Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters—a randomized, double-blind, placebo-controlled trial

Kamil Detyniecki, Peter J. Van Ess, David J. Sequeira, James W. Wheless, Tze Chiang Meng, William E. Pullman

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Objective: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ–NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). Methods: This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age ≥12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ–NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout. Results: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ–NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ–NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ–NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ–NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ–NS and placebo groups, respectively, experienced ≥1 TEAE. Significance: MDZ–NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile.

Original languageEnglish (US)
Pages (from-to)1797-1808
Number of pages12
JournalEpilepsia
Volume60
Issue number9
DOIs
StatePublished - Sep 1 2019
Externally publishedYes

Keywords

  • acute intervention
  • acute repetitive seizures
  • benzodiazepine
  • epilepsy
  • intranasal
  • rescue

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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