Study to Evaluate the Long-term Safety and Tolerability of USL261 in Patients With Seizure Clusters

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to examine the long-term safety and tolerability of USL261 in the treatment of seizure clusters.

Detailed Description
-----------------
Participants who completed study P261-401 (NCT01390220), a randomized double-blind study of USL261 (intranasal midazolam) versus placebo to acutely treat a seizure cluster episode, were eligible to to enroll in this open-label extension study (P261-402). The participant's caregiver administered a USL261 5 milligram (mg) dose for a seizure episode meeting study criteria. A second USL261 5 mg dose could be administered after 10 minutes and up to 6 hours after the first dose for persistent or recurrent seizures, unless the participant met exclusions to administration of the second dose. A participant could have more than 1 seizure cluster episode treated during his/her study participation.

Official Title
-----------------
An Open-Label Safety Study of USL261 in the Outpatient Treatment of Subjects With Seizure Clusters

Conditions
-----------------
Epilepsy

Intervention / Treatment
-----------------
* Drug: USL261


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has a competent, adult caregiver who can recognize and observe the subject's seizure cluster episodes Has successfully completed study P261-401, and the subject and caregiver have demonstrated adequate compliance with P261-401 study procedures as determined by the investigator Exclusion Criteria: Has experienced status epilepticus during or since the P261-401 study In the opinion of the investigator, is experiencing an ongoing, uncontrolled, clinically significant adverse event(s) from P261-401 at Visit 1 or did experience a clinically significant adverse event in study P261-401 that might prevent the subject from safely participating in the study Has a neurological disorder that is likely to progress in the next year Has a history of acute narrow-angle glaucoma Has a medical condition including uncontrolled cardiac, pulmonary, renal, hepatic, or gastrointestinal disease that could interfere with the study, subject safety/safety monitoring, or is not stable despite current therapy Subject has severe chronic cardio-respiratory disease or the need for ambulatory oxygen Has had psychogenic, non-epileptic seizure(s) during or since the P261-401 study Has active suicidal plan or intent as determined by the C-SSRS at Visit 1 or medical history Subject has had vagus nerve stimulator (VNS) implanted since the completion of study P261-401

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: USL261<br>Intranasal midazolam 5 mg | Drug: USL261<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Safety Observation | Duration of participant study participation for collection of long term safety data | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants Meeting Predefined Safety Criteria for Vital Signs | Participants meeting predefined safety criteria for vital signs (systolic blood pressure [SBP] <85 mm Hg, SBP change from baseline >/= 40 mm Hg, diastolic BP [DBP] <50 mm Hg, DBP change from baseline >/=30 mm Hg, pulse rate <50 beats per minute (bpm), pulse rate >120 bpm, pulse rate change >/= 40 bpm at any visit post baseline or for caregiver recorded participant respiration rate [RR] <8 breaths per minute (brpm) or >24 brpm) after any USL261 treated seizure cluster episode. Abnormal vital signs were assessed separately by investigator and recorded as adverse events if applicable. | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants With Laboratory Abnormalities Meeting Predefined Criteria | Participants with abnormal laboratory finding, at any time post baseline, meeting predefined criteria. Abnormal laboratory findings were assessed separately by investigator and recorded as adverse events if applicable. Alanine aminotransferase (ALT); Alkaline phosphatase (ALP); Aspartate aminotransferase (AST); Gamma glutamyl transferase (GGT); upper limit of normal (ULN) | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants With Clinically Significant Abnormalities Physical Examination | Participants with abnormal findings, at any time post baseline, on physical examination considered clinically significant by the investigator. | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants With Clinically Significant Abnormalities on Neurologic Examination | Participants with abnormal findings, at any time post baseline, on neurologic examination considered clinically significant by the investigator | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants With Clinically Significant Abnormalities on Nasal Examination | Participants with abnormal findings, at any time post baseline, on nasal examination considered clinically significant by the investigator | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participant Change in B-SIT Score | Change in participant Brief Smell Identification Test (B-SIT) score from baseline to last visit with assessment. The B-SIT is a self-administered 12-item test; the score indicates odors correctly identified (0 to 12). The B-SIT was added while the study was already ongoing (Protocol Amendment 4, 20 May 2015) in response to a regulatory request. The test was only implemented at sites in the United States and included only participants considered by the investigator to have adequate cognitive ability to perform the test. Baseline was defined as the latest non-missing value prior to administration of USL261 in the Test Dose Phase of Study P261-401. | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Participants With Suicidal Ideation | Participants with suicidal ideation reported on Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire at any post-baseline visit. Responses including: Wish to be Dead; Non-Specific Active Suicidal Thoughts; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent; and Any Suicidal Ideation Regardless of Type. | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 
| Emergency Room/Emergency Medical Service Visits | Participants requiring emergency room (ER)/emergency medical service (EMS) visit within 24 hours after any USL261 treated seizure cluster (including for continued seizures) | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treated Seizure Clusters Meeting Criteria for Treatment Success | Number of Treated Seizure Clusters Meeting Criteria for Treatment Success: Termination of seizure(s) within 10 minutes and no recurrence within 6 hours after administration of first dose of USL261 (intranasal midazolam 5 mg) | 6 hours after first dose of USL261 for each treated seizure cluster | 

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