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

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

Study Overview

• Status: Terminated
• Conditions: Epilepsy
• Intervention / Treatment: Drug: USL261

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.

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia
      • Australia, New South Wales
  • Victoria
    • Heidelberg west, Victoria, Australia
      • Australia, Victoria
    • Parkville, Victoria, Australia
      • Australia, Victoria
• Canada
  • Ontario
    • Montreal, Ontario, Canada
      • Canada
    • Toronto, Ontario, Canada
      • Canada, Toronto
  • Quebec
    • Toronto, Quebec, Canada
      • Canada
• Germany
  • Bayern
    • Munchen, Bayern, Germany
      • Germany
  • Hessen
    • Marberg, Hessen, Germany
      • Germany
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany
      • Germany
  • Westfalen-Lippe
    • Bielefeld, Westfalen-Lippe, Germany
      • Germany
• Hungary
  • Budapest, Hungary
    • Hungary
• Israel
  • Haifa, Israel
    • ISRAEL
  • Petah Tikvah, Israel
    • ISRAEL
  • Ramat Gan, Israel
    • ISRAEL
• New Zealand
  • Canterbury
    • Christchurch, Canterbury, New Zealand
      • New Zealand
• Poland
  • Gdansk, Poland
    • Poland
  • Katowice, Poland
    • Poland
  • Lublin, Poland
    • Poland
• Spain
  • Madrid, Spain
    • Spain
  • Andalucia
    • Sevilla, Andalucia, Spain
      • Spain
  • Cataluyna
    • Gerona, Cataluyna, Spain
      • Spain
• Ukraine
  • Ivano-Frankivsk, Ukraine
    • Ukraine
  • Kharkiv, Ukraine
    • Ukraine
  • Odessa, Ukraine
    • Ukraine
  • Poltava, Ukraine
    • Ukraine
  • Ternopil, Ukraine
    • Ukraine
  • Vinnytsa, Ukraine
    • Ukraine
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • United States, Arizona
    • Scottsdale, Arizona, United States
      • United States, Arizona
    • Tucson, Arizona, United States
      • United States, Arizona
  • Arkansas
    • Little Rock, Arkansas, United States
      • United States, Arkansas
  • California
    • Fresno, California, United States
      • United States, California
    • Sacramento, California, United States
      • United States, California
    • Ventura, California, United States
      • United States, California
  • Colorado
    • Aurora, Colorado, United States
      • United States, Colorado
  • Connecticut
    • New Haven, Connecticut, United States
      • United States, Connecticut
  • Florida
    • Port Charlotte, Florida, United States
      • United States, Florida
    • Wellington, Florida, United States
      • United States, Florida
  • Idaho
    • Boise, Idaho, United States
      • United States, Idaho
  • Illinois
    • Chicago, Illinois, United States
      • United States, Illinois
  • Kentucky
    • Lexington, Kentucky, United States
      • United States, Kentucky
  • Maryland
    • Baltimore, Maryland, United States
      • United States, Maryland
  • Michigan
    • Detroit, Michigan, United States
      • United States, Michigan
  • Minnesota
    • Saint Paul, Minnesota, United States
      • United States, Minnesota
  • Missouri
    • Saint Louis, Missouri, United States
      • United States, Missouri
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • United States, New Hampshire
  • New Jersey
    • Hackensack, New Jersey, United States
      • United States, New Jersey
  • New York
    • Bronx, New York, United States
      • United States, New York
    • New York, New York, United States
      • United States, New York
    • Stony Brook, New York, United States
      • United States, New York
  • North Carolina
    • Durham, North Carolina, United States
      • United States, North Carolina
    • Winston-Salem, North Carolina, United States
      • United States, North Carolina
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • United States, Oklahoma
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • United States, Pennsylvania
  • Tennessee
    • Memphis, Tennessee, United States
      • United States, Tennessee
    • Nashville, Tennessee, United States
      • United States, Tennessee
  • Texas
    • Dallas, Texas, United States
      • United States, Texas
    • Greenville, Texas, United States
      • United States, Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: USL261; Intranasal midazolam 5 mg	Drug: USL261

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

Collaborators and Investigators

• Sponsor: UCB Biopharma S.P.R.L.

Publications and helpful links

General Publications

• Meng TC, Szaflarski JP, Chen L, Brunnert M, Campos R, Van Ess P, Pullman WE, Fakhoury T. Psychosocial outcomes of repeated treatment of seizure clusters with midazolam nasal spray: Results of a phase 3, open-label extension trial. Epilepsy Behav. 2023 Jan;138:108989. doi: 10.1016/j.yebeh.2022.108989. Epub 2022 Nov 18.
• Wheless JW, Meng TC, Van Ess PJ, Detyniecki K, Sequeira DJ, Pullman WE. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open-label extension trial. Epilepsia. 2019 Sep;60(9):1809-1819. doi: 10.1111/epi.16300. Epub 2019 Jul 29.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2012
• Primary Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: February 3, 2012
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (Estimate): February 8, 2012

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: January 19, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Epilepsy; seizure clusters; acute repetitive seizures; rescue treatment
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures
• Other Study ID Numbers: P261-402; 2011-004109-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No