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    Clinical Trial Results:
    Efficacy and safety of 3 doses of S 38093 (2, 5 and 20 mg/day) versus placebo in patients with mild to moderate Alzheimer’s disease. A 24-week international, multi-centre, randomised, double-blind, placebo-controlled phase IIb study followed by a 24-week extension period.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2010-024626-37
    Trial protocol
    DE   CZ   PT   HU   BG  
    Global end of trial date
    21 Mar 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    22 Jul 2016
    First version publication date
    31 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT – Results

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-38093-011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier (I.R.I.S.)
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, +33 1 55 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
    17 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this trial was to assess the efficacy and safety of S 38093 versus placebo in patients with mild to moderate Alzheimer’s disease (AD).
    Protection of trial subjects
    Reasons could lead to premature discontinuation of treatment: - Adverse event: any medical reason or circumstance justifying the discontinuation of the treatment in the investigator’s opinion. The patient was to be withdrawn from the study in case of a repeated demonstration of a QTcF > 500 ms or a delta > 60 ms over baseline (inclusion) value. The following changes in hepatic enzymes should led to treatment discontinuation of a study participant: ALAT or ASAT > 8x ULN. ALAT or ASAT > 5x ULN for more than 2 weeks. ALAT or ASAT > 3x ULN and total bilirubin > 2x ULN. ALAT or ASAT > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). - Protocol deviation: in case of a missing informed consent or if there was any deviation that could compromise the patient’s safety. - Lack of efficacy (in the investigator’s opinion). - Non medical reason (e.g. patient’s consent withdrawal). - Lost to follow-up: when the investigator had no news from the patient, s/he had to make every effort to contact him/her, to establish if the study treatment had been discontinued, obtain information on the reason for the treatment discontinuation, and to suggest the patient to come to an end-of-study visit. If all attempts to contact the participant failed, the investigator could then declare the participant “lost to follow-up”. The investigator had to document all attempts in the corresponding medical file.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Czech Republic: 57
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Bulgaria: 70
    Country: Number of subjects enrolled
    Germany: 75
    Country: Number of subjects enrolled
    Hungary: 48
    Country: Number of subjects enrolled
    Australia: 43
    Country: Number of subjects enrolled
    Brazil: 53
    Country: Number of subjects enrolled
    Chile: 65
    Country: Number of subjects enrolled
    Mexico: 51
    Country: Number of subjects enrolled
    Romania: 36
    Country: Number of subjects enrolled
    Russian Federation: 115
    Country: Number of subjects enrolled
    South Africa: 53
    Worldwide total number of subjects
    711
    EEA total number of subjects
    331
    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)
    112
    From 65 to 84 years
    588
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Six hundred (600) out-patients aged 55 to 85 years with mild to moderate Alzheimer’s disease were to be included and randomly assigned either S 38093 2 mg/day or S 38093 5 mg/day or S 38093 20 mg/day or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S 38093 2 mg
    Arm description
    -
    Arm type
    Test drug

    Investigational medicinal product name
    S 38093
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet, orally, with a glass of water, once a day, upon waking in the morning.

    Arm title
    S 38093 5 mg
    Arm description
    -
    Arm type
    Test drug

    Investigational medicinal product name
    S 38093
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet, orally, with a glass of water, once a day, upon waking in the morning.

    Arm title
    S 38093 20 mg
    Arm description
    -
    Arm type
    Test drug

    Investigational medicinal product name
    S 38093
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet, orally, with a glass of water, once a day, upon waking in the morning.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet, orally, with a glass of water, once a day, upon waking in the morning.

    Number of subjects in period 1
    S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Started
    176
    175
    181
    179
    Completed
    151
    158
    162
    162
    Not completed
    25
    17
    19
    17
         Adverse event, non-fatal
    6
    6
    7
    6
         Non-medical reason
    14
    9
    8
    7
         Protocol deviation
    5
    -
    3
    4
         Lack of efficacy
    -
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S 38093 2 mg
    Reporting group description
    -

    Reporting group title
    S 38093 5 mg
    Reporting group description
    -

    Reporting group title
    S 38093 20 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo Total
    Number of subjects
    176 175 181 179 711
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    22 29 27 34 112
        From 65-84 years
    152 142 151 143 588
        85 years and over
    2 4 3 2 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    73 ± 7 71.9 ± 7.2 72.2 ± 7.2 71.4 ± 7.2 -
    Gender categorical
    Units: Subjects
        Female
    101 105 120 116 442
        Male
    75 70 61 63 269

    End points

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    End points reporting groups
    Reporting group title
    S 38093 2 mg
    Reporting group description
    -

    Reporting group title
    S 38093 5 mg
    Reporting group description
    -

    Reporting group title
    S 38093 20 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Randomised Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All included patients were randomised (711 patients).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Consisted of 690 patients

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Consisted of 569 patients

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Consisted of 709 patients.

    Primary: ADAS-Cog total score

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    End point title
    ADAS-Cog total score
    End point description
    To assess the efficacy of 3 fixed doses of S 38093 (2, 5 and 20 mg/ day) versus placebo after 24 weeks of treatment, on cognitive performance measured with the ADAS-Cog 11-item in patients with mild to moderate AD.
    End point type
    Primary
    End point timeframe
    From baseline to W24
    End point values
    S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Number of subjects analysed
    153 [1]
    161 [2]
    166 [3]
    161 [4]
    Units: score
        arithmetic mean (standard deviation)
    -0.45 ± 5.32
    0.1 ± 5.53
    -0.12 ± 5.22
    0.34 ± 5.55
    Notes
    [1] - FAS having a value of the change from baseline at W24 of the ADAS-Cog total score
    [2] - FAS having a value of the change from baseline at W24 of the ADAS-Cog total score
    [3] - FAS having a value of the change from baseline at W24 of the ADAS-Cog total score
    [4] - FAS having a value of the change from baseline at W24 of the ADAS-Cog total score
    Statistical analysis title
    S 38093 2 mg vs Placebo
    Comparison groups
    Placebo v S 38093 2 mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47
    Method
    Mixed-effects Model Repeated Measures
    Parameter type
    Ajusted Mean difference
    Point estimate
    -0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59
    Statistical analysis title
    S 38093 20 mg vs Placebo
    Comparison groups
    Placebo v S 38093 20 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.835
    Method
    Mixed-effects Model Repeated Measures
    Parameter type
    Ajusted Mean difference
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.78
         upper limit
    0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Statistical analysis title
    S 38093 5 mg vs Placebo
    Comparison groups
    S 38093 5 mg v Placebo
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Mixed-effects Model Repeated Measures
    Parameter type
    Ajusted Mean difference
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the 48-week treatment period for S 38093 2mg, 5mg and 20 mg During the 24-week double-blind treatment period for Placebo
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    S 38093 2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    S 38093 20 mg
    Reporting group description
    -

    Reporting group title
    S 38093 5 mg
    Reporting group description
    -

    Serious adverse events
    S 38093 2 mg Placebo S 38093 20 mg S 38093 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 176 (14.77%)
    12 / 178 (6.74%)
    34 / 180 (18.89%)
    26 / 175 (14.86%)
         number of deaths (all causes)
    5
    0
    3
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 176 (1.14%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Abasia
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Choking
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydropneumothorax
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 178 (0.56%)
    7 / 180 (3.89%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Middle insomnia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 176 (1.14%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Heart rate decreased
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 176 (2.84%)
    3 / 178 (1.69%)
    3 / 180 (1.67%)
    7 / 175 (4.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    2 / 175 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusion postoperative
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital contusion
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    2 / 180 (1.11%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Tachycardia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    3 / 175 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    2 / 175 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Dysarthria
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hemiparesis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circadian rhythm sleep disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coordination abnormal
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune thrombocytopenia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocele
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (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
    Skin ulcer
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Dupuytren's contracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 176 (1.14%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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: 3%
    Non-serious adverse events
    S 38093 2 mg Placebo S 38093 20 mg S 38093 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 176 (57.95%)
    90 / 178 (50.56%)
    126 / 180 (70.00%)
    115 / 175 (65.71%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 176 (3.98%)
    3 / 178 (1.69%)
    5 / 180 (2.78%)
    2 / 175 (1.14%)
         occurrences all number
    7
    3
    5
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    13 / 176 (7.39%)
    4 / 178 (2.25%)
    16 / 180 (8.89%)
    15 / 175 (8.57%)
         occurrences all number
    14
    4
    23
    16
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 176 (4.55%)
    8 / 178 (4.49%)
    12 / 180 (6.67%)
    8 / 175 (4.57%)
         occurrences all number
    9
    8
    13
    8
    Orthostatic hypotension
         subjects affected / exposed
    6 / 176 (3.41%)
    3 / 178 (1.69%)
    6 / 180 (3.33%)
    3 / 175 (1.71%)
         occurrences all number
    6
    3
    6
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 176 (1.70%)
    4 / 178 (2.25%)
    7 / 180 (3.89%)
    6 / 175 (3.43%)
         occurrences all number
    3
    5
    8
    7
    Headache
         subjects affected / exposed
    6 / 176 (3.41%)
    4 / 178 (2.25%)
    6 / 180 (3.33%)
    7 / 175 (4.00%)
         occurrences all number
    6
    4
    8
    7
    Somnolence
         subjects affected / exposed
    2 / 176 (1.14%)
    6 / 178 (3.37%)
    5 / 180 (2.78%)
    4 / 175 (2.29%)
         occurrences all number
    2
    6
    5
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 176 (3.41%)
    4 / 178 (2.25%)
    12 / 180 (6.67%)
    3 / 175 (1.71%)
         occurrences all number
    7
    4
    12
    3
    Nausea
         subjects affected / exposed
    1 / 176 (0.57%)
    3 / 178 (1.69%)
    7 / 180 (3.89%)
    5 / 175 (2.86%)
         occurrences all number
    1
    3
    7
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 176 (1.14%)
    2 / 178 (1.12%)
    11 / 180 (6.11%)
    4 / 175 (2.29%)
         occurrences all number
    2
    2
    11
    4
    Anxiety
         subjects affected / exposed
    1 / 176 (0.57%)
    3 / 178 (1.69%)
    8 / 180 (4.44%)
    5 / 175 (2.86%)
         occurrences all number
    1
    4
    9
    5
    Insomnia
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 178 (0.56%)
    5 / 180 (2.78%)
    7 / 175 (4.00%)
         occurrences all number
    0
    1
    5
    7
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    9 / 176 (5.11%)
    3 / 178 (1.69%)
    8 / 180 (4.44%)
    14 / 175 (8.00%)
         occurrences all number
    9
    3
    9
    15
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    5 / 176 (2.84%)
    5 / 178 (2.81%)
    2 / 180 (1.11%)
    13 / 175 (7.43%)
         occurrences all number
    5
    5
    2
    13
    Urinary tract infection bacterial
         subjects affected / exposed
    6 / 176 (3.41%)
    3 / 178 (1.69%)
    4 / 180 (2.22%)
    9 / 175 (5.14%)
         occurrences all number
    8
    3
    4
    11
    Urinary tract infection
         subjects affected / exposed
    3 / 176 (1.70%)
    2 / 178 (1.12%)
    8 / 180 (4.44%)
    7 / 175 (4.00%)
         occurrences all number
    3
    2
    8
    10
    Nasopharyngitis
         subjects affected / exposed
    4 / 176 (2.27%)
    0 / 178 (0.00%)
    8 / 180 (4.44%)
    3 / 175 (1.71%)
         occurrences all number
    4
    0
    8
    3
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    9 / 176 (5.11%)
    3 / 178 (1.69%)
    4 / 180 (2.22%)
    9 / 175 (5.14%)
         occurrences all number
    9
    4
    5
    9
    Hypertriglyceridaemia
         subjects affected / exposed
    9 / 176 (5.11%)
    2 / 178 (1.12%)
    7 / 180 (3.89%)
    3 / 175 (1.71%)
         occurrences all number
    11
    2
    9
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2011
    Amendment No. 1 was applicable only in Czech Republic. The competent Authorities requested that in addition to be at least in personal contact for 10h per week with the patient and to have known him for at least one year, the informant was also to be either in a common household with the patient or to be in daily contact with him.
    07 Dec 2011
    Amendment No. 2 concerned all centres in all countries (international amendment). The main changes were: - Specification of international units for vitamin B12 cut-off levels (in pmol/L instead of pg/mL) in the biological non-inclusion criteria, without change of the cut-off value. - Addition of an antidepressant, agomelatine, to the list of forbidden treatments. - Further explanations concerning the eligibility of the patient for MMSE were added. - Checklist for brain MRI and corresponding MRI non-inclusion criteria had been updated to be adapted to the 1 Tesla machines that were to be used in the study. - MDRDs formula had been corrected since there was an error in the initial protocol. - Addition of heart rate data collection to the vital signs recorded during the study, using the Automatic Blood Pressure Monitor each time the blood pressure was recorded. - For “Surgery for cataract”, event that did not require immediate notification, it was specified that it applied only if surgery for cataract was not associated with any worsening after randomisation. - DMC was given access to the study treatment via IRS, and was allowed to recommend continuation of the study with modification(s) on study design. - Some scale instructions and worksheets were updated to be in line with the versions finally used in the study (the scales concerned were MMSE, ADCS-CGIC, ADAS-Cog, NPI). - Additional information on the management of the therapeutics units and dispensing of study treatment. - Administrative changes, correction of typing errors and update on logistics.
    03 Jan 2012
    Amendment No. 3, was applicable only in Portugal. The Ethics Committee of Portugal (CEIC) requested that patients previously treated with AchEI and / or memantine and who were non-responders or did not tolerate the treatment, were eligible for selection into the study.
    27 Apr 2012
    Amendment No. 4, concerned all centres in all countries (international amendment). The objective of this amendment was to allow patients suffering from mild to moderate Alzheimer’s disease, with a slightly higher load of concomitant vascular lesions, to participate in this study. Consequently, the non-inclusion criteria of the brain MRI were modified to allow patients with white matter lesions grade 1 and grade 2 (classified according to the Fazekas scale), common in patients with Alzheimer’s disease, to be included in the study. In addition, ADAS-Cog wordlists for recall and recognition tasks were corrected. Additional updates (on drug concentration measurements, glossary and definitions) and corrections of typing errors noted in the protocol were also implemented.

    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.
    The section NSAE presented EAEs on treatment and included SEAEs. The causality and seriousness of reported SAE can be ultimately upgraded by the sponsor. The sponsor took these decisions to be compliant with the existing ICH E3 Clinical Study Report.
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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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