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    Clinical Trial Results:
    Driving fitness under acute and subchronic application of Silexan® (WS® 1265) in comparison to placebo and Lorazepam with healthy volunteers in two successive, randomized, double-blind, crossover designed trial parts

    Summary
    EudraCT number
    		 2015-001101-14
    Trial protocol
    		 DE  
    Global end of trial date
    07 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2019
    First version publication date
    17 Jul 2019
    Other versions
    Summary report(s)
    		 750253.01.030 Summuary of results V1.0

    Trial information

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    Trial identification
    Sponsor protocol code
    750253.01.030
    Additional study identifiers
    ISRCTN number
    		 ISRCTN32209377
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Willmar Schwabe GmbH & Co. KG
    Sponsor organisation address
    Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany, 76227
    Public contact
    Head of Clinical Research Department, Dr. Willmar Schwabe GmbH & Co. KG, +49 7214005573,
    Scientific contact
    Head of Clinical Research Department, Dr. Willmar Schwabe GmbH & Co. KG, +49 7214005573,
    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
    03 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial is divided in two parts. The first part of the trial is conducted in order to test the non-inferiority and equivalence, respectively, of driving fitness after acute application of 80 mg Silexan® (WS® 1265) in comparison to placebo. The second part of the trial is conducted in order to show superiority of 160 mg and 320 mg Silexan® (WS® 1265) with respect to driving fitness in comparison to 1.0 mg Lorazepam. In the second part of the trial, the comparison of 1.0 mg Lorazepam with placebo will serves to ensure the internal validity of the experimental set-up. Driving fitness is assessed using a representative, alcohol-validated test course in a high-fidelity driving simulator.
    Protection of trial subjects
    Possibility to withdraw informed consent. Monitoring of adverse events and laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 Lorazepam (Tavor, 0,5 mg, 1,0 mg, 2,0 mg and 2,5 mg) has a marketing authorisation in Germany for the symptomatic short-time treatment of anxiety, stress and agitational states as well as thereby caused sleeping disorders. It is also used as a sedative for diagnostic procedures and as a sedative pre- and aftermedication for surgery. 1 mg Lorazepam is used as the standard active drug (verum) definitely causing impairment according to the guidelines of the International Council on Alcohol, Drugs and Traffic Safety (ICADTS, 2009).
    Actual start date of recruitment
    04 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 201
    Worldwide total number of subjects
    201
    EEA total number of subjects
    201
    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)
    0
    Adults (18-64 years)
    201
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First part: A total of 51 subjects were screened for eligibility. Of these, 1 subject was not included due to an adverse event. 2 drop out subjects were replaced. Second part: A total of 25 subjects were screened for eligibility. All subjects were included. 1 drop out subject was replaced.

    Pre-assignment
    Screening details
    		 First part: 50 subjects were randomised to one of two treatment sequences (Silexan 80 mg/placebo) in a 2-period, 2-way cross-over design. Second part: 25 subjects were randomised to one of four treatment sequences (Silexan 80 mg/Silexan 160mg/Lorazepam 1mg/placebo) in a 4-period, 4-way cross-over design.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Silexan 80 mg (first part)
    Arm description
    		 WS® 1265 1x80 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Silexan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    WS® 1265 1x1

    Arm title
    		 Placebo (first part)
    Arm description
    		 WS® 1265 Placebo 1x1
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 1x1

    Arm title
    		 Silexan 160 mg (second part)
    Arm description
    		 WS® 1265 2x80 mg + WS® 1265 Placebo 2x1 + Lorazepam Placebo 1x1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Silexan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 purple capsules (2 Silexan® WS® 1265 + 2 Silexan® placebo) + 1 orange capsule (Lorazepam placebo)

    Arm title
    		 Silexan 320 mg (second part)
    Arm description
    		 WS® 1265 4x80 mg + Lorazepam Placebo 1x1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Silexan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 purple capsules (Silexan® WS® 1265) + 1 orange capsule (Lorazepam placebo)

    Arm title
    		 Lorazepam 1 mg (second part)
    Arm description
    		 WS® 1265 Placebo 4x1 + Lorazepam 1x1mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorazepam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 purple capsules (Silexan® placebo) + 1 orange capsule (Lorazepam verum)

    Arm title
    		 Placebo (second part)
    Arm description
    		 WS® 1265 Placebo 4x1 + Lorazepam Placebo 1x1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 purple capsules (Silexan® placebo) + 1 orange capsule (Lorazepam placebo)

    Number of subjects in period 1 [1]
    		Silexan 80 mg (first part) Placebo (first part) Silexan 160 mg (second part) Silexan 320 mg (second part) Lorazepam 1 mg (second part) Placebo (second part)
    Started
    50
    50
    25
    25
    25
    25
    Completed
    48
    48
    25
    25
    25
    25
    Not completed
    2
    2
    0
    0
    0
    0
         Pregnancy
    1
    1
    -
    -
    -
    -
         schedule conflict
    1
    1
    -
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this database each sequence of a cross over trial is counting as separate study participant. The number of participants is therefore counting up to 2x50 plus 4x25, since the first part of this study has a twofold cross over design, while in the second part each participant is passing through four sequences. One participant was not included after screening, the dummy "number of subjects enrolled" is therefore adding up to 201.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Silexan 80 mg (first part)
    Reporting group description
    		 WS® 1265 1x80 mg

    Reporting group title
    Placebo (first part)
    Reporting group description
    		 WS® 1265 Placebo 1x1

    Reporting group title
    Silexan 160 mg (second part)
    Reporting group description
    		 WS® 1265 2x80 mg + WS® 1265 Placebo 2x1 + Lorazepam Placebo 1x1

    Reporting group title
    Silexan 320 mg (second part)
    Reporting group description
    		 WS® 1265 4x80 mg + Lorazepam Placebo 1x1

    Reporting group title
    Lorazepam 1 mg (second part)
    Reporting group description
    		 WS® 1265 Placebo 4x1 + Lorazepam 1x1mg

    Reporting group title
    Placebo (second part)
    Reporting group description
    		 WS® 1265 Placebo 4x1 + Lorazepam Placebo 1x1

    Reporting group values
    		 Silexan 80 mg (first part) Placebo (first part) Silexan 160 mg (second part) Silexan 320 mg (second part) Lorazepam 1 mg (second part) Placebo (second part) Total
    Number of subjects
    		 50 50 25 25 25 25 200
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 50 50 25 25 25 25 200
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.2 ± 8.90 34.2 ± 8.90 33.1 ± 9.77 33.1 ± 9.77 33.1 ± 9.77 33.1 ± 9.77 -
    Gender categorical
    Units: Subjects
        Female
    		 23 23 14 14 14 14 102
        Male
    		 27 27 11 11 11 11 98
    Subject analysis sets

    Subject analysis set title
    Silexan 80 mg (first part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the first part, which received Silexan on day 1-8 or day 15-22.

    Subject analysis set title
    Placebo Part (first part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the first part, which received placebo on day 1-8 or day 15-22.

    Subject analysis set title
    Silexan 160 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Silexan 2x80 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Silexan 320 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Silexan 4x80 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Lorazepam 1 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Lorazepam 1x1 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Placebo Part (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Placebo on day 1, day 8, day 15 or day 22.

    Subject analysis sets values
    		 Silexan 80 mg (first part) Placebo Part (first part) Silexan 160 mg (second part) Silexan 320 mg (second part) Lorazepam 1 mg (second part) Placebo Part (second part)
    Number of subjects
    48
    48
    25
    25
    25
    25
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    48
    48
    25
    25
    25
    25
        From 65-84 years
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    33.9 ± 8.99
    33.9 ± 8.99
    33.1 ± 9.77
    33.1 ± 9.77
    33.1 ± 9.77
    33.1 ± 9.77
    Gender categorical
    Units: Subjects
        Female
    22
    22
    14
    14
    14
    14
        Male
    26
    26
    11
    11
    11
    11

    End points

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    End points reporting groups
    Reporting group title
    Silexan 80 mg (first part)
    Reporting group description
    		 WS® 1265 1x80 mg

    Reporting group title
    Placebo (first part)
    Reporting group description
    		 WS® 1265 Placebo 1x1

    Reporting group title
    Silexan 160 mg (second part)
    Reporting group description
    		 WS® 1265 2x80 mg + WS® 1265 Placebo 2x1 + Lorazepam Placebo 1x1

    Reporting group title
    Silexan 320 mg (second part)
    Reporting group description
    		 WS® 1265 4x80 mg + Lorazepam Placebo 1x1

    Reporting group title
    Lorazepam 1 mg (second part)
    Reporting group description
    		 WS® 1265 Placebo 4x1 + Lorazepam 1x1mg

    Reporting group title
    Placebo (second part)
    Reporting group description
    		 WS® 1265 Placebo 4x1 + Lorazepam Placebo 1x1

    Subject analysis set title
    Silexan 80 mg (first part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the first part, which received Silexan on day 1-8 or day 15-22.

    Subject analysis set title
    Placebo Part (first part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the first part, which received placebo on day 1-8 or day 15-22.

    Subject analysis set title
    Silexan 160 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Silexan 2x80 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Silexan 320 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Silexan 4x80 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Lorazepam 1 mg (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Lorazepam 1x1 mg on day 1, day 8, day 15 or day 22.

    Subject analysis set title
    Placebo Part (second part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects of the second part, which received Placebo on day 1, day 8, day 15 or day 22.

    Primary: Standard deviation of lane position SDLP

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    End point title
    		 Standard deviation of lane position SDLP [1] [2]
    End point description
    Note: This document in its section "End points" specifies commercially confidential information of Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe referred to in Article 81 Section (4) b) Regulation (EU) 536/2014 that is a trade secret and released by the holder for purposes of Regulation (EU) 536/2014 only under the condition of confidence. Trade secrets may not - even in part - be published or released to third parties other than to competent authorities without express permission of the trade secret holder.
    End point type
    Primary
    End point timeframe
    Day 1 and day 15
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The reported results are chosen freely. See document for a complete description of the statistical methods and results. Statistical analyses were conducted for the end point. Refer to the attached summary of results for details.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The reported results are chosen freely. See document for a complete description of the statistical methods and results. Statistical analyses were conducted for the end point. Refer to the attached summary of results for details.
    End point values
    		 Silexan 80 mg (first part) Placebo (first part)
    Number of subjects analysed
    48
    48
    Units: cm
        median (inter-quartile range (Q1-Q3))
    9999.99 (9999.99 to 9999.99)
    9999.99 (9999.99 to 9999.99)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    9 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    No active treatment
    Reporting group description
    		 No active treatment

    Reporting group title
    Lorazepam
    Reporting group description
    		 Compare medication

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Silexan
    Reporting group description
    		 Study medication

    Serious adverse events
    		 No active treatment Lorazepam Placebo Silexan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 25 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 No active treatment Lorazepam Placebo Silexan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 74 (8.11%)
    14 / 25 (56.00%)
    33 / 74 (44.59%)
    53 / 74 (71.62%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 25 (12.00%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
         occurrences all number
    0
    3
    1
    5
    Headache
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 25 (4.00%)
    5 / 74 (6.76%)
    7 / 74 (9.46%)
         occurrences all number
    1
    1
    5
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 74 (1.35%)
    12 / 25 (48.00%)
    22 / 74 (29.73%)
    27 / 74 (36.49%)
         occurrences all number
    1
    12
    26
    32
    Gastrointestinal disorders
    Eructation
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 25 (0.00%)
    1 / 74 (1.35%)
    37 / 74 (50.00%)
         occurrences all number
    0
    0
    1
    39
    Nausea
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 25 (0.00%)
    8 / 74 (10.81%)
    5 / 74 (6.76%)
         occurrences all number
    0
    0
    8
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 25 (0.00%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
         occurrences all number
    4
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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