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    Clinical Trial Results:
    A randomized discontinuation study of XL184 in subjects with advanced solid tumors

    Summary
    EudraCT number
    		 2009-012964-14
    Trial protocol
    		 BE   GB  
    Global end of trial date
    23 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2022
    First version publication date
    24 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    XL184-203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00940225
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Exelixis, Inc.
    Sponsor organisation address
    1851 Harbor Bay Parkway, Alameda, United States, 94502
    Public contact
    Medical Information, Exelixis Inc, +1 866939 4041,
    Scientific contact
    Medical Information, Exelixis Inc, +1 866939 4041,
    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
    30 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is: - To evaluate the efficacy of XL184 in subjects with advanced solid tumors
    Protection of trial subjects
    An independent data monitoring committee was in place to monitor safety during the randomized discontinuation portion of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Sep 2009
    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
    United Kingdom: 15
    Country: Number of subjects enrolled
    Belgium: 43
    Country: Number of subjects enrolled
    Israel: 49
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    United States: 600
    Worldwide total number of subjects
    730
    EEA total number of subjects
    43
    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)
    403
    From 65 to 84 years
    314
    85 years and over
    13

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Enrollment into the Randomized Discontinuation Trial (RDT) Cohorts: September 2009 - July 2011. Enrollment into the Non Randomized Expansion (NRE) Cohorts: February 2011 - April 2012.

    Pre-assignment
    Screening details
    		 Screening evaluations were completed prior to enrollment to determine the eligibility of subjects per protocol inclusion/exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RDT Cohort - Castration Resistant Prostate Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Melanoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Non Small Cell Lung Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Pancreatic Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Gastric/Gastroesophageal Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Hepatocellular Carcinoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Small Cell Lung Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Ovarian Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 RDT Cohort - Metastatic Breast Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 NRE Cohort - Castration Resistant Prostate Cancer (100 mg)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 NRE Cohort - Castration Resistant Prostate Cancer (40 mg)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Arm title
    		 NRE Cohort - Ovarian Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily, at the assigned dose

    Number of subjects in period 1
    		RDT Cohort - Castration Resistant Prostate Cancer RDT Cohort - Melanoma RDT Cohort - Non Small Cell Lung Cancer RDT Cohort - Pancreatic Cancer RDT Cohort - Gastric/Gastroesophageal Cancer RDT Cohort - Hepatocellular Carcinoma RDT Cohort - Small Cell Lung Cancer RDT Cohort - Ovarian Cancer RDT Cohort - Metastatic Breast Cancer NRE Cohort - Castration Resistant Prostate Cancer (100 mg) NRE Cohort - Castration Resistant Prostate Cancer (40 mg) NRE Cohort - Ovarian Cancer
    Started
    171
    77
    60
    20
    21
    41
    21
    70
    45
    93
    51
    60
    Completed
    171
    77
    60
    20
    21
    41
    21
    70
    45
    93
    51
    60

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RDT Cohort - Castration Resistant Prostate Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Melanoma
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Non Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Pancreatic Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Gastric/Gastroesophageal Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Hepatocellular Carcinoma
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Ovarian Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Metastatic Breast Cancer
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Castration Resistant Prostate Cancer (100 mg)
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Castration Resistant Prostate Cancer (40 mg)
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Ovarian Cancer
    Reporting group description
    		 -

    Reporting group values
    		 RDT Cohort - Castration Resistant Prostate Cancer RDT Cohort - Melanoma RDT Cohort - Non Small Cell Lung Cancer RDT Cohort - Pancreatic Cancer RDT Cohort - Gastric/Gastroesophageal Cancer RDT Cohort - Hepatocellular Carcinoma RDT Cohort - Small Cell Lung Cancer RDT Cohort - Ovarian Cancer RDT Cohort - Metastatic Breast Cancer NRE Cohort - Castration Resistant Prostate Cancer (100 mg) NRE Cohort - Castration Resistant Prostate Cancer (40 mg) NRE Cohort - Ovarian Cancer Total
    Number of subjects
    		 171 77 60 20 21 41 21 70 45 93 51 60 730
    Age categorical
    Units: Subjects
        Adult (18 - 65 years)
    		 64 39 27 13 13 29 14 48 39 44 29 44 403
        Adult (over 65 years)
    		 107 38 33 7 8 12 7 22 6 49 22 16 327
    Age continuous
    Units: years
        median (full range (min-max))
    		 68.0 (47 to 88) 65.0 (30 to 90) 66.0 (36 to 87) 63.0 (40 to 78) 62.0 (40 to 80) 60.0 (32 to 82) 65.0 (47 to 81) 60.5 (26 to 79) 56.0 (27 to 74) 66.0 (46 to 85) 65.0 (43 to 83) 59.5 (38 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 171 35 27 7 5 10 12 70 44 0 0 60 441
        Male
    		 0 42 33 13 16 31 9 0 1 93 51 0 289

    End points

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    End points reporting groups
    Reporting group title
    RDT Cohort - Castration Resistant Prostate Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Melanoma
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Non Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Pancreatic Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Gastric/Gastroesophageal Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Hepatocellular Carcinoma
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Ovarian Cancer
    Reporting group description
    		 -

    Reporting group title
    RDT Cohort - Metastatic Breast Cancer
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Castration Resistant Prostate Cancer (100 mg)
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Castration Resistant Prostate Cancer (40 mg)
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Ovarian Cancer
    Reporting group description
    		 -

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    assessed every 6 weeks until radiographic disease progression, and analyzed at the time of the primary analysis
    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: Descriptive endpoint (single arm, no across-arm comparison)
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was only assessed for certain tumor types.
    End point values
    		 RDT Cohort - Castration Resistant Prostate Cancer RDT Cohort - Melanoma RDT Cohort - Non Small Cell Lung Cancer RDT Cohort - Pancreatic Cancer RDT Cohort - Gastric/Gastroesophageal Cancer RDT Cohort - Hepatocellular Carcinoma RDT Cohort - Small Cell Lung Cancer RDT Cohort - Ovarian Cancer RDT Cohort - Metastatic Breast Cancer NRE Cohort - Ovarian Cancer
    Number of subjects analysed
    171
    77
    60
    20
    21
    41
    21
    70
    45
    60
    Units: Percentage of subjects
        number (confidence interval 95%)
    4.7 (2.0 to 8.7)
    5.2 (1.8 to 12.4)
    10.0 (4.4 to 20.3)
    0 (0 to 15.4)
    4.8 (0.2 to 21.8)
    4.9 (0.9 to 16.1)
    4.8 (0.2 to 21.8)
    21.7 (13.1 to 32.4)
    10.0 (6.0 to 25.7)
    10.0 (3.3 to 21.8)
    No statistical analyses for this end point

    Primary: Bone scan response

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    End point title
    		 Bone scan response [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed approximately every 6 weeks using MRI, CT, and/or bone scans
    Notes
    [3] - 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: Descriptive endpoint (single arm, no across-arm comparison)
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: End point was only appropriate for prostate cancer, and was only prospectively measured in the two NRE cohorts.
    End point values
    		 NRE Cohort - Castration Resistant Prostate Cancer (100 mg) NRE Cohort - Castration Resistant Prostate Cancer (40 mg)
    Number of subjects analysed
    93
    51
    Units: Percentage of subjects
        number (confidence interval 95%)
    74.2 (64.1 to 82.7)
    47.1 (32.9 to 61.5)
    No statistical analyses for this end point

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed approximately every 6 weeks using MRI/CT until progressive disease
    Notes
    [5] - 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: Descriptive endpoint (single arm, no across-arm comparison)
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was only assessed for certain tumor types.
    End point values
    		 RDT Cohort - Castration Resistant Prostate Cancer RDT Cohort - Melanoma RDT Cohort - Non Small Cell Lung Cancer RDT Cohort - Pancreatic Cancer RDT Cohort - Gastric/Gastroesophageal Cancer RDT Cohort - Hepatocellular Carcinoma RDT Cohort - Small Cell Lung Cancer RDT Cohort - Ovarian Cancer RDT Cohort - Metastatic Breast Cancer
    Number of subjects analysed
    171
    77
    60
    20
    21
    41
    21
    70
    45
    Units: months
        median (confidence interval 95%)
    6.8 (3.9 to 9.7)
    2.8 (1.4 to 6.9)
    4.0 (1.4 to 5.7)
    2.7 (1.3 to 5.5)
    1.4 (1.3 to 1.4)
    5.2 (3.6 to 9.3)
    3.4 (1.4 to 8.2)
    5.5 (2.7 to 11.0)
    4.3 (1.4 to 8.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed at regular study visits from baseline until discontinuation from study, through to the date of the primary analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    RDT - All Cohorts
    Reporting group description
    		 Includes subjects in all 9 of the RDT cohorts.

    Reporting group title
    NRE Cohort - CRPC 100 mg
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - CRPC 40 mg
    Reporting group description
    		 -

    Reporting group title
    NRE Cohort - Ovarian Cancer
    Reporting group description
    		 -

    Serious adverse events
    		 RDT - All Cohorts NRE Cohort - CRPC 100 mg NRE Cohort - CRPC 40 mg NRE Cohort - Ovarian Cancer
    Total subjects affected by serious adverse events
         subjects affected / exposed
    223 / 526 (42.40%)
    53 / 93 (56.99%)
    30 / 51 (58.82%)
    34 / 60 (56.67%)
         number of deaths (all causes)
    54
    12
    12
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    4 / 526 (0.76%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    metastases to the central nervous system
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    metastatic pain
         subjects affected / exposed
    2 / 526 (0.38%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    12 / 526 (2.28%)
    1 / 93 (1.08%)
    2 / 51 (3.92%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    5 / 12
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 526 (0.95%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous stenosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Acute hepatic failure
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    9 / 526 (1.71%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 526 (0.38%)
    5 / 93 (5.38%)
    1 / 51 (1.96%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    multi-organ failure
         subjects affected / exposed
    4 / 526 (0.76%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 526 (0.38%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 526 (0.95%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    4 / 60 (6.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopleural fistula
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 526 (1.52%)
    4 / 93 (4.30%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 526 (0.19%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 526 (1.14%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 526 (0.38%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 526 (0.57%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    23 / 526 (4.37%)
    7 / 93 (7.53%)
    8 / 51 (15.69%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    16 / 23
    6 / 7
    7 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 526 (1.33%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    6 / 526 (1.14%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    9 / 526 (1.71%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    laceration
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tachycardia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    8 / 526 (1.52%)
    4 / 93 (4.30%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 526 (0.76%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pericardial effusion
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    6th nerve paralysis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    convulsion
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Occipital neuralgia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural effusion
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 526 (0.57%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    idiopathic thrombocytopenia purpura
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal epithelium defect
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parophthalmia
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    9 / 526 (1.71%)
    2 / 93 (2.15%)
    2 / 51 (3.92%)
    7 / 60 (11.67%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 526 (0.76%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    15 / 526 (2.85%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    11 / 15
    2 / 2
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    4 / 60 (6.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    4 / 526 (0.76%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    12 / 526 (2.28%)
    9 / 93 (9.68%)
    0 / 51 (0.00%)
    8 / 60 (13.33%)
         occurrences causally related to treatment / all
    10 / 12
    6 / 9
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    peritoneal haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    5 / 60 (8.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    15 / 526 (2.85%)
    7 / 93 (7.53%)
    0 / 51 (0.00%)
    11 / 60 (18.33%)
         occurrences causally related to treatment / all
    10 / 15
    3 / 7
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    2 / 51 (3.92%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    5 / 526 (0.95%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 526 (0.19%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute prerenal failure
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    3 / 526 (0.57%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    renal failure acute
         subjects affected / exposed
    11 / 526 (2.09%)
    4 / 93 (4.30%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 526 (0.95%)
    5 / 93 (5.38%)
    4 / 51 (7.84%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 526 (0.57%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 526 (0.19%)
    2 / 93 (2.15%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Bronchitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Douglas' abscess
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lung infection
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 526 (3.04%)
    3 / 93 (3.23%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 526 (1.33%)
    5 / 93 (5.38%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    17 / 526 (3.23%)
    6 / 93 (6.45%)
    2 / 51 (3.92%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    7 / 17
    4 / 6
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    3 / 526 (0.57%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 526 (0.38%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    5 / 526 (0.95%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 526 (0.57%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    7 / 526 (1.33%)
    2 / 93 (2.15%)
    0 / 51 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    4 / 7
    2 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RDT - All Cohorts NRE Cohort - CRPC 100 mg NRE Cohort - CRPC 40 mg NRE Cohort - Ovarian Cancer
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    524 / 526 (99.62%)
    93 / 93 (100.00%)
    51 / 51 (100.00%)
    60 / 60 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    4 / 51 (7.84%)
    1 / 60 (1.67%)
         occurrences all number
    0
    6
    4
    1
    Hot flush
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    0 / 51 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    5
    0
    2
    Hypertension
         subjects affected / exposed
    127 / 526 (24.14%)
    25 / 93 (26.88%)
    10 / 51 (19.61%)
    19 / 60 (31.67%)
         occurrences all number
    127
    25
    10
    19
    Hypotension
         subjects affected / exposed
    0 / 526 (0.00%)
    11 / 93 (11.83%)
    2 / 51 (3.92%)
    1 / 60 (1.67%)
         occurrences all number
    0
    11
    2
    1
    Pallor
         subjects affected / exposed
    0 / 526 (0.00%)
    7 / 93 (7.53%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences all number
    0
    7
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    1
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    118 / 526 (22.43%)
    18 / 93 (19.35%)
    7 / 51 (13.73%)
    10 / 60 (16.67%)
         occurrences all number
    118
    18
    7
    10
    Chest discomfort
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    3 / 51 (5.88%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    3
    3
    Chills
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    0 / 51 (0.00%)
    5 / 60 (8.33%)
         occurrences all number
    0
    5
    0
    5
    Oedema peripheral
         subjects affected / exposed
    78 / 526 (14.83%)
    13 / 93 (13.98%)
    11 / 51 (21.57%)
    7 / 60 (11.67%)
         occurrences all number
    78
    13
    11
    7
    Fatigue
         subjects affected / exposed
    345 / 526 (65.59%)
    77 / 93 (82.80%)
    32 / 51 (62.75%)
    47 / 60 (78.33%)
         occurrences all number
    345
    77
    32
    47
    Mucosal inflammation
         subjects affected / exposed
    84 / 526 (15.97%)
    14 / 93 (15.05%)
    8 / 51 (15.69%)
    10 / 60 (16.67%)
         occurrences all number
    84
    14
    8
    10
    Pain
         subjects affected / exposed
    38 / 526 (7.22%)
    6 / 93 (6.45%)
    6 / 51 (11.76%)
    4 / 60 (6.67%)
         occurrences all number
    38
    6
    6
    4
    Pyrexia
         subjects affected / exposed
    50 / 526 (9.51%)
    7 / 93 (7.53%)
    1 / 51 (1.96%)
    6 / 60 (10.00%)
         occurrences all number
    50
    7
    1
    6
    Spinal pain
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    2 / 51 (3.92%)
    0 / 60 (0.00%)
         occurrences all number
    0
    5
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    88 / 526 (16.73%)
    14 / 93 (15.05%)
    3 / 51 (5.88%)
    11 / 60 (18.33%)
         occurrences all number
    88
    14
    3
    11
    Dysphonia
         subjects affected / exposed
    142 / 526 (27.00%)
    34 / 93 (36.56%)
    9 / 51 (17.65%)
    16 / 60 (26.67%)
         occurrences all number
    142
    34
    9
    16
    Dyspnoea
         subjects affected / exposed
    109 / 526 (20.72%)
    30 / 93 (32.26%)
    13 / 51 (25.49%)
    11 / 60 (18.33%)
         occurrences all number
    109
    30
    13
    11
    Dyspnoea exertional
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    3 / 51 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    0
    5
    3
    2
    Epistaxis
         subjects affected / exposed
    36 / 526 (6.84%)
    7 / 93 (7.53%)
    1 / 51 (1.96%)
    7 / 60 (11.67%)
         occurrences all number
    36
    7
    1
    7
    Hypoxia
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    60 / 526 (11.41%)
    3 / 93 (3.23%)
    4 / 51 (7.84%)
    11 / 60 (18.33%)
         occurrences all number
    60
    3
    4
    11
    Pleural effusion
         subjects affected / exposed
    28 / 526 (5.32%)
    8 / 93 (8.60%)
    1 / 51 (1.96%)
    4 / 60 (6.67%)
         occurrences all number
    28
    8
    1
    4
    Productive cough
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    0 / 51 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    3
    0
    4
    Pulmonary embolism
         subjects affected / exposed
    29 / 526 (5.51%)
    8 / 93 (8.60%)
    9 / 51 (17.65%)
    2 / 60 (3.33%)
         occurrences all number
    29
    8
    9
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    34 / 526 (6.46%)
    3 / 93 (3.23%)
    1 / 51 (1.96%)
    8 / 60 (13.33%)
         occurrences all number
    34
    3
    1
    8
    Confusional state
         subjects affected / exposed
    38 / 526 (7.22%)
    8 / 93 (8.60%)
    0 / 51 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    38
    8
    0
    2
    Depression
         subjects affected / exposed
    38 / 526 (7.22%)
    4 / 93 (4.30%)
    2 / 51 (3.92%)
    4 / 60 (6.67%)
         occurrences all number
    38
    4
    2
    4
    Insomnia
         subjects affected / exposed
    44 / 526 (8.37%)
    7 / 93 (7.53%)
    2 / 51 (3.92%)
    4 / 60 (6.67%)
         occurrences all number
    44
    7
    2
    4
    Sleep disorder
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    71 / 526 (13.50%)
    7 / 93 (7.53%)
    3 / 51 (5.88%)
    16 / 60 (26.67%)
         occurrences all number
    71
    7
    3
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    94 / 526 (17.87%)
    10 / 93 (10.75%)
    5 / 51 (9.80%)
    21 / 60 (35.00%)
         occurrences all number
    94
    10
    5
    21
    Blood albumin decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    3 / 51 (5.88%)
    11 / 60 (18.33%)
         occurrences all number
    0
    2
    3
    11
    Blood creatinine increased
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    3 / 51 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    3
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    1
    0
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    1 / 51 (1.96%)
    7 / 60 (11.67%)
         occurrences all number
    0
    2
    1
    7
    Haemoglobin decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    2 / 51 (3.92%)
    0 / 60 (0.00%)
         occurrences all number
    0
    5
    2
    0
    Lipase increased
         subjects affected / exposed
    35 / 526 (6.65%)
    2 / 93 (2.15%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    35
    2
    1
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    0 / 51 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    6
    0
    2
    Transaminases increased
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    0 / 51 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    0
    3
    Weight decreased
         subjects affected / exposed
    165 / 526 (31.37%)
    42 / 93 (45.16%)
    19 / 51 (37.25%)
    18 / 60 (30.00%)
         occurrences all number
    165
    42
    19
    18
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    2
    1
    3
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    2 / 51 (3.92%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    2
    3
    Dizziness
         subjects affected / exposed
    87 / 526 (16.54%)
    15 / 93 (16.13%)
    7 / 51 (13.73%)
    18 / 60 (30.00%)
         occurrences all number
    87
    15
    7
    18
    Dysgeusia
         subjects affected / exposed
    156 / 526 (29.66%)
    35 / 93 (37.63%)
    14 / 51 (27.45%)
    21 / 60 (35.00%)
         occurrences all number
    156
    35
    14
    21
    Headache
         subjects affected / exposed
    80 / 526 (15.21%)
    13 / 93 (13.98%)
    8 / 51 (15.69%)
    17 / 60 (28.33%)
         occurrences all number
    80
    13
    8
    17
    Hypoaesthesia
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    5 / 51 (9.80%)
    2 / 60 (3.33%)
         occurrences all number
    0
    3
    5
    2
    Neuropathy peripheral
         subjects affected / exposed
    38 / 526 (7.22%)
    7 / 93 (7.53%)
    0 / 51 (0.00%)
    6 / 60 (10.00%)
         occurrences all number
    38
    7
    0
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    2 / 51 (3.92%)
    2 / 60 (3.33%)
         occurrences all number
    0
    5
    2
    2
    Syncope
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    2
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    66 / 526 (12.55%)
    30 / 93 (32.26%)
    6 / 51 (11.76%)
    10 / 60 (16.67%)
         occurrences all number
    66
    30
    6
    10
    Leukopenia
         subjects affected / exposed
    27 / 526 (5.13%)
    7 / 93 (7.53%)
    3 / 51 (5.88%)
    5 / 60 (8.33%)
         occurrences all number
    27
    7
    3
    5
    Neutropenia
         subjects affected / exposed
    35 / 526 (6.65%)
    8 / 93 (8.60%)
    3 / 51 (5.88%)
    7 / 60 (11.67%)
         occurrences all number
    35
    8
    3
    7
    Thrombocytopenia
         subjects affected / exposed
    58 / 526 (11.03%)
    10 / 93 (10.75%)
    4 / 51 (7.84%)
    9 / 60 (15.00%)
         occurrences all number
    58
    10
    4
    9
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    1
    3
    Vision blurred
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    4 / 51 (7.84%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    4
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    0
    4
    Abdominal distension
         subjects affected / exposed
    31 / 526 (5.89%)
    4 / 93 (4.30%)
    3 / 51 (5.88%)
    10 / 60 (16.67%)
         occurrences all number
    31
    4
    3
    10
    Abdominal pain
         subjects affected / exposed
    126 / 526 (23.95%)
    18 / 93 (19.35%)
    9 / 51 (17.65%)
    28 / 60 (46.67%)
         occurrences all number
    126
    18
    9
    28
    Abdominal pain upper
         subjects affected / exposed
    52 / 526 (9.89%)
    6 / 93 (6.45%)
    3 / 51 (5.88%)
    7 / 60 (11.67%)
         occurrences all number
    52
    6
    3
    7
    Ascites
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    6 / 60 (10.00%)
         occurrences all number
    0
    0
    0
    6
    Chest pain
         subjects affected / exposed
    0 / 526 (0.00%)
    8 / 93 (8.60%)
    3 / 51 (5.88%)
    3 / 60 (5.00%)
         occurrences all number
    0
    8
    3
    3
    Constipation
         subjects affected / exposed
    171 / 526 (32.51%)
    33 / 93 (35.48%)
    16 / 51 (31.37%)
    22 / 60 (36.67%)
         occurrences all number
    171
    33
    16
    22
    Diarrhoea
         subjects affected / exposed
    317 / 526 (60.27%)
    66 / 93 (70.97%)
    23 / 51 (45.10%)
    47 / 60 (78.33%)
         occurrences all number
    317
    66
    23
    47
    Dry mouth
         subjects affected / exposed
    87 / 526 (16.54%)
    9 / 93 (9.68%)
    4 / 51 (7.84%)
    12 / 60 (20.00%)
         occurrences all number
    87
    9
    4
    12
    Dyspepsia
         subjects affected / exposed
    64 / 526 (12.17%)
    12 / 93 (12.90%)
    7 / 51 (13.73%)
    15 / 60 (25.00%)
         occurrences all number
    64
    12
    7
    15
    Dysphagia
         subjects affected / exposed
    38 / 526 (7.22%)
    6 / 93 (6.45%)
    0 / 51 (0.00%)
    8 / 60 (13.33%)
         occurrences all number
    38
    6
    0
    8
    Early satiety
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    1
    3
    Oesophagitis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    4 / 60 (6.67%)
         occurrences all number
    0
    1
    1
    4
    Flatulence
         subjects affected / exposed
    33 / 526 (6.27%)
    8 / 93 (8.60%)
    3 / 51 (5.88%)
    5 / 60 (8.33%)
         occurrences all number
    33
    8
    3
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    46 / 526 (8.75%)
    6 / 93 (6.45%)
    5 / 51 (9.80%)
    9 / 60 (15.00%)
         occurrences all number
    46
    6
    5
    9
    Glossodynia
         subjects affected / exposed
    42 / 526 (7.98%)
    2 / 93 (2.15%)
    3 / 51 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    42
    2
    3
    2
    Haemorrhoids
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    2 / 51 (3.92%)
    3 / 60 (5.00%)
         occurrences all number
    0
    2
    2
    3
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    3 / 51 (5.88%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Intestinal obstruction
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    6 / 60 (10.00%)
         occurrences all number
    0
    0
    0
    6
    Nausea
         subjects affected / exposed
    273 / 526 (51.90%)
    66 / 93 (70.97%)
    30 / 51 (58.82%)
    39 / 60 (65.00%)
         occurrences all number
    273
    66
    30
    39
    Proctalgia
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    1 / 51 (1.96%)
    1 / 60 (1.67%)
         occurrences all number
    0
    6
    1
    1
    Small intestinal obstruction
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    5 / 60 (8.33%)
         occurrences all number
    0
    0
    0
    5
    Stomatitis
         subjects affected / exposed
    99 / 526 (18.82%)
    15 / 93 (16.13%)
    5 / 51 (9.80%)
    17 / 60 (28.33%)
         occurrences all number
    99
    15
    5
    17
    Toothache
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    4 / 60 (6.67%)
         occurrences all number
    0
    1
    1
    4
    Vomiting
         subjects affected / exposed
    196 / 526 (37.26%)
    39 / 93 (41.94%)
    19 / 51 (37.25%)
    30 / 60 (50.00%)
         occurrences all number
    196
    39
    19
    30
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    43 / 526 (8.17%)
    1 / 93 (1.08%)
    0 / 51 (0.00%)
    8 / 60 (13.33%)
         occurrences all number
    43
    1
    0
    8
    Dry skin
         subjects affected / exposed
    54 / 526 (10.27%)
    6 / 93 (6.45%)
    4 / 51 (7.84%)
    7 / 60 (11.67%)
         occurrences all number
    54
    6
    4
    7
    Hair colour changes
         subjects affected / exposed
    53 / 526 (10.08%)
    4 / 93 (4.30%)
    0 / 51 (0.00%)
    8 / 60 (13.33%)
         occurrences all number
    53
    4
    0
    8
    Hyperhidrosis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    2 / 51 (3.92%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    2
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    179 / 526 (34.03%)
    24 / 93 (25.81%)
    7 / 51 (13.73%)
    20 / 60 (33.33%)
         occurrences all number
    179
    24
    7
    20
    Pruritus
         subjects affected / exposed
    0 / 526 (0.00%)
    4 / 93 (4.30%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    4
    1
    3
    Rash
         subjects affected / exposed
    102 / 526 (19.39%)
    19 / 93 (20.43%)
    6 / 51 (11.76%)
    12 / 60 (20.00%)
         occurrences all number
    102
    19
    6
    12
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    27 / 526 (5.13%)
    3 / 93 (3.23%)
    4 / 51 (7.84%)
    4 / 60 (6.67%)
         occurrences all number
    27
    3
    4
    4
    Haematuria
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    6 / 51 (11.76%)
    0 / 60 (0.00%)
         occurrences all number
    0
    3
    6
    0
    Micturition urgency
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    3 / 51 (5.88%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    3
    1
    Pollakiuria
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    3 / 51 (5.88%)
    0 / 60 (0.00%)
         occurrences all number
    0
    6
    3
    0
    Proteinuria
         subjects affected / exposed
    34 / 526 (6.46%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    34
    0
    0
    0
    renal failure acute
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    1 / 51 (1.96%)
    1 / 60 (1.67%)
         occurrences all number
    0
    5
    1
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    4 / 51 (7.84%)
    0 / 60 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    66 / 526 (12.55%)
    30 / 93 (32.26%)
    4 / 51 (7.84%)
    15 / 60 (25.00%)
         occurrences all number
    66
    30
    4
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    39 / 526 (7.41%)
    29 / 93 (31.18%)
    6 / 51 (11.76%)
    5 / 60 (8.33%)
         occurrences all number
    39
    29
    6
    5
    Back pain
         subjects affected / exposed
    79 / 526 (15.02%)
    30 / 93 (32.26%)
    15 / 51 (29.41%)
    10 / 60 (16.67%)
         occurrences all number
    79
    30
    15
    10
    Bone pain
         subjects affected / exposed
    0 / 526 (0.00%)
    16 / 93 (17.20%)
    7 / 51 (13.73%)
    1 / 60 (1.67%)
         occurrences all number
    0
    16
    7
    1
    Flank pain
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 93 (5.38%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences all number
    0
    5
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 93 (2.15%)
    3 / 51 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    3
    2
    Muscle spasms
         subjects affected / exposed
    56 / 526 (10.65%)
    10 / 93 (10.75%)
    9 / 51 (17.65%)
    13 / 60 (21.67%)
         occurrences all number
    56
    10
    9
    13
    Muscular weakness
         subjects affected / exposed
    0 / 526 (0.00%)
    13 / 93 (13.98%)
    7 / 51 (13.73%)
    0 / 60 (0.00%)
         occurrences all number
    0
    13
    7
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    27 / 526 (5.13%)
    13 / 93 (13.98%)
    4 / 51 (7.84%)
    2 / 60 (3.33%)
         occurrences all number
    27
    13
    4
    2
    Musculoskeletal pain
         subjects affected / exposed
    34 / 526 (6.46%)
    21 / 93 (22.58%)
    7 / 51 (13.73%)
    2 / 60 (3.33%)
         occurrences all number
    34
    21
    7
    2
    Myalgia
         subjects affected / exposed
    36 / 526 (6.84%)
    9 / 93 (9.68%)
    1 / 51 (1.96%)
    4 / 60 (6.67%)
         occurrences all number
    36
    9
    1
    4
    Neck pain
         subjects affected / exposed
    0 / 526 (0.00%)
    4 / 93 (4.30%)
    4 / 51 (7.84%)
    0 / 60 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Pain in extremity
         subjects affected / exposed
    90 / 526 (17.11%)
    29 / 93 (31.18%)
    12 / 51 (23.53%)
    9 / 60 (15.00%)
         occurrences all number
    90
    29
    12
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    0 / 51 (0.00%)
    5 / 60 (8.33%)
         occurrences all number
    0
    0
    0
    5
    Pneumonia
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    1 / 51 (1.96%)
    0 / 60 (0.00%)
         occurrences all number
    0
    6
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 526 (0.00%)
    4 / 93 (4.30%)
    3 / 51 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    0
    4
    3
    2
    Urinary tract infection
         subjects affected / exposed
    64 / 526 (12.17%)
    9 / 93 (9.68%)
    4 / 51 (7.84%)
    11 / 60 (18.33%)
         occurrences all number
    64
    9
    4
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    271 / 526 (51.52%)
    70 / 93 (75.27%)
    23 / 51 (45.10%)
    31 / 60 (51.67%)
         occurrences all number
    271
    70
    23
    31
    Dehydration
         subjects affected / exposed
    84 / 526 (15.97%)
    22 / 93 (23.66%)
    5 / 51 (9.80%)
    9 / 60 (15.00%)
         occurrences all number
    84
    22
    5
    9
    Hyperglycaemia
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 93 (3.23%)
    1 / 51 (1.96%)
    10 / 60 (16.67%)
         occurrences all number
    0
    3
    1
    10
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 93 (1.08%)
    1 / 51 (1.96%)
    7 / 60 (11.67%)
         occurrences all number
    0
    1
    1
    7
    Hypocalcaemia
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 93 (6.45%)
    2 / 51 (3.92%)
    5 / 60 (8.33%)
         occurrences all number
    0
    6
    2
    5
    Hypokalaemia
         subjects affected / exposed
    64 / 526 (12.17%)
    14 / 93 (15.05%)
    6 / 51 (11.76%)
    9 / 60 (15.00%)
         occurrences all number
    64
    14
    6
    9
    Hypomagnesaemia
         subjects affected / exposed
    70 / 526 (13.31%)
    6 / 93 (6.45%)
    3 / 51 (5.88%)
    12 / 60 (20.00%)
         occurrences all number
    70
    6
    3
    12
    Hyponatraemia
         subjects affected / exposed
    30 / 526 (5.70%)
    7 / 93 (7.53%)
    3 / 51 (5.88%)
    4 / 60 (6.67%)
         occurrences all number
    30
    7
    3
    4
    Hypophosphataemia
         subjects affected / exposed
    41 / 526 (7.79%)
    5 / 93 (5.38%)
    3 / 51 (5.88%)
    5 / 60 (8.33%)
         occurrences all number
    41
    5
    3
    5
    Malnutrition
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 93 (0.00%)
    1 / 51 (1.96%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2010
    Suspended randomization stage and specified that all randomized subjects would undergo unblinding. Added new non-randomized cohorts ("NRE") for prostate cancer and ovarian cancer, with specific inclusion/exclusion criteria and endpoints. Updates to safety management guidelines.
    22 Aug 2011
    A second non-randomized cohort at a lower dose was added for prostate cancer. Inclusion/exclusion criteria for the non-randomized cohorts (prostate cancer and ovarian cancer) were revised. Updated safety management guidelines, including potential drug interactions. Added clarifications on dose modifications.
    13 Aug 2012
    Decreased some study procedures for subjects on study longer than 12 months.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28426123
    http://www.ncbi.nlm.nih.gov/pubmed/30528315
    http://www.ncbi.nlm.nih.gov/pubmed/27714541
    http://www.ncbi.nlm.nih.gov/pubmed/23169517
    http://www.ncbi.nlm.nih.gov/pubmed/29059635
    http://www.ncbi.nlm.nih.gov/pubmed/28755607
    http://www.ncbi.nlm.nih.gov/pubmed/28103611
    http://www.ncbi.nlm.nih.gov/pubmed/24631409
    http://www.ncbi.nlm.nih.gov/pubmed/25225437
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