Clinical Trial Results:
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)
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Summary
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EudraCT number |
2014-003961-49 |
Trial protocol |
BE CZ IT DE ES AT LT |
Global end of trial date |
26 Aug 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jan 2019
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First version publication date |
19 Jan 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
P261-301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01999777 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Proximagen, LLC
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Sponsor organisation address |
505 North Highway 169, Plymouth, MN , United States, 55441
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Public contact |
David Sequeira, Proximagen, LLC, +1 9526587437, dsequeira@proximagen.com
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Scientific contact |
David Sequeira, Proximagen, LLC, +1 9526587437, dsequeira@proximagen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Oct 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Aug 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The study objective was 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.
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Protection of trial subjects |
Prior to the initiation of the clinical study, the protocol, consent form, assent form and advertisements for the recruitment of subjects were reviewed and approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) of the participating study center in the relevant country in accordance with current Good Clinical Practices (GCP) and all applicable regulatory requirements. This clinical study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki, 1964, and with adherence to the principles of GCP, outlined by the International Conference on Harmonisation’s GCP Guidelines, effective 1997. An IRB/IEC-approved written informed consent was obtained from each subject or legally acceptable representative (LAR) and the subject’s caregiver prior to the initiation of any subject-specific procedures.
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Background therapy |
Background therapy was permitted, but changes were not allowed during the treatment period. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
01 Nov 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Czech Republic: 4
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Lithuania: 5
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Country: Number of subjects enrolled |
United States: 44
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Worldwide total number of subjects |
62
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EEA total number of subjects |
18
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
4
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Adults (18-64 years) |
58
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This multicenter trial was conducted at 61 trial sites in the following 10 countries: Australia, Austria, Belgium, Czech Republic, France, Germany, Italy, Lithuania, Spain and the United States of America (USA). This includes sites/countries that may have screened a subject(s) but had no subjects who were enrolled. | |||||||||
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Pre-assignment
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Screening details |
Eligible subjects entered Pretreatment Observation during which they were monitored in Epilepsy monitoring unit (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. | |||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
Blinding implementation details |
Drug supplies were labeled in a double-blind fashion with information including the protocol number, kit identification number, and instructions for use. The label did not specify whether the kit contained USL261 or placebo, and the investigator, study center staff, and subject did not know the identity of the randomized study drug.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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USL261 | |||||||||
Arm description |
Randomized subjects received a single dose of IN USL261 according to randomized assignment. A dose of USL261 (5 mg midazolam [MDZ]) was delivered with a single actuation of the unit dose pump. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
USL261
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Investigational medicinal product code |
USL261
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Other name |
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Pharmaceutical forms |
Nasal spray, solution
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Routes of administration |
Intranasal use
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Dosage and administration details |
A dose of USL261 (5 mg MDZ) was delivered with a single actuation of the unit dose pump.
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Arm title
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Placebo | |||||||||
Arm description |
Randomized subjects received single doses of IN placebo according to randomized assignment. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
USL261
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Other name |
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Pharmaceutical forms |
Nasal spray, solution
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Routes of administration |
Intranasal use
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Dosage and administration details |
Matching placebo was administered.
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Baseline characteristics reporting groups
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Reporting group title |
USL261
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Reporting group description |
Randomized subjects received a single dose of IN USL261 according to randomized assignment. A dose of USL261 (5 mg midazolam [MDZ]) was delivered with a single actuation of the unit dose pump. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Randomized subjects received single doses of IN placebo according to randomized assignment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
USL261
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Reporting group description |
Randomized subjects received a single dose of IN USL261 according to randomized assignment. A dose of USL261 (5 mg midazolam [MDZ]) was delivered with a single actuation of the unit dose pump. | ||
Reporting group title |
Placebo
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Reporting group description |
Randomized subjects received single doses of IN placebo according to randomized assignment. | ||
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End point title |
Number of subjects that were seizure-free | ||||||||||||
End point description |
A subject was considered "seizure-free" if he or she completed the 6-hour Treatment Phase without any seizures recorded, premature discontinuation of study drug, rescue intervention for acute central respiratory depression adverse event (AE), and alteration to background anti-epileptic drug (AED) therapy; all criteria needed to be met to be considered seizure-free.
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End point type |
Primary
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End point timeframe |
6 hours
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
USL261 v Placebo
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1972 [1] | ||||||||||||
Method |
Wald asymptotic | ||||||||||||
Parameter type |
Proportions | ||||||||||||
Point estimate |
16.1
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.4 | ||||||||||||
upper limit |
40.6 | ||||||||||||
| Notes [1] - The p-value was based on a standard Wald asymptotic test for equality without a continuity correction. |
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End point title |
Time to first seizure following treatment (TFSFT) | ||||||||||||
End point description |
TFSFT was defined as the 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. An arbitrary value of '99999' indicates value was not estimable. Unable to estimate median in USL261 group as > 50% were seizure-free throughout the 6-hour treatment phase. No upper CI boundary as observations stopped at 6 hours.
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End point type |
Secondary
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End point timeframe |
6 hours
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
USL261 v Placebo
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1388 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
From informed consent until up to 48 hours of completion of the Treatment Phase.
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Adverse event reporting additional description |
Adverse events were collected from time 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. Treatment-Emergent Adverse Events have been presented in the following table.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
USL261
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Reporting group description |
Randomized subjects received a single dose of IN USL261 according to randomized assignment. A dose of USL261 (5 mg MDZ) was delivered with a single actuation of the unit dose pump. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Randomized subjects received single doses of IN placebo according to randomized assignment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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24 Sep 2014 |
•The primary efficacy measure analysis was changed in 2 ways. •The sample size was changed from N = 48 to N = 62.•The secondary efficacy endpoint and analysis were clarified to state that the time to event data would be presented with Kaplan-Meier estimates of median and 2-sided 95% CI.•The exploratory efficacy variables and analysis were updated.•A statistical gatekeeping procedure was specified to control for multiplicity effects for Type 1 error across the primary and secondary efficacy outcomes.•Inclusion Criterion 4 was modified to remove the upper age restriction (previously </= 65 years of age). •Exclusion Criterion 4 was modified to exempt the requirement for a Urine drug screen (UDS) in individuals with cognitive disability that precluded the collection of a urine sample by conventional methods.•Exclusion Criterion 14 was modified to specify that exclusion (current or prior use of investigational device within 60 days of screening) did not apply to non-interventional devices. •The pharmacokinetic assessments were modified in 2 ways. •The analysis of clinical laboratory parameters was altered to no longer specify that urinalysis results would be described with summary statistics and shift tables. •The AE reporting timeframe was reduced from 30 days after administration of study drug to 7 days after administration of study drug.•The analysis of electrocardiogram results was changed to reflect that baseline parameters would not be presented. •The requirement for the UDS to be performed by the local laboratory was changed that if the local laboratory could not provide the results within a 24 hour period for any particular drug, a commercially available dipstick test kit that included the drug could be used for that particular drug.•Several mild and moderate inhibitors of cytochrome P450 3A4 metabolism were removed from the list of prohibited concomitant substances in Appendix 1. •The required washout period for fentanyl, morphine, and propofol were modified. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
