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    Clinical Trial Results:
    A PHASE 3B, PROSPECTIVE, RANDOMIZED, OPEN-LABEL, BLIND EVALUATOR (PROBE) STUDY EVALUATING THE EFFICACY AND SAFETY OF (LMW) HEPARIN/EDOXABAN VERSUS DALTEPARIN IN VENOUS THROMBOEMBOLISM ASSOCIATED WITH CANCER

    Summary
    EudraCT number
    2014-004708-30
    Trial protocol
    HU   CZ   BE   IT   DE   ES   AT   NL  
    Global end of trial date
    15 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Oct 2018
    First version publication date
    12 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-D-U311
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02073682
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND number: 63,266
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Daiichi Sankyo US Contact for Clinical Trial Results, Daiichi Sankyo, Inc., 1 908-992-6400, CTRinfo@DSI.com
    Scientific contact
    Daiichi Sankyo US Contact for Clinical Trial Results, Daiichi Sankyo, Inc., 1 908-992-6400, CTRinfo@DSI.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
    12 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate the non-inferiority of edoxaban (preceded by a short course of LMWH) compared with dalteparin for the prevention of the combined outcome of recurrent venous thromboembolism (VTE) or major bleeding in subjects with VTE associated with cancer during a 12-month study period. If non-inferiority is established, LMWH/edoxaban will be compared with dalteparin for superiority.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline. The study oversight was managed by a Steering Management Coordinating Committee (SMCC) whose members were country coordinators, as well as non-voting representatives of the Sponsor and Academic Research Organization (ARO). In this study, ITREAS functioned as the ARO. An Executive Committee to the SMCC had a scientific advisory function and was not involved in operational matters. Ongoing study oversight and management was the responsibility of a joint supervisory committee. The members of this committee were the chairman and co-chair of the SMCC and designated representatives from the Sponsor, Contract Research Organization (CRO), and ARO. An independent Clinical Events Committee (CEC) was established to objectively adjudicate and categorize the presenting index diagnosis, VTE outcomes, cardiovascular events, bleeding events, selected hepatic events, and death. Adjudicators were blinded to subject treatment allocation.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Jul 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
    Netherlands: 118
    Country: Number of subjects enrolled
    Spain: 70
    Country: Number of subjects enrolled
    Austria: 28
    Country: Number of subjects enrolled
    Belgium: 41
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    France: 122
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Italy: 90
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    New Zealand: 25
    Country: Number of subjects enrolled
    United States: 207
    Country: Number of subjects enrolled
    Canada: 200
    Worldwide total number of subjects
    1046
    EEA total number of subjects
    582
    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)
    507
    From 65 to 84 years
    521
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    1050 patients were randomized from 114 sites in Western Europe (31), Central Europe (11), South Europe (36), Australia/New Zealand (13) and North America (23)

    Pre-assignment
    Screening details
    Of 1050 patients randomized, 1046 took study drug and were included in the modified Intent to Treat (mITT) and Safety Analysis Sets

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Edoxaban
    Arm description
    After 5 days of low molecular weight heparin (LMWH), edoxaban treatment daily
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    DU-176b
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After the 5 day treatment with LMWH, patients receive edoxaban 60 mg once daily (QD) as 2 × 30 mg tablets (or 1 x 30 mg tablet QD for patients requiring dose adjustment) for the remainder of the treatment period.

    Investigational medicinal product name
    Low molecular weight heparin (LMWH)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Therapeutic doses of subcutaneous LMWH were administered for at least 5 days; this 5-day period may have included the pre-randomization LMWH (if applicable). The choice of parenteral LMWH was up to the treating physician.

    Arm title
    Dalteparin
    Arm description
    Dalteparin treatment daily
    Arm type
    Active comparator

    Investigational medicinal product name
    Dalteparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dalteparin was administered via subcutaneous injection at a dose of 200 IU/kg (maximum daily dose 18,000 IU) for 30 days, and at a dose of 150 IU/kg from Day 31 to the end of treatment.

    Number of subjects in period 1
    Edoxaban Dalteparin
    Started
    522
    524
    Completed
    200
    154
    Not completed
    322
    370
         Low Creatinine Clearance
    1
    2
         Death
    86
    100
         Cancer Cured
    10
    15
         Investigator Decision: Patient Non-compliance
    1
    2
         Investigator Decision: Palliative Treatment Only
    10
    7
         Prohibited Concomitant Medication Use
    -
    1
         Platelet Count <50,000/mL
    1
    2
         Surgery/Medical Procedure
    3
    1
         Consent withdrawn by subject
    6
    8
         Start of New Chemotherapy Regimen
    6
    3
         Cancer Progression
    53
    33
         Protocol Violation
    1
    -
         Adverse event, non-fatal
    79
    62
         No Reason Provided
    11
    9
         Patient Decision: Inconvenience of Dosing
    21
    78
         Lost to follow-up
    1
    1
         Investigator Decision: Benefit/Risk Judgment
    32
    46

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    After 5 days of low molecular weight heparin (LMWH), edoxaban treatment daily

    Reporting group title
    Dalteparin
    Reporting group description
    Dalteparin treatment daily

    Reporting group values
    Edoxaban Dalteparin Total
    Number of subjects
    522 524 1046
    Age categorical
    Units: Subjects
        18-64 years
    246 261 507
        65-84 years
    267 254 521
        85 years and over
    9 9 18
    Age continuous
    Units: years
        median (full range (min-max))
    66 (22 to 91) 65 (21 to 89) -
    Gender categorical
    Units: Subjects
        Female
    245 261 506
        Male
    277 263 540
    Type of Cancer
    Units: Subjects
        Solid Tumor
    465 467 932
        Haematological Malignancy
    56 55 111
        Solid Tumor and Haematological Malignancy
    1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    After 5 days of low molecular weight heparin (LMWH), edoxaban treatment daily

    Reporting group title
    Dalteparin
    Reporting group description
    Dalteparin treatment daily

    Primary: Number of Patients With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event

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    End point title
    Number of Patients With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    Edoxaban Dalteparin
    Number of subjects analysed
    522
    524
    Units: Patients
    67
    71
    Statistical analysis title
    Non-Inferiority Analysis - VTE or Major Bleed
    Comparison groups
    Edoxaban v Dalteparin
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.0056
    Method
    Cox proportional hazard
    Parameter type
    Cox proportional hazard
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.696
         upper limit
    1.359
    Notes
    [1] - Edoxaban was considered non-inferior to dalteparin if the upper limit of the two-sided 95% confidence interval (CI) for the hazard ratio ([LMW] Edoxaban to Dalteparin) was less than 1.5.
    Statistical analysis title
    Superiority analysis - VTE or Major Bleed
    Statistical analysis description
    The HR, two-sided CI and superiority p-value for pairwise comparisons versus Dalteparin are based on the Cox proportional hazard model including treatment and the two stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
    Comparison groups
    Edoxaban v Dalteparin
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8712
    Method
    Cox proportional hazard
    Confidence interval

    Secondary: Number of Patients With Adjudicated Major Bleeding Events While on Treatment

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    End point title
    Number of Patients With Adjudicated Major Bleeding Events While on Treatment
    End point description
    The primary safety endpoint was major bleeding events during the On-Treatment Study Period (defined as on-study drug or up to 3 days after the last dose of study drug).
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Edoxaban Dalteparin
    Number of subjects analysed
    522
    524
    Units: Patients
    32
    16
    Statistical analysis title
    Cox regression with counting process approach
    Statistical analysis description
    The HR, 2-sided CI and p-value are based on the Cox regression model with counting process approach for on-treatment including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
    Comparison groups
    Edoxaban v Dalteparin
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0254
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.089
         upper limit
    3.657

    Secondary: Number of Patients With Recurrent VTE During the Overall Study Period

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    End point title
    Number of Patients With Recurrent VTE During the Overall Study Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Edoxaban Dalteparin
    Number of subjects analysed
    522
    524
    Units: Patients
    41
    59
    Statistical analysis title
    Superiority - VTE Overall Study Period
    Statistical analysis description
    The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
    Comparison groups
    Edoxaban v Dalteparin
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0931
    Method
    Cox proportional hazard
    Parameter type
    Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.476
         upper limit
    1.059

    Secondary: Number of Patients with Additional Categorical Secondary Endpoints during the Overall Study Period

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    End point title
    Number of Patients with Additional Categorical Secondary Endpoints during the Overall Study Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Edoxaban Dalteparin
    Number of subjects analysed
    522
    524
    Units: Patients
        Recurrent Deep Vein Thrombosis (DVT)
    19
    35
        Recurrent Non-Fatal Pulmonary Embolism (PE)
    21
    24
        VTE-Related Death
    6
    4
        Recurrent VTE, Major Bleed or All-Cause Death
    235
    228
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    After 5 days of low molecular weight heparin (LMWH), edoxaban treatment daily

    Reporting group title
    Dalteparin
    Reporting group description
    Dalteparin treatment daily

    Serious adverse events
    Edoxaban Dalteparin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    276 / 522 (52.87%)
    251 / 524 (47.90%)
         number of deaths (all causes)
    206
    192
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    13 / 522 (2.49%)
    8 / 524 (1.53%)
         occurrences causally related to treatment / all
    5 / 13
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery embolism
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 522 (0.19%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    2 / 522 (0.38%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Adenocarcinoma gastric
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 522 (0.00%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Cervix cancer metastatic
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon cancer metastatic
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Colorectal cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Colorectal cancer metastatic
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Endometrial cancer
         subjects affected / exposed
    2 / 522 (0.38%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Endometrial cancer metastatic
         subjects affected / exposed
    1 / 522 (0.19%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Gallbladder cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric cancer
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Huerthle cell carcinoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liposarcoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    3 / 522 (0.57%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Lung cancer metastatic
         subjects affected / exposed
    3 / 522 (0.57%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Lung neoplasm malignant
         subjects affected / exposed
    8 / 522 (1.53%)
    6 / 524 (1.15%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 8
    0 / 6
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malignant anorectal neoplasm
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    69 / 522 (13.22%)
    67 / 524 (12.79%)
         occurrences causally related to treatment / all
    1 / 69
    0 / 67
         deaths causally related to treatment / all
    0 / 68
    0 / 67
    Metastases to central nervous system
         subjects affected / exposed
    3 / 522 (0.57%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to rectum
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 522 (0.19%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    1 / 522 (0.19%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Neoplasm progression
         subjects affected / exposed
    24 / 522 (4.60%)
    21 / 524 (4.01%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 21
         deaths causally related to treatment / all
    0 / 24
    0 / 21
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 522 (0.38%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian cancer
         subjects affected / exposed
    0 / 522 (0.00%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    4 / 522 (0.77%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    2 / 522 (0.38%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Plasma cell myeloma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 522 (0.00%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Prostate cancer metastatic
         subjects affected / exposed
    3 / 522 (0.57%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal cancer metastatic
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sarcoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vulval cancer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unintended pregnancy
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 522 (0.77%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Disease progression
         subjects affected / exposed
    4 / 522 (0.77%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Euthanasia
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 522 (0.38%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Oedema peripheral
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 522 (0.57%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 522 (0.00%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 522 (0.00%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 522 (0.57%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 522 (0.19%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Cardiac failure
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiovascular disorder
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac mass
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 522 (0.19%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulseless electrical activity
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 522 (0.19%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 522 (0.57%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    5 / 522 (0.96%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 522 (0.19%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    8 / 522 (1.53%)
    16 / 524 (3.05%)
         occurrences causally related to treatment / all
    3 / 9
    3 / 17
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    7 / 522 (1.34%)
    6 / 524 (1.15%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 522 (0.77%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 522 (0.00%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal ganglia haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 522 (0.57%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 522 (0.38%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    6 / 522 (1.15%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukoencephalopathy
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    11 / 522 (2.11%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    8 / 12
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 522 (0.00%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 522 (0.38%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    4 / 522 (0.77%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    5 / 522 (0.96%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 522 (0.77%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 522 (0.00%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    5 / 522 (0.96%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 522 (0.38%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal infarct
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    4 / 522 (0.77%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Dehydration
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 522 (0.38%)
    2 / 524 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 522 (0.19%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningococcal sepsis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 522 (3.07%)
    13 / 524 (2.48%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 13
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    Pneumonia bacterial
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Postoperative abscess
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 522 (0.00%)
    3 / 524 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 522 (0.77%)
    7 / 524 (1.34%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Septic shock
         subjects affected / exposed
    3 / 522 (0.57%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdiaphragmatic abscess
         subjects affected / exposed
    0 / 522 (0.00%)
    1 / 524 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 522 (0.19%)
    4 / 524 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 522 (0.19%)
    0 / 524 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Edoxaban Dalteparin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 522 (14.37%)
    67 / 524 (12.79%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    34 / 522 (6.51%)
    37 / 524 (7.06%)
         occurrences all number
    40
    45
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    41 / 522 (7.85%)
    30 / 524 (5.73%)
         occurrences all number
    44
    42

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2015
    Addendum A (Protocol V3.0), dated 16 Jun 2015, made the following changes: - Addendum A incorporated changes based on feedback from the Czech Republic Health Authorities. This country-specific addendum applied to all Czech Republic sites and subjects enrolled into DU176b-D-U311
    17 Dec 2015
    Amendment 1 (Protocol V2.0), dated 17 Dec 2015, made the following changes: - The number of study sites was increased - Frequency of liver function test monitoring was reduced - A hierarchal process for statistical analysis was described - Minor inconsistencies throughout the protocol were corrected in order to add clarity to the text/study procedures - Protocol title was changed
    11 Jan 2016
    Amendment 2 (Protocol V3.0), dated 11 Jan 2016, made the following changes: - The updated protocol title in Version 2.0 was reverted back to original as in Version 1.0 (A Phase 3b, prospective, randomized, open-label, blind evaluator (PROBE) study evaluating the efficacy and safety of LMW heparin/edoxaban versus dalteparin in VTE associated with cancer)

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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