Most of the seizure clusters (SCs) occur outside a hospital, necessitating the immediate initiation of acute intervention to minimize adverse sequelae (including potentially life‐threatening status epilepticus). Intravenous benzodiazepines are the mainstay of treatment, but non-medical people cannot administer them to patients. Diazepam rectal gel also finds limited use due to physical and social constraints. Management of acute seizures thus remains a problem without a solution. Intranasal administration of midazolam is a feasible option for treatment of acute seizures in children.
To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single‐dose nasal spray (MDZ–NS) for the outpatient treatment of SCs in patients.
- Patients with epilepsy and a history of SCs (age ≥12 years)
- All patients were already on a stable regimen of antiepileptic drugs (AEDs)
- Acute Rescue Therapy in Epilepsy with Midazolam Intranasal Spray (ARTEMIS-1) was a phase III, randomized, double‐blind, placebo‐controlled trial
- Following an in‐clinic test dose phase (TDP; n=292), patients entered an outpatient comparative phase (CP; n=262)
- Two hundred and one patients randomized 2:1 to receive MDZ–NS 5 mg (n=134) or placebo nasal spray (n=67) were included in the modified intent-to-treat (mITT) analysis. The spray was to be administered by caregivers when the patient experienced an SC
- A six-month window was maintained for patients to receive double-blind treatment for a qualifying SC
- The double-blind dose was followed by an optional open-label MDZ-NS 5 mg if the cluster failed to terminate within 10 min or another seizure occurred up to 6 hours after initial drug administration
Primary Efficacy Outcome
- Treatment success, defined as; seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration
Secondary Efficacy Outcomes
- Proportion of patients with seizure recurrence 10 minutes to 4 hours after administration of trial drug
- Time‐to‐next seizure >10 minutes after double‐blind drug administration
- Treatment-emergent adverse events (TEAE)
- As per the miTT analysis, a significantly greater proportion of patients treated with MDZ–NS than placebo achieved treatment success (53.7% vs. 34.4%; P = 0.0109). The treatment success rate remained high for the MDZ-NS group vs. placebo group even in the sensitivity analysis (54.4% vs. 32.8%; p=0.0049) (figure1)
- With-respect to the component seizure(s), the termination occurred within 10 minutes in 80.6% of the MDZ–NS- treated patients vs. 70.1% of the placebo-treated patients
- Significantly higher proportion of patients treated with MDZ–NS rather than placebo remained seizure free starting 10 minutes and up to 6 hours after administration of trial drug (58.2% vs. 37.3%).
- Significantly lower proportion of patients treated with MDZ-NS rather than placebo experienced seizure recurrence 10 minutes up to 4 hours after administration of trial drug (38.1% vs. 59.7%; P = 0.0043)
- Time-to-next seizure after double-blind drug administration was significantly longer (P = 0.0124) in patients treated with MDZ-NS vs. placebo (25th percentile, 2.6 vs. 0.9 hours; 21% difference at 24 hours; P = 0.0124). Separation between MDZ–NS and placebo curves was evident from 30 minutes after double-blind administration.
- Fewer patients treated with MDZ-NS rather than placebo experienced recurrence of seizure within 24 hours of drug administration (37.3% vs. 46.3%)
- Fewer patients treated with MDZ-NS rather than placebo required administration of open-label dose (31.3% vs. 61.2%)
- Treatment discontinuation rate due to TEAE was 5.5% (n=16) during TDP but none discontinued the treatment due to TEAE during the CP.
- The incidence of at least 1TEAE during the CP was 27.6% and 22.4% for patients in the MDZ–NS and placebo groups, respectively.
- Treatment with MDZ–NS in the outpatient setting resulted in rapid and sustained seizure control in patients experiencing SCs
- MDZ-NS also had an acceptable safety profile, in patients as young as 12 years.
- MDZ–NS can potentially provide a solution for a critical unmet clinical need of acute treatment of SCs in outpatient setting.
Epilepsia. 2019 Sep;60(9):1797-1808.