Evaluation of Diazepam Nasal Spray in Patients with Seizure Clusters Concomitantly Receiving Clobazam: A Subgroup Analysis from a Completed Phase 3, Long-Term, Open-Label Safety Study
Abstract number :
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Submission ID :
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 12:44 PM
Michael Sperling, MD - Thomas Jefferson University; Daniel Tarquinio, DO - Center for Rare Neurological Diseases; James Wheless, MD - Le Bonheur Children’s Hospital, University of Tennessee Health Science Center; Gregory Cascino, MD - Mayo Clinic; Jay Desai, MD - Children’s Hospital of Los Angeles; R. Edward Hogan, MD - Washington University in St. Louis; Kore Liow, MD - Hawaii Pacific Neuroscience; David Cook, PhD - Neurelis, Inc.; Adrian Rabinowicz, MD - Neurelis, Inc.; Enrique Carrazana, MD - Neurelis, Inc.
Rationale: Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Benzodiazepines are the mainstay of seizure-cluster treatment and are also included in some daily antiseizure drug (ASD) regimens. Thus, it is clinically relevant to understand whether effectiveness and safety of diazepam nasal spray is altered by use of other benzodiazepines, including chronic treatment with clobazam. This subanalysis from a long-term safety study evaluates the eﬀectiveness and safety of diazepam nasal spray in subgroups of patients receiving clobazam or other benzodiazepines.
Methods: Data from a phase 3, open-label, repeat-dose safety study of diazepam nasal spray were analyzed by subgroups receiving chronic clobazam or other intermittent and chronic benzodiazepines. Patients were aged 6–65 years with frequent seizure clusters despite stable ASDs. Care partners and patients were trained to administer diazepam nasal spray (5, 10, 15, or 20 mg), with second doses 4–12 hours later if needed. Investigators could adjust doses for effectiveness or safety reasons. Seizures, drug administration, and treatment-emergent adverse events (TEAEs) were recorded in seizure diaries. Second doses were assessed during the 24 hours after the seizure.
Results: Among 175 enrolled patients, 163 were treated. Of these, 125 patients (52.8% female) took concomitant benzodiazepines; 46 (36.8%; mean age, 17.7 years) used clobazam and 79 (63.2%; mean age, 26.0 years) used other benzodiazepines. Exposure to diazepam nasal spray was ≥12 months in most patients (clobazam, 81.0%; other benzodiazepines, 91.3%) and retention rates (study completion irrespective of study closure) were 72.2% and 80.4% in the clobazam and other benzodiazepine subgroups, respectively. The subgroups had similar mean total doses per patient (clobazam, 26.1; other benzodiazepines, 27.8) and doses per month (clobazam, 2.5; other benzodiazepines, 2.3). In both subgroups, < 15% of seizure episodes were treated with a second dose (Figure).
The proportion of patients with TEAEs was slightly higher in the clobazam subgroup (89.1% vs 83.5%); however, treatment-related TEAE rates were similar (~20%) (Table). Serious TEAEs were higher in the clobazam subgroup (47.8% vs 25.3%), but no serious TEAEs were deemed treatment-related. No events of respiratory depression were reported. The only treatment-related TEAE in ≥5% of patients in either group was nasal discomfort (8.9%, other benzodiazepines; 4.3%, clobazam).
Conclusions: Final results from a long-term study show that the effectiveness and safety profile of diazepam nasal spray was not substantially altered by concomitant benzodiazepine treatment. There was no notable effect of chronic clobazam on the number of second doses needed per episode (used as a proxy of effectiveness), on the safety/tolerability profile of diazepam nasal spray, or study retention compared with other chronic or intermittent benzodiazepines.
Funding: Please list any funding that was received in support of this abstract.: Neurelis, Inc.