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(Abst. 2.243), 2019

Somnolence and Time to Return to Baseline Functionality After Midazolam Nasal Spray Delivery in Patients with Seizure Clusters: Post Hoc Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Kamil Detniecki, Yale Comprehensive Epilepsy Center, Department of Neurology, Yale School of Medicine, New Haven, CT, USA; Rita Campos, UCB Pharma, Smyrna, GA, USA; Teresa Gasalla, UCB Pharma, Raleigh NC, USA; Jody Cleveland, UCB Pharma, Raleigh NC, USA; Toufic Fakhoury, Catholic Health Initiatives Saint Joseph Health, Lexington, KY, USA
Content: Rationale: Somnolence is a common adverse event after rescue treatment with benzodiazepines in patients with seizure clusters (SCs). The time taken for patients to return to full baseline functionality is an important factor in assessing the effect of treatment for SCs. Midazolam nasal spray (MDZ-NS) has been shown to be superior to placebo (PBO) in providing rapid, sustained seizure control when administered to patients experiencing SCs in the outpatient setting, and has been associated with a favorable safety profile (Detyniecki K, et al. Epilepsia 2019; doi: 10.1111/epi.15159; epub ahead of print). This post hoc analysis further characterizes somnolence and its potential effect on patients returning to full baseline functionality after MDZ-NS administration. Methods: Post hoc analysis of Phase III trial (P261-401; ARTEMIS-1; NCT01390220) evaluating safety and efficacy of MDZ-NS in patients (≥12 yrs) with SC. After an in-clinic open-label Test Dose Phase (TDP; two 5 mg MDZ-NS doses 10min apart), patients entered an outpatient double-blind Comparative Phase (CP; randomization 2:1 to 5 mg MDZ-NS or PBO). An optional open-label 5 mg MDZ-NS dose could be given if the SC did not terminate within 10min or another seizure occurred up to 6h after initial study drug administration (CP). Time to onset of somnolence, duration of somnolence, and return to full baseline functionality (i.e. caregiver opinion on time taken for patient to return to what he/she was doing) within 24h of MDZ-NS administration in patients reporting vs. not reporting somnolence were analyzed. Results: 292 patients received a test dose and were included in the TDP Safety Set (SS); 201 patients were randomized and received MDZ-NS or PBO (Randomized Safety Set); 175 received ≥1 dose of MDZ-NS (91 MDZ-NS 5 mg; 43 MDZ-NS 5+5 mg; 41 PBO+MDZ-NS 5 mg) and 26 received PBO only. Somnolence was reported by 10.6% of patients during the TDP, and by 9.7% of patients who received ≥1 MDZ-NS dose during the CP (PBO, 3.8% [1 patient]). Onset of somnolence generally occurred shortly after MDZ-NS administration, with a median time to onset of 15.0min during the TDP and 5.0min during the CP (Table 1). Median somnolence duration was 1.14h during the TDP and 4.13h in patients who received ≥1 dose of MDZ-NS during the CP. The proportion of patients returning to full baseline functionality within 24h after first MDZ-NS dose administration (CP) was not affected by somnolence but by administration of the open-label MDZ-NS dose (MDZ-NS 5 mg vs. MDZ-NS 5+5 mg vs. PBO+MDZ-NS 5 mg) (Table 2). Regardless of somnolence occurrence, for patients who returned to full baseline functionality within 24h, the median time to return to full baseline functionality after MDZ-NS first dose administration was within 2h (CP; 1.05h in patients not reporting somnolence vs. 1.54h in patients reporting somnolence). Conclusions: This post hoc analysis suggested that the incidence of somnolence after MDZ-NS dosing was low; when somnolence was reported, the onset occurred shortly after MDZ-NS administration (5min) and had a median duration of ~4h. The proportion of patients returning to full baseline functionality within 24h after MDZ-NS administration was not affected by occurrence of somnolence but by SC control and the need for additional MDZ-NS dose administration. Funding: UCB Pharma-sponsored
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