Study to Evaluate the Safety and Efficacy of USL261 in Patients With Increased Bouts of Seizure Activity in the EMU

• Sponsor: UCB Biopharma S.P.R.L. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01999777
• Collaborator: (none)
• Enrollment: 62
• Locations: 51
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is designed to evaluate the efficacy, safety, and tolerability of USL261 compared with that of intranasal (IN) placebo for the treatment of intermittent bouts of increased seizure activity.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: USL261; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled Trial Examining the Safety and Efficacy of Midazolam Intranasal Spray (USL261) for the Treatment of Intermittent Bouts of Increased Seizure Activity in the Epilepsy Monitoring Unit (EMU)
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: USL261 5 mg intranasal midazolam	Drug: USL261
Placebo Comparator: Placebo intranasal placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants That Were Seizure-free [6 hours]

   A participant was considered "seizure-free" if he or she completed the 6-hour Treatment Phase without seizures recorded, premature discontinuation of study drug, rescue intervention for acute central respiratory depression adverse event (AE), and alterations to background anti-epileptic drug (AED) therapy. Otherwise, the participant was included in the analysis for seizure-free events with the outcome of "seizure."

Secondary Outcome Measures

1. Time to First Seizure Following Treatment (TFSFT) [6 hours]

   Time to first seizure following treatment was defined as time from treatment with study drug to the onset of the next seizure, rescue intervention (for acute central respiratory depression AE) to maintain subject safety, alterations to background AED therapy, early termination, or 6 hours, whichever came first.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has been admitted to the institution's EMU for seizure characterization or pre-surgical evaluation, or such admission is planned within 28 days

• Subject body weight is ≥ 40 kg to ≤ 125 kg (inclusive)

• Subject has an established diagnosis of partial or generalized epilepsy

Exclusion Criteria:

• Subject has history of status epilepticus in the 6 months prior to Screening

• Subject has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 12 months

• Subject has respiratory failure (or is at risk for respiratory failure) or other severe cardiorespiratory disease with New York Heart Association Class III or IV functional status, or requires supplemental oxygen

• Subject has acute narrow-angle glaucoma

• Subject is receiving chronic benzodiazepine treatment (defined as an average of ≥ 4 administrations per week) and cannot safely withdraw from such treatment within the washout period prior to treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States
2		Tucson	Arizona	United States
3		La Jolla	California	United States
4		Orange	California	United States
5		San Francisco	California	United States
6		Denver	Colorado	United States
7		Englewood	Colorado	United States
8		New Haven	Connecticut	United States
9		Tampa	Florida	United States
10		Augusta	Georgia	United States
11		Chicago	Illinois	United States
12		Winfield	Illinois	United States
13		Wichita	Kansas	United States
14		New Orleans	Louisiana	United States
15		Boston	Massachusetts	United States
16		Ann Arbor	Michigan	United States
17		Grand Rapids	Michigan	United States
18		Jackson	Mississippi	United States
19		Saint Louis	Missouri	United States
20		Lebanon	New Hampshire	United States
21		Edison	New Jersey	United States
22		Brooklyn	New York	United States
23		Rochester	New York	United States
24		Chapel Hill	North Carolina	United States
25		Durham	North Carolina	United States
26		Winston-Salem	North Carolina	United States
27		Columbus	Ohio	United States
28		Oklahoma City	Oklahoma	United States
29		Portland	Oregon	United States
30		Hershey	Pennsylvania	United States
31		Philadelphia	Pennsylvania	United States
32		Memphis	Tennessee	United States
33		Nashville	Tennessee	United States
34		Dallas	Texas	United States
35		San Antonio	Texas	United States
36		Temple	Texas	United States
37		Madison	Wisconsin	United States
38		Melbourne	Victoria	Australia
39		Linz		Austria
40		Brussels		Belgium
41		Gent		Belgium
42		Leuven		Belgium
43		Brno		Czechia
44		Prague		Czechia
45		Bonn		Germany
46		Kork		Germany
47		Tübingen		Germany
48		Vilnius		Lithuania
49		Barcelona		Spain
50		Madrid		Spain
51		Valencia		Spain

Sponsors and Collaborators

• UCB Biopharma S.P.R.L.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: UCB Biopharma S.P.R.L.
• ClinicalTrials.gov Identifier: NCT01999777
• Other Study ID Numbers: USL261-301
• First Posted: Dec 3, 2013
• Last Update Posted: Oct 10, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by UCB Biopharma S.P.R.L.: Epilepsy; seizure clusters; acute repetitive seizures; rescue treatment
• Additional relevant MeSH terms: Epilepsy; Seizures

Study Results

Participant Flow

Pre-assignment Detail	188 eligible subjects entered Pretreatment Observation during which they were monitored in EMU for seizure events. Only subjects who met entry criteria and presented with seizure events meeting the treatment decision criteria were eligible to enter the Treatment Phase. Participant flow represents subjects who took at least 1 dose of study drug.

Arm/Group Title	USL261	Placebo
Arm/Group Description	5 mg intranasal midazolam USL261	intranasal placebo Placebo
Period Title: Overall Study
STARTED	31	31
COMPLETED	31	31
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	USL261	Placebo	Total
Arm/Group Description	5 mg intranasal midazolam USL261	intranasal placebo Placebo	Total of all reporting groups
Overall Participants	31	31	62
Age (Count of Participants)
<=18 years	2 6.5%	2 6.5%	4 6.5%
Between 18 and 65 years	29 93.5%	29 93.5%	58 93.5%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.7 (12.94)	35.9 (13.56)	34.3 (13.24)
Sex: Female, Male (Count of Participants)
Female	18 58.1%	21 67.7%	39 62.9%
Male	13 41.9%	10 32.3%	23 37.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 9.7%	2 6.5%	5 8.1%
Not Hispanic or Latino	28 90.3%	29 93.5%	57 91.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 3.2%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 9.7%	3 9.7%	6 9.7%
White	26 83.9%	27 87.1%	53 85.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 6.5%	0 0%	2 3.2%
Region of Enrollment (participants) [Number]
Belgium	1 3.2%	0 0%	1 1.6%
United States	22 71%	22 71%	44 71%
Czechia	2 6.5%	2 6.5%	4 6.5%
Lithuania	3 9.7%	2 6.5%	5 8.1%
Germany	0 0%	1 3.2%	1 1.6%
Spain	3 9.7%	4 12.9%	7 11.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants That Were Seizure-free
Description	A participant was considered "seizure-free" if he or she completed the 6-hour Treatment Phase without seizures recorded, premature discontinuation of study drug, rescue intervention for acute central respiratory depression adverse event (AE), and alterations to background anti-epileptic drug (AED) therapy. Otherwise, the participant was included in the analysis for seizure-free events with the outcome of "seizure."
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	USL261	Placebo
Arm/Group Description	5 mg intranasal midazolam USL261	intranasal placebo Placebo
Measure Participants	31	31
Count of Participants [Participants]	17 54.8%	12 38.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261, Placebo
	Comments	Assumptions included that the proportion of seizures occurring within 6 hours after placebo administration was ~65% and a relative reduction of 50% would result in a reduction of ≥ 32.5 percentage points. Based on a 2-sided 95% confidence interval (CI) for the differences in proportions, a sample size of 62 analyzable subjects was chosen to detect a 0.35 difference between group. Sample size estimations were based on nQuery Version 7.0 using the table for CIs for differences in 2 proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1972
	Comments
	Method	Wald asymptotic
	Comments	P-value based on a standard Wald asymptotic test for equality without a continuity correction.

2. Secondary Outcome

Title	Time to First Seizure Following Treatment (TFSFT)
Description	Time to first seizure following treatment was defined as time from treatment with study drug to the onset of the next seizure, rescue intervention (for acute central respiratory depression AE) to maintain subject safety, alterations to background AED therapy, early termination, or 6 hours, whichever came first.
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	USL261	Placebo
Arm/Group Description	5 mg intranasal midazolam USL261	intranasal placebo Placebo
Measure Participants	31	31
Median (95% Confidence Interval) [hours]	NA	3.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1388
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	From informed consent until up to 48 hours of completion of the Treatment Phase
Adverse Event Reporting Description	Adverse events were collected from time of informed consent until subject completion or early termination. Exit assessments were to be conducted within 48 hours of completion of the Treatment Phase (6 hours) and prior to discharge for the EMU.
Arm/Group Title	USL261		Placebo
Arm/Group Description	5 mg intranasal midazolam USL261		intranasal placebo Placebo
All Cause Mortality
	USL261		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/31 (0%)
Serious Adverse Events
	USL261		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	USL261		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/31 (51.6%)		17/31 (54.8%)
Gastrointestinal disorders
Nausea	3/31 (9.7%)		1/31 (3.2%)
General disorders
Product taste abnormal	2/31 (6.5%)		6/31 (19.4%)
Infections and infestations
Rhinitis	0/31 (0%)		2/31 (6.5%)
Injury, poisoning and procedural complications
Tongue injury	0/31 (0%)		2/31 (6.5%)
Nervous system disorders
Headache	1/31 (3.2%)		5/31 (16.1%)
Somnolence	2/31 (6.5%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal discomfort	5/31 (16.1%)		5/31 (16.1%)
Throat irritation	3/31 (9.7%)		3/31 (9.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A manuscript or abstract should not be submitted by investigator(s) for publication or presentation until a New Drug Application is approved by the US FDA or permission is granted in writing by the sponsor.