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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-004109-25 | EudraCT Number |
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The purpose of this study is to examine the long-term safety and tolerability of USL261 in the treatment of seizure clusters.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| USL261 | Experimental | Intranasal midazolam 5 mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| USL261 | Drug |
|
| 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. |
| 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 |
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Inclusion Criteria:
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 | Result | 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. | |
| 31353457 | Derived |
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The participant flow refers to the enrolled population and includes participants who did not treat a seizure cluster episode.
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| ID | Title | Description |
|---|---|---|
| FG000 | USL261 | 5 mg intranasal midazolam USL261 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
| 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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| 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. |
| Scottsdale |
| Arizona |
| United States |
| United States, Arizona | Tucson | Arizona | United States |
| United States, Arkansas | Little Rock | Arkansas | United States |
| United States, California | Fresno | 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 | Port Charlotte | 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, 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 | St Louis | Missouri | United States |
| United States, New Hampshire | Lebanon | New Hampshire | 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, Oklahoma | Oklahoma City | Oklahoma | 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 | Greenville | Texas | United States |
| Australia, New South Wales | Randwick | New South Wales | Australia |
| Australia, Victoria | Heidelberg West | Victoria | Australia |
| Australia, Victoria | Parkville | Victoria | Australia |
| Canada | Montreal | Ontario | Canada |
| Canada, Toronto | Toronto | Ontario | Canada |
| Canada | Toronto | Quebec | Canada |
| Germany | München | Bavaria | Germany |
| Germany | Marberg | Hesse | Germany |
| Germany | Bonn | North Rhine-Westphalia | Germany |
| Germany | Bielefeld | Westfalen-Lippe | Germany |
| Hungary | Budapest | Hungary |
| Israel | Haifa | Israel |
| Israel | Petah Tikvah | Israel |
| Israel | Ramat Gan | Israel |
| New Zealand | Christchurch | Canterbury | New Zealand |
| Poland | Gdansk | Poland |
| Poland | Katowice | Poland |
| Poland | Lublin | Poland |
| Spain | Seville | Andalusia | Spain |
| Spain | Girona | Cataluyna | Spain |
| Spain | Madrid | Spain |
| Ukraine | Ivano-Frankivsk | Ukraine |
| Ukraine | Kharkiv | Ukraine |
| Ukraine | Odesa | Ukraine |
| Ukraine | Poltava | Ukraine |
| Ukraine | Ternopil | Ukraine |
| Ukraine | Vinnytsa | Ukraine |
| 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. |
| Exposed |
|
| COMPLETED |
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| NOT COMPLETED |
|
|
Participants exposed to at least 1 dose of USL261
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| ID | Title | Description |
|---|---|---|
| BG000 | USL261 | 5 mg intranasal midazolam USL261 |
| 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 | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Participant in Race unknown category reported race as "Slavic" | Count of Participants | Participants |
| |||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||||
| Body Mass Index | Height not reported for some participants | Median | Full Range | kg/m˄2 |
| ||||||||||||||||
| Seizure cluster episodes in year before Visit 1 in Study P261-401 | Median | Full Range | seizure cluster episodes |
| |||||||||||||||||
| Years had seizure cluster episodes prior to Study P261-401 | Unknown or data entered as indefinite (eg >3) for some participants | Median | Full Range | years |
| ||||||||||||||||
| Typical number of seizures in seizure cluster episode | Median | Full Range | seizures |
| |||||||||||||||||
| Typical duration of seizure cluster episode | Non-numerical duration (eg "several" hours) reported for some participants | Median | Full Range | hours |
|
| 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 | Duration of Safety Observation | Duration of participant study participation for collection of long term safety data | Participants who received at least 1 dose of USL261 5mg on study | Posted | Median | Full Range | months | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
|
| |||||||||||||||||||||||||
| Primary | 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. | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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) | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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. | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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 | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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 | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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. | Participants who received at least 1 dose of USL261 5 mg on study, had a baseline B-SIT in Study P261-401, and a post-baseline B-SIT in Study P261-402. | Posted | Mean | Standard Deviation | score on a scale | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| ||||||||||||||||||||||||||
| Primary | 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. | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Primary | 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) | Participants who received at least 1 dose of USL261 5 mg on study | Posted | Count of Participants | Participants | From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study. |
|
| |||||||||||||||||||||||||||
| Secondary | 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) | Seizure cluster episodes treated with first dose of USL261 | Posted | Count of Units | Seizure cluster episodes | 6 hours after first dose of USL261 for each treated seizure cluster | Seizure cluster episodes | Seizure cluster episodes |
|
|
Original protocol - each participant 2 years from enrollment; Amended protocol - each participant open-ended from enrollment (up to 4 years or longer as approved by Health Authority where study being conducted). Actual individual participant duration 1.0 to 55.7 months.
Adverse events collected at each visit from participant and/or caregiver. Due to intermittent treatment (qualifying seizure clusters), short systemic half-life of active (midazolam), and long participant duration, treatment emergent adverse event within 2 days after each treated seizure cluster are reported. Seizures were not considered adverse events unless worsening from underlying condition.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | USL261 | USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode | 0 | 161 | 8 | 161 | 33 | 161 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure cluster | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Convulsion | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Status epilepticus | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Epilepsy | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Blood pressure increased | Investigations | MedDRA 16.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasal discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
|
Open-label, non-comparative design. Potential participation bias due to participants and/or caregiver perceived efficacy/safety in prior study. Seizure data capture in diaries diminished over time in some participants due to length of study.
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 | May 15, 2017 | May 9, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
Not provided
Not provided
| >=65 years |
|
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
| United States |
|
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| Ukraine |
|
|
| Poland |
|
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| Israel |
|
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| Australia |
|
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| Germany |
|
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| Spain |
|
|
|
|
|
|
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| Seizure cluster episodes |
|
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