Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double‐blind, randomized, placebo‐controlled trial

Abstract

Objective: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. Methods: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). Results: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. Significance: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 2416 | SPENCER Et al.

Overcoming the challenges of developing an intranasal diazepam rescue therapy for the treatment of seizure clusters

“…The proportion of patients without seizures in the 6 h posttreatment was higher in the midazolam group (54.8% vs. 38.7%), but the difference was not statistically significant ( p = .1972) compared with placebo. Safety for midazolam was generally comparable to placebo 46 …”

“…Safety for midazolam was generally comparable to placebo. 46 T A B L E 2 Characteristics of absorption-enhancing agents suitable for intranasal administration 39…”

“…A recent randomized, double‐blind, placebo‐controlled Phase 3 study of patients admitted to an epilepsy monitoring unit evaluated the efficacy and safety of IN midazolam in patients with epilepsy who had two or more seizures in the 6 h preceding the trial (31 patients each in the midazolam and placebo groups) 46 . The proportion of patients without seizures in the 6 h posttreatment was higher in the midazolam group (54.8% vs. 38.7%), but the difference was not statistically significant ( p = .1972) compared with placebo.…”

The Evaluation of the Efficacy and Safety of Midazolam Nasal Spray in Patients With Seizure Clusters: A Systematic Review and Meta-Analysis

“…Randomized controlled trials comparing the midazolam nasal spray with a placebo (consisting of the same inactive ingredients of MDZ-NS) have been conducted, and only two RCTs (Detyniecki et al [ 21 ] and Spencer et al [ 22 ]) are available yet present. It is a new emerging drug for SCs and has been recently approved only in the USA as a rescue medication.…”

Design of a Personalized Nasal Device (Matrix-Piston Nasal Device, MPD) for Drug Delivery: a 3D-Printing Application

“…Such non-invasive strategies gain greater acceptance by the physicians and patients. Since 2019, three nasal products have been approved for the management of epileptic seizures (midazolam, Nayzilam®; diazepam, Valtoco®) [ 1 , 2 ] and resistant depression (esketamine, Spravato®) [ 3 ].…”