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

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.

Keywords: acute intervention; acute repetitive seizures; benzodiazepine; epilepsy; intranasal; rescue.

Figure 1

Trial design. At screening, each patient's individualized patient management plan (PMP) was reviewed by a member of the Epilepsy Study Consortium who determined whether the cluster description met the protocol definition and provided final approval for trial participation. A review of safety data from at least the first 25 patients who completed the TDP was required before patients could progress to the CP. The review was conducted by an independent Data and Safety Monitoring Board (DSMB), as were further reviews at periodic intervals during the trial. MDZ–NS, midazolam nasal spray

Figure 2

Patient disposition over the course of the trial and analysis populations. DB, double‐blind; MDZ–NS, midazolam nasal spray; mITT, modified intent‐to‐treat; OL, open‐label ^aOther reasons for discontinuation included: patient did not experience/treat seizure cluster(s) according to trial criteria within protocol‐specified time period; caregiver no longer available; trial drug unavailable at site; patient/caregiver unable to comply with trial procedures/visits; trial terminated; site closure ^bOne patient received treatment in the CP and had postdose efficacy assessments, but subsequently withdrew consent before completing procedures at visit 4

Figure 3

Secondary efficacy outcome: probability of experiencing no seizures over the 24‐hour observation period after 10 minutes of double‐blind trial drug administration based on a Kaplan‐Meier analysis of time‐to‐next seizure in the modified intent‐to‐treat population. Patients who did not have another seizure before the end of the 24‐hour observation period, and who had not been administered the second dose of trial drug, were censored at the end of the observation period. Those administered the second dose of trial drug who did not have a seizure before the administration of the second dose were censored at the time of the second dose