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Study to Evaluate the Long-term Safety and Tolerability of USL261 in Patients With Seizure Clusters

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ClinicalTrials.gov Identifier: NCT01529034
Recruitment Status : Terminated
First Posted : February 8, 2012
Results First Posted : June 25, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Proximagen, LLC

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Epilepsy
Intervention Drug: USL261
Enrollment 175
Recruitment Details  
Pre-assignment Details The participant flow refers to the enrolled population and includes participants who did not treat a seizure cluster episode.
Arm/Group Title USL261
Hide Arm/Group Description

5 mg intranasal midazolam

USL261

Period Title: Overall Study
Started 175 [1]
Exposed 161 [2]
Completed 1 [3]
Not Completed 174
Reason Not Completed
Discontinued prior to study treatment             14
Site closure             62
Study termination             29
Withdrawal by Subject             25
No treated SCs within protocol window             13
Noncompliance             8
Caregiver no longer available             7
Adverse Event             4
Protocol Violation             4
Lack of Efficacy             4
Caregiver not available             2
Study drug not available             2
[1]
Completed Study P261-401 and rolled over to Study P261-402
[2]
Treated at least 1 seizure cluster with USL261
[3]
Completed under initial protocol duration of 2 years; amended protocol open-ended duration
Arm/Group Title USL261
Hide Arm/Group Description

5 mg intranasal midazolam

USL261

Overall Number of Baseline Participants 161
Hide Baseline Analysis Population Description
Participants exposed to at least 1 dose of USL261
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 161 participants
<=18 years
8
   5.0%
Between 18 and 65 years
153
  95.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 161 participants
32.9  (11.96)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 161 participants
Female
80
  49.7%
Male
81
  50.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 161 participants
Hispanic or Latino
8
   5.0%
Not Hispanic or Latino
153
  95.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 161 participants
American Indian or Alaska Native
2
   1.2%
Asian
1
   0.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
4
   2.5%
White
152
  94.4%
More than one race
0
   0.0%
Unknown or Not Reported
2
   1.2%
[1]
Measure Description: Participant in Race unknown category reported race as "Slavic"
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Canada Number Analyzed 161 participants
1
Hungary Number Analyzed 161 participants
10
United States Number Analyzed 161 participants
56
Ukraine Number Analyzed 161 participants
53
Poland Number Analyzed 161 participants
12
Israel Number Analyzed 161 participants
5
Australia Number Analyzed 161 participants
12
Germany Number Analyzed 161 participants
7
Spain Number Analyzed 161 participants
5
Body Mass Index   [1] 
Median (Full Range)
Unit of measure:  Kg/m˄2
Number Analyzed 159 participants
24.7
(17.7 to 43.0)
[1]
Measure Analysis Population Description: Height not reported for some participants
Seizure cluster episodes in year before Visit 1 in Study P261-401  
Median (Full Range)
Unit of measure:  Seizure cluster episodes
Number Analyzed 161 participants
18.0
(3 to 999)
Years had seizure cluster episodes prior to Study P261-401   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 157 participants
5.00
(0.3 to 48.0)
[1]
Measure Analysis Population Description: Unknown or data entered as indefinite (eg >3) for some participants
Typical number of seizures in seizure cluster episode  
Median (Full Range)
Unit of measure:  Seizures
Number Analyzed 161 participants
6.0
(2 to 170)
Typical duration of seizure cluster episode   [1] 
Median (Full Range)
Unit of measure:  Hours
Number Analyzed 154 participants
1.00
(0.0 to 72.0)
[1]
Measure Analysis Population Description: Non-numerical duration (eg "several" hours) reported for some participants
1.Primary Outcome
Title Duration of Safety Observation
Hide Description Duration of participant study participation for collection of long term safety data
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5mg on study
Arm/Group Title USL261
Hide Arm/Group Description:

5 mg intranasal midazolam

USL261

Overall Number of Participants Analyzed 161
Median (Full Range)
Unit of Measure: months
16.80
(1.0 to 55.7)
2.Primary Outcome
Title Participants Meeting Predefined Safety Criteria for Vital Signs
Hide Description 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) 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.
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
SBP <85 mm Hg
0
   0.0%
SBP change from baseline ≥ 40 mm Hg
1
   0.6%
DBP <50 mm Hg
2
   1.2%
DBP change from baseline ≥ 30 mm Hg
3
   1.9%
Caregiver recorded RR <8 brpm
1
   0.6%
aregiver recorded RR >24 brpm
29
  18.0%
3.Primary Outcome
Title Participants With Laboratory Abnormalities Meeting Predefined Criteria
Hide Description 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)
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
ALT >ULN & ≤3xULN
26
  16.1%
Albumin <30 g/L
2
   1.2%
ALP >2.5xULN
1
   0.6%
AST >ULN & ≤3xULN
17
  10.6%
AST >5x ULN & <20xULN
1
   0.6%
Bicarbonate <15.9 mmol/L
6
   3.7%
Cholesterol >7.75 mmol/L
5
   3.1%
Creatinine >1.5xULN
1
   0.6%
Creatinine >2x baseline
2
   1.2%
GGT >2.5xULN
14
   8.7%
Glucose <3 mmol/L
3
   1.9%
Glucose <8.9 mmol/L
5
   3.1%
Phosphate <0.8 mmol/L
13
   8.1%
Potassium >5.5 mmol/L
5
   3.1%
Sodium <130 mmol/L
11
   6.8%
Sodium >150 mmol/L
1
   0.6%
Hemoglobin <100 g/L
5
   3.1%
Hemoglobin decrease 20 g/L
10
   6.2%
Leukocytes <3x10^9/L
4
   2.5%
Lymphocytes <0.8x10^9/L
4
   2.5%
Neutrophils <1.5x10^9/L
8
   5.0%
4.Primary Outcome
Title Participants With Clinically Significant Abnormalities Physical Examination
Hide Description Participants with abnormal findings, at any time post baseline, on physical examination considered clinically significant by the investigator.
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
Skin
2
   1.2%
Head/Eyes/Ears/Nose/Throat
0
   0.0%
Neck
1
   0.6%
Thyroid
0
   0.0%
Lungs
0
   0.0%
Heart
0
   0.0%
Abdomen
0
   0.0%
Lymph nodes
0
   0.0%
Extremities
0
   0.0%
5.Primary Outcome
Title Participants With Clinically Significant Abnormalities on Neurologic Examination
Hide Description Participants with abnormal findings, at any time post baseline, on neurologic examination considered clinically significant by the investigator
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
Mental status
10
   6.2%
Cranial nerves II-XII
1
   0.6%
Motor strength of limbs
2
   1.2%
Deep tendon reflexes
2
   1.2%
Sensory exam
1
   0.6%
Station and gait
5
   3.1%
Hopping
0
   0.0%
Romberg test
0
   0.0%
Finger-to-nose test
1
   0.6%
Heel-to-shin test
1
   0.6%
Rapid alternating movements
2
   1.2%
Nystagmus
0
   0.0%
Tremor/Other abnormal movements
0
   0.0%
6.Primary Outcome
Title Participants With Clinically Significant Abnormalities on Nasal Examination
Hide Description Participants with abnormal findings, at any time post baseline, on nasal examination considered clinically significant by the investigator
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
1
   0.6%
7.Primary Outcome
Title Participant Change in B-SIT Score
Hide Description 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.
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 9
Mean (Standard Deviation)
Unit of Measure: score on a scale
-0.6  (1.2)
8.Primary Outcome
Title Participants With Suicidal Ideation
Hide Description 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.
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
Wish to be dead
3
   1.9%
Non-specific active
3
   1.9%
Active without specific plan
3
   1.9%
Active with specific plan/intent
1
   0.6%
Any suicidal ideation
4
   2.5%
9.Primary Outcome
Title Emergency Room/Emergency Medical Service Visits
Hide Description Participants requiring emergency room (ER)/emergency medical service (EMS) visit within 24 hours after any USL261 treated seizure cluster (including for continued seizures)
Time Frame From Baseline/(Screening) to End of Safety-Follow-up (up to 56 months) as per assessment table of the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of USL261 5 mg on study
Arm/Group Title USL261
Hide Arm/Group Description:
USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
Overall Number of Participants Analyzed 161
Measure Type: Count of Participants
Unit of Measure: Participants
20
  12.4%
10.Secondary Outcome
Title Number of Treated Seizure Clusters Meeting Criteria for Treatment Success
Hide Description 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)
Time Frame 6 hours after first dose of USL261 for each treated seizure cluster
Hide Outcome Measure Data
Hide Analysis Population Description
Seizure cluster episodes treated with first dose of USL261
Arm/Group Title USL261
Hide Arm/Group Description:

5 mg intranasal midazolam

USL261

Overall Number of Participants Analyzed 161
Overall Number of Units Analyzed
Type of Units Analyzed: Seizure cluster episodes
1998
Count of Units
Unit of Measure: Seizure cluster episodes
1108
  55.5%
Time Frame 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 Event Reporting Description 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.
 
Arm/Group Title USL261
Hide Arm/Group Description USL261 5 mg or USL261 5 mg + 5 mg for a treated seizure cluster episode
All-Cause Mortality
USL261
Affected / at Risk (%)
Total   0/161 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
USL261
Affected / at Risk (%) # Events
Total   8/161 (4.97%)    
Gastrointestinal disorders   
Nausea  1  1/161 (0.62%)  1
General disorders   
Pyrexia  1  1/161 (0.62%)  1
Investigations   
Blood pressure increased  1  1/161 (0.62%)  1
Nervous system disorders   
Seizure cluster  1  2/161 (1.24%)  4
Convulsion  1  2/161 (1.24%)  3
Status epilepticus  1  2/161 (1.24%)  2
Epilepsy  1  1/161 (0.62%)  1
1
Term from vocabulary, MedDRA 16.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
USL261
Affected / at Risk (%) # Events
Total   33/161 (20.50%)    
Nervous system disorders   
Somnolence  1  15/161 (9.32%)  92
Headache  1  10/161 (6.21%)  27
Respiratory, thoracic and mediastinal disorders   
Nasal discomfort  1  20/161 (12.42%)  96
1
Term from vocabulary, MedDRA 16.1
Indicates events were collected by 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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: David Sequeira
Organization: Proximagen, LLC
Phone: 952-658-7438
Responsible Party: Proximagen, LLC
ClinicalTrials.gov Identifier: NCT01529034     History of Changes
Other Study ID Numbers: P261-402
2011-004109-25 ( EudraCT Number )
First Submitted: February 3, 2012
First Posted: February 8, 2012
Results First Submitted: May 9, 2019
Results First Posted: June 25, 2019
Last Update Posted: June 25, 2019