Trial Outcomes & Findings for Study to Evaluate the Long-term Safety and Tolerability of USL261 in Patients With Seizure Clusters (NCT NCT01529034)
NCT ID: NCT01529034
Last Updated: 2023-01-20
Results Overview
Duration of participant study participation for collection of long term safety data
Recruitment status
TERMINATED
Study phase
PHASE3
Target enrollment
175 participants
Primary outcome timeframe
From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Results posted on
2023-01-20
Participant Flow
The participant flow refers to the enrolled population and includes participants who did not treat a seizure cluster episode.
Participant milestones
| Measure |
USL261
5 mg intranasal midazolam
USL261
|
|---|---|
|
Overall Study
STARTED
|
175
|
|
Overall Study
Exposed
|
161
|
|
Overall Study
COMPLETED
|
1
|
|
Overall Study
NOT COMPLETED
|
174
|
Reasons for withdrawal
| Measure |
USL261
5 mg intranasal midazolam
USL261
|
|---|---|
|
Overall Study
Discontinued prior to study treatment
|
14
|
|
Overall Study
Site closure
|
62
|
|
Overall Study
Study termination
|
29
|
|
Overall Study
Withdrawal by Subject
|
25
|
|
Overall Study
No treated SCs within protocol window
|
13
|
|
Overall Study
Noncompliance
|
8
|
|
Overall Study
Caregiver no longer available
|
7
|
|
Overall Study
Adverse Event
|
4
|
|
Overall Study
Protocol Violation
|
4
|
|
Overall Study
Lack of Efficacy
|
4
|
|
Overall Study
Investigator no longer available
|
2
|
|
Overall Study
Study drug not available
|
2
|
Baseline Characteristics
Height not reported for some participants
Baseline characteristics by cohort
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Age, Categorical
<=18 years
|
8 Participants
n=161 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
153 Participants
n=161 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=161 Participants
|
|
Age, Continuous
|
32.9 years
STANDARD_DEVIATION 11.96 • n=161 Participants
|
|
Sex: Female, Male
Female
|
80 Participants
n=161 Participants
|
|
Sex: Female, Male
Male
|
81 Participants
n=161 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
8 Participants
n=161 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
153 Participants
n=161 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=161 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
2 Participants
n=161 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=161 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=161 Participants
|
|
Race (NIH/OMB)
Black or African American
|
4 Participants
n=161 Participants
|
|
Race (NIH/OMB)
White
|
152 Participants
n=161 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=161 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
2 Participants
n=161 Participants
|
|
Region of Enrollment
Canada
|
1 participants
n=161 Participants
|
|
Region of Enrollment
Hungary
|
10 participants
n=161 Participants
|
|
Region of Enrollment
United States
|
56 participants
n=161 Participants
|
|
Region of Enrollment
Ukraine
|
53 participants
n=161 Participants
|
|
Region of Enrollment
Poland
|
12 participants
n=161 Participants
|
|
Region of Enrollment
Israel
|
5 participants
n=161 Participants
|
|
Region of Enrollment
Australia
|
12 participants
n=161 Participants
|
|
Region of Enrollment
Germany
|
7 participants
n=161 Participants
|
|
Region of Enrollment
Spain
|
5 participants
n=161 Participants
|
|
Body Mass Index
|
24.7 kg/m˄2
n=159 Participants • Height not reported for some participants
|
|
Seizure cluster episodes in year before Visit 1 in Study P261-401
|
18.0 seizure cluster episodes
n=161 Participants
|
|
Years had seizure cluster episodes prior to Study P261-401
|
5.00 years
n=157 Participants • Unknown or data entered as indefinite (eg \>3) for some participants
|
|
Typical number of seizures in seizure cluster episode
|
6.0 seizures
n=161 Participants
|
|
Typical duration of seizure cluster episode
|
1.00 hours
n=154 Participants • Non-numerical duration (eg "several" hours) reported for some participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5mg on study
Duration of participant study participation for collection of long term safety data
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Duration of Safety Observation
|
16.80 months
Interval 1.0 to 55.7
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
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.
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
SBP <85 mm Hg
|
0 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
SBP change from baseline ≥ 40 mm Hg
|
1 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
DBP <50 mm Hg
|
2 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
DBP change from baseline ≥ 30 mm Hg
|
3 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
Pulse rate <50 bpm
|
2 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
Pulse rate >120 bpm
|
1 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
Pulse rate change from baseline >/= 40 bpm
|
4 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
Caregiver recorded RR <8 brpm
|
1 Participants
|
|
Participants Meeting Predefined Safety Criteria for Vital Signs
Caregiver recorded RR >24 brpm
|
29 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
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)
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
ALT >ULN & ≤3xULN
|
26 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Albumin <30 g/L
|
2 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
ALP >2.5xULN
|
1 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
AST >ULN & ≤3xULN
|
17 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
AST >5x ULN & <20xULN
|
1 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Bicarbonate <15.9 mmol/L
|
6 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Cholesterol >7.75 mmol/L
|
5 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Creatinine >1.5xULN
|
1 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Creatinine >2x baseline
|
2 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
GGT >2.5xULN
|
14 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Glucose <3 mmol/L
|
3 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Glucose <8.9 mmol/L
|
5 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Phosphate <0.8 mmol/L
|
13 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Potassium >5.5 mmol/L
|
5 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Sodium <130 mmol/L
|
11 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Sodium >150 mmol/L
|
1 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Hemoglobin <100 g/L
|
5 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Hemoglobin decrease 20 g/L
|
10 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Leukocytes <3x10^9/L
|
4 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Lymphocytes <0.8x10^9/L
|
4 Participants
|
|
Participants With Laboratory Abnormalities Meeting Predefined Criteria
Neutrophils <1.5x10^9/L
|
8 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
Participants with abnormal findings, at any time post baseline, on physical examination considered clinically significant by the investigator.
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants With Clinically Significant Abnormalities Physical Examination
Skin
|
2 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Head/Eyes/Ears/Nose/Throat
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Neck
|
1 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Thyroid
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Lungs
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Heart
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Abdomen
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Lymph nodes
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities Physical Examination
Extremities
|
0 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
Participants with abnormal findings, at any time post baseline, on neurologic examination considered clinically significant by the investigator
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Mental status
|
10 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Cranial nerves II-XII
|
1 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Motor strength of limbs
|
2 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Deep tendon reflexes
|
2 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Sensory exam
|
1 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Station and gait
|
5 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Hopping
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Romberg test
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Finger-to-nose test
|
1 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Heel-to-shin test
|
1 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Rapid alternating movements
|
2 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Nystagmus
|
0 Participants
|
|
Participants With Clinically Significant Abnormalities on Neurologic Examination
Tremor/Other abnormal movements
|
0 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
Participants with abnormal findings, at any time post baseline, on nasal examination considered clinically significant by the investigator
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants With Clinically Significant Abnormalities on Nasal Examination
|
1 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: 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.
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.
Outcome measures
| Measure |
USL261
n=9 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participant Change in B-SIT Score
|
-0.6 score on a scale
Standard Deviation 1.2
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
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.
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Participants With Suicidal Ideation
Wish to be dead
|
3 Participants
|
|
Participants With Suicidal Ideation
Non-specific active
|
3 Participants
|
|
Participants With Suicidal Ideation
Active without specific plan
|
3 Participants
|
|
Participants With Suicidal Ideation
Active with specific plan/intent
|
1 Participants
|
|
Participants With Suicidal Ideation
Any suicidal ideation
|
4 Participants
|
PRIMARY outcome
Timeframe: From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.Population: Participants who received at least 1 dose of USL261 5 mg on study
Participants requiring emergency room (ER)/emergency medical service (EMS) visit within 24 hours after any USL261 treated seizure cluster (including for continued seizures)
Outcome measures
| Measure |
USL261
n=161 Participants
5 mg intranasal midazolam
USL261
|
|---|---|
|
Emergency Room/Emergency Medical Service Visits
|
20 Participants
|
SECONDARY outcome
Timeframe: 6 hours after first dose of USL261 for each treated seizure clusterPopulation: Seizure cluster episodes treated with first dose of USL261
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)
Outcome measures
| Measure |
USL261
n=1998 Seizure cluster episodes
5 mg intranasal midazolam
USL261
|
|---|---|
|
Number of Treated Seizure Clusters Meeting Criteria for Treatment Success
|
1108 Seizure cluster episodes
|
Adverse Events
USL261
Serious events: 8 serious events
Other events: 33 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
USL261
n=161 participants at risk
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
|
|---|---|
|
Nervous system disorders
Seizure cluster
|
1.2%
2/161 • Number of events 4 • 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.
|
|
Nervous system disorders
Convulsion
|
1.2%
2/161 • Number of events 3 • 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.
|
|
Nervous system disorders
Status epilepticus
|
1.2%
2/161 • Number of events 2 • 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.
|
|
Nervous system disorders
Epilepsy
|
0.62%
1/161 • Number of events 1 • 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.
|
|
Gastrointestinal disorders
Nausea
|
0.62%
1/161 • Number of events 1 • 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.
|
|
General disorders
Pyrexia
|
0.62%
1/161 • Number of events 1 • 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.
|
|
Investigations
Blood pressure increased
|
0.62%
1/161 • Number of events 1 • 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.
|
Other adverse events
| Measure |
USL261
n=161 participants at risk
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Nasal discomfort
|
12.4%
20/161 • Number of events 96 • 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.
|
|
Nervous system disorders
Somnolence
|
9.3%
15/161 • Number of events 92 • 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.
|
|
Nervous system disorders
Headache
|
6.2%
10/161 • Number of events 27 • 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.
|
Additional Information
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.
- Publication restrictions are in place
Restriction type: OTHER