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

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01529034

Enrollment

175

Registered

2012-02-08

Start date

2012-07-31

Completion date

Unknown

Last updated

2023-01-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Epilepsy

Keywords

Epilepsy, seizure clusters, acute repetitive seizures, rescue treatment

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.

Interventions

DRUGUSL261

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Emergency Room/Emergency Medical Service Visits	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	Participants requiring emergency room (ER)/emergency medical service (EMS) visit within 24 hours after any USL261 treated seizure cluster (including for continued seizures)
Duration of Safety Observation	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	Duration of participant study participation for collection of long term safety data
Participants Meeting Predefined Safety Criteria for Vital Signs	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 (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.
Participants With Laboratory Abnormalities Meeting Predefined Criteria	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	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)
Participants With Clinically Significant Abnormalities Physical Examination	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	Participants with abnormal findings, at any time post baseline, on physical examination considered clinically significant by the investigator.
Participants With Clinically Significant Abnormalities on Neurologic Examination	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	Participants with abnormal findings, at any time post baseline, on neurologic examination considered clinically significant by the investigator
Participants With Clinically Significant Abnormalities on Nasal Examination	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	Participants with abnormal findings, at any time post baseline, on nasal examination considered clinically significant by the investigator
Participant Change in B-SIT Score	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	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.
Participants With Suicidal Ideation	From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.	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.

Secondary

Measure	Time frame	Description
Number of Treated Seizure Clusters Meeting Criteria for Treatment Success	6 hours after first dose of USL261 for each treated seizure cluster	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)

Countries

Australia, Canada, Germany, Hungary, Israel, New Zealand, Poland, Spain, Ukraine, United States

Participant flow

Pre-assignment details

The participant flow refers to the enrolled population and includes participants who did not treat a seizure cluster episode.

Participants by arm

Arm	Count
USL261 5 mg intranasal midazolam USL261	161
Total	161

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	4
Overall Study	Caregiver no longer available	7
Overall Study	Discontinued prior to study treatment	14
Overall Study	Investigator no longer available	2
Overall Study	Lack of Efficacy	4
Overall Study	Noncompliance	8
Overall Study	No treated SCs within protocol window	13
Overall Study	Protocol Violation	4
Overall Study	Site closure	62
Overall Study	Study drug not available	2
Overall Study	Study termination	29
Overall Study	Withdrawal by Subject	25

Baseline characteristics

Characteristic	USL261
Age, Categorical <=18 years	8 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	153 Participants
Age, Continuous	32.9 years STANDARD_DEVIATION 11.96
Body Mass Index	24.7 kg/m˄2
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	153 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	4 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	152 Participants
Region of Enrollment Australia	12 participants
Region of Enrollment Canada	1 participants
Region of Enrollment Germany	7 participants
Region of Enrollment Hungary	10 participants
Region of Enrollment Israel	5 participants
Region of Enrollment Poland	12 participants
Region of Enrollment Spain	5 participants
Region of Enrollment Ukraine	53 participants
Region of Enrollment United States	56 participants
Seizure cluster episodes in year before Visit 1 in Study P261-401	18.0 seizure cluster episodes
Sex: Female, Male Female	80 Participants
Sex: Female, Male Male	81 Participants
Typical duration of seizure cluster episode	1.00 hours
Typical number of seizures in seizure cluster episode	6.0 seizures
Years had seizure cluster episodes prior to Study P261-401	5.00 years

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 161
other Total, other adverse events	33 / 161
serious Total, serious adverse events	8 / 161