Authors :
Presenting Author: 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
Steven M Wolf, MD – Westchester Medical Center, Hawthorne, NY, United States
Muhammad Zafar, MD – Duke University School of Medicine
Genei Bougher, MSN, APRN – Northwest Florida Clinical Research Group
Charles Davis, PhD – CSD Biostatistics, Inc.
Leock Ngo, PhD – Neurelis, Inc.
Miguel Lopez-Toledano, PhD – Neurelis, Inc.
Enrique Carrazana, MD – Neurelis, Inc., John A. Burns School of Medicine; University of Hawaii, Honolulu, HI
Adrian Rabinowicz, MD – Neurelis, Inc., Center for Molecular Biology and Biotechnology (CMBB) in the Charles E. Schmidt Collage of Science at Florida Atlantic University
Rationale:
Some people with epilepsy experience seizure clusters (eg, ≥2 seizures within 24 h), and diazepam nasal spray is approved for treatment in patients aged ≥2 years. In a post hoc analysis from a phase 3 study of diazepam nasal spray in patients aged 6-65 years, earlier treatment of seizures was associated with shorter time to seizure cessation. Here, we examined time from seizure onset to dose of diazepam nasal spray and time from dose to seizure cessation in children aged 2-5 years enrolled in a phase 1/2a, open-label pharmacokinetics study of diazepam nasal spray that included a 180-day open-label safety period and an optional extension period (NCT05076838).Methods:
Caregivers administered diazepam nasal spray to patients aged 2-5 years (0.5 mg/kg) for the treatment of seizure clusters. Time from seizure onset to dose and from dose to seizure cessation and total seizure duration were derived from seizure diaries. Seizures lasting >24 hours, negative duration, or invalid dose date/time were excluded. Descriptive statistics were calculated.Results:
Of the 36 patients enrolled, 27 (75%) completed the optional extension; mean age was 3.9 years (range, 2.0-5.8), and mean exposure to diazepam nasal spray was 15.45 months (SD, 8.4). Of 435 treatment doses, complete seizure and dose-timing records were available for 370 seizure episodes, with 163 (44.1%) treated < 5 minutes, 175 (47.3%) treated 5-15 minutes, and 32 (8.6%) treated >15 minutes from seizure onset. In seizures treated < 5 minutes from onset (median time [range], 1 [0-4] min), median time from dose to seizure cessation was 1 (0-60) minute, and median total seizure duration was 3 (0-60) minutes (Figure 1). The median time from dose to seizure cessation was 3 (0-120) and 9.5 (0-2750) minutes for seizures treated 5-15 and >15 minutes, respectively, after seizure onset (Figure 1). Similar temporal patterns of shorter time to seizure cessation with shorter time to treatment were noted for the smaller 2-3 and 4-5 age subgroups (Figure 2). Treatment-emergent adverse events (TEAEs) and treatment-related TEAEs were reported by 66.7% and 19.4% of patients in the safety period and 88.9% and 3.7% in the extension period. Respiratory depression, acute respiratory failure, and respiratory failure occurred in 1 patient each and none were considered treatment-related.
Conclusions:
In children aged 2-5 years, early treatment of seizures with immediate-use diazepam nasal spray was associated with early seizure cessation and shorter overall seizure duration. Treatment within 5 minutes of seizure start showed a rapid onset from dose to seizure cessation. No new safety signals were observed. These data are consistent with temporal patterns observed in a phase 3 safety study conducted in older patients aged 6-65 years and reinforce the value of prompt treatment of seizure clusters.Funding: Neurelis, Inc.