Rationale:
Long-term effectiveness of benzodiazepine rescue therapy for seizure clusters may be affected if tolerance develops acutely or over time; tolerance has been demonstrated in epilepsy models. Diazepam nasal spray (Valtoco®), a proprietary formulation indicated for acute treatment of seizure clusters in patients with epilepsy aged 6 years and older, is designed to provide a rapid, noninvasive, and socially acceptable route of administration. Use of diazepam nasal spray in a long-term phase 3 safety study was assessed post hoc to determine if administration of a second dose, as a proxy for effectiveness, was maintained.
Method:
Subjects aged 6–65 years were enrolled. Patients and caregivers were trained to administer age- and weight-based doses of diazepam nasal spray; if needed, a second dose could be given 4–12 hours later. Tolerance was assessed by defining two adjacent periods (period 1 [initial] and period 2 [subsequent]), for each patient and comparing the proportion of events for which second doses were required in periods 1 and 2. Two methods were used to define “initial” and “subsequent”: based on a minimum number of events in both periods and based on a specific number of months in both periods. For all methods, consideration was restricted to subjects with ≥8 events in the initial period. Seizure clusters were defined as including any seizures within 24 hours of the initial event.
Results:
Of 177 patients enrolled at the interim cutoff of October 31, 2019, 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. Based on the range of exposure across the patient population, 191 analyses were conducted with time cutoffs from 2–15 mo in each period (totals of 4–30 mo) and 1–18 events in each period (totals of 2–36 events; Table 1). Only 5 (2.6%) analyses showed nominally statistically significant changes (P< 0.05) in number of second doses between periods 1 and 2; fewer than expected by chance. Of nominally significant changes, period 2 mean rate was greater than period 1 in 3 instances and smaller in 2 instances. Across all analyses, rate of second doses was generally lower in period 2, with fewer second doses in period 2 in 139 (72.8%) analyses and fewer second doses in period 1 in 52 (27.2%) analyses. Adverse events (AEs) were reported for 119 (75.3%) patients; none lead to discontinuation. None of the 26 treatment-related AEs were assessed as serious.
Conclusion:
This array of analyses on use of a second dose in a phase 3 safety study suggest that diazepam nasal spray retains its effectiveness over time for treatment of seizure clusters with no evidence of tolerance. Across multiple analyses, only 2.6% of analyses were nominally statistically significant, below the 5% level suggested by chance. Moreover, observed changes were directionally inconsistent, suggesting that the finding of nominal significant differences was random. There was no safety signal with continued use.
Funding:
:Neurelis, Inc.
FIGURES
Figure 1