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    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)

    Summary
    EudraCT number
    2014-003961-49
    Trial protocol
    BE   CZ   IT   DE   ES   AT   LT  
    Global end of trial date
    26 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jan 2019
    First version publication date
    19 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P261-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01999777
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Proximagen, LLC
    Sponsor organisation address
    505 North Highway 169, Plymouth, MN , United States, 55441
    Public contact
    David Sequeira, Proximagen, LLC, +1 9526587437, dsequeira@proximagen.com
    Scientific contact
    David Sequeira, Proximagen, LLC, +1 9526587437, dsequeira@proximagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    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.
    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
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    62
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    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.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    Investigational medicinal product code
    USL261
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    A dose of USL261 (5 mg MDZ) was delivered with a single actuation of the unit dose pump.

    Arm title
    Placebo
    Arm description
    Randomized subjects received single doses of IN placebo according to randomized assignment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    USL261
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Matching placebo was administered.

    Number of subjects in period 1
    USL261 Placebo
    Started
    31
    31
    Completed
    31
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    USL261
    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
    Reporting group description
    Randomized subjects received single doses of IN placebo according to randomized assignment.

    Reporting group values
    USL261 Placebo Total
    Number of subjects
    31 31 62
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    2 2 4
        Adults (18-64 years)
    29 29 58
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32.7 ± 12.94 35.9 ± 13.56 -
    Gender categorical
    Units: Subjects
        Female
    18 21 39
        Male
    13 10 23
    Race
    Units: Subjects
        White
    26 27 53
        American Indian or Alaska Native
    0 0 0
        Asian
    0 1 1
        Black or African American
    3 3 6
        Native Hawaiian or other Pacific Islander
    0 0 0
        Other
    2 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    3 2 5
        Non-Hispanic or Latino
    28 29 57

    End points

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    End points reporting groups
    Reporting group title
    USL261
    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
    Reporting group description
    Randomized subjects received single doses of IN placebo according to randomized assignment.

    Primary: Number of subjects that were seizure-free

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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.
    End point type
    Primary
    End point timeframe
    6 hours
    End point values
    USL261 Placebo
    Number of subjects analysed
    31
    31
    Units: Subjects
        number (not applicable)
    17
    12
    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.
    Comparison groups
    USL261 v Placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1972 [1]
    Method
    Wald asymptotic
    Parameter type
    Proportions
    Point estimate
    16.1
    Confidence interval
         level
    95%
         sides
    2-sided
         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.

    Secondary: Time to first seizure following treatment (TFSFT)

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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.
    End point type
    Secondary
    End point timeframe
    6 hours
    End point values
    USL261 Placebo
    Number of subjects analysed
    31
    31
    Units: Hours
        median (confidence interval 95%)
    99999 (4.0 to 99999)
    3.9 (1.8 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    USL261 v Placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1388
    Method
    Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until up to 48 hours of completion of the Treatment Phase.
    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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    USL261
    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
    Reporting group description
    Randomized subjects received single doses of IN placebo according to randomized assignment.

    Serious adverse events
    USL261 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    USL261 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 31 (51.61%)
    17 / 31 (54.84%)
    Injury, poisoning and procedural complications
    Tongue injury
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    5 / 31 (16.13%)
    5 / 31 (16.13%)
         occurrences all number
    5
    5
    Throat irritation
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 31 (9.68%)
         occurrences all number
    3
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 31 (3.23%)
    5 / 31 (16.13%)
         occurrences all number
    1
    5
    Somnolence
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Product taste abnormal
         subjects affected / exposed
    2 / 31 (6.45%)
    6 / 31 (19.35%)
         occurrences all number
    2
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 31 (3.23%)
         occurrences all number
    3
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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