Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients With Seizure Clusters

Study Overview
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Brief Summary
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The purpose of this study is to examine the safety and effectiveness of USL261 for the outpatient treatment of seizure clusters.

Detailed Description
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Qualifying participants underwent an in-clinic administration (Test Dose Phase [TDP]) of two doses of USL261 (intranasal midazolam 5 mg), separated by 10 minutes, in the absence of seizures. Eligible participants were then randomized to USL261 versus Placebo in an outpatient Comparative Phase (CP). When the participant had a qualifying seizure cluster episode, as described in an individualized patient management plan, the participant's caregiver administered the double-blind dose. An open-label USL261 dose could be administered after 10 minutes and up to 6 hours after the double-blind dose, if the participant had persistent or recurrent seizures. Initial participants could not proceed to CP until an independent data safety monitoring board (DSMB) reviewed safety data from at least the first 25 participants in TDP; the DSMB performed additional safety reviews at pre-set intervals based on enrollment.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects With Seizure Clusters. ARTEMIS-1: Acute Rescue Therapy in Epilepsy With Midazolam Intranasal Spray-1

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: USL261
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a competent, adult caregiver who can recognize and observe the subject's seizure cluster episodes Has an established diagnosis of partial or generalized epilepsy that includes the following: A documented history of seizure clusters lasting a minimum of 10 minutes Seizure cluster pattern is observable, stereotyped, and recognizably different from the subject's other non-cluster seizure activity (if any) A second seizure in the seizure cluster typically occurring within 6 hours from the time of cluster recognition A seizure cluster pattern composed of multiple (≥ 2) partial or generalized seizures A seizure cluster pattern established > 3 months before Visit 1 A frequency of ≥ 3 seizure clusters during the year before Visit 1 At least 1 seizure cluster occurring ≤ 4 months before Visit 1 Seizure cluster pattern is confirmed by a central reviewer Currently on a stable regimen of anti-epileptic drugs (AEDs) with no changes in type of AEDs since Visit 1 and for ≥ 7 days before Visit 2, with or without intermittent use of benzodiazepines at a constant dose Weight is 40 kg to 125 kg, inclusive Exclusion Criteria: Has a neurological disorder that is likely to progress in the next year Has severe chronic cardio-respiratory disease Has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1 Has a history of their stereotypical seizure cluster progressing to status epilepticus within the 2 years before Visit 1 Has a history of acute narrow-angle glaucoma. Has had active suicidal plan/intent or active suicidal thoughts in the 6 months before Visit 1 or a suicide attempt in the past 5 years Currently using a vagal nerve stimulator (VNS) unless the device has been implanted for at least 6 months and the setting stable for 4 weeks before Visit 1

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: USL261<br>intranasal midazolam 5mg | Drug: USL261<br> <br> * Other names: Midazolam nasal spray (MDZ NS);|
| Experimental: Placebo<br>Intranasal placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP) | Treatment Success is defined as achieving both of the following: 1) termination of seizure(s) within 10 minutes after double-blind study drug administration, and 2) no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after study drug administration. Participants who received the open-label second dose within 6 hours of administration of the double-blind dose were analyzed as having had a seizure. | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose | Participants with recurrence of seizure(s) >10 minutes and up to 4 hours after administration of the double-blind dose in the CP. Participants who received the open-label second dose within 4 hours of administration of the double-blind dose were analyzed as having had a seizure. | 4 hours | 
| Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | Occurrence of next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration. | 24 hours | 
| Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose | Time to next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, seizure clusters, acute repetitive seizures, rescue treatment, ARTEMIS