Rationale:
Benzodiazepines have been the mainstay of rescue therapy for seizure clusters. Diazepam nasal spray (Valtoco®) is US Food and Drug Administration approved for acute treatment of seizure clusters in patients with epilepsy aged 6 years or older. The long-term safety of diazepam nasal spray is being evaluated in a 12-month phase 3 open-label safety study. Interim results from this study are reported here.
Method:
The study included patients aged 6 to 65 years. Diazepam nasal spray was administered by caregivers or patients in doses of 5, 10, 15, or 20 mg, based on patient age and weight; if needed, a second dose was administered 4–12 hours later. Investigators could adjust doses for efficacy/safety. Seizures, drug administration, and treatment-emergent adverse events (TEAEs) were recorded in subject diaries and reported at regularly scheduled visits. These visits also included physical/neurological examinations, vital signs, laboratory tests, assessment of nasal irritation on a 0- to 4-point scale and smell tests.
Results:
Of 177 patients enrolled, 158 patients received diazepam nasal spray as of the October 31, 2019, cutoff (53.8% female, 82.3% white, mean age 23.5 years). Eleven (7.0%) patients had < 6 months drug exposure, 31 (19.6%) had 6 to < 12 months exposure, and 116 (73.4%) had ≥ 12 months exposure. Total doses received were 1–2 in 14.6% of patients, 3–10 in 31.0%, 11–20 in 15.2%, 21–40 in 22.8%, and > 40 doses in 16.5% of patients; 56.3% of patients averaged ≥2 doses per month. A total of 119 (75.3%) patients had ≥ 1 TEAE (Table). Serious TEAEs were recorded in 45 (28.5%) patients; none of these was deemed to be treatment-related. No patients discontinued the study due to adverse events. TEAEs assessed by investigators as being possibly treatment-related were seen in 26 (16.5%) of patients (Table), most commonly nasal discomfort (5.7%). Of note, there were no reports of cardiac or respiratory depression. Trained observers reported few occurrences of nasal irritation, which was mild (score of 0, 1A, or 1B) and transient. Smell tests showed no median change from baseline at any measured timepoint. There were no trends in effects on blood pressure, pulse rate, respiratory rate, hematology, chemistry, or urinalysis values. The retention rate was 83% in this long-term study. Of the 27 patients who discontinued, 3 were lost to follow-up, 16 withdrew, and 8 discontinued for other reasons.
Conclusion:
In this updated interim analysis of a phase 3 long-term, repeated dosing safety study of diazepam nasal spray for patients with seizure clusters, the safety profile was as expected with other diazepam formulations. Treatment-related TEAEs were reported in only 16.5% of patients. Nasal irritation was mild and transient, and no clinically relevant olfactory changes were observed. Exposure was greater than a year in 73% of patients, and the retention rate was high.
Funding:
:Neurelis, Inc.
FIGURES
Figure 1