Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients With Seizure Clusters (ARTEMIS1)

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

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

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 292
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Chatswood, New South Wales, Australia
      • Australia, New South Wales
    • Randwick, New South Wales, Australia
      • Australia, New South Wales
  • Queensland
    • Herston, Queensland, Australia
      • Australia, Queensland
  • Victoria
    • Heidelberg West, Victoria, Australia
      • Australia, Vctoria
    • Parkville, Victoria, Australia
      • Australia, Victoria
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Canada, Ontario
  • Quebec
    • Montreal, Quebec, Canada
      • Canada, Quebec
• Germany
  • Baden-Wurttemberg
    • Freiburg, Baden-Wurttemberg, Germany
      • Germany, Baden-Wurttemberg
  • Bayern
    • Munich, Bayern, Germany
      • Germany, Bayern
  • Hessen
    • Marburg, Hessen, Germany
      • Germany, Hessen
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany
      • Germany, Nordrhein-Westfalen
  • Wetsfalen-Lippe
    • Bielefeld, Wetsfalen-Lippe, Germany
      • Germany, Westfalen-Lippe
• Hungary
  • Budapest, Hungary
    • Hungary
  • Kazincbarcika, Hungary
    • Hungary
• Israel
  • Haifa, Israel
    • ISRAEL
  • Holon, Israel
    • ISRAEL
  • Jerusalem, Israel
    • ISRAEL
  • Petach Tikva, Israel
    • ISRAEL
  • Ramat Gan, Israel
    • ISRAEL
  • Tel Aviv, Israel
    • ISRAEL
• Italy
  • Firenze, Italy
    • Italy
  • Genova, Italy
    • Italy
  • Milano, Italy
    • Italy
  • Napoli, Italy
    • Italy
  • Pavia, Italy
    • Italy
  • San Fermo della Battaglia, Italy
    • Italy
• New Zealand
  • Auklund
    • Grafton, Auklund, New Zealand
      • New Zealand, Auklund
  • Canterbury
    • Christchurch, Canterbury, New Zealand
      • New Zealand, Canterbury
• Poland
  • Gdansk, Poland
    • Poland
  • Katowice, Poland
    • Poland
  • Krakow, Poland
    • Poland
  • Olsztyn, Poland
    • Poland
• Spain
  • Andalucia
    • Sevilla, Andalucia, Spain
      • Spain, Andalucia
  • Catalonia
    • Barcelona, Catalonia, Spain
      • Spain, Catalonia
    • Girona, Catalonia, Spain
      • Spain, Catalonia
  • Madrid
    • Fuencarral-El Pardo, Madrid, Spain
      • Spain, Madrid
    • Moncloa-Aravaca, Madrid, Spain
      • Spain, Madrid
    • Pozuelo De Alarcón, Madrid, Spain
      • Spain, Madrid
• Ukraine
  • Ivano-Frankivsk, Ukraine
    • Ukraine, Ivano-Frankivsk
  • Kharkiv, Ukraine
    • Ukraine
  • Odessa, Ukraine
    • Ukraine
  • Poltava, Ukraine
    • Ukraine
  • Ternopil, Ukraine
    • Ukraine
  • Vinnytsya, Ukraine
    • Ukraine
• United States
  • Arizona
    • Phoenix, 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
    • Irvine, California, United States
      • United States, California
    • Loma Linda, 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
    • Gainesville, Florida, United States
      • United States, Florida
    • Gulf Breeze, Florida, United States
      • United States, Florida
    • Port Charlotte, Florida, United States
      • United States, Florida
    • Tampa, 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
  • Kansas
    • Manhattan, Kansas, United States
      • United States, Kansas
  • 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
    • Chesterfield, Missouri, United States
      • United States, Missouri
    • Saint Louis, Missouri, United States
      • United States, Missouri
  • Nevada
    • Reno, Nevada, United States
      • United States, Nevada
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • United States, New Hampshire
  • New Jersey
    • Flemington, New Jersey, United States
      • United States, 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
  • Ohio
    • Columbus, Ohio, United States
      • United States, Ohio
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • United States, Oklahoma
  • Oregon
    • Portland, Oregon, United States
      • United States, Oregon
  • 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
    • Fort Worth, Texas, United States
      • United States, Texas
    • Greenville, Texas, United States
      • United States, Texas
    • San Antonio, Texas, United States
      • United States, Texas
    • Temple, Texas, United States
      • United States, Texas
  • Virginia
    • Norfolk, Virginia, United States
      • United States, Virginia
  • Wisconsin
    • Madison, Wisconsin, United States
      • United States, Wisconsin

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: USL261; intranasal midazolam 5mg	Drug: USL261; Other Names: Midazolam nasal spray (MDZ NS)
Experimental: Placebo; Intranasal placebo	Drug: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UCB Biopharma S.P.R.L.

Publications and helpful links

General Publications

• Detyniecki K, Van Ess PJ, Sequeira DJ, Wheless JW, Meng TC, Pullman WE. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial. Epilepsia. 2019 Sep;60(9):1797-1808. doi: 10.1111/epi.15159. Epub 2019 May 29.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2011
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: July 6, 2011
• First Submitted That Met QC Criteria: July 7, 2011
• First Posted (Estimate): July 8, 2011

Study Record Updates

• Last Update Posted (Actual): October 10, 2019
• Last Update Submitted That Met QC Criteria: October 8, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Epilepsy; seizure clusters; acute repetitive seizures; rescue treatment; ARTEMIS
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: P261-401; 2011-001318-32 (EudraCT Number)

Plan for Individual participant data (IPD)

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