Authors :
Presenting Author: Steven M Wolf, MD – Westchester Medical Center, Hawthorne, NY, United States
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES, FCNS – University of Tennessee Health Science Center and Le Bonheur Children's Hospital
Eric Segal, MD – Hackensack University Medical Center and Northeast Regional Epilepsy Group and Hackensack Meridian School of Medicine
Jurriaan Peters, MD PhD – Boston Children's Hospital
Muhammad Zafar, MD – Duke University School of Medicine
Charles Davis, PhD – CSD Biostatistics, Inc.
Leock Ngo, PhD – Neurelis, Inc.
Miguel Lopez-Toledano, PhD – Neurelis, Inc.
Adrian Rabinowicz, MD – Neurelis, Inc., Center for Molecular Biology and Biotechnology (CMBB) in the Charles E. Schmidt Collage of Science at Florida Atlantic University
Enrique Carrazana, MD – Neurelis, Inc., John A. Burns School of Medicine; University of Hawaii, Honolulu, HI
Rationale:
Diazepam nasal spray is approved for the treatment of seizure clusters in patients with epilepsy age ≥2 y. A second dose may be used ≥4 h after the first if needed. The use of second doses within 24 hours of the initial dose was evaluated as a proxy measure of treatment effectiveness in a phase 3 study in patients aged 6–65 y. A phase 1/2a study in patients aged 2–5 y is now completed. Here, we present the final data on the use of second doses for patients aged 2–5 years from that recent study.Methods:
Patients aged 2–5 y with epilepsy and seizure clusters participated in a phase 1/2a, open-label study that included a 180-day safety period and an optional extension period (NCT05076838). The main objective of the study was to investigate the pharmacokinetics and drug safety in this young population. Caregivers were supplied with diazepam nasal spray to administer as needed to treat seizure clusters. Weight-based doses were 5, 10, or 15 mg, (ie, 0.5 mg/kg), and a second dose could be administered if needed 4–12 hours after the initial dose. Dosage could be adjusted by the investigator for efficacy or safety reasons. Seizure diary data, including nasal-spray usage, collected during the 180-day open-label safety period and the optional extension period, were included in this analysis.Results:
Of the 36 patients who were enrolled and treated, 31 (86.1%) completed the 180-day safety period and 27 (75.0%) entered and completed the optional extension period. Mean age was 3.9 y (range: 2.0–5.8 y), with 19 aged 2-3 years and 17 aged 4-5 years. A total of 471 doses of diazepam nasal spray were administered during the 180-day period and the optional extension study (5 mg, 30 doses [n=3 patients]; 10 mg, 371 doses [n=29]; 15 mg, 70 doses [n=4]). 64 (13.6%) of the doses were administered as second doses ≤24 hours after the first; thus, 86.4% of doses were given without a second dose (Figure). Twelve (33.3%) patients received a second dose within 24 hours of a first dose. Of these patients, 11 received a second dose in < 4 hours on at least one occasion. Treatment-related treatment-emergent adverse events were reported in 7 patients (19.4%) in the 180-day safety period, and 1 patient (3.7%) in the optional extension period, none were serious. Respiratory depression, acute respiratory failure, and respiratory failure occurred in 1 patient each and none were considered treatment related.
Conclusions:
In this study of diazepam nasal spray for seizure clusters in children aged 2–5 y, >85% of seizure events did not use a second dose within 24 hours of the first. This finding is consistent with studies in older children and adults (Figure) and supports the effectiveness of diazepam nasal spray in this population and the established 0.5 mg/kg dosing paradigm for diazepam. The low use of second doses may reduce patients’ seizure burden and caregivers’ treatment burden.Funding: Neurelis, Inc.