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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 co-administration with donepezil (10 mg/day) in patients with moderate Alzheimer’s Disease. A 24-week international, multi-centre, randomised, double-blind, placebo-controlled phase IIb study.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2011-005862-40
    Trial protocol
    		 DE   AT   FI   ES   GB   SE   PT   SK   IT   PL  
    Global end of trial date
    29 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2016
    First version publication date
    04 May 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL2-38093-012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, 33 155724366, 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
    29 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of 3 fixed doses of S 38093 (2, 5 and 20 mg/ day) versus placebo, in co-administration with donepezil 10 mg/day, after 24 weeks of treatment, on cognitive performance measured with the ADAS-Cog 11-items in patients with moderate Alzheimer's Disease
    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
    		 -
    Evidence for comparator
    		 Placebo
    Actual start date of recruitment
    04 Oct 2012
    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
    Argentina: 44
    Country: Number of subjects enrolled
    Australia: 52
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Brazil: 41
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    Finland: 15
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Italy: 76
    Country: Number of subjects enrolled
    Mexico: 48
    Country: Number of subjects enrolled
    Poland: 130
    Country: Number of subjects enrolled
    Portugal: 42
    Country: Number of subjects enrolled
    Slovakia: 60
    Country: Number of subjects enrolled
    Spain: 115
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    United Kingdom: 67
    Worldwide total number of subjects
    806
    EEA total number of subjects
    586
    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)
    138
    From 65 to 84 years
    640
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 Investigators were neuropsychiatrists, neurologists or geriatricians

    Pre-assignment
    Screening details
    		 Out-patients aged 55-90 years (Amendment n°6), school education ≥ 4 years, with memory impairment (DSM-IV-TR criteria for dementia of AD type and NINCDS/ADRDA criteria for probable AD), MMSE at selection = 12-20 inclusive, brain MRI at selection, identified informant, and stable donepezil 10 mg/day for at least 3 months before selection.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study products of identical appareance, S 38093 2 mg, S38093 5 mg, S38093 20 mg or placebo, were assigned by a balanced, non-adaptive randomisation, with stratification by country. Treatment randomisation and allocations centralised (Interactive Response System).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S 38093 2 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S 38093 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of S 38093 2 mg, with a glass of water, once a day, upon waking in the morning. In addition, the patients had to take 1 tablet of donepezil (10mg) orally once daily.

    Arm title
    		 S 38093 5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S 38093 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of S 38093 5 mg, with a glass of water, once a day, upon waking in the morning. In addition, the patients had to take 1 tablet of donepezil (10mg) orally once daily.

    Arm title
    		 S 38093 20 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S 38093 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of S 38093 20 mg, with a glass of water, once a day, upon waking in the morning. In addition, the patients had to take 1 tablet of donepezil (10mg) orally once daily.

    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 oral film-coated tablet of Placebo, with a glass of water, once a day, upon waking in the morning. In addition, the patients had to take 1 tablet of donepezil (10mg) orally once daily.

    Number of subjects in period 1
    		S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Started
    201
    202
    203
    200
    Completed
    181
    178
    173
    181
    Not completed
    20
    24
    30
    19
         Adverse event, serious fatal
    1
    1
    2
    2
         Adverse event, non-fatal
    8
    12
    12
    8
         Non-medical reason
    6
    6
    8
    3
         Protocol deviation
    3
    5
    7
    6
         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
    		 201 202 203 200 806
    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)
    		 31 39 29 39 138
        From 65-84 years
    		 160 159 165 156 640
        85 years and over
    		 10 4 9 5 28
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.7 ( 7.6 ) 72.1 ( 7.6 ) 73.3 ( 7.4 ) 72.5 ( 8.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 129 130 131 114 504
        Male
    		 72 72 72 86 302
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the Randomised Set having taken at least one dose of study drug and having a value at baseline and at least one post-baseline value for the primary criterion.

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    765
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    132
        From 65-84 years
    606
        85 years and over
    27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    72.6 ( 7.7 )
    Gender categorical
    Units: Subjects
        Female
    481
        Male
    284

    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
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the Randomised Set having taken at least one dose of study drug and having a value at baseline and at least one post-baseline value for the primary criterion.

    Primary: 11-item ADAS-Cog total score

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    End point title
    		 11-item ADAS-Cog total score
    End point description
    End point type
    Primary
    End point timeframe
    Evaluation at inclusion, week 12 and week 24 or in case of premature withdrawal. The main analytical approach was the change from baseline to W24.
    End point values
    		 S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Number of subjects analysed
    191
    192
    193
    189
    Units: no unit
        arithmetic mean (standard error)
    1.08 ( 5.07 )
    1.08 ( 5.93 )
    0.48 ( 6.26 )
    0.52 ( 6 )
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    S 38093 2 mg v Placebo
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 1.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    S 38093 20 mg v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 1.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    S 38093 5 mg v Placebo
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred or worsened or became serious according to the investigator, or upgraded by the Sponsor, between the first study drug intake and the last study drug intake date + 10 days (both included).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    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
    		 -

    Serious adverse events
    		 S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 199 (6.03%)
    15 / 200 (7.50%)
    19 / 202 (9.41%)
    23 / 199 (11.56%)
         number of deaths (all causes)
    1
    2
    2
    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
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Colon cancer
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Diffuse large B-cell lymphoma stage IV
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Hypertension
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Sudden death
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 200 (0.50%)
    2 / 202 (0.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    1 / 199 (0.50%)
         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
    Delusion
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Depression
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Depressive symptom
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Hallucination
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    0 / 199 (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
    Hallucinations, mixed
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    2 / 202 (0.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Major depression
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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 creatinine increased
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Fall
         subjects affected / exposed
    2 / 199 (1.01%)
    3 / 200 (1.50%)
    3 / 202 (1.49%)
    4 / 199 (2.01%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Head injury
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Humerus fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Ligament rupture
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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 fume inhalation disorder
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Road traffic accident
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Tibia fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    0 / 199 (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
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Vascular procedure complication
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Wound
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Wrist fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Angina unstable
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    3 / 199 (1.51%)
         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
    Atrial fibrillation
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Cardiac failure
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Cardiogenic shock
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Dementia
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    2 / 202 (0.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    0 / 199 (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
    Dizziness
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Loss of consciousness
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Paraesthesia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Parkinsonism
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Somnolence
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Syncope
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    5 / 202 (2.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 199 (0.00%)
    2 / 200 (1.00%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Diarrhoea
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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
    Faecaloma
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Gastritis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Vomiting
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Skin and subcutaneous tissue disorders
    Panniculitis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Nephrolithiasis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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 failure
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Urethral stenosis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Urinary retention
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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 and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Myalgia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    0 / 199 (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 perforated
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    Bronchitis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Diverticulitis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    0 / 199 (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
    Erysipelas
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Herpes simplex encephalitis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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 / 1
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    2 / 202 (0.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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 / 1
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    0 / 199 (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 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Urinary tract infection
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    0 / 199 (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
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (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
    1 / 199 (0.50%)
    0 / 200 (0.00%)
    2 / 202 (0.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         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
    Frequency threshold for reporting non-serious adverse events: 1.5%
    Non-serious adverse events
    		 S 38093 2 mg S 38093 5 mg S 38093 20 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 199 (51.26%)
    106 / 200 (53.00%)
    101 / 202 (50.00%)
    113 / 199 (56.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 199 (2.51%)
    1 / 200 (0.50%)
    3 / 202 (1.49%)
    4 / 199 (2.01%)
         occurrences all number
    5
    1
    3
    5
    Hypotension
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
    2 / 202 (0.99%)
    4 / 199 (2.01%)
         occurrences all number
    0
    0
    2
    4
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    1 / 199 (0.50%)
    3 / 200 (1.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences all number
    1
    3
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 199 (0.50%)
    5 / 200 (2.50%)
    1 / 202 (0.50%)
    0 / 199 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 200 (0.00%)
    5 / 202 (2.48%)
    0 / 199 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Gait disturbance
         subjects affected / exposed
    2 / 199 (1.01%)
    2 / 200 (1.00%)
    0 / 202 (0.00%)
    3 / 199 (1.51%)
         occurrences all number
    2
    2
    0
    3
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    7 / 199 (3.52%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    4 / 199 (2.01%)
         occurrences all number
    7
    0
    1
    4
    Agitation
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    6 / 202 (2.97%)
    6 / 199 (3.02%)
         occurrences all number
    0
    1
    6
    6
    Anxiety
         subjects affected / exposed
    2 / 199 (1.01%)
    5 / 200 (2.50%)
    3 / 202 (1.49%)
    4 / 199 (2.01%)
         occurrences all number
    2
    5
    3
    4
    Depression
         subjects affected / exposed
    4 / 199 (2.01%)
    2 / 200 (1.00%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         occurrences all number
    4
    2
    0
    1
    Insomnia
         subjects affected / exposed
    4 / 199 (2.01%)
    1 / 200 (0.50%)
    2 / 202 (0.99%)
    3 / 199 (1.51%)
         occurrences all number
    4
    1
    2
    3
    Irritability
         subjects affected / exposed
    4 / 199 (2.01%)
    2 / 200 (1.00%)
    3 / 202 (1.49%)
    2 / 199 (1.01%)
         occurrences all number
    4
    2
    3
    2
    Nightmare
         subjects affected / exposed
    2 / 199 (1.01%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    4 / 199 (2.01%)
         occurrences all number
    2
    1
    1
    5
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    3 / 199 (1.51%)
         occurrences all number
    0
    1
    1
    3
    Weight decreased
         subjects affected / exposed
    2 / 199 (1.01%)
    2 / 200 (1.00%)
    5 / 202 (2.48%)
    3 / 199 (1.51%)
         occurrences all number
    2
    2
    5
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 200 (0.50%)
    5 / 202 (2.48%)
    0 / 199 (0.00%)
         occurrences all number
    1
    1
    5
    0
    Fall
         subjects affected / exposed
    5 / 199 (2.51%)
    13 / 200 (6.50%)
    11 / 202 (5.45%)
    5 / 199 (2.51%)
         occurrences all number
    8
    13
    11
    5
    Head injury
         subjects affected / exposed
    0 / 199 (0.00%)
    3 / 200 (1.50%)
    0 / 202 (0.00%)
    1 / 199 (0.50%)
         occurrences all number
    0
    3
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 199 (2.01%)
    4 / 200 (2.00%)
    8 / 202 (3.96%)
    6 / 199 (3.02%)
         occurrences all number
    4
    7
    8
    7
    Headache
         subjects affected / exposed
    4 / 199 (2.01%)
    7 / 200 (3.50%)
    7 / 202 (3.47%)
    7 / 199 (3.52%)
         occurrences all number
    4
    9
    7
    8
    Somnolence
         subjects affected / exposed
    3 / 199 (1.51%)
    0 / 200 (0.00%)
    3 / 202 (1.49%)
    2 / 199 (1.01%)
         occurrences all number
    3
    0
    3
    2
    Tension headache
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    3 / 199 (1.51%)
         occurrences all number
    0
    1
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 200 (0.00%)
    1 / 202 (0.50%)
    3 / 199 (1.51%)
         occurrences all number
    2
    0
    1
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 199 (4.02%)
    1 / 200 (0.50%)
    4 / 202 (1.98%)
    5 / 199 (2.51%)
         occurrences all number
    9
    1
    5
    5
    Nausea
         subjects affected / exposed
    4 / 199 (2.01%)
    5 / 200 (2.50%)
    8 / 202 (3.96%)
    3 / 199 (1.51%)
         occurrences all number
    4
    5
    9
    3
    Vomiting
         subjects affected / exposed
    2 / 199 (1.01%)
    5 / 200 (2.50%)
    2 / 202 (0.99%)
    2 / 199 (1.01%)
         occurrences all number
    2
    5
    2
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 199 (2.01%)
    1 / 200 (0.50%)
    1 / 202 (0.50%)
    3 / 199 (1.51%)
         occurrences all number
    4
    1
    1
    3
    Leukocyturia
         subjects affected / exposed
    4 / 199 (2.01%)
    7 / 200 (3.50%)
    7 / 202 (3.47%)
    4 / 199 (2.01%)
         occurrences all number
    5
    7
    7
    4
    Urinary incontinence
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 200 (0.50%)
    5 / 202 (2.48%)
    1 / 199 (0.50%)
         occurrences all number
    0
    1
    5
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 199 (1.51%)
    1 / 200 (0.50%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 199 (0.50%)
    4 / 200 (2.00%)
    3 / 202 (1.49%)
    3 / 199 (1.51%)
         occurrences all number
    1
    4
    3
    3
    Gastroenteritis
         subjects affected / exposed
    4 / 199 (2.01%)
    2 / 200 (1.00%)
    0 / 202 (0.00%)
    0 / 199 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 199 (2.01%)
    7 / 200 (3.50%)
    3 / 202 (1.49%)
    7 / 199 (3.52%)
         occurrences all number
    4
    9
    3
    9
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 199 (1.01%)
    1 / 200 (0.50%)
    6 / 202 (2.97%)
    1 / 199 (0.50%)
         occurrences all number
    2
    1
    6
    1
    Urinary tract infection
         subjects affected / exposed
    13 / 199 (6.53%)
    9 / 200 (4.50%)
    7 / 202 (3.47%)
    9 / 199 (4.52%)
         occurrences all number
    15
    10
    7
    9
    Urinary tract infection bacterial
         subjects affected / exposed
    5 / 199 (2.51%)
    4 / 200 (2.00%)
    2 / 202 (0.99%)
    5 / 199 (2.51%)
         occurrences all number
    6
    4
    2
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 199 (1.51%)
    2 / 200 (1.00%)
    2 / 202 (0.99%)
    5 / 199 (2.51%)
         occurrences all number
    3
    2
    2
    5
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 199 (1.51%)
    4 / 200 (2.00%)
    4 / 202 (1.98%)
    1 / 199 (0.50%)
         occurrences all number
    3
    4
    4
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 199 (1.51%)
    4 / 200 (2.00%)
    1 / 202 (0.50%)
    3 / 199 (1.51%)
         occurrences all number
    3
    4
    1
    3
    Hypokalaemia
         subjects affected / exposed
    3 / 199 (1.51%)
    0 / 200 (0.00%)
    0 / 202 (0.00%)
    2 / 199 (1.01%)
         occurrences all number
    3
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    The non-inclusion criteria referring to the ECG findings (PR< 280 ms was replaced by PR > 280 ms) were corrected. New laboratory assessments (LDL and HDL, in order to complete the lipid metabolism analysis already done with the total cholesterol) were introduced. Anticipated benefits/risks and conditions of use of forbidden concomitant treatment were added in he "background" section. Some scale instructions and worksheets to be used in this study were finalized.
    03 Jul 2013
    Withdrawal criterion was updated in accordance with the last version of the Summary of Product Characteristics for donepezil.
    13 Dec 2013
    The selection criteria referring to age were updated to include very old patients with Alzheimer's disease (the upper limit to participate to the study was changed from 85 to 90 years old. both inclusive). In order to get a more accurate value for the inclusion of patients, 3 ECGs in close succession were to be performed at the selection visit (ASSE) instead of one. The MRI criteria were updated to allow the inclusion of patients with cerebrovascular disease, a common radiological finding, especially in the elderly, as long as the cerebrovascular lesions were unlikely to contribute to the dementia syndrome. Change in authorised concommitant tretament (antipsychotic treatment with typical or atypical neuroleptics was prohibited anymore before and during the study).
    15 Apr 2014
    Due to strategic reasons and recruitment difficulties, the number of planned included patient was updated (around 700 instead of 1000).
    22 Jul 2014
    New safety data and information regarding the stage of the other studies, in particular the phase IIb monotherapy study which was ended (CL2-38093-011) were added in the "background" section.

    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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