Trial Outcomes & Findings for Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients With Seizure Clusters (NCT NCT01390220)

Last Updated: 2019-10-10

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

292 participants

Primary outcome timeframe

6 hours

Results posted on

2019-10-10

Participant Flow

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.

Participant milestones

Participant milestones
Measure	USL261 TDP Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)	USL261 CP Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	Placebo CP Participants completing TDP who received placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)
Test Dose Phase STARTED	292	0	0
Test Dose Phase COMPLETED	201	0	0
Test Dose Phase NOT COMPLETED	91	0	0
Comparative Phase STARTED	0	134	67
Comparative Phase COMPLETED	0	133	67
Comparative Phase NOT COMPLETED	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	USL261 TDP Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)	USL261 CP Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)
Test Dose Phase Adverse Event	17	0
Test Dose Phase Withdrawal by Subject	8	0
Test Dose Phase Lost to Follow-up	2	0
Test Dose Phase Protocol Violation	8	0
Test Dose Phase No treated seizure cluster episode	37	0
Test Dose Phase Study/Site closure	6	0
Test Dose Phase Caregiver no longer available	5	0
Test Dose Phase Noncompliance	2	0
Test Dose Phase Logistical	6	0
Comparative Phase Withdrawal by Subject	0	1

Baseline Characteristics

Height not measurable in some patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	USL261 Test Dose n=292 Participants Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)
Age, Categorical <=18 years	18 Participants n=292 Participants
Age, Categorical Between 18 and 65 years	272 Participants n=292 Participants
Age, Categorical >=65 years	2 Participants n=292 Participants
Age, Continuous	31.5 years n=292 Participants
Sex: Female, Male Female	146 Participants n=292 Participants
Sex: Female, Male Male	146 Participants n=292 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants n=292 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	270 Participants n=292 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=292 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=292 Participants
Race (NIH/OMB) Asian	2 Participants n=292 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=292 Participants
Race (NIH/OMB) Black or African American	7 Participants n=292 Participants
Race (NIH/OMB) White	275 Participants n=292 Participants
Race (NIH/OMB) More than one race	0 Participants n=292 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=292 Participants
Region of Enrollment New Zealand	1 participants n=292 Participants
Region of Enrollment Canada	4 participants n=292 Participants
Region of Enrollment Hungary	18 participants n=292 Participants
Region of Enrollment United States	118 participants n=292 Participants
Region of Enrollment Ukraine	70 participants n=292 Participants
Region of Enrollment Poland	14 participants n=292 Participants
Region of Enrollment Italy	5 participants n=292 Participants
Region of Enrollment Israel	18 participants n=292 Participants
Region of Enrollment Australia	19 participants n=292 Participants
Region of Enrollment Germany	13 participants n=292 Participants
Region of Enrollment Spain	12 participants n=292 Participants
Body mass index	24.69 kg/m^2 n=287 Participants • Height not measurable in some patients
Seizure cluster episodes in year before Visit 1 of study	15 seizure cluster episodes n=292 Participants
Years had seizure cluster episodes prior to study	6.0 years n=283 Participants • Unknown or data entered as indefinite (eg \>3) for some participants
Typical number of seizures in seizure cluster episode	6.0 seizures n=291 Participants • Not reported for 1 subject
Typical duration of seizure cluster episode	67.5 minutes n=278 Participants • Non-numerical duration (eg "several" hours reported for some participants

PRIMARY outcome

Timeframe: 6 hours

Population: Randomized participants who received the double-blind dose in the CP.

Outcome measures

Outcome measures
Measure	USL261 CP n=134 Participants 5 mg intranasal midazolam USL261	Placebo CP n=67 Participants Intranasal placebo Placebo
Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP)	72 Participants	23 Participants

SECONDARY outcome

Timeframe: 4 hours

Population: Randomized participants who received the double-blind dose in the CP.

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.

Outcome measures

Outcome measures
Measure	USL261 CP n=134 Participants 5 mg intranasal midazolam USL261	Placebo CP n=67 Participants Intranasal placebo Placebo
Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose	51 Participants	40 Participants

SECONDARY outcome

Timeframe: 24 hours

Population: Randomized participants who received the double-blind dose in the CP.

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.

Outcome measures

Outcome measures
Measure	USL261 CP n=134 Participants 5 mg intranasal midazolam USL261	Placebo CP n=67 Participants Intranasal placebo Placebo
Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose	50 Participants	31 Participants

SECONDARY outcome

Timeframe: 24 hours

Population: Randomized participants who received the double-blind dose in the CP

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.

Outcome measures

Outcome measures
Measure	USL261 CP n=134 Participants 5 mg intranasal midazolam USL261	Placebo CP n=67 Participants Intranasal placebo Placebo
Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose	NA Hours Interval 17.9 to Median was not estimable as probability of no seizures through 24 hours was above 50%. Upper bound of 95% CI was not estimable.	12.1 Hours Interval 2.2 to Upper bound of 95% CI was not estimable.

Adverse Events

USL261 TDP

Serious events: 2 serious events

Other events: 78 other events

Deaths: 0 deaths

USL261 CP, USL261 5 mg Only

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

USL261 CP, USL261 5 mg + 5 mg

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Placebo CP, Placebo Only

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Placebo CP, Placebo + USL261 5 mg

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	USL261 TDP n=292 participants at risk Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)	USL261 CP, USL261 5 mg Only n=91 participants at risk Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	USL261 CP, USL261 5 mg + 5 mg n=43 participants at risk 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)	Placebo CP, Placebo Only n=26 participants at risk Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	Placebo CP, Placebo + USL261 5 mg n=41 participants at risk 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)
Nervous system disorders Sedation	0.34% 1/292 • Number of events 1 • 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.	0.00% 0/91 • 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.	0.00% 0/43 • 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.	0.00% 0/26 • 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.	0.00% 0/41 • 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.
Nervous system disorders Somnolence	0.34% 1/292 • Number of events 1 • 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.	0.00% 0/91 • 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.	0.00% 0/43 • 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.	0.00% 0/26 • 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.	0.00% 0/41 • 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.
Nervous system disorders Seizure cluster	0.00% 0/292 • 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.	0.00% 0/91 • 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.	0.00% 0/43 • 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.	0.00% 0/26 • 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.	2.4% 1/41 • Number of events 1 • 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.

Other adverse events

Other adverse events
Measure	USL261 TDP n=292 participants at risk Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)	USL261 CP, USL261 5 mg Only n=91 participants at risk Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	USL261 CP, USL261 5 mg + 5 mg n=43 participants at risk 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)	Placebo CP, Placebo Only n=26 participants at risk Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	Placebo CP, Placebo + USL261 5 mg n=41 participants at risk 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)
Respiratory, thoracic and mediastinal disorders Nasal discomfort	16.1% 47/292 • Number of events 61 • 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.	5.5% 5/91 • Number of events 5 • 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.	16.3% 7/43 • Number of events 8 • 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.	7.7% 2/26 • Number of events 2 • 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.	7.3% 3/41 • Number of events 3 • 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.
Respiratory, thoracic and mediastinal disorders Throat irritation	5.1% 15/292 • Number of events 15 • 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.	2.2% 2/91 • Number of events 2 • 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.	7.0% 3/43 • Number of events 3 • 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.	0.00% 0/26 • 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.	2.4% 1/41 • Number of events 1 • 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.
Nervous system disorders Somnolence	9.6% 28/292 • Number of events 30 • 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.	9.9% 9/91 • Number of events 9 • 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.	9.3% 4/43 • Number of events 4 • 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.	3.8% 1/26 • Number of events 1 • 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.	9.8% 4/41 • Number of events 4 • 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.
Eye disorders Lacrimation increased	6.8% 20/292 • Number of events 26 • 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.	1.1% 1/91 • Number of events 1 • 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.	2.3% 1/43 • Number of events 1 • 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.	0.00% 0/26 • 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.	2.4% 1/41 • Number of events 1 • 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.
General disorders Product taste abnormal	5.8% 17/292 • Number of events 19 • 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.	4.4% 4/91 • Number of events 4 • 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.	0.00% 0/43 • 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.	0.00% 0/26 • 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.	0.00% 0/41 • 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.
Nervous system disorders Headache	0.34% 1/292 • Number of events 1 • 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.	6.6% 6/91 • Number of events 6 • 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.	2.3% 1/43 • Number of events 1 • 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.	0.00% 0/26 • 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.	0.00% 0/41 • 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.

Additional Information

David Sequeira

Proximagen, LLC

Phone: 952-658-7438

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
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