Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   37504   clinical trials with a EudraCT protocol, of which   6153   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3b, Multi-center, Open-label Trial to Evaluate the Long Term Safety of Immediate-release Tolvaptan (OPC-41061, 30 mg to 120 mg/day, Split Dose) in Subjects With Autosomal Dominant Polycystic Kidney Disease

    Summary
    EudraCT number
    2014-001516-19
    Trial protocol
    GB   IT   SE   NL   BE   PL   ES   CZ   HU   DK  
    Global end of trial date
    09 Nov 2018

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    156-13-211
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02251275
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, MD, United States, 20850,
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.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
    05 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the trial was to evaluate and describe the long term safety of tolvaptan in participants with autosomal dominant polycystic kidney disease (ADPKD).
    Protection of trial subjects
    This trial was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the trial was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Apr 2015
    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: 45
    Country: Number of subjects enrolled
    Australia: 59
    Country: Number of subjects enrolled
    Belgium: 90
    Country: Number of subjects enrolled
    Canada: 62
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Germany: 174
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 91
    Country: Number of subjects enrolled
    Netherlands: 66
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 83
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    United Kingdom: 116
    Country: Number of subjects enrolled
    United States: 804
    Worldwide total number of subjects
    1803
    EEA total number of subjects
    775
    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)
    1773
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Eligible participants could enroll into Trial 156-13-211 after completing follow-up visit(s) of their previous trial (156-13-210, 156-08-271, 156-04-251, or 156-09-290).

    Pre-assignment
    Screening details
    One participant screened, but withdrew consent on the same day (prior to study drug treatment) and is not included in the study data. Starting doses depended on the participant’s previous trial.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tolvaptan (From 156-13-210: Tolvaptan)
    Arm description
    Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

    Arm title
    Tolvaptan (From 156-13-210: Placebo)
    Arm description
    Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose regimens used in this trial were 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

    Arm title
    Tolvaptan (From 156-08-271: Tolvaptan)
    Arm description
    Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.
    Arm type
    Experimental

    Investigational medicinal product name
    tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

    Arm title
    Tolvaptan (From Other: Tolvaptan)
    Arm description
    Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

    Arm title
    Tolvaptan (From Other: Placebo)
    Arm description
    Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

    Number of subjects in period 1
    Tolvaptan (From 156-13-210: Tolvaptan) Tolvaptan (From 156-13-210: Placebo) Tolvaptan (From 156-08-271: Tolvaptan) Tolvaptan (From Other: Tolvaptan) Tolvaptan (From Other: Placebo)
    Started
    506
    570
    718
    6
    3
    Received at Least 1 Dose of Study Drug
    505
    569
    717
    6
    3
    Completed
    434
    423
    624
    5
    2
    Not completed
    72
    147
    94
    1
    1
         Protocol Deviation
    -
    -
    1
    -
    -
         Physician decision
    19
    30
    26
    -
    1
         Adverse event, non-fatal
    23
    60
    28
    -
    -
         Consent withdrawn by subject
    25
    51
    35
    1
    -
         Lost to follow-up
    5
    6
    4
    -
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Tolvaptan (From 156-13-210: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-13-210: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-08-271: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

    Reporting group title
    Tolvaptan (From Other: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From Other: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group values
    Tolvaptan (From 156-13-210: Tolvaptan) Tolvaptan (From 156-13-210: Placebo) Tolvaptan (From 156-08-271: Tolvaptan) Tolvaptan (From Other: Tolvaptan) Tolvaptan (From Other: Placebo) Total
    Number of subjects
    506 570 718 6 3 1803
    Age categorical
    Units:
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    48.9 ± 8.1 48.6 ± 8.0 45.5 ± 7.8 41.2 ± 11.4 47.0 ± 2.6 -
    Gender categorical
    Units: Subjects
        Female
    234 290 343 5 2 874
        Male
    272 280 375 1 1 929
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    3 0 0 0 0 3
        Asian
    16 16 10 0 0 42
        Native Hawaiian or Other Pacific Islander
    1 0 2 0 0 3
        Black or African American
    19 23 6 0 0 48
        White
    461 525 694 6 3 1689
        More than one race
    0 0 0 0 0 0
        Unknown or Not Reported
    6 6 6 0 0 18
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    27 25 49 1 0 102
        Not Hispanic or Latino
    479 545 669 5 3 1701
        Unknown or Not Reported
    0 0 0 0 0 0

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Tolvaptan (From 156-13-210: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-13-210: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-08-271: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

    Reporting group title
    Tolvaptan (From Other: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From Other: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Primary: Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)

    Close Top of page
    End point title
    Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was as any untoward medical occurrence associated with the use of an investigational medicinal product (IMP), whether or not considered IMP related. A TEAE was an AE that started after trial drug treatment; or if the event was continuous from baseline and was serious, related to IMP, or resulted in death, discontinuation, interruption or reduction of trial therapy. A serious TEAE included any event that resulted in: death, life-threatening, persistent or significant incapacity, substantial disruption of ability to conduct normal life functions, required inpatient hospitalization, prolonged hospitalization, congenital anomaly/birth defect, or other medically significant events as per medical judgment, that jeopardized the participant and that required medical or surgical intervention. A severe TEAE was an inability to work or perform normal daily activity. A summary of serious and all other non-serious TEAEs, regardless of causality, is located in the AE section.
    End point type
    Primary
    End point timeframe
    Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment (+ 7 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses were planned.
    End point values
    Tolvaptan (From 156-13-210: Tolvaptan) Tolvaptan (From 156-13-210: Placebo) Tolvaptan (From 156-08-271: Tolvaptan) Tolvaptan (From Other: Tolvaptan) Tolvaptan (From Other: Placebo)
    Number of subjects analysed
    505
    569
    717
    6
    3
    Units: participants
    number (not applicable)
        Participants with TEAEs
    473
    531
    640
    6
    3
        Participants with serious TEAEs
    87
    96
    103
    1
    2
        Participants with severe TEAEs
    74
    78
    83
    2
    1
        Discontinued due to TEAEs
    33
    65
    38
    0
    1
        Deaths
    1
    5
    3
    0
    0
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment (+ 7 days)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Tolvaptan (From 156-13-210: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-13-210: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From 156-08-271: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

    Reporting group title
    Tolvaptan (From Other: Tolvaptan)
    Reporting group description
    Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Reporting group title
    Tolvaptan (From Other: Placebo)
    Reporting group description
    Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

    Serious adverse events
    Tolvaptan (From 156-13-210: Tolvaptan) Tolvaptan (From 156-13-210: Placebo) Tolvaptan (From 156-08-271: Tolvaptan) Tolvaptan (From Other: Tolvaptan) Tolvaptan (From Other: Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 505 (17.23%)
    96 / 569 (16.87%)
    103 / 717 (14.37%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
         number of deaths (all causes)
    1
    5
    3
    0
    0
         number of deaths resulting from adverse events
    1
    5
    3
    0
    0
    Vascular disorders
    Thrombophlebitis Superficial
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 505 (0.00%)
    2 / 569 (0.35%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteritis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Dissection
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Aneurysm
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Aneurysm
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Head and Neck
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Neoplasm
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed [1]
    1 / 272 (0.37%)
    1 / 280 (0.36%)
    0 / 375 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Theca Cell Tumour
         subjects affected / exposed [2]
    0 / 234 (0.00%)
    1 / 290 (0.34%)
    0 / 343 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Meninges
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Carcinoid Tumour
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Adrenals
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Liver
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    2 / 505 (0.40%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Cancer Metastatic
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-Cell Small Lymphocytic Lymphoma
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial Carcinoma
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thirst
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic Attack
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Rectocele
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed [3]
    1 / 234 (0.43%)
    0 / 290 (0.00%)
    0 / 343 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Enlargement
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed [4]
    0 / 234 (0.00%)
    1 / 290 (0.34%)
    0 / 343 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius Fracture
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirenal Haematoma
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Haemothorax
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Contusion
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous Fistula Site Haematoma
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic Complication
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental Overdose
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight Decreased
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour Marker Increased
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    0 / 505 (0.00%)
    3 / 569 (0.53%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International Normalised Ratio Fluctuation
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    2 / 505 (0.40%)
    3 / 569 (0.53%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular Filtration Rate Decreased
         subjects affected / exposed
    2 / 505 (0.40%)
    3 / 569 (0.53%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-Reactive Protein Increased
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    2 / 505 (0.40%)
    2 / 569 (0.35%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 505 (0.59%)
    5 / 569 (0.88%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    2 / 505 (0.40%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine Aminotransferase Abnormal
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 505 (0.20%)
    5 / 569 (0.88%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Glucose Increased
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Urine Present
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Prolapse
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Incompetence
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Left Ventricular Failure
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Polycystic Liver Disease
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urachal Abnormality
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sinus Polyp
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Toxicity
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 505 (0.40%)
    1 / 569 (0.18%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured Cerebral Aneurysm
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vith Nerve Paralysis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basilar Artery Aneurysm
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar Ischaemia
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal Detachment
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Borderline Glaucoma
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine Ophthalmopathy
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia, Obstructive
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated Umbilical Hernia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Perforation
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 505 (0.20%)
    3 / 569 (0.53%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    3 / 505 (0.59%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Pain
         subjects affected / exposed
    2 / 505 (0.40%)
    5 / 569 (0.88%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    6 / 505 (1.19%)
    2 / 569 (0.35%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 2
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Haemorrhage
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    2 / 505 (0.40%)
    1 / 569 (0.18%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Haemorrhage
         subjects affected / exposed
    3 / 505 (0.59%)
    4 / 569 (0.70%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Ruptured
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    5 / 505 (0.99%)
    8 / 569 (1.41%)
    7 / 717 (0.98%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 9
    3 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney Enlargement
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    End Stage Renal Disease
         subjects affected / exposed
    3 / 505 (0.59%)
    0 / 569 (0.00%)
    8 / 717 (1.12%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Polyuria
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Cyst
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Pain
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Hepatitis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash Vesicular
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Laxity
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Lesion
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal Osteoarthritis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Deformity
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    3 / 505 (0.59%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Abscess
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Infection
         subjects affected / exposed
    5 / 505 (0.99%)
    8 / 569 (1.41%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 10
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 505 (0.00%)
    2 / 569 (0.35%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    3 / 505 (0.59%)
    2 / 569 (0.35%)
    5 / 717 (0.70%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Staphylococcal
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 505 (0.79%)
    5 / 569 (0.88%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Wall Abscess
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic Herpes Zoster
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cat Scratch Disease
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis Bacterial
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea Infectious
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 505 (0.40%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Bacteraemia
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 505 (0.40%)
    3 / 569 (0.53%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Cyst Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster Oticus
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected Cyst
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 505 (0.00%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in only male participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in only female participants.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in only female participants.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in only female participants.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tolvaptan (From 156-13-210: Tolvaptan) Tolvaptan (From 156-13-210: Placebo) Tolvaptan (From 156-08-271: Tolvaptan) Tolvaptan (From Other: Tolvaptan) Tolvaptan (From Other: Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    469 / 505 (92.87%)
    525 / 569 (92.27%)
    633 / 717 (88.28%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    87 / 505 (17.23%)
    77 / 569 (13.53%)
    139 / 717 (19.39%)
    4 / 6 (66.67%)
    1 / 3 (33.33%)
         occurrences all number
    116
    97
    163
    4
    1
    Lymphoedema
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 505 (0.20%)
    2 / 569 (0.35%)
    3 / 717 (0.42%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    3
    1
    0
    Immune system disorders
    Type I Hypersensitivity
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Fatigue
         subjects affected / exposed
    47 / 505 (9.31%)
    74 / 569 (13.01%)
    34 / 717 (4.74%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    55
    85
    37
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    5 / 505 (0.99%)
    5 / 569 (0.88%)
    4 / 717 (0.56%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    5
    4
    1
    0
    Oedema Peripheral
         subjects affected / exposed
    32 / 505 (6.34%)
    39 / 569 (6.85%)
    42 / 717 (5.86%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    37
    46
    49
    0
    0
    Pain
         subjects affected / exposed
    6 / 505 (1.19%)
    1 / 569 (0.18%)
    3 / 717 (0.42%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    9
    1
    3
    1
    0
    Thirst
         subjects affected / exposed
    139 / 505 (27.52%)
    183 / 569 (32.16%)
    91 / 717 (12.69%)
    4 / 6 (66.67%)
    0 / 3 (0.00%)
         occurrences all number
    176
    213
    99
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 505 (1.78%)
    9 / 569 (1.58%)
    13 / 717 (1.81%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    9
    9
    15
    1
    0
    Stress
         subjects affected / exposed
    2 / 505 (0.40%)
    4 / 569 (0.70%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    4
    1
    1
    0
    Reproductive system and breast disorders
    Vaginal Haemorrhage
         subjects affected / exposed [5]
    0 / 234 (0.00%)
    1 / 290 (0.34%)
    3 / 343 (0.87%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    3
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 505 (1.58%)
    9 / 569 (1.58%)
    11 / 717 (1.53%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    10
    10
    11
    1
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    7 / 505 (1.39%)
    19 / 569 (3.34%)
    17 / 717 (2.37%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    9
    26
    21
    1
    0
    Blood Calcium Increased
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood Creatinine Increased
         subjects affected / exposed
    77 / 505 (15.25%)
    87 / 569 (15.29%)
    69 / 717 (9.62%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    104
    129
    87
    0
    1
    Kidney Palpable
         subjects affected / exposed
    1 / 505 (0.20%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Weight Decreased
         subjects affected / exposed
    4 / 505 (0.79%)
    5 / 569 (0.88%)
    2 / 717 (0.28%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    6
    3
    0
    1
    Weight Increased
         subjects affected / exposed
    1 / 505 (0.20%)
    3 / 569 (0.53%)
    4 / 717 (0.56%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    5
    1
    0
    Cardiac disorders
    Left Ventricular Hypertrophy
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Palpitations
         subjects affected / exposed
    5 / 505 (0.99%)
    6 / 569 (1.05%)
    14 / 717 (1.95%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    6
    15
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 505 (5.35%)
    27 / 569 (4.75%)
    28 / 717 (3.91%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    30
    31
    31
    0
    0
    Wheezing
         subjects affected / exposed
    2 / 505 (0.40%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 505 (3.56%)
    31 / 569 (5.45%)
    31 / 717 (4.32%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    20
    37
    37
    0
    1
    Headache
         subjects affected / exposed
    51 / 505 (10.10%)
    72 / 569 (12.65%)
    51 / 717 (7.11%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    61
    83
    68
    2
    0
    Tremor
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    2 / 717 (0.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    2
    1
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    3 / 505 (0.59%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    1
    1
    0
    Motion Sickness
         subjects affected / exposed
    1 / 505 (0.20%)
    1 / 569 (0.18%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    9 / 505 (1.78%)
    14 / 569 (2.46%)
    4 / 717 (0.56%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    10
    16
    5
    1
    0
    Abdominal Hernia
         subjects affected / exposed
    7 / 505 (1.39%)
    1 / 569 (0.18%)
    6 / 717 (0.84%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    7
    1
    6
    0
    1
    Abdominal Pain Lower
         subjects affected / exposed
    6 / 505 (1.19%)
    6 / 569 (1.05%)
    6 / 717 (0.84%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    6
    7
    6
    1
    0
    Abdominal Pain Upper
         subjects affected / exposed
    20 / 505 (3.96%)
    19 / 569 (3.34%)
    12 / 717 (1.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    24
    24
    12
    1
    0
    Constipation
         subjects affected / exposed
    16 / 505 (3.17%)
    28 / 569 (4.92%)
    10 / 717 (1.39%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    17
    34
    11
    0
    1
    Diarrhoea
         subjects affected / exposed
    37 / 505 (7.33%)
    38 / 569 (6.68%)
    33 / 717 (4.60%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    41
    43
    39
    0
    1
    Dry Mouth
         subjects affected / exposed
    22 / 505 (4.36%)
    38 / 569 (6.68%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    24
    41
    4
    0
    0
    Dyspepsia
         subjects affected / exposed
    17 / 505 (3.37%)
    27 / 569 (4.75%)
    10 / 717 (1.39%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    19
    28
    10
    1
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    11 / 505 (2.18%)
    19 / 569 (3.34%)
    17 / 717 (2.37%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    11
    22
    17
    0
    1
    Gingival Pain
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    1 / 717 (0.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Nausea
         subjects affected / exposed
    37 / 505 (7.33%)
    51 / 569 (8.96%)
    38 / 717 (5.30%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    40
    59
    40
    0
    1
    Vomiting
         subjects affected / exposed
    24 / 505 (4.75%)
    38 / 569 (6.68%)
    32 / 717 (4.46%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    27
    41
    36
    0
    0
    Renal and urinary disorders
    Chronic Kidney Disease
         subjects affected / exposed
    4 / 505 (0.79%)
    6 / 569 (1.05%)
    7 / 717 (0.98%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    6
    7
    0
    1
    Haematuria
         subjects affected / exposed
    27 / 505 (5.35%)
    52 / 569 (9.14%)
    48 / 717 (6.69%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    34
    63
    53
    0
    2
    Nocturia
         subjects affected / exposed
    77 / 505 (15.25%)
    124 / 569 (21.79%)
    58 / 717 (8.09%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    105
    150
    63
    4
    2
    Pollakiuria
         subjects affected / exposed
    27 / 505 (5.35%)
    34 / 569 (5.98%)
    12 / 717 (1.67%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    36
    38
    18
    2
    0
    Polyuria
         subjects affected / exposed
    117 / 505 (23.17%)
    180 / 569 (31.63%)
    53 / 717 (7.39%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    141
    203
    56
    2
    0
    Renal Cyst Ruptured
         subjects affected / exposed
    4 / 505 (0.79%)
    9 / 569 (1.58%)
    7 / 717 (0.98%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    12
    8
    0
    1
    Renal Impairment
         subjects affected / exposed
    12 / 505 (2.38%)
    29 / 569 (5.10%)
    14 / 717 (1.95%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    12
    31
    16
    0
    0
    Renal Pain
         subjects affected / exposed
    98 / 505 (19.41%)
    110 / 569 (19.33%)
    141 / 717 (19.67%)
    3 / 6 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    139
    179
    209
    4
    3
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    7 / 505 (1.39%)
    4 / 569 (0.70%)
    3 / 717 (0.42%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    9
    5
    3
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 505 (6.53%)
    25 / 569 (4.39%)
    26 / 717 (3.63%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    42
    26
    36
    0
    0
    Back Pain
         subjects affected / exposed
    53 / 505 (10.50%)
    57 / 569 (10.02%)
    51 / 717 (7.11%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    59
    71
    55
    1
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    8 / 505 (1.58%)
    18 / 569 (3.16%)
    4 / 717 (0.56%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    9
    19
    4
    0
    1
    Gout
         subjects affected / exposed
    28 / 505 (5.54%)
    25 / 569 (4.39%)
    30 / 717 (4.18%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    49
    46
    42
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    4 / 505 (0.79%)
    5 / 569 (0.88%)
    7 / 717 (0.98%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    5
    7
    1
    0
    Polydipsia
         subjects affected / exposed
    27 / 505 (5.35%)
    53 / 569 (9.31%)
    14 / 717 (1.95%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    29
    54
    14
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    23 / 505 (4.55%)
    29 / 569 (5.10%)
    31 / 717 (4.32%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    25
    34
    35
    1
    0
    Ear Infection
         subjects affected / exposed
    8 / 505 (1.58%)
    9 / 569 (1.58%)
    5 / 717 (0.70%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    9
    9
    8
    1
    0
    Gastroenteritis
         subjects affected / exposed
    14 / 505 (2.77%)
    22 / 569 (3.87%)
    41 / 717 (5.72%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    15
    24
    44
    1
    0
    Gingivitis
         subjects affected / exposed
    2 / 505 (0.40%)
    3 / 569 (0.53%)
    2 / 717 (0.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    3
    2
    2
    0
    Influenza
         subjects affected / exposed
    34 / 505 (6.73%)
    43 / 569 (7.56%)
    39 / 717 (5.44%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    38
    49
    52
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    92 / 505 (18.22%)
    100 / 569 (17.57%)
    94 / 717 (13.11%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    129
    143
    123
    0
    1
    Sinusitis
         subjects affected / exposed
    22 / 505 (4.36%)
    31 / 569 (5.45%)
    35 / 717 (4.88%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    30
    37
    47
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    58 / 505 (11.49%)
    53 / 569 (9.31%)
    86 / 717 (11.99%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    64
    83
    129
    1
    0
    Urinary Tract Infection
         subjects affected / exposed
    52 / 505 (10.30%)
    58 / 569 (10.19%)
    65 / 717 (9.07%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    86
    79
    117
    1
    0
    Vulvovaginal Mycotic Infection
         subjects affected / exposed [6]
    3 / 234 (1.28%)
    1 / 290 (0.34%)
    6 / 343 (1.75%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    3
    1
    7
    0
    1
    Zika Virus Infection
         subjects affected / exposed
    0 / 505 (0.00%)
    0 / 569 (0.00%)
    0 / 717 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Notes
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The adverse event occurs in only female participants.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The adverse event occurs in only female participants.

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2014
    Protocol procedures were revised to accommodate the treatment and monitoring of participants enrolling into the protocol from additional tolvaptan trials. The sample size was increased, the inclusion criteria were slightly modified, schedules for initiation of treatment and liver function testing were further defined, and pharmacokinetic sampling was included to assess compliance.
    06 Mar 2015
    The window was increased from 30 days to up to 3 months to allow use of historical laboratory values for screening, to add flexibility and allow combining of screening and baseline visits in the trial, and to provide clarification on trial discontinuation.

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA