptable route of administration. This interim analysis evaluated long-term safety of diazepam nasal spray among patients defined as having moderate and frequent monthly usage.
Method:
In this interim phase 3 safety study, caregivers and patients with epilepsy were trained in the use of the intranasal sprayer. Diazepam nasal spray was administered at 5, 10, 15, or 20 mg based on the patient’s age and weight, with a second dose administered, if needed, 4 to 12 hours later. Frequency of use was stratified based on average number of doses/month, defined as moderate (< 2 doses/month) and frequent (≥ 2 doses/month). Treatment-emergent adverse events (TEAEs) and severity of common TEAEs are reported. Tolerability assessments included nasal irritation measured objectively on a 6-point scale.
Results:
A total of 177 subjects were enrolled at the October 31, 2019, interim cutoff date, and 158 were treated with diazepam nasal spray (6 to 65 years old; 53.8% female; 82.3% white). Use of diazepam nasal spray was moderate in 69 patients (43.7%) and frequent in 89 patients (56.3%). Duration of exposure to diazepam nasal spray was ≥12 months for the majority of patients (overall, 116 patients [73.4%]; moderate use, 53 patients [76.8%]; frequent use, 63 patients [70.8%]). Overall, 119 patients (75.3%) had TEAEs (Table 1), with 49 patients (71.0%) in the moderate and 70 patients (78.7%) in the frequent-use groups. There were no TEAE-related discontinuations; 45 patients (28.5%) had serious TEAEs, none of which was deemed related to treatment. Although there were relatively few treatment-related TEAEs overall, the most common of these (nasal discomfort, headache, epistaxis, somnolence, rhinalgia, and rhinorrhea) were numerically higher in frequent users. There was one report of the TEAE of sedation each among the moderate users and frequent users. Among the most common TEAEs, most were mild or moderate in both groups (Figure 1). The few observations of nasal irritation were mild (maximum grade 1B; superficial mucosal erosion) with an apparently slightly higher incidence in frequent users. The study retention rate was similar for the 2 groups (moderate-use, 84.1%; frequent-use, 82.0%).
Conclusion:
In this interim analysis of long-term safety and tolerability, repeat dosing of diazepam nasal spray demonstrated a safety profile consistent with what may be expected for diazepam and which appeared to be independent of usage frequency. Nasal irritation was mild and transient in both groups. Retention rate was high.
Funding:
:Neurelis, Inc.