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(Abst. 1.308), 2019

Tolerability and Efficacy of Midazolam Nasal Spray in Outpatient Treatment of Patients with Seizure Clusters by Concomitant AEDs: Post-Hoc Analysis of Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Steve S. Chung, Banner University Medical Center, University of Arizona, Phoenix, AZ, USA; James W. Wheless, Division of Pediatric Neurology, University of Tennessee Health Science Center; Le Bonheur Comprehensive Epilepsy Program & Neuroscience Institute, LeBonHeur Children's Hospital, Memphis TN, USA; Svetlana Dimova, UCB Pharma, Brussels, Belgium; Eun Jung Choi, UCB Pharma, Smyrna, GA, USA; Aliceson King, UCB Pharma, Smyrna, GA, USA; Jody Cleveland, UCB Pharma, Raleigh NC, USA
Content: Rationale: 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 seizure clusters (SCs), and has been associated with a favorable safety profile (Detyniecki K, et al. Epilepsia 2019; doi: 10.1111/epi.15159; epub ahead of print). In order to explore the influence of concomitant antiepileptic drugs (AEDs) on treatment outcomes, a post hoc analysis of a Phase III trial (P261-401; NCT01390220) was conducted to evaluate the tolerability and efficacy of MDZ-NS in patients (≥12 yrs) with SCs according to concomitant enzyme-inducing AED (EIAED)/non-enzyme-inducing AED (NEIAED) status and by number of concomitant AEDs. Methods: The trial consisted of a Test Dose Phase followed by an outpatient double-blind (DB) Comparative Phase (CP; randomization 2:1 to 5 mg MDZ-NS or PBO). During the CP, if the SC did not terminate within 10min or another seizure occurred up to 6h after initial trial drug administration, the DB dose could be followed by an optional, open-label 5 mg MDZ-NS dose. Treatment-emergent adverse events (TEAEs), treatment success (seizure termination within 10min and no recurrence 10min–6h after trial drug administration), no seizure recurrence 10min–24h after trial drug administration, and return to full baseline (BL) functionality within 24h were analyzed during the CP in patients on concomitant EIAEDs or NEIAEDs, and in subgroups of patients on <2, 2–3, or ≥4 concomitant AEDs. Results: During the CP, the overall incidence of TEAEs in patients with ≥1 MDZ-NS dose was numerically lower in patients on EIAEDs vs. NEIAEDs and increased with the number of concomitant AEDs. A similar pattern was observed with the incidence of somnolence (Table 1). During the DB CP, a similar proportion of patients on EIAEDs and NEIAEDs, and patients on <2, 2–3, and ≥4 AEDs reported treatment success with MDZ-NS 5 mg (Table 2). Most patients (87.2%) randomized to MDZ-NS who did not have a seizure 10min–6h after one MDZ-NS 5 mg dose remained seizure free over 24h. This proportion was generally similar in patients on EIAEDs (88.9%) and NEIAEDs (84.8%), and across patient subgroups by number of concomitant AEDs (95.0%, 78.8%, and 92.0% in patients on <2, 2–3, and ≥4 AEDs). Amongst patients randomized to MDZ-NS who received only one MDZ-NS 5 mg dose, 96.2% on EIAEDs (n=53), 97.4% on NEIAEDs (n=38), and 100%, 94.3%, and 97.2% on <2 (n=20), 2–3 (n=35), and ≥4 (n=36) AEDs returned to full BL functionality within 24h of trial drug administration (median time to return: 1.25h, 1.00h, 0.95h, 1.25h, and 1.23h, respectively). Conclusions: In this post hoc analysis, incidences of TEAEs overall and somnolence post MDZ-NS administration in patients with SCs were numerically lower in those on EIAEDs and rose with number of concomitant AEDs. Most patients with no seizure within 6h remained seizure free over 24h; this proportion and treatment success with MDZ-NS were independent of EIAED use and number of concomitant AEDs. Regardless of EIAED use and number of concomitant AEDs, most patients returned to full BL functionality within 24h of trial drug administration. Funding: UCB Pharma-sponsored
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