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    Clinical Trial Results:
    Efficacy and safety of S 47445 versus placebo as adjunctive treatment of Major Depressive Disorder in patients with an inadequate response to antidepressant therapy. A randomised, double-blind, placebo controlled international, multicentre study.

    Summary
    EudraCT number
    2015-003867-13
    Trial protocol
    HU   FI   SK   CZ   BG  
    Global end of trial date
    06 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Mar 2018
    First version publication date
    08 Mar 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CL2-47445-014
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02805439
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assessment of the efficacy of the two doses of S 47445 (15mg/day and 50mg/day) compared to placebo in add on to serotonine selective reuptake inhibitor after two periods of 4-week treatment using the Hamilton Depression Rating Scale 17 items (HAM-D).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    S 47445 was compared to placebo in add on to an antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). SSRIs taken by the patient concomitantly to S 47455 or placebo were managed as recommended in their Summary of Product Characterisitics for the treatment of a depressive episode. Fluvoxamine was contraindicated.
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 71
    Country: Number of subjects enrolled
    Bulgaria: 76
    Country: Number of subjects enrolled
    Czech Republic: 57
    Country: Number of subjects enrolled
    Finland: 25
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Ukraine: 93
    Worldwide total number of subjects
    414
    EEA total number of subjects
    271
    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)
    414
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Male or female patients aged from 18 to 65 years suffering from moderate to severe major depressive episode with an inadequate response to current SSRI after at least 6 weeks of treatment.

    Period 1
    Period 1 title
    First 4-week treatment period (W0-W4)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S 47445 15 mg (W0-W4)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S 47445 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of S47445 15 mg was administered once a day during breakfast with a glass of water.

    Arm title
    S 47445 50 mg (W0-W4)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S 47445 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of S47445 50 mg was administered once a day during breakfast with a glass of water.

    Arm title
    Placebo (W0-W4)
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of placebo was administered once a day during breakfast with a glass of water.

    Number of subjects in period 1
    S 47445 15 mg (W0-W4) S 47445 50 mg (W0-W4) Placebo (W0-W4)
    Started
    70
    66
    278
    Completed
    68
    64
    267
    Not completed
    2
    2
    11
         Consent withdrawn by subject
    1
    1
    4
         Patient left the city.
    -
    -
    1
         Adverse event, non-fatal
    1
    -
    3
         Lack of efficacy
    -
    1
    2
         Protocol deviation
    -
    -
    1
    Period 2
    Period 2 title
    Second 4-week treatment period (W4-W8)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S 47445 15 mg (W4-W8)
    Arm description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to S 47445 15 mg before entering in the second 4-week treatment period (W4-W8).
    Arm type
    Experimental

    Investigational medicinal product name
    S 47445 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of S 47445 15 mg was administered once a day during breakfast with a glass of water.

    Arm title
    S 47445 50 mg (W4-W8)
    Arm description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to S 47445 50 mg before entering in the second 4-week treatment period (W4-W8).
    Arm type
    Experimental

    Investigational medicinal product name
    S 47445 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of S47445 50 mg was administered once a day during breakfast with a glass of water.

    Arm title
    Placebo (W4-W8)
    Arm description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to placebo before entering in the second 4-week treatment period (W4-W8).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of placebo was administered once a day during breakfast with a glass of water.

    Number of subjects in period 2 [1]
    S 47445 15 mg (W4-W8) S 47445 50 mg (W4-W8) Placebo (W4-W8)
    Started
    74
    77
    76
    Completed
    73
    77
    76
    Not completed
    1
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A sequential parallel comparison design was used for the study. Patients starting the period 2 (W4-W8) have not been defined as all patients completing the period 1 (W0-W4) but as those of the placebo not sufficiently improved at the end the period 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S 47445 15 mg (W0-W4)
    Reporting group description
    -

    Reporting group title
    S 47445 50 mg (W0-W4)
    Reporting group description
    -

    Reporting group title
    Placebo (W0-W4)
    Reporting group description
    -

    Reporting group values
    S 47445 15 mg (W0-W4) S 47445 50 mg (W0-W4) Placebo (W0-W4) Total
    Number of subjects
    70 66 278 414
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    69 63 275 407
        From 65-84 years
    1 3 3 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.5 ( 11.6 ) 45.8 ( 12.2 ) 46.7 ( 11.6 ) -
    Gender categorical
    Units: Subjects
        Female
    49 41 198 288
        Male
    21 25 80 126
    Subject analysis sets

    Subject analysis set title
    Re-randomised Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients in placebo group not sufficiently improved at the end of the first 4-week treatment period (W4) were re-randomised either to placebo, S 47445 15 mg or S 47445 50 mg. Re-randomised Full Analysis Set (RFAS) were those re-randomised patients having taken at least one dose of IMP after W4 and having a value at W4 and at least one post W4 value during the second 4-week treatment period (W4-W8) for the primary efficacy endpoint.

    Subject analysis sets values
    Re-randomised Full Analysis Set
    Number of subjects
    227
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    225
        From 65-84 years
    2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.8 ( 11.1 )
    Gender categorical
    Units: Subjects
        Female
    157
        Male
    70

    End points

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    End points reporting groups
    Reporting group title
    S 47445 15 mg (W0-W4)
    Reporting group description
    -

    Reporting group title
    S 47445 50 mg (W0-W4)
    Reporting group description
    -

    Reporting group title
    Placebo (W0-W4)
    Reporting group description
    -
    Reporting group title
    S 47445 15 mg (W4-W8)
    Reporting group description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to S 47445 15 mg before entering in the second 4-week treatment period (W4-W8).

    Reporting group title
    S 47445 50 mg (W4-W8)
    Reporting group description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to S 47445 50 mg before entering in the second 4-week treatment period (W4-W8).

    Reporting group title
    Placebo (W4-W8)
    Reporting group description
    These patients were in the placebo group during W0-W4 and not sufficiently improved at the end of the first 4-week treatment period (W0-W4). They were re-randomised at W4 to placebo before entering in the second 4-week treatment period (W4-W8).

    Subject analysis set title
    Re-randomised Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients in placebo group not sufficiently improved at the end of the first 4-week treatment period (W4) were re-randomised either to placebo, S 47445 15 mg or S 47445 50 mg. Re-randomised Full Analysis Set (RFAS) were those re-randomised patients having taken at least one dose of IMP after W4 and having a value at W4 and at least one post W4 value during the second 4-week treatment period (W4-W8) for the primary efficacy endpoint.

    Primary: Change in HAM-D total score (W0-W4 and W4-W8)

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    End point title
    Change in HAM-D total score (W0-W4 and W4-W8)
    End point description
    During the treatment period W0-W4, expression of the endpoint was change in HAM-D total score between W0 (baseline for this period) and W4. During the treatment period W4-W8, expression of the endpoint was change in HAM-D total score between W4 (baseline for this period) and W8.
    End point type
    Primary
    End point timeframe
    This endpoint was based on the weighted average of W0-W4 and W4-W8 treatment effects.
    End point values
    S 47445 15 mg (W0-W4) S 47445 15 mg (W4-W8) S 47445 50 mg (W0-W4) S 47445 50 mg (W4-W8) Placebo (W0-W4) Placebo (W4-W8)
    Number of subjects analysed
    69
    73
    65
    77
    272
    76
    Units: no units
        arithmetic mean (standard deviation)
    -5.6 ( 4.1 )
    -5.9 ( 4.0 )
    -4.9 ( 4.0 )
    -6.8 ( 4.5 )
    -6.2 ( 4.6 )
    -6.7 ( 5.2 )
    Statistical analysis title
    Primary analysis (W0-W4)
    Statistical analysis description
    All the longitudinal observations at each post-baseline visit on the W0-W4 period of all patients in the FAS were considered.
    Comparison groups
    S 47445 15 mg (W0-W4) v Placebo (W0-W4)
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    1.45
    Variability estimate
    Standard deviation
    Dispersion value
    0.57
    Statistical analysis title
    Primary analysis (W0-W4)
    Statistical analysis description
    All the longitudinal observations at each post-baseline visit on the W0-W4 period of all patients in the FAS were considered.
    Comparison groups
    S 47445 50 mg (W0-W4) v Placebo (W0-W4)
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    2.44
    Variability estimate
    Standard deviation
    Dispersion value
    0.58
    Statistical analysis title
    Primary analysis (W4-W8)
    Statistical analysis description
    All the longitudinal observations at each post-baseline visit on the W4-W8 period of all patients in the RFAS were considered.
    Comparison groups
    S 47445 15 mg (W4-W8) v Placebo (W4-W8)
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    2.36
    Variability estimate
    Standard deviation
    Dispersion value
    0.73
    Statistical analysis title
    Primary analysis (W4-W8)
    Statistical analysis description
    All the longitudinal observations at each post-baseline visit on the W4-W8 period of all patients in the RFAS were considered.
    Comparison groups
    S 47445 50 mg (W4-W8) v Placebo (W4-W8)
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.39
         upper limit
    1.44
    Variability estimate
    Standard deviation
    Dispersion value
    0.72
    Statistical analysis title
    Primary analysis (W0-W4 and W4-W8)
    Statistical analysis description
    The comparison of S47445 15 mg to placebo was based on the weighted average of period W0-W4 and period W4-W8 treatment effects, in the FAS and the RFAS respectively. A weight w=0.5 for each period was used. All the longitudinal observations at each post-baseline visit on the W0-W8 period of all patients in the FAS were considered. Note: the groups to be taken in account for the comparison are [S47445 15 mg (W0-W4) and S47445 15 mg (W4-W8)] versus [Placebo (W0-W4) and Placebo (W4-W8)].
    Comparison groups
    S 47445 15 mg (W0-W4) v Placebo (W0-W4)
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1 [1]
    Method
    Mixed-effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    1.53
    Variability estimate
    Standard deviation
    Dispersion value
    0.46
    Notes
    [1] - One-sided adjusted p-value taking into account Holm procedure for multiplicity adjustment (to be compared to 0.025)
    Statistical analysis title
    Primary analysis (W0-W4 and W4-W8)
    Statistical analysis description
    The comparison of S47445 15 mg to placebo was based on the weighted average of period W0-W4 and period W4-W8 treatment effects, in the FAS and the RFAS respectively. A weight w=0.5 for each period was used. All the longitudinal observations at each post-baseline visit on the W0-W8 period of all patients in the FAS were considered. Note: the groups to be taken in account for the comparison are [S47445 50 mg (W0-W4) and S47445 50 mg (W4-W8)] versus [Placebo (W0-W4) and Placebo (W4-W8)].
    Comparison groups
    S 47445 50 mg (W0-W4) v Placebo (W0-W4)
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1 [2]
    Method
    Mixed-effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    1.57
    Variability estimate
    Standard deviation
    Dispersion value
    0.46
    Notes
    [2] - p-value to be compared to 0.025

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred or worsened or became serious between the first intake and last IMP intake + 15 days (both included), except those for patients in placebo during W0-W4 re-randomised in S 47445 groups between first and last IMP intakes.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    S 47445 15 mg - W0-W4
    Reporting group description
    -

    Reporting group title
    S 47445 50 mg - W0-W4
    Reporting group description
    -

    Reporting group title
    Placebo - W0-W4
    Reporting group description
    -

    Reporting group title
    S 47445 15 mg - W4-W8
    Reporting group description
    -

    Reporting group title
    S 47445 50 mg - W4-W8
    Reporting group description
    -

    Reporting group title
    S 47445 15 mg - W0-W8
    Reporting group description
    -

    Reporting group title
    Placebo - W4-W8
    Reporting group description
    -

    Reporting group title
    S 47445 50 mg - W0-W8
    Reporting group description
    -

    Reporting group title
    Placebo - W0-W8
    Reporting group description
    -

    Serious adverse events
    S 47445 15 mg - W0-W4 S 47445 50 mg - W0-W4 Placebo - W0-W4 S 47445 15 mg - W4-W8 S 47445 50 mg - W4-W8 S 47445 15 mg - W0-W8 Placebo - W4-W8 S 47445 50 mg - W0-W8 Placebo - W0-W8
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    2 / 127 (1.57%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    S 47445 15 mg - W0-W4 S 47445 50 mg - W0-W4 Placebo - W0-W4 S 47445 15 mg - W4-W8 S 47445 50 mg - W4-W8 S 47445 15 mg - W0-W8 Placebo - W4-W8 S 47445 50 mg - W0-W8 Placebo - W0-W8
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 70 (20.00%)
    11 / 66 (16.67%)
    60 / 278 (21.58%)
    10 / 74 (13.51%)
    17 / 77 (22.08%)
    14 / 70 (20.00%)
    17 / 116 (14.66%)
    15 / 66 (22.73%)
    33 / 127 (25.98%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Hangover
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Social circumstances
    Activities of daily living impaired
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Menstruation delayed
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Premenstrual headache
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Emotional poverty
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Suicidal ideation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Tension
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    2 / 66 (3.03%)
    0 / 127 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    2 / 116 (1.72%)
    0 / 66 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    2
    ECG signs of ventricular hypertrophy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    2 / 66 (3.03%)
    0 / 127 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    0
    Electrocardiogram J wave abnormal
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    1 / 77 (1.30%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    3 / 278 (1.08%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    2 / 127 (1.57%)
         occurrences all number
    0
    1
    4
    0
    1
    0
    0
    1
    2
    Dizziness exertional
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    1
    Dizziness postural
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    4 / 278 (1.44%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    4
    0
    1
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    4 / 70 (5.71%)
    4 / 66 (6.06%)
    8 / 278 (2.88%)
    2 / 74 (2.70%)
    3 / 77 (3.90%)
    4 / 70 (5.71%)
    1 / 116 (0.86%)
    4 / 66 (6.06%)
    5 / 127 (3.94%)
         occurrences all number
    4
    4
    8
    2
    3
    5
    1
    4
    5
    Intercostal neuralgia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    2
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 66 (3.03%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    2 / 66 (3.03%)
    0 / 127 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    2
    0
    Tension headache
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Chronic gastritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    2 / 77 (2.60%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Gastroenteritis eosinophilic
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    6 / 278 (2.16%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    2 / 70 (2.86%)
    2 / 116 (1.72%)
    0 / 66 (0.00%)
    3 / 127 (2.36%)
         occurrences all number
    0
    0
    6
    0
    1
    2
    2
    0
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    1
    Urethral prolapse
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 66 (1.52%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 116 (0.00%)
    1 / 66 (1.52%)
    0 / 127 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    1
    0
    Conjunctivitis viral
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    2 / 278 (0.72%)
    1 / 74 (1.35%)
    2 / 77 (2.60%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    3
    1
    2
    0
    1
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 66 (1.52%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    1 / 77 (1.30%)
    2 / 70 (2.86%)
    2 / 116 (1.72%)
    2 / 66 (3.03%)
    3 / 127 (2.36%)
         occurrences all number
    2
    1
    1
    0
    1
    2
    2
    2
    3
    Respiratory tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    3 / 278 (1.08%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    2 / 116 (1.72%)
    0 / 66 (0.00%)
    4 / 127 (3.15%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    2
    0
    5
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    2 / 70 (2.86%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    1 / 74 (1.35%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    0 / 127 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 278 (0.00%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 116 (0.86%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    1 / 278 (0.36%)
    0 / 74 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 116 (0.00%)
    0 / 66 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2016
    Breast Cancer Resistance Protein substrate was forbidden as concomitant treatment except those prescribed at lower dosage and already described in the protocol. To ensure a more accurate follow-up and analysis of suicidal ideation, these symptoms when collected with Columbia Suicide Severity Rating Scale had to be reported as adverse event.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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