Lack of Tolerance with Diazepam Nasal Spray for Seizure Clusters After Long-term Use: Final Results from a Phase 3, Open-Label, 12-Month Repeat Dose Safety Study
Abstract number :
2.204
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2021
Submission ID :
1825622
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Kore Liow, MD - Hawaii Pacific Neuroscience; Gregory Cascino - Mayo Clinic; Daniel Tarquinio, DO - Center for Rare Neurological Diseases; James Wheless, MD - Le Bonheur Children’s Hospital, University of Tennessee Health Science Center; R. Edward Hogan, MD - Washington University in St. Louis; Michael Sperling, MD - Thomas Jefferson University; Jay Desai, MD - Children’s Hospital of Los Angeles; Charles Davis, PhD - CSD Biostatistics; Enrique Carrazana, MD - Neurelis, Inc.; Adrian Rabinowicz, MD - Neurelis, Inc.
Rationale: Long-term effectiveness of benzodiazepine rescue therapy for seizure clusters may be affected if tolerance develops. Diazepam nasal spray (Valtoco®) is approved for acute treatment of seizure clusters in patients aged ≥6 years with epilepsy and is designed to provide a rapid, noninvasive, and socially acceptable route of administration. This analysis updates interim results assessing whether use of a second dose of diazepam nasal spray, as a proxy for effectiveness, is maintained, using final results from a long-term phase 3 safety study.
Methods: Patients aged 6–65 years with epilepsy and seizure clusters 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 in 2 adjacent periods (period 1 [initial] and period 2 [subsequent]) for each patient and comparing the proportion of events for which second doses were used in periods 1 and 2. Two methods were used to define “initial” and “subsequent” in both periods: (1) minimum number of events and (2) specific number of months. For all methods, consideration was restricted to subjects with ≥8 events in the initial period. Seizure clusters included any seizures within 24 hours of the initial event.
Results: Of 175 patients enrolled, 163 were treated with diazepam nasal spray for 3853 seizure-clusters during a mean of 1.5 years. Based on the range of exposure across the patient population, 256 analyses were conducted with time cutoffs from 4–36 mo in each period (totals of 8–72 mo) and 1–22 events in each period (totals of 2–44 events; Table). Only 6 (2.3%) analyses showed changes for which P< 0.05 in number of second doses between periods 1 and 2; fewer than expected by chance. Of changes with P< 0.05, period 2 mean rate was greater than period 1 in 4 instances and smaller in 2 instances. Across all analyses, rate of second doses was lower in period 2, with fewer second doses in period 2 for 167 (65.2%) analyses and fewer second doses in period 1 for 89 (34.8%) analyses. Treatment-emergent adverse events (TEAEs) occurred in 134 (82.2%) patients. One patient discontinued due to a TEAE (major depression), deemed not treatment related. One death occurred (sudden unexpected death in epilepsy), deemed unlikely related to treatment. None of the treatment-related TEAEs (30 [18.4%] patients) were serious.
Anti-seizure Medications