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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-001318-32 | EudraCT Number |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| USL261 | Experimental | intranasal midazolam 5mg |
|
| Placebo | Experimental | Intranasal placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| USL261 | Drug |
|
| |
| Placebo |
| 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 |
| 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 |
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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:
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:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| United States, Arizona | Phoenix | Arizona | United States | |||
| United States, Arizona |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36410152 | Derived | 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. | |
| 31140596 |
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Participants underwent in-clinic administration of open-label USL261 5 mg followed by USL261 5 mg 10 minutes in absence of a seizure (Test Dose Phase [TDP]). Participants were then randomized to double-blind USL261 5 mg or Placebo to be administered by caregiver to treat a seizure cluster in Comparative Phase (CP) in the outpatient setting.
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| ID | Title | Description |
|---|---|---|
| FG000 | USL261 TDP | Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP) |
| FG001 | USL261 CP | Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Test Dose Phase |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 20, 2015 | May 9, 2019 |
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| Drug |
|
| 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 |
| Tucson |
| Arizona |
| United States |
| United States, Arkansas | Little Rock | Arkansas | United States |
| United States, 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, Colorado | Aurora | Colorado | United States |
| United States, Connecticut | New Haven | Connecticut | United States |
| United States, 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, Idaho | Boise | Idaho | United States |
| United States, Illinois | Chicago | Illinois | United States |
| United States, Kansas | Manhattan | Kansas | United States |
| United States, Kentucky | Lexington | Kentucky | United States |
| United States, Maryland | Baltimore | Maryland | United States |
| United States, Michigan | Detroit | Michigan | United States |
| United States, Minnesota | Saint Paul | Minnesota | United States |
| United States, Missouri | Chesterfield | Missouri | United States |
| United States, Missouri | St Louis | Missouri | United States |
| United States, Nevada | Reno | Nevada | United States |
| United States, New Hampshire | Lebanon | New Hampshire | United States |
| United States, New Jersey | Flemington | New Jersey | United States |
| United States, New Jersey | Hackensack | New Jersey | 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 | The Bronx | New York | United States |
| United States, North Carolina | Durham | North Carolina | United States |
| United States, North Carolina | Winston-Salem | North Carolina | United States |
| United States, Ohio | Columbus | Ohio | United States |
| United States, Oklahoma | Oklahoma City | Oklahoma | United States |
| United States, Oregon | Portland | Oregon | United States |
| United States, Pennsylvania | Philadelphia | Pennsylvania | United States |
| United States, Tennessee | Memphis | Tennessee | United States |
| United States, Tennessee | Nashville | Tennessee | United States |
| United States, 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, Virginia | Norfolk | Virginia | United States |
| United States, Wisconsin | Madison | Wisconsin | United States |
| Australia, New South Wales | Chatswood | New South Wales | Australia |
| Australia, New South Wales | Randwick | New South Wales | Australia |
| Australia, Queensland | Herston | Queensland | Australia |
| Australia, Vctoria | Heidelberg West | Victoria | Australia |
| Australia, Victoria | Parkville | Victoria | Australia |
| Canada, Ontario | Toronto | Ontario | Canada |
| Canada, Quebec | Montreal | Quebec | Canada |
| Germany, Baden-Wurttemberg | Freiburg im Breisgau | Baden-Wurttemberg | Germany |
| Germany, Bayern | Munich | Bavaria | Germany |
| Germany, Hessen | Marburg | Hesse | Germany |
| Germany, Nordrhein-Westfalen | Bonn | North Rhine-Westphalia | Germany |
| Germany, Westfalen-Lippe | Bielefeld | Wetsfalen-Lippe | Germany |
| Hungary | Budapest | Hungary |
| Hungary | Kazincbarcika | Hungary |
| Israel | Haifa | Israel |
| Israel | Holon | Israel |
| Israel | Jerusalem | Israel |
| Israel | Petah Tikva | Israel |
| Israel | Ramat Gan | Israel |
| Israel | Tel Aviv | Israel |
| Italy | Florence | Italy |
| Italy | Genova | Italy |
| Italy | Milan | Italy |
| Italy | Naples | Italy |
| Italy | Pavia | Italy |
| Italy | San Fermo della Battaglia | Italy |
| New Zealand, Auklund | Grafton | Auklund | New Zealand |
| New Zealand, Canterbury | Christchurch | Canterbury | New Zealand |
| Poland | Gdansk | Poland |
| Poland | Katowice | Poland |
| Poland | Krakow | Poland |
| Poland | Olsztyn | Poland |
| Spain, Andalucia | Seville | Andalusia | Spain |
| Spain, Catalonia | Barcelona | Catalonia | Spain |
| Spain, Catalonia | Girona | Catalonia | Spain |
| Spain, Madrid | Fuencarral-El Pardo | Madrid | Spain |
| Spain, Madrid | Moncloa-Aravaca | Madrid | Spain |
| Spain, Madrid | Pozuelo de Alarcón | Madrid | Spain |
| Ukraine, Ivano-Frankivsk | Ivano-Frankivsk | Ukraine |
| Ukraine | Kharkiv | Ukraine |
| Ukraine | Odesa | Ukraine |
| Ukraine | Poltava | Ukraine |
| Ukraine | Ternopil | Ukraine |
| Ukraine | Vinnytsia | Ukraine |
| 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. |
| FG002 | Placebo CP | Participants completing TDP who received placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP) |
| COMPLETED |
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| NOT COMPLETED |
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| Comparative Phase |
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USL261 Test Dose: All patients receiving at least 1 dose of USL261 5 mg in TDP.
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| ID | Title | Description |
|---|---|---|
| BG000 | USL261 Test Dose | Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Median | Full Range | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Self reported. Unknown or not reported includes Other, eg. "Slavic". | Count of Participants | Participants |
| |||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||||
| Body mass index | Height not measurable in some patients | Median | Full Range | kg/m^2 |
| ||||||||||||||||
| Seizure cluster episodes in year before Visit 1 of study | Median | Full Range | seizure cluster episodes |
| |||||||||||||||||
| Years had seizure cluster episodes prior to study | Unknown or data entered as indefinite (eg >3) for some participants | Median | Full Range | years |
| ||||||||||||||||
| Typical number of seizures in seizure cluster episode | Not reported for 1 subject | Median | Full Range | seizures |
| ||||||||||||||||
| Typical duration of seizure cluster episode | Non-numerical duration (eg "several" hours reported for some participants | Median | Full Range | minutes |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Randomized participants who received the double-blind dose in the CP. | Posted | Count of Participants | Participants | 6 hours |
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| Secondary | 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. | Randomized participants who received the double-blind dose in the CP. | Posted | Count of Participants | Participants | 4 hours |
|
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| Secondary | 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. | Randomized participants who received the double-blind dose in the CP. | Posted | Count of Participants | Participants | 24 hours |
|
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| Secondary | 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. | Randomized participants who received the double-blind dose in the CP | Posted | Median | 95% Confidence Interval | Hours | 24 hours |
|
|
Treatment emergent adverse events (TEAEs) collected from administration of first open-label dose of USL261 5 mg in Test Dose Phase (TDP) until completion of the final study visit or 7 days after the last administration of study drug, whichever was later. The duration of individual participant participation was variable as administration of the double-blind dose in the Comparative Phase (CP) was dependent on occurrence of a seizure cluster episode meeting trial criteria after randomization.
Adverse events collected at each visit from participant and/or caregiver. TEAEs presented for TDP and CP separately. Due to the short systemic half-life of active (midazolam), TEAEs within 2 days after administration of first open-label USL261 5 mg dose presented for TDP, and within 2 days after administration of double-blind dose for CP.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | USL261 TDP | Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP) | 0 | 292 | 2 | 292 | 78 | 292 |
| EG001 | USL261 CP, USL261 5 mg Only | Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP) | 0 | 91 | 0 | 91 | 17 | 91 |
| EG002 | USL261 CP, USL261 5 mg + 5 mg | Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode and received an open-label USL261 5 mg dose in the Comparative Phase (CP) | 0 | 43 | 0 | 43 | 10 | 43 |
| EG003 | Placebo CP, Placebo Only | Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP) | 0 | 26 | 0 | 26 | 3 | 26 |
| EG004 | Placebo CP, Placebo + USL261 5 mg | Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode and received an open-label USL261 5 mg dose in the Comparative Phase (CP) | 0 | 41 | 1 | 41 | 7 | 41 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sedation | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Seizure cluster | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasal discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Lacrimation increased | Eye disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Product taste abnormal | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
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A manuscript or abstract should not be submitted by investigator(s) for publication or presentation until a New Drug Application is approved by the US FDA or permission is granted in writing by sponsor.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Sequeira | Proximagen, LLC | 952-658-7438 | dsequeira@proximagen.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 14, 2017 | May 9, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D004827 | Epilepsy |
| C537589 | Severe combined immunodeficiency with sensitivity to ionizing radiation |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| >=65 years |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Hungary |
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| United States |
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| Ukraine |
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| Poland |
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| Italy |
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| Israel |
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| Australia |
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| Germany |
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| Spain |
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