Authors :
Presenting Author: Muhammad Zafar, MD – Duke University School of Medicine
Eric Segal, MD – Hackensack University Medical Center and Northeast Regional Epilepsy Group and Hackensack Meridian School of Medicine
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES, FCNS – University of Tennessee Health Science Center and Le Bonheur Children's Hospital
Jurriaan Peters, MD PhD – Boston Children's Hospital
Steven M Wolf, MD – Westchester Medical Center, Hawthorne, NY, United States
Genei Bougher, MSN, APRN – Northwest Florida Clinical Research Group
Charles Davis, PhD – CSD Biostatistics, Inc.
Miguel Lopez-Toledano, PhD – Neurelis, Inc.
Leock Ngo, 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:
Diazepam nasal spray (Valtoco®) is approved for the treatment of seizure clusters in patients with epilepsy aged ≥2 y. In patients aged 6-65 y, a safety profile consistent with that of diazepam rectal gel has been demonstrated. A phase 1/2a study investigated diazepam nasal spray in children with epilepsy aged 2-5 y. Here, we focus on local safety and tolerability at the administration site, serious respiratory-related TEAEs, and device dosing errors as a measure of device suitability for this younger, physically smaller population.
Methods:
Patients aged 2-5 y with focal or generalized epilepsy with motor seizures or seizures with clear alteration of awareness participated in a phase 1/2a, open-label study with a single-dose pharmacokinetic (PK) period, a 180-day safety period, and an optional extension period. The main objective of the study was to investigate PK and safety of 0.5 mg/kg (body weight) diazepam nasal spray, administered as needed for seizure control as single sprays of 5 or 10 mg or two sprays totaling 15 mg. Second doses could be given if needed. Nasal irritation was assessed objectively by trained observers at each study visit, using separate predefined scales to assess nasal irritation, nasal discharge, and mucosal erythema, edema, crusting and epistaxis. TEAE data were gathered via spontaneous reports and direct questioning at study visits and telephone calls. Dosing errors could include incorrect (eg, partial) dose, inappropriate timing, or an administration error. Results:
Safety was evaluable in all 36 patients who were enrolled and treated. 31 (86.1%) patients completed the 180-day safety period, and 27 (75.0%) completed the optional extension period. Patients (mean age: 3.9 y, range: 2.0-5.8 y) received a total of 471 doses (mean [SD] total of 13.1 [18.3] doses per patient) over 15.45 (8.4) months of exposure. Dosage was 5 mg in 3 patients, 10 mg in 29 patients, and 15 mg in 4 patients. Most nasal irritation and mucosal assessments were normal, and all other findings were transient and graded as mild (Table). There were no reports of mucosal epistaxis . Serious TEAEs of respiratory depression, respiratory failure, and acute respiratory failure were reported in 1 patient each but were not considered related to treatment. Dosing errors were rare, occurring in 3 (0.6%) of the 471 doses administered during the study, yielding a correct dosing rate of 99.4%, which was similar to that in older patients. Two of the errors involved the administration of a partial dose, and the third was classified as an administration error.Conclusions:
Diazepam nasal spray demonstrated favorable local safety and tolerability profile in children aged 2-5 years, with no serious treatment-related TEAE (including respiratory depression), and a low rate of dosing errors comparable to that seen in studies in older children and adults. These findings support the dosing paradigm and the device’s suitability in treating seizure clusters for this age group.Funding: Neurelis, Inc.