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    Clinical Trial Results:
    Multi-center, double-blind, placebo-controlled, randomized phase IIIb study to prove the efficacy, safety and tolerability of Silexan (WS®1265) in patients with mixed anxiety and depressive disorder (ICD-10, F41.2).

    Summary
    EudraCT number
    		 2012-000438-21
    Trial protocol
    		 DE  
    Global end of trial date
    08 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    750201.01.035
    Additional study identifiers
    ISRCTN number
    		 ISRCTN65844716
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Willmar Schwabe GmbH & Co. KG
    Sponsor organisation address
    Willmar Schwabe Str. 4, Karlsruhe, Germany, 76227
    Public contact
    Clinical Research Department, Dr. Willmar Schwabe GmbH & Co. KG, +49 7214005573,
    Scientific contact
    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
    12 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to prove the efficacy of Silexan in the treatment of patients with mixed anxiety and depressive disorder in comparing the change of the HAMA total score and the MADRS total score between baseline and Week 10 between Silexan and placebo.
    Protection of trial subjects
    Possibility to withdraw consent by patient. Monitoring of adverse events and laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2012
    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: 348
    Worldwide total number of subjects
    348
    EEA total number of subjects
    348
    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)
    348
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Thirty patients were not randomized and did not receive the investigational product since they did not fulfill all in-/exclusion criteria or withdrew informed consent.

    Pre-assignment period milestones
    Number of subjects started
    		 348
    Number of subjects completed
    		 318

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 11
    Reason: Number of subjects
    		 Protocol deviation: 16
    Reason: Number of subjects
    		 Patients decision: 3
    Period 1
    Period 1 title
    Treatment period (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
    Arm description
    		 Investigational medical product containing Silexan, 80 mg, one additional Patient was randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Silexan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 80 mg daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo, two additional Patients were randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1 capsule daily

    Number of subjects in period 1 [1]
    		Silexan Placebo
    Started
    160
    158
    Completed
    145
    145
    Not completed
    15
    13
         private reasons
    3
    -
         Consent withdrawn by subject
    4
    4
         Adverse event, non-fatal
    1
    1
         Patients decision
    -
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    6
    7
    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: Silexan: Investigational medical product Silexan, 80 mg, one additional Patient was randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period. Placebo, two additional Patients were randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the ran

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Silexan
    Reporting group description
    		 Investigational medical product containing Silexan, 80 mg, one additional Patient was randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, two additional Patients were randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.

    Reporting group values
    		 Silexan Placebo Total
    Number of subjects
    		 160 158 318
    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)
    		 0 0 0
        Adults (18-64 years)
    		 160 158 318
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.5 ± 12.8 47.8 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    		 106 113 219
        Male
    		 54 45 99
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full analysis set (FAS) included all patients who received the investigational medical product (Silexan or placebo) at least once and had at least one measure of one of the primary efficacy parameters (HAMA total score or MADRS total score) during active treatment period after baseline visit and patients who terminated the study prematurely because of lack of efficacy or an AE, for which a causal relationship to the investigational product could not be excluded (even if these patients had no efficacy measurement during active treatment period)

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    315
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    315
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.8 ± 12.6
    Gender categorical
    Units: Subjects
        Female
    218
        Male
    97

    End points

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    End points reporting groups
    Reporting group title
    Silexan
    Reporting group description
    		 Investigational medical product containing Silexan, 80 mg, one additional Patient was randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, two additional Patients were randomized and started Treatment but had no post-baseline measurements of the primary efficacy parameter (HAMA-A total score and MADRS total score) during the randomized ten-week treatment period.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full analysis set (FAS) included all patients who received the investigational medical product (Silexan or placebo) at least once and had at least one measure of one of the primary efficacy parameters (HAMA total score or MADRS total score) during active treatment period after baseline visit and patients who terminated the study prematurely because of lack of efficacy or an AE, for which a causal relationship to the investigational product could not be excluded (even if these patients had no efficacy measurement during active treatment period)

    Primary: Change of HAMA total score between baseline and end of treatment

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    End point title
    		 Change of HAMA total score between baseline and end of treatment
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -10.8 ± 9.6
    -8.4 ± 8.9
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA with factor treatment, center and the respective baseline total score value as covariate, LOCF Method was used.
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0077 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.471
         upper limit
    		 -0.477
    Notes
    [1] - one sided p-value

    Primary: Change of MADRS total score between baseline and end of treatment

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    End point title
    		 Change of MADRS total score between baseline and end of treatment
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -9.2 ± 9.9
    -6.1 ± 7.6
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA with factor treatment, center and the respective baseline total score value as covariate, LOCF Method was used.
    Comparison groups
    Placebo v Silexan
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -3.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.144
         upper limit
    		 -1.362
    Notes
    [2] - one sided p-value

    Secondary: Change of HAMA Subscore Somatic Anxiety

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    End point title
    		 Change of HAMA Subscore Somatic Anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -4.2 ± 4.4
    -3.1 ± 4.4
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 -0.14

    Secondary: Change of HAMA Subscore Physic Anxiety

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    End point title
    		 Change of HAMA Subscore Physic Anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -6.6 ± 5.7
    -5.3 ± 5.1
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.51
         upper limit
    		 -0.1

    Secondary: HAMA total score improvement >= 50 %

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    End point title
    		 HAMA total score improvement >= 50 %
    End point description
    HAMA total score improvement >= 50 percent between baseline and week 10
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    66
    54
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.208 [3]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - two sided

    Secondary: HAMA total score < 10

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    End point title
    		 HAMA total score < 10
    End point description
    End point type
    Secondary
    End point timeframe
    End of Treatment (week 10)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    55
    45
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.273 [4]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - two-sided

    Secondary: Change of HAMA Item 2 (tension)

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    End point title
    		 Change of HAMA Item 2 (tension)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -1.2 ± 1.2
    -0.9 ± 1.2
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.01

    Secondary: Change of HAMA Item 14 (Behavior at interview)

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    End point title
    		 Change of HAMA Item 14 (Behavior at interview)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -0.7 ± 1
    -0.5 ± 0.9
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.02

    Secondary: MADRS total score improvement >= 50 %

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    End point title
    		 MADRS total score improvement >= 50 %
    End point description
    MADRS total score improvement >= 50 percent between baseline and week 10
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    64
    50
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [5]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [5] - two-sided

    Secondary: MADRS total score < =10

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    End point title
    		 MADRS total score < =10
    End point description
    Remission: MADRS total score <=10 at week 10
    End point type
    Secondary
    End point timeframe
    End of Treatment (week 10)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    74
    53
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.023 [6]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - two-sided

    Secondary: Change of STAI X1 (state anxiety) score

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    End point title
    		 Change of STAI X1 (state anxiety) score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -7.8 ± 13.5
    -6.6 ± 12
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.424
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.99
         upper limit
    		 1.68

    Secondary: Change of STAI X2 (trait anxiety) score

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    End point title
    		 Change of STAI X2 (trait anxiety) score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -6.9 ± 11.7
    -6.1 ± 10
    Statistical analysis title
    		 ANOVA
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.496
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.25
         upper limit
    		 1.58

    Secondary: Sheehan disability scale: Impairment (Work/School/University)

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    End point title
    		 Sheehan disability scale: Impairment (Work/School/University)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -1.7 ± 3.8
    -0.9 ± 3.1
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 -0.05

    Secondary: Sheehan disability scale: Impairment (Social Life)

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    End point title
    		 Sheehan disability scale: Impairment (Social Life)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -1.6 ± 3.1
    -0.8 ± 2.6
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.015
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 -0.16

    Secondary: Sheehan disability scale: Impairment (Family Life / Home Responsibilities)

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    End point title
    		 Sheehan disability scale: Impairment (Family Life / Home Responsibilities)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -1.9 ± 3
    -0.7 ± 2.6
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 -0.54

    Secondary: Sheehan disability scale: Global Impairment

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    End point title
    		 Sheehan disability scale: Global Impairment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -5.1 ± 8.5
    -2.3 ± 6.6
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 -1.08

    Secondary: SF 36 total scores: Physical Health

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    End point title
    		 SF 36 total scores: Physical Health
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    12.9 ± 25
    6.3 ± 16.7
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    6.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 11.4

    Secondary: SF 36 total scores: Mental Health

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    End point title
    		 SF 36 total scores: Mental Health
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    20.6 ± 29.5
    11.3 ± 20.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.73
         upper limit
    		 15.06

    Secondary: SF 36 individual scores: Physical Functioning

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    End point title
    		 SF 36 individual scores: Physical Functioning
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    7.3 ± 23.7
    2.9 ± 17.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    4.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 9.11

    Secondary: SF 36 individual scores: Role-Physical

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    End point title
    		 SF 36 individual scores: Role-Physical
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    20.2 ± 46.5
    11.9 ± 39.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.091
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    8.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 17.95

    Secondary: SF 36 individual scores: Bodily Pain

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    End point title
    		 SF 36 individual scores: Bodily Pain
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    12.3 ± 31.1
    6.1 ± 23
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    6.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 12.34

    Secondary: SF 36 individual scores: General Health

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    End point title
    		 SF 36 individual scores: General Health
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    11.9 ± 20.8
    4.4 ± 16
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    7.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.41
         upper limit
    		 11.71

    Secondary: SF 36 individual scores: Vitality

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    End point title
    		 SF 36 individual scores: Vitality
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    17.2 ± 26.8
    10 ± 17.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    7.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 12.31

    Secondary: SF 36 individual scores: Social Functioning

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    End point title
    		 SF 36 individual scores: Social Functioning
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    18.9 ± 32.9
    10.7 ± 23.9
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.75
         upper limit
    		 14.65

    Secondary: SF 36 individual scores: Role-Emotional

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    End point title
    		 SF 36 individual scores: Role-Emotional
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    30.1 ± 48.3
    15.2 ± 42.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    14.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.79
         upper limit
    		 25.12

    Secondary: SF 36 individual scores: Mental Health

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    End point title
    		 SF 36 individual scores: Mental Health
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    16.5 ± 25.9
    9.2 ± 19.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    7.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.21
         upper limit
    		 12.43

    Secondary: CGI tem 1: Severity of Illness

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    End point title
    		 CGI tem 1: Severity of Illness
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    155
    154
    Units: Points
        arithmetic mean (standard deviation)
    -1.1 ± 1.5
    -0.7 ± 1.2
    Statistical analysis title
    		 Non-parametric analysis
    Statistical analysis description
    LOCF, two-sided, end of Treatment (10 week Treatment period)
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - two-sided

    Secondary: CGI Item 2: Global Improvement

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    End point title
    		 CGI Item 2: Global Improvement
    End point description
    End point type
    Secondary
    End point timeframe
    End of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    155
    154
    Units: Points
        arithmetic mean (standard deviation)
    2.7 ± 1.3
    3.1 ± 1.2
    Statistical analysis title
    		 Non-parametric analysis
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - two-sided

    Secondary: CGI Item 3.1: Therapeutic Effect

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    End point title
    		 CGI Item 3.1: Therapeutic Effect
    End point description
    End point type
    Secondary
    End point timeframe
    End of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    154
    153
    Units: Points
        arithmetic mean (standard deviation)
    2.4 ± 1.2
    2.9 ± 1.1
    Statistical analysis title
    		 Non-parametric analysis
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Placebo v Silexan
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - two-sided

    Secondary: Hospital anxiety and depression scale (HADS) total score

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    End point title
    		 Hospital anxiety and depression scale (HADS) total score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -4.8 ± 9.5
    -3.8 ± 7.5
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Placebo v Silexan
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.313
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.87
         upper limit
    		 0.92

    Secondary: Hospital anxiety and depression scale (HADS) anxiety score

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    End point title
    		 Hospital anxiety and depression scale (HADS) anxiety score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -2.6 ± 5.1
    -2 ± 3.9
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 0.36

    Secondary: Hospital anxiety and depression scale (HADS) depression score

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    End point title
    		 Hospital anxiety and depression scale (HADS) depression score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and end of Treatment (10 week Treatment period)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Points
        arithmetic mean (standard deviation)
    -2.2 ± 5
    -1.8 ± 4.1
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    LOCF
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.524
    Method
    		 t-test, 2-sided
    Parameter type
    		 mean difference (change from baseline)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 0.69

    Secondary: CGI Item 1 Improvement by >= 2 categories at week 10

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    End point title
    		 CGI Item 1 Improvement by >= 2 categories at week 10
    End point description
    End point type
    Secondary
    End point timeframe
    End of Treatment (week 10)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    55
    27
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [10] - two-sided

    Secondary: CGI Item 2 <= 2 at week 10

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    End point title
    		 CGI Item 2 <= 2 at week 10
    End point description
    End point type
    Secondary
    End point timeframe
    End of Treatment (week 10)
    End point values
    		 Silexan Placebo
    Number of subjects analysed
    159
    156
    Units: Subjects
    74
    48
    Statistical analysis title
    		 Chi square test
    Statistical analysis description
    LOCF, two-sided
    Comparison groups
    Silexan v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029 [11]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [11] - two-sided

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    10 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    No active treatment
    Reporting group description
    		 No active treatment

    Reporting group title
    Silexan
    Reporting group description
    		 Verum treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Serious adverse events
    		 No active treatment Silexan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 160 (0.63%)
    2 / 158 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 160 (0.63%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 160 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 160 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticular perforation
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 160 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 No active treatment Silexan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 318 (0.63%)
    20 / 160 (12.50%)
    15 / 158 (9.49%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 318 (0.63%)
    4 / 160 (2.50%)
    9 / 158 (5.70%)
         occurrences all number
    2
    5
    10
    Gastrointestinal disorders
    Eructation
         subjects affected / exposed
    0 / 318 (0.00%)
    16 / 160 (10.00%)
    0 / 158 (0.00%)
         occurrences all number
    0
    16
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 318 (0.00%)
    3 / 160 (1.88%)
    8 / 158 (5.06%)
         occurrences all number
    0
    4
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2012
    Amendment No. 2 extended the validity of the exclusion criterion “MADRS item 10 ≥ 2” from screening and baseline visit to the whole course of the trial. Subjects with a score ≥ 2 for item 10 in a visit had to discontinue treatment with the investigational product.
    18 Oct 2012
    Amendment No. 1 comprised a clarification in wording regarding some details of the pre-planned interim analysis.

    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
    For support, Contact us.
    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
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