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    Clinical Trial Results:
    Multi-centre, double-blind, placebo- and reference-controlled, randomised trial to prove the efficacy and safety of Silexan (WS®1265) in patients with a major depressive episode of mild to moderate severity

    Summary
    EudraCT number
    		 2020-000688-22
    Trial protocol
    		 DE   PL  
    Global end of trial date
    29 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2024
    First version publication date
    18 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    750203.01.002
    Additional study identifiers
    ISRCTN number
    		 ISRCTN36202964
    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
    Anna Wacker, Dr. Willmar Schwabe GmbH & Co. KG, +49 7214005628, Anna.Wacker@schwabe.de
    Scientific contact
    Anna Wacker, Dr. Willmar Schwabe GmbH & Co. KG, +49 7214005628, Anna.Wacker@schwabe.de
    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
    17 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate superiority of 80 mg/day Silexan once daily vs placebo with respect to the change of the MADRS total score between baseline and week 8 when treating Major Depressive Disorders (MDD) of mild to moderate intensity, regardless of adherence to the treatment regime and under the hypothetical condition that treatments which ease depressive symptoms are not available for patients who discontinue from the randomised treatment.
    Protection of trial subjects
    Possibility to withdraw consent by patient. Monitoring of adverse events and laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 The comparator Sertraline to be used in this study is a Selective Serotonin Reuptake Inhibitor (SSRIs) indicated for the treatment of MDD. For our outpatient population with mild to moderate MDD we intend to implement a dosage of 50 mg Sertraline. This dose has shown effectiveness (Fabre et al. 1995) and is related with a relatively lower adverse event rate, compared to higher dosages. For the outpatient sample being examined in this study we deem it crucial to have a low adverse event and hence dropout rate.
    Actual start date of recruitment
    01 Oct 2020
    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
    Poland: 129
    Country: Number of subjects enrolled
    Germany: 448
    Worldwide total number of subjects
    577
    EEA total number of subjects
    577
    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)
    530
    From 65 to 84 years
    46
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 577 subjects were screened for eligibility. Of these, 77 subjects were not randomised, 2 subjects were randomised but did not take any dose of IMP

    Pre-assignment period milestones
    Number of subjects started
    		 577
    Number of subjects completed
    		 498

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 13
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 In-Exclusion criteria not fulfilled: 53
    Reason: Number of subjects
    		 Lost to Follow-Up: 1
    Reason: Number of subjects
    		 Other: 9
    Reason: Number of subjects
    		 Randomised without intake of IMP: 2
    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 80 mg
    Arm description
    		 1 x 1 capsule with a daily total of 80 mg Silexan (WS® 1265) and 1 x 1 capsule Sertraline placebo/day
    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 1 capsule Silexan + 1 x 1 capsule Sertraline placebo

    Arm title
    		 Sertraline 50 mg
    Arm description
    		 1 x 1 capsule with a daily total of 50 mg Sertraline and 1 x 1 capsule Silexan placebo/day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1 capsule Sertraline + 1 x 1 capsule Silexan placebo

    Arm title
    		 Placebo
    Arm description
    		 1 x 1 capsule Silexan placebo and 1 x 1 capsule Sertraline placebo/day
    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
    1 x 1 capsule Silexan placebo and 1 x 1 capsule Sertraline placebo

    Number of subjects in period 1 [1]
    		Silexan 80 mg Sertraline 50 mg Placebo
    Started
    170
    171
    157
    Completed
    154
    151
    141
    Not completed
    16
    20
    16
         Consent withdrawn by subject
    1
    3
    3
         Adverse event, non-fatal
    8
    10
    5
         Other
    4
    2
    2
         Lost to Follow-Up
    1
    3
    4
         In-Exclusion criteria not fulfilled
    -
    -
    2
         Lack of efficacy
    2
    2
    -
    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: Two subjects of the Placebo-group were randomised but did not take any dose of the IMP

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Silexan 80 mg
    Reporting group description
    		 1 x 1 capsule with a daily total of 80 mg Silexan (WS® 1265) and 1 x 1 capsule Sertraline placebo/day

    Reporting group title
    Sertraline 50 mg
    Reporting group description
    		 1 x 1 capsule with a daily total of 50 mg Sertraline and 1 x 1 capsule Silexan placebo/day

    Reporting group title
    Placebo
    Reporting group description
    		 1 x 1 capsule Silexan placebo and 1 x 1 capsule Sertraline placebo/day

    Reporting group values
    		 Silexan 80 mg Sertraline 50 mg Placebo Total
    Number of subjects
    		 170 171 157 498
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 159 159 138 456
        From 65-84 years
    		 11 12 19 42
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.7 ( 14.52 ) 44.7 ( 14.36 ) 46.6 ( 15.66 ) -
    Gender categorical
    Units: Subjects
        Female
    		 118 110 99 327
        Male
    		 52 61 58 171
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants who took at least one dose of the IMP (participants were analysed as treated).

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    498
    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)
    456
        From 65-84 years
    42
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.7 ( 14.83 )
    Gender categorical
    Units: Subjects
        Female
    327
        Male
    171

    End points

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    End points reporting groups
    Reporting group title
    Silexan 80 mg
    Reporting group description
    		 1 x 1 capsule with a daily total of 80 mg Silexan (WS® 1265) and 1 x 1 capsule Sertraline placebo/day

    Reporting group title
    Sertraline 50 mg
    Reporting group description
    		 1 x 1 capsule with a daily total of 50 mg Sertraline and 1 x 1 capsule Silexan placebo/day

    Reporting group title
    Placebo
    Reporting group description
    		 1 x 1 capsule Silexan placebo and 1 x 1 capsule Sertraline placebo/day

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants who took at least one dose of the IMP (participants were analysed as treated).

    Primary: Change from Baseline in MADRS total score - Silexan and Placebo

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    End point title
    		 Change from Baseline in MADRS total score - Silexan and Placebo [1]
    End point description
    MADRS total score change from baseline to week 8 (Comparison between Silexan and Placebo)
    End point type
    Primary
    End point timeframe
    Baseline and Week 8
    Notes
    [1] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -12.12 (-13.26 to -10.98)
    -9.95 (-11.13 to -8.77)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.76
         upper limit
    		 -0.58
    Notes
    [2] - one-sided

    Secondary: Change from Baseline in MADRS total score - Sertraline and Placebo

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    End point title
    		 Change from Baseline in MADRS total score - Sertraline and Placebo [3]
    End point description
    MADRS total score change from baseline to week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [3] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -12.61 (-13.74 to -11.49)
    -10.02 (-11.19 to -8.85)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.17
         upper limit
    		 -1.02
    Notes
    [4] - two-sided

    Secondary: At least 50% reduction of MADRS total score (responder) - Silexan and Placebo

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    End point title
    		 At least 50% reduction of MADRS total score (responder) - Silexan and Placebo [5]
    End point description
    At least 50% reduction of MADRS total score from baseline to week 8 (responder) (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    At week 8
    Notes
    [5] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Patients
    91
    65
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0337 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 2.55
    Notes
    [6] - two-sided

    Secondary: At least 50% reduction of MADRS total score (responder) - Sertraline and Placebo

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    End point title
    		 At least 50% reduction of MADRS total score (responder) - Sertraline and Placebo [7]
    End point description
    At least 50% reduction of MADRS total score from baseline to week 8 (responder) (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [7] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Patients
    92
    65
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0311 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.61
    Notes
    [8] - two-sided

    Secondary: MADRS total score < 10 (remitter) - Silexan and Placebo

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    End point title
    		 MADRS total score < 10 (remitter) - Silexan and Placebo [9]
    End point description
    MADRS total score < 10 at week 8 (remitter) (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [9] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Patients
    75
    51
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0315 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.63
    Notes
    [10] - two-sided

    Secondary: MADRS total score < 10 (remitter) - Sertraline and Placebo

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    End point title
    		 MADRS total score < 10 (remitter) - Sertraline and Placebo [11]
    End point description
    MADRS total score < 10 at week 8 (remitter) (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [11] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Patients
    77
    51
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0246 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 2.72
    Notes
    [12] - two-sided

    Secondary: Change from Baseline in CGI (Item 1, severity) - Silexan and Placebo

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    End point title
    		 Change from Baseline in CGI (Item 1, severity) - Silexan and Placebo [13]
    End point description
    CGI (Item 1, severity) change from baseline to week 8 (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [13] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -0.95 (-1.11 to -0.80)
    -0.78 (-0.94 to -0.62)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1114 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.04
    Notes
    [14] - two-sided

    Secondary: Change from Baseline in CGI (Item 1, severity) - Sertraline and Placebo

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    End point title
    		 Change from Baseline in CGI (Item 1, severity) - Sertraline and Placebo [15]
    End point description
    CGI (Item 1, severity) change from baseline to week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [15] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -1.04 (-1.19 to -0.89)
    -0.79 (-0.94 to -0.63)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.04
    Notes
    [16] - two-sided

    Secondary: Clinical global impression (CGI) Item 2 (change) - Silexan and Placebo

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    End point title
    		 Clinical global impression (CGI) Item 2 (change) - Silexan and Placebo [17]
    End point description
    Clinical global impression (CGI) Item 2 (change) at week 8 (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [17] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    2.51 (2.32 to 2.70)
    2.72 (2.52 to 2.91)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1271 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.06
    Notes
    [18] - two-sided

    Secondary: Clinical global impression (CGI) Item 2 (change) - Sertraline and Placebo

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    End point title
    		 Clinical global impression (CGI) Item 2 (change) - Sertraline and Placebo [19]
    End point description
    Clinical global impression (CGI) Item 2 (change) at week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [19] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    2.37 (2.18 to 2.56)
    2.74 (2.55 to 2.94)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0058 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 -0.11
    Notes
    [20] - two-sided

    Secondary: Change from Baseline in Patient health questionnaire (PHQ-9) total score - Silexan and Placebo

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    End point title
    		 Change from Baseline in Patient health questionnaire (PHQ-9) total score - Silexan and Placebo [21]
    End point description
    Patient health questionnaire (PHQ-9) total score change from baseline to week 8 (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [21] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -5.10 (-5.77 to -4.42)
    -4.26 (-4.95 to -3.57)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0768 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 0.09
    Notes
    [22] - two-sided

    Secondary: Change from Baseline in Patient health questionnaire (PHQ-9) total score - Sertraline and Placebo

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    End point title
    		 Change from Baseline in Patient health questionnaire (PHQ-9) total score - Sertraline and Placebo [23]
    End point description
    Patient health questionnaire (PHQ-9) total score change from baseline to week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [23] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -5.42 (-6.05 to -4.79)
    -4.18 (-4.83 to -3.53)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0057 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.12
         upper limit
    		 -0.36
    Notes
    [24] - two-sided

    Secondary: Change from Baseline in Beck depression inventory (BDI-II) total score - Silexan and Placebo

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    End point title
    		 Change from Baseline in Beck depression inventory (BDI-II) total score - Silexan and Placebo [25]
    End point description
    Beck depression inventory (BDI-II) total score change from baseline to week 8 (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [25] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -10.06 (-11.36 to -8.76)
    -8.48 (-9.82 to -7.13)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0847 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.38
         upper limit
    		 0.02
    Notes
    [26] - two-sided

    Secondary: Change from Baseline in Beck depression inventory (BDI-II) total score - Sertraline and Placebo

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    End point title
    		 Change from Baseline in Beck depression inventory (BDI-II) total score - Sertraline and Placebo [27]
    End point description
    Beck depression inventory (BDI-II) total score change from baseline to week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [27] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -10.84 (-12.13 to -9.54)
    -8.41 (-9.75 to -7.07)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Sertraline 50 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0083 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.23
         upper limit
    		 -0.63
    Notes
    [28] - two-sided

    Secondary: Change from Baseline in Sheehan disability (SDS) total score - Silexan and Placebo

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    End point title
    		 Change from Baseline in Sheehan disability (SDS) total score - Silexan and Placebo [29]
    End point description
    Sheehan disability (SDS) total score change from baseline to week 8 (Comparison between Silexan and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [29] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Silexan 80 mg Placebo
    Number of subjects analysed
    170
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -6.07 (-7.03 to -5.10)
    -3.67 (-4.68 to -2.65)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Silexan 80 mg v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.76
         upper limit
    		 -1.04
    Notes
    [30] - two-sided

    Secondary: Change from Baseline in Sheehan disability (SDS) total score - Sertraline and Placebo

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    End point title
    		 Change from Baseline in Sheehan disability (SDS) total score - Sertraline and Placebo [31]
    End point description
    Sheehan disability (SDS) total score change from baseline to week 8 (Comparison between Sertraline and Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [31] - 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: Pairwise comparisons between active treatment groups and placebo are presented
    End point values
    		 Sertraline 50 mg Placebo
    Number of subjects analysed
    171
    157
    Units: Points
        least squares mean (confidence interval 95%)
    -4.35 (-5.39 to -3.31)
    -3.54 (-4.60 to -2.47)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model including the baseline value as a covariate and factors for trial site and treatment Full Analysis Set based on multiple imputations with n=100
    Comparison groups
    Placebo v Sertraline 50 mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2671 [32]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 0.63
    Notes
    [32] - two-sided

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    9 weeks
    Adverse event reporting additional description
    Multi-centre, double-blind, placebo- and reference-controlled, randomised trial to prove the efficacy and safety of Silexan (WS1265) in patients with a major depressive episode of mild to moderate severity
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Sertraline
    Reporting group description
    		 Compare medication

    Reporting group title
    Silexan
    Reporting group description
    		 Study medication

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Reporting group title
    No active treatment
    Reporting group description
    		 No active treatment

    Serious adverse events
    		 Sertraline Silexan Placebo No active treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 171 (3.51%)
    7 / 170 (4.12%)
    4 / 157 (2.55%)
    0 / 498 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 157 (0.64%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 157 (0.64%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Acute disseminated encephalomyelitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 171 (1.17%)
    2 / 170 (1.18%)
    2 / 157 (1.27%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 157 (0.00%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sertraline Silexan Placebo No active treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 171 (21.64%)
    46 / 170 (27.06%)
    22 / 157 (14.01%)
    7 / 498 (1.41%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 171 (8.77%)
    5 / 170 (2.94%)
    10 / 157 (6.37%)
    0 / 498 (0.00%)
         occurrences all number
    16
    6
    11
    0
    Gastrointestinal disorders
    Eructation
         subjects affected / exposed
    0 / 171 (0.00%)
    28 / 170 (16.47%)
    1 / 157 (0.64%)
    0 / 498 (0.00%)
         occurrences all number
    0
    29
    1
    0
    Nausea
         subjects affected / exposed
    9 / 171 (5.26%)
    4 / 170 (2.35%)
    6 / 157 (3.82%)
    1 / 498 (0.20%)
         occurrences all number
    9
    5
    6
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 171 (5.26%)
    4 / 170 (2.35%)
    3 / 157 (1.91%)
    2 / 498 (0.40%)
         occurrences all number
    9
    4
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    10 / 171 (5.85%)
    15 / 170 (8.82%)
    4 / 157 (2.55%)
    4 / 498 (0.80%)
         occurrences all number
    10
    15
    4
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2021
    Reduction of the number of German trial sites that participate in the trial and adjusting of the maximal number of patients that should be recruited by a single site. Refence document for the assessment of the expectedness of an adverse event was set to the current version of the Fachinformation for Lasea®. Positive German ethics committee vote: 07. May 2021 / Approval of the German competent authority: 13. April 2021.
    18 Oct 2021
    Adapting of timelines due to slower recruitment during corona pandemic and the actions that might be taken in case of a new lockdown, taking in consideration the EMA Guidance on the Management of Clinical Trials during the Covid-19 (Coronavirus) pandemic (Version 4 from 04.02.2021). Change of project leader of the sponsor. Change to a multinational clinical trial by additional participation of Polish centres, involvement of a second contract research organisation to conduct the trial in Poland, and adaptation of the maximum number of patients per site. Including a section ‘Regional Variability’. Randomisation process was described for Poland. Updating the expected percentage for an intercurrent event to take into account the greater number of patients discontinuing treatment due to an adverse event, which was found after analysing about 100 randomised patients. Subgroup analysis by country was added. Positive German ethics committee vote: 15. December 2021 / Approval of the German competent authority: 30. November 2021. This amended protocol version was also submitted in Poland: positive Polish ethics committee vote: 18. January 2022 / Approval of the Polish competent authority: 01. May 2022.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38558147
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