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    Clinical Trial Results:
    Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event. International, multi-centre, randomized, double-blind placebo-controlled phase II study.

    Summary
    EudraCT number
    2016-001005-16
    Trial protocol
    HU   GB   SE   DE   BE   NL   ES   PL   CZ   SI   IT  
    Global end of trial date
    10 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Nov 2019
    First version publication date
    16 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-44819-004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1180-8991
    Sponsors
    Sponsor organisation name
    Laboratorios Servier
    Sponsor organisation address
    Avd de los Madronos, 33, Madrid, Spain, 28043
    Public contact
    Maria de Quintana Barajas, Laboratorios Servier S.L., +34 917489670, maria.dequintanabarajas@ervier.com
    Scientific contact
    Maria de Quintana Barajas, Laboratorios Servier S.L., +34 917489670, maria.dequintanabarajas@ervier.com
    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
    Sponsor organisation name
    Servier Research and Development Ltd
    Sponsor organisation address
    Rowley, Wexham springs, Framewood Road, Wexham, United Kingdom, SL3 6PJ
    Public contact
    Julia Crepineau, Servier Research and Development Ltd, +44 1753662744, julia.crepineau@servier.com
    Scientific contact
    Julia Crepineau, Servier Research and Development Ltd, +44 1753662744, julia.crepineau@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
    10 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the superiority of at least one of the two doses of S44819 versus placebo on functional recovery from ischemic stroke measured with the modified Rankin Scale (mRS) after 90 days of treatment. The secondary objectives were: - To assess the efficacy of the two doses of S44819 versus placebo in stroke recovery using neurological evaluation (NIHSS), activities of daily living test (BI), and cognitive performance tests (Moca, TMT). - To assess the safety and tolerability of S44819.
    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
    -
    Actual start date of recruitment
    19 Dec 2016
    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
    Spain: 121
    Country: Number of subjects enrolled
    United Kingdom: 72
    Country: Number of subjects enrolled
    Australia: 40
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Brazil: 34
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 101
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 58
    Worldwide total number of subjects
    585
    EEA total number of subjects
    477
    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)
    211
    From 65 to 84 years
    363
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    The investigators and/or coordinators were Neurologists.

    Pre-assignment
    Screening details
    Patients, aged 18-85 years (both inclusive), with a recent [between 72 hours (or 3 days) and 192 hours (or 8 days)] cortical or combined cortical-subcortical ischaemic stroke, with NIHSS 7-20 (both inclusive) and with no previous disability (i.e. neither physical nor pre-stroke cognitive impairment).

    Period 1
    Period 1 title
    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
    S44819 150mg bid
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S44819
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage form: S44819 – sachet of 150 mg twice a day. Mode of administration: The study medication was administered in the morning and in the evening (during or within 30 minutes following the meal). The interval between two intakes of the study treatment was to be at least 8 hours. Three methods of sachet administration were possible: - With a glass of water. - With thickened water, yoghurt, stewed fruit or mashed food. - Through a nasogastric tube or a percutaneous feeding tube.

    Arm title
    S44819 300mg bid
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S44819
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage form: S44819 – 300 mg: sachets of 150 mg twice a day. Mode of administration: The study medication was administered in the morning and in the evening (during or within 30 minutes following the meal). The interval between two intakes of the study treatment was to be at least 8 hours. Three methods of sachet administration were possible: - With a glass of water. - With thickened water, yoghurt, stewed fruit or mashed food. - Through a nasogastric tube or a percutaneous feeding tube.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage form: Placebo: sachets twice a day. Mode of administration: The study medication was administered in the morning and in the evening (during or within 30 minutes following the meal). The interval between two intakes of the study treatment was to be at least 8 hours. Three methods of sachet administration were possible: - With a glass of water. - With thickened water, yoghurt, stewed fruit or mashed food. - Through a nasogastric tube or a percutaneous feeding tube.

    Number of subjects in period 1
    S44819 150mg bid S44819 300mg bid Placebo
    Started
    197
    195
    193
    Completed
    153
    159
    154
    Not completed
    44
    36
    39
         Adverse event, serious fatal
    7
    9
    5
         Non medical reason
    16
    17
    11
         Adverse event, non-fatal
    11
    7
    20
         Lack of efficacy
    1
    -
    -
         Protocol deviation
    9
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S44819 150mg bid
    Reporting group description
    -

    Reporting group title
    S44819 300mg bid
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    S44819 150mg bid S44819 300mg bid Placebo Total
    Number of subjects
    197 195 193 585
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    75 57 79 211
        From 65-84 years
    117 135 111 363
        85 years and over
    5 3 3 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.9 ± 11.2 68.5 ± 11.5 66.2 ± 12.4 -
    Gender categorical
    Units: Subjects
        Female
    91 93 80 264
        Male
    106 102 113 321

    End points

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    End points reporting groups
    Reporting group title
    S44819 150mg bid
    Reporting group description
    -

    Reporting group title
    S44819 300mg bid
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    In accordance with the intention-to-treat principle and the Section 5.2.1 of ICH E9 guideline, all patients of the RS having taken at least one dose of IMP and having at least a value of the primary efficacy endpoint after D5 (excluded). Of note, patients deceased after D5 are included in the FAS.

    Primary: Modified Rankin Scale score at D90

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    End point title
    Modified Rankin Scale score at D90
    End point description
    The modified Rankin Scale (mRS) assigns a subjective grading of disability from 0 (No symptom) to 6 (Dead) with reference to pre-stroke activities rather than on observed performance of specific tasks. This scale had to be administered by a trained and certified rater whether he/she is a medical doctor or not. The rater was to have previous clinical experience with stroke patients and with this scale.
    End point type
    Primary
    End point timeframe
    The mRS was assessed at visits D5, D30, D60, D90 and D105 (follow-up visit) and in case of premature withdrawal.
    End point values
    S44819 150mg bid S44819 300mg bid Placebo
    Number of subjects analysed
    189
    188
    191
    Units: No unit
    189
    188
    191
    Statistical analysis title
    Comparison S44819 150mg bid to Placebo
    Comparison groups
    S44819 150mg bid v Placebo
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.31
    Notes
    [1] - Two-sided adjusted p-value taking into account Holm adjustment (to be compared to 0.05).
    Statistical analysis title
    Comparison S44819 300mg bid to Placebo
    Comparison groups
    S44819 300mg bid v Placebo
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.67
    Notes
    [2] - Two-sided adjusted p-value taking into account Holm adjustment (to be compared to 0.05)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All emergent adverse events that occurred or worsened or became serious between the first intake and last IMP intake + 3 days (both included)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    S44819 150mg bid
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    S44819 300mg bid
    Reporting group description
    -

    Serious adverse events
    S44819 150mg bid Placebo S44819 300mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 195 (36.41%)
    65 / 193 (33.68%)
    56 / 194 (28.87%)
         number of deaths (all causes)
    7
    4
    9
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 195 (0.51%)
    4 / 193 (2.07%)
    6 / 194 (3.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    4 / 195 (2.05%)
    2 / 193 (1.04%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 193 (1.04%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 193 (1.04%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 195 (0.51%)
    3 / 193 (1.55%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 195 (1.03%)
    6 / 193 (3.11%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sputum retention
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Anxiety
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 193 (1.04%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Apathy
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 193 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 195 (1.54%)
    2 / 193 (1.04%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post stroke depression
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 193 (1.04%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 195 (0.00%)
    3 / 193 (1.55%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 193 (1.04%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood albumin decreased
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 195 (0.51%)
    3 / 193 (1.55%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial bypass thrombosis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Drug administration error
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 195 (1.03%)
    4 / 193 (2.07%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    10 / 195 (5.13%)
    6 / 193 (3.11%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 195 (2.05%)
    3 / 193 (1.55%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac pseudoaneurysm
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    3 / 195 (1.54%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    3 / 195 (1.54%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 193 (1.04%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    1 / 195 (0.51%)
    4 / 193 (2.07%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Neurological decompensation
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post stroke seizure
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 195 (1.54%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 195 (1.03%)
    3 / 193 (1.55%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 193 (0.52%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    3 / 195 (1.54%)
    5 / 193 (2.59%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial prostatitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 195 (1.54%)
    4 / 193 (2.07%)
    5 / 194 (2.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 193 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 195 (1.54%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 193 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 195 (1.03%)
    2 / 193 (1.04%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 195 (1.54%)
    1 / 193 (0.52%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 193 (0.52%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 193 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    S44819 150mg bid Placebo S44819 300mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 195 (70.77%)
    140 / 193 (72.54%)
    123 / 194 (63.40%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 195 (1.54%)
    6 / 193 (3.11%)
    3 / 194 (1.55%)
         occurrences all number
    3
    6
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 195 (2.05%)
    6 / 193 (3.11%)
    3 / 194 (1.55%)
         occurrences all number
    4
    6
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 195 (1.03%)
    5 / 193 (2.59%)
    1 / 194 (0.52%)
         occurrences all number
    2
    5
    1
    Weight decreased
         subjects affected / exposed
    6 / 195 (3.08%)
    5 / 193 (2.59%)
    3 / 194 (1.55%)
         occurrences all number
    6
    5
    3
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    5 / 195 (2.56%)
    4 / 193 (2.07%)
    5 / 194 (2.58%)
         occurrences all number
    6
    5
    6
    Fall
         subjects affected / exposed
    3 / 195 (1.54%)
    13 / 193 (6.74%)
    13 / 194 (6.70%)
         occurrences all number
    3
    19
    20
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 195 (6.15%)
    12 / 193 (6.22%)
    15 / 194 (7.73%)
         occurrences all number
    12
    12
    16
    Hypotension
         subjects affected / exposed
    7 / 195 (3.59%)
    5 / 193 (2.59%)
    7 / 194 (3.61%)
         occurrences all number
    7
    5
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 195 (4.62%)
    9 / 193 (4.66%)
    6 / 194 (3.09%)
         occurrences all number
    9
    10
    6
    Muscle spasticity
         subjects affected / exposed
    5 / 195 (2.56%)
    3 / 193 (1.55%)
    3 / 194 (1.55%)
         occurrences all number
    5
    4
    3
    Neuralgia
         subjects affected / exposed
    5 / 195 (2.56%)
    5 / 193 (2.59%)
    2 / 194 (1.03%)
         occurrences all number
    5
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 195 (1.03%)
    4 / 193 (2.07%)
    5 / 194 (2.58%)
         occurrences all number
    2
    4
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    24 / 195 (12.31%)
    18 / 193 (9.33%)
    13 / 194 (6.70%)
         occurrences all number
    24
    18
    13
    Diarrhoea
         subjects affected / exposed
    7 / 195 (3.59%)
    9 / 193 (4.66%)
    10 / 194 (5.15%)
         occurrences all number
    8
    11
    11
    Vomiting
         subjects affected / exposed
    5 / 195 (2.56%)
    10 / 193 (5.18%)
    8 / 194 (4.12%)
         occurrences all number
    5
    12
    9
    Nausea
         subjects affected / exposed
    6 / 195 (3.08%)
    5 / 193 (2.59%)
    11 / 194 (5.67%)
         occurrences all number
    6
    5
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 195 (1.03%)
    5 / 193 (2.59%)
    2 / 194 (1.03%)
         occurrences all number
    2
    5
    2
    Depressed mood
         subjects affected / exposed
    6 / 195 (3.08%)
    5 / 193 (2.59%)
    4 / 194 (2.06%)
         occurrences all number
    6
    5
    4
    Depression
         subjects affected / exposed
    10 / 195 (5.13%)
    8 / 193 (4.15%)
    10 / 194 (5.15%)
         occurrences all number
    10
    8
    10
    Insomnia
         subjects affected / exposed
    5 / 195 (2.56%)
    9 / 193 (4.66%)
    6 / 194 (3.09%)
         occurrences all number
    5
    9
    6
    Post stroke depression
         subjects affected / exposed
    2 / 195 (1.03%)
    6 / 193 (3.11%)
    2 / 194 (1.03%)
         occurrences all number
    2
    6
    2
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    3 / 195 (1.54%)
    5 / 193 (2.59%)
    2 / 194 (1.03%)
         occurrences all number
    3
    6
    2
    Urinary tract infection
         subjects affected / exposed
    14 / 195 (7.18%)
    17 / 193 (8.81%)
    13 / 194 (6.70%)
         occurrences all number
    15
    17
    15
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    4 / 193 (2.07%)
    6 / 194 (3.09%)
         occurrences all number
    1
    4
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2016
    Applicable in all countries. - Implementation of a Data Monitoring Committee of safety in RESTORE Brain study. - Removal of barrier method of contraception from the acceptable list of contraception methods for women of child-bearing potential - Addition of a pregnancy test at DEND and in case of withdrawal (WD). - Clarifications made on exclusion criteria in order to have all results available for inclusion.
    24 May 2017
    Applicable in all countries. - Contraception: collectively the non-clinical toxicological studies did not indicate a risk to the foetus that would have necessitated the requirement for highly effective methods of contraception in clinical trials. - Update of the list of forbidden treatments in RESTORE Brain study as well as contraceptive methods following complementary results showing that CYP1A2 is the major enzyme involved in S44819 metabolism. - Selection/inclusion and exclusion criteria following major difficulties in recruitment in all countries involved in the study: * Inclusion of patients who underwent only brain CT when MRI was not possible has been possible. * The inclusion of patients with an acute symptomatic ischemic cortical or combined cortical-subcortical lesion responsible for the clinical presentation associated or not with another cerebral ischemic lesions as long as the clinical symptoms, according to the investigator’s judgment, appeared mainly related to the cortical or cortical-subcortical lesion has been possible. * The maximum age increased up to 85 years (inclusive). * Selection and inclusion visits possible until 8 days after stroke onset. * For patients with unknown exact stroke onset time, the time of stroke discovery was considered as time of stroke onset. For these patients, the time interval between last known well and stroke discovery was not to exceed 18 hours.
    23 Jul 2018
    Applicable in all countries. - Update of the list of forbidden concomitant treatments based on scientific elements.

    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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