Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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


    The EU Clinical Trials Register currently displays   42733   clinical trials with a EudraCT protocol, of which   7035   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on Enzalutamide Alone

    Summary
    EudraCT number
    2013-004711-50
    Trial protocol
    CZ   IT   GB   DE   SE   ES   GR   BE   FR   AT   PL   NL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Oct 2021
    First version publication date
    15 Oct 2021
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    9785-MA-1001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02288247
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe Ltd. (APEL)
    Sponsor organisation address
    300 Dashwood Lang Road, Bourne Business Park, Addlestone, United Kingdom, KT15 2NX
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd. (APEL), +31 0 71 5455 050, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd. (APEL), +31 0 71 5455 050, astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    30 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of continuing treatment with enzalutamide after adding docetaxel and prednisolone versus placebo plus docetaxel and prednisolone, as measured by Progression Free Survival (PFS) in participants with chemotherapy-naïve metastatic Castration-Resistant Prostate Cancer (mCRPC) with progression during treatment with enzalutamide alone.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 2014
    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
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czechia: 30
    Country: Number of subjects enrolled
    France: 69
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Italy: 60
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Poland: 70
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Spain: 81
    Country: Number of subjects enrolled
    Sweden: 60
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Turkey: 55
    Country: Number of subjects enrolled
    United Kingdom: 89
    Worldwide total number of subjects
    688
    EEA total number of subjects
    487
    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)
    128
    From 65 to 84 years
    541
    85 years and over
    19

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Male participants with metastatic Castration-Resistant Prostate Cancer (mCRPC) who had progressed while on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or after receiving a bilateral orchiectomy and had not yet received chemotherapy were enrolled in the study.

    Pre-assignment
    Screening details
    Following Screening, participants received open-label (OL) treatment with enzalutamide in period 1 followed by period 2 randomized double-blind (DB) treatment with continued enzalutamide or placebo, adding with docetaxel and prednisolone. Participants were stratified by disease progression in Period 1 (evidence of radiographic progression or not).

    Period 1
    Period 1 title
    Period 1: OL Treatment (Max: 315 weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Period 1: Enzalutamide
    Arm description
    Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg orally once daily.

    Number of subjects in period 1
    Period 1: Enzalutamide
    Started
    688
    Treated
    687
    Completed
    41
    Not completed
    647
         Death
    35
         Protocol deviation
    9
         Withdrawal by Subject
    52
         Adverse event
    52
         Not specified
    106
         Progressive Disease
    392
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Period 2: DB Treatment (Max: 180 weeks)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Period 2: Enzalutamide
    Arm description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg orally once daily.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received prednisolone 5 mg orally twice daily.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks

    Arm title
    Period 2: Placebo
    Arm description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matched to enzalutamide orally once daily

    Number of subjects in period 2 [1]
    Period 2: Enzalutamide Period 2: Placebo
    Started
    1
    1
    Completed
    1
    1
    Not completed
    136
    135
         Randomized but not treated
    1
    -
         Death
    8
    4
         Protocol deviation
    2
    1
         Withdrawal by Subject
    7
    7
         Adverse event
    10
    8
         Not specified
    20
    21
         Progressive Disease
    87
    94
         Lost to follow-up
    1
    -
    Joined
    136
    135
         Joined period 2 from period 1
    136
    135
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who did not complete Period 1 could also join Period 2.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Period 1: OL Treatment (Max: 315 weeks)
    Reporting group description
    Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules/placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Reporting group values
    Period 1: OL Treatment (Max: 315 weeks) Total
    Number of subjects
    688
    Age categorical
    Units: Subjects
    Age
    Number of participants analyzed for age (continuous) data is 687.
    Units: years
        arithmetic mean (standard deviation)
    71.0 ± 7.8 -
    Sex
    Units: Subjects
        Male
    687 687
        Unknown
    1 1
    Analysis Race
    Units: Subjects
        Black
    5 5
        Other
    1 1
        White
    681 681
        Unknown
    1 1

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Period 1: Enzalutamide
    Reporting group description
    Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first.
    Reporting group title
    Period 2: Enzalutamide
    Reporting group description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Reporting group title
    Period 2: Placebo
    Reporting group description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Subject analysis set title
    Enzalutamide
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Primary: Progression Free Survival (PFS)

    Close Top of page
    End point title
    Progression Free Survival (PFS)
    End point description
    PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.
    End point type
    Primary
    End point timeframe
    From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136 [1]
    135 [2]
    Units: months
        median (confidence interval 95%)
    9.53 (8.25 to 10.87)
    8.28 (6.28 to 8.71)
    Notes
    [1] - Full Analysis Set (FAS) included all randomized participants who received at least one dose of IMP.
    [2] - Full Analysis Set (FAS) included all randomized participants who received at least one dose of IMP.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Enzalutamide v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.027 [3]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    0.96
    Notes
    [3] - From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).

    Secondary: Time to Prostate-specific Antigen (PSA) progression

    Close Top of page
    End point title
    Time to Prostate-specific Antigen (PSA) progression
    End point description
    Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later. FAS.
    End point type
    Secondary
    End point timeframe
    From date of randomization to the first PSA value (median duration: 35 weeks)
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136
    135
    Units: months
        median (confidence interval 95%)
    8.44 (8.18 to 9.00)
    6.24 (5.42 to 8.31)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Enzalutamide v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [4]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    0.82
    Notes
    [4] - From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).

    Secondary: Prostate-specific Antigen (PSA) Response

    Close Top of page
    End point title
    Prostate-specific Antigen (PSA) Response
    End point description
    PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported. FAS.
    End point type
    Secondary
    End point timeframe
    Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136
    135
    Units: percentage of participants
    number (not applicable)
        Week 13
    44.9
    25.2
        Any time after randomization (median of 35 weeks)
    55.9
    37.0
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

    Close Top of page
    End point title
    Objective Response Rate (ORR)
    End point description
    ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. Percentage of participants with ORR were reported. FAS.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to median duration of 35 weeks
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136
    135
    Units: percentage of participants
        number (not applicable)
    31.6
    25.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Enzalutamide v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.142 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - From the Cochran-Mantel-Haenszel test stratified by disease progression (radiographic, non-radiographic) in Period 1.

    Secondary: Time to pain progression

    Close Top of page
    End point title
    Time to pain progression
    End point description
    Time to an increase of >=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3,4,5,6) at two consecutive evaluations >=3 weeks apart without decrease in analgesic score according to World health Organization (WHO). Only participants with average pain intensity item score >=4 were considered. BPI-SF: an instrument to document pain-related functional impairment, contains 7 questions which included pain intensity [(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)] and pain interference ](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)]. BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items. FAS. “99999”= none of the participants met the criteria for pain progression.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to median duration of 35 weeks
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    139
    135
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to opiate use for cancer-related pain

    Close Top of page
    End point title
    Time to opiate use for cancer-related pain
    End point description
    Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia [parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks]. FAS. “99999”= none of the participants had cancer-related pain.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to median duration of 35 weeks
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136
    135
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to first Skeletal-related Event (SRE)

    Close Top of page
    End point title
    Time to first Skeletal-related Event (SRE)
    End point description
    Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. FAS. “99999”= upper limit of 95% confidence interval was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to median duration of 35 weeks
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    136
    135
    Units: months
        median (confidence interval 95%)
    21.98 (15.18 to 99999)
    17.35 (17.35 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Enzalutamide v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.994 [6]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    2.13
    Notes
    [6] - From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).

    Secondary: Change from Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)

    Close Top of page
    End point title
    Change from Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)
    End point description
    The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains: physical well-being (PWB) (7 items), social/family well-being (SWB) (7 items), emotional well-being (EWB) (6 items), and functional well-being (FWB) (7 items), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale [PCS]). Each item is rated on a 0 to 4 Likert-type scale (0=Not at all, 1=A little bit, 2=Some-what, 3=Quite a bit, 4=Very much), and then combined to a global quality of life score ranging between 0 to 156, with higher scores representing better quality of life. Participants in the FAS population with available data were analyzed. “99999”= No participants/only 1 participant was analyzed for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    124
    133
    Units: score on a scale
    arithmetic mean (standard deviation)
        EWB: Baseline (n= 122, 132)
    0.00 ± 0.00
    0.00 ± 0.00
        EWB: Change at Week 1 (n= 104, 115)
    0.00 ± 0.00
    0.00 ± 0.00
        EWB: Change at Week 13 (n= 88, 99)
    1.15 ± 4.15
    1.36 ± 3.63
        EWB: Change at Week 25 (n= 60, 64)
    0.69 ± 3.85
    1.03 ± 3.58
        EWB: Change at Week 37 (n= 55, 45)
    1.91 ± 3.85
    1.43 ± 3.73
        EWB: Change at Week 49 (n= 38, 22)
    1.22 ± 3.62
    0.73 ± 4.24
        EWB: Change at Week 61 (n= 18, 6)
    0.59 ± 4.52
    2.00 ± 3.58
        EWB: Change at Week 73 (n= 11, 1)
    1.69 ± 3.13
    -1.00 ± 99999
        EWB: Change at Week 85 (n= 5, 1)
    1.00 ± 4.06
    -5.00 ± 99999
        EWB: Change at Week 97 (n= 4, 0)
    3.90 ± 4.75
    99999 ± 99999
        EWB: Change at Week 109 (n= 3, 0)
    2.93 ± 3.49
    99999 ± 99999
        EWB: Change at Week 121 (n= 2, 0)
    4.00 ± 2.83
    99999 ± 99999
        EWB: Change at Week 133 (n= 2, 0)
    2.00 ± 0.00
    99999 ± 99999
        EWB: Change at Week 145 (n= 1, 0)
    2.00 ± 99999
    99999 ± 99999
        EWB: Change at Week 157 (n= 1, 0)
    2.00 ± 99999
    99999 ± 99999
        EWB: Change at Week 169 (n= 1, 0)
    1.00 ± 99999
    99999 ± 99999
        EWB: Change at Week 181 (n= 1, 0)
    2.00 ± 99999
    99999 ± 99999
        FWB: Baseline (n= 122, 132)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        FWB: Change at Week 1 (n= 104, 115)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        FWB: Change at Week 13 (n= 88, 99)
    -1.8144 ± 5.0586
    -0.3121 ± 4.7437
        FWB: Change at Week 25 (n= 60, 64)
    -2.4472 ± 5.2508
    -0.8229 ± 5.2563
        FWB: Change at Week 37 (n= 55, 45)
    -1.5697 ± 6.3251
    -0.1459 ± 3.2857
        FWB: Change at Week 49 (n= 38, 22)
    -1.1579 ± 6.7284
    -1.3818 ± 4.5238
        FWB: Change at Week 61 (n= 18, 6)
    0.0000 ± 4.7651
    -2.3333 ± 2.8048
        FWB: Change at Week 73 (n= 11, 1)
    -1.8182 ± 3.5726
    -2.0000 ± 99999
        FWB: Change at Week 85 (n= 5, 1)
    1.2000 ± 4.8166
    0.0000 ± 99999
        FWB: Change at Week 97 (n= 4, 0)
    -0.5000 ± 1.7321
    99999 ± 99999
        FWB: Change at Week 109 (n= 3, 0)
    -1.3333 ± 3.2146
    99999 ± 99999
        FWB: Change at Week 121 (n= 2, 0)
    -1.5000 ± 0.7071
    99999 ± 99999
        FWB: Change at Week 133 (n= 2, 0)
    -0.5000 ± 2.1213
    99999 ± 99999
        FWB: Change at Week 145 (n= 1, 0)
    -2.0000 ± 99999
    99999 ± 99999
        FWB: Change at Week 157 (n= 1, 0)
    0.0000 ± 99999
    99999 ± 99999
        FWB: Change at Week 169 (n= 1, 0)
    -1.0000 ± 99999
    99999 ± 99999
        FWB: Change at Week 181 (n= 1, 0)
    0.0000 ± 99999
    99999 ± 99999
        Global Score: Baseline (n= 121, 129)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        Global Score: Change at Week 1 (n= 104, 113)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        Global Score: Change at Week 13 (n= 84, 95)
    -0.7836 ± 17.7356
    1.7986 ± 16.3294
        Global Score: Change at Week 25 (n= 58, 61)
    -5.9204 ± 18.2107
    1.0762 ± 17.0168
        Global Score: Change at Week 37 (n= 52, 43)
    -1.5351 ± 20.3721
    0.1649 ± 15.8335
        Global Score: Change at Week 49 (n= 37, 21)
    -4.4880 ± 24.6865
    -4.6202 ± 17.9530
        Global Score: Change at Week 61 (n= 17, 6)
    -0.2957 ± 17.6915
    6.0939 ± 8.8208
        Global Score: Change at Week 73 (n= 11, 0)
    -0.3917 ± 18.3346
    99999 ± 99999
        Global Score: Change at Week 85 (n= 5, 0)
    1.7636 ± 11.7476
    99999 ± 99999
        Global Score: Change at Week 97 (n= 4, 0)
    6.2864 ± 9.8128
    99999 ± 99999
        Global Score: Change at Week 109 (n= 3, 0)
    -2.7333 ± 17.6299
    99999 ± 99999
        Global Score: Change at Week 121 (n= 1, 0)
    4.0000 ± 99999
    99999 ± 99999
        Global Score: Change at Week 133 (n= 2, 0)
    -7.0000 ± 4.2426
    99999 ± 99999
        Global Score: Change at Week 145 (n= 1, 0)
    -11.0000 ± 99999
    99999 ± 99999
        Global Score: Change at Week 157 (n= 1, 0)
    -1.0000 ± 99999
    99999 ± 99999
        Global Score: Change at Week 169 (n= 1, 0)
    -10.0000 ± 99999
    99999 ± 99999
        Global Score: Change at Week 181 (n= 1, 0)
    -4.0000 ± 99999
    99999 ± 99999
        PWB: Baseline (n= 124, 133)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        PWB: Change at Week 1 (n= 106, 115)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        PWB: Change at Week 13 (n= 90, 100)
    -1.3322 ± 6.0823
    -0.6347 ± 4.4643
        PWB: Change at Week 25 (n= 62, 65)
    -3.1317 ± 6.5208
    -0.4590 ± 4.2887
        PWB: Change at Week 37 (n= 56, 45)
    -2.1786 ± 5.5611
    -0.9556 ± 4.3691
        PWB: Change at Week 49 (n= 38, 23)
    -2.5316 ± 8.0882
    -1.3913 ± 6.1625
        PWB: Change at Week 61 (n= 18, 6)
    -1.3889 ± 6.9886
    1.3333 ± 3.8297
        PWB: Change at Week 73 (n= 11, 1)
    -0.3636 ± 8.0408
    3.0000 ± 99999
        PWB: Change at Week 85 (n= 5, 1)
    1.0000 ± 10.3682
    3.0000 ± 99999
        PWB: Change at Week 97 (n= 4, 0)
    1.7500 ± 10.4363
    99999 ± 99999
        PWB: Change at Week 109 (n= 3, 0)
    -0.6667 ± 13.6504
    99999 ± 99999
        PWB: Change at Week 121 (n= 2, 0)
    -4.0000 ± 1.4142
    99999 ± 99999
        PWB: Change at Week 133 (n= 2, 0)
    -4.5000 ± 0.7071
    99999 ± 99999
        PWB: Change at Week 145 (n= 1, 0)
    -4.0000 ± 99999
    99999 ± 99999
        PWB: Change at Week 157 (n= 1, 0)
    0.0000 ± 99999
    99999 ± 99999
        PWB: Change at Week 169 (n= 1, 0)
    -4.0000 ± 99999
    99999 ± 99999
        PWB: Change at Week 181 (n= 1, 0)
    -2.0000 ± 99999
    99999 ± 99999
        PCS: Baseline (n= 123, 130)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        PCS: Change at Week 1 (n= 106, 113)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        PCS: Change at Week 13 (n= 86, 95)
    1.1842 ± 6.1843
    1.6011 ± 6.0731
        PCS: Change at Week 25 (n= 60, 63)
    -0.4775 ± 6.2665
    1.8632 ± 6.3433
        PCS: Change at Week 37 (n= 53, 44)
    -1.1433 ± 7.3006
    0.6988 ± 7.1353
        PCS: Change at Week 49 (n= 37, 22)
    -1.8465 ± 8.6083
    -0.7223 ± 7.8442
        PCS: Change at Week 61 (n= 17, 6)
    0.3690 ± 6.0031
    4.2606 ± 3.1148
        PCS: Change at Week 73 (n= 11, 0)
    0.9174 ± 7.8001
    99999 ± 99999
        PCS: Change at Week 85 (n= 5, 0)
    2.1636 ± 5.6123
    99999 ± 99999
        PCS: Change at Week 97 (n= 4, 0)
    3.8864 ± 3.3380
    99999 ± 99999
        PCS: Change at Week 109 (n= 3, 0)
    -1.6667 ± 5.8595
    99999 ± 99999
        PCS: Change at Week 121 (n= 1, 0)
    2.0000 ± 99999
    99999 ± 99999
        PCS: Change at Week 133 (n= 2, 0)
    -3.0000 ± 4.2426
    99999 ± 99999
        PCS: Change at Week 145 (n= 1, 0)
    -5.0000 ± 99999
    99999 ± 99999
        PCS: Change at Week 157 (n= 1, 0)
    0.0000 ± 99999
    99999 ± 99999
        PCS: Change at Week 169 (n= 1, 0)
    -3.0000 ± 99999
    99999 ± 99999
        PCS: Change at Week 181 (n= 1, 0)
    -2.0000 ± 99999
    99999 ± 99999
        SWB: Baseline (n= 124, 133)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        SWB: Change at Week 1 (n= 106, 115)
    0.0000 ± 0.0000
    0.0000 ± 0.0000
        SWB: Change at Week 13 (n= 90, 100)
    -0.1581 ± 4.1893
    -0.2953 ± 5.0738
        SWB: Change at Week 25 (n= 62, 65)
    -0.3634 ± 5.6959
    -0.0462 ± 3.7933
        SWB: Change at Week 37 (n= 56, 45)
    0.8798 ± 4.6897
    -0.3963 ± 3.3279
        SWB: Change at Week 49 (n= 38, 23)
    -0.0719 ± 6.2561
    -0.7536 ± 4.3164
        SWB: Change at Week 61 (n= 18, 6)
    -0.8167 ± 3.3323
    0.8333 ± 5.7067
        SWB: Change at Week 73 (n= 11, 1)
    -0.8182 ± 2.7863
    -24.0000 ± 99999
        SWB: Change at Week 85 (n= 5, 1)
    -3.6000 ± 3.7815
    -24.0000 ± 99999
        SWB: Change at Week 97 (n= 4, 0)
    -2.7500 ± 5.8523
    99999 ± 99999
        SWB: Change at Week 109 (n= 3, 0)
    -2.0000 ± 4.3589
    99999 ± 99999
        SWB: Change at Week 121 (n= 2, 0)
    0.5000 ± 0.7071
    99999 ± 99999
        SWB: Change at Week 133 (n= 2, 0)
    -1.0000 ± 1.4142
    99999 ± 99999
        SWB: Change at Week 145 (n= 1, 0)
    -2.0000 ± 99999
    99999 ± 99999
        SWB: Change at Week 157 (n= 1, 0)
    -3.0000 ± 99999
    99999 ± 99999
        SWB: Change at Week 169 (n= 1, 0)
    -3.0000 ± 99999
    99999 ± 99999
        SWB: Change at Week 181 (n= 1, 0)
    -2.0000 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)

    Close Top of page
    End point title
    Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
    End point description
    EQ-5D-5L is a health status instrument for self-reported assessment of 5 domains of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain is rated by selecting 1 of 5 standardized categorizations ranging from no problem to extreme problem. The final question is a visual analogue scale (VAS) to rank health status from 0 (best health imaginable) to 100 (worst health imaginable). Participants in the FAS population with available data were analyzed. “99999”= No participants/only 1 participant was analyzed for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181
    End point values
    Enzalutamide Placebo
    Number of subjects analysed
    121
    130
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 121, 130)
    0.0 ± 0.0
    0.0 ± 0.0
        Change at Week 1 (n= 106,113)
    0.0 ± 0.0
    0.0 ± 0.0
        Change at Week 13 (n= 89, 100)
    2.3 ± 19.7
    -0.8 ± 17.8
        Change at Week 25 (n= 63, 64)
    -3.0 ± 18.6
    -0.2 ± 17.7
        Change at Week 37 (n= 55, 47)
    -1.3 ± 21.7
    0.4 ± 15.8
        Change at Week 49 (n= 42, 24)
    -2.5 ± 25.7
    -8.3 ± 23.3
        Change at Week 61 (n= 19, 6)
    1.3 ± 22.6
    2.5 ± 25.2
        Change at Week 73 (n= 11, 1)
    -3.5 ± 30.8
    -20.0 ± 99999
        Change at Week 85 (n= 5, 1)
    7.2 ± 20.7
    -10.0 ± 99999
        Change at Week 97 (n= 4, 0)
    17.8 ± 27.0
    99999 ± 99999
        Change at Week 109 (n= 3, 0)
    17.7 ± 23.6
    99999 ± 99999
        Change at Week 121 (n= 2, 0)
    -7.0 ± 4.2
    99999 ± 99999
        Change at Week 133 (n= 2, 0)
    0.5 ± 13.4
    99999 ± 99999
        Change at Week 145 (n= 1, 0)
    1.0 ± 99999
    99999 ± 99999
        Change at Week 157 (n= 1, 0)
    -4.0 ± 99999
    99999 ± 99999
        Change at Week 169 (n= 1, 0)
    2.0 ± 99999
    99999 ± 99999
        Change at Week 181 (n= 1, 0)
    -4.0 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 30 days after last dose (median duration: 35 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    v23
    Reporting groups
    Reporting group title
    Period 1: Enzalutamide
    Reporting group description
    Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first.

    Reporting group title
    Period 2: Placebo
    Reporting group description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Reporting group title
    Period 2: Enzalutamide
    Reporting group description
    Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

    Serious adverse events
    Period 1: Enzalutamide Period 2: Placebo Period 2: Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    235 / 687 (34.21%)
    52 / 135 (38.52%)
    67 / 136 (49.26%)
         number of deaths (all causes)
    50
    14
    18
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial insufficiency
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Malignant hypertension
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bone operation
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel decompression
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker removal
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheterisation venous
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    4 / 687 (0.58%)
    1 / 135 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma recurrent
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant peritoneal neoplasm
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of pleura
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    23 / 687 (3.35%)
    6 / 135 (4.44%)
    6 / 136 (4.41%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 14
    0 / 3
    0 / 5
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myeloproliferative neoplasm
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue sarcoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 687 (0.58%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 687 (0.58%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 687 (0.73%)
    3 / 135 (2.22%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    5 / 687 (0.73%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 687 (0.29%)
    2 / 135 (1.48%)
    6 / 136 (4.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Scrotal pain
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    8 / 687 (1.16%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    6 / 687 (0.87%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product dispensing error
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    5 / 687 (0.73%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    12 / 687 (1.75%)
    2 / 135 (1.48%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 14
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    6 / 687 (0.87%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    8 / 687 (1.16%)
    0 / 135 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    Left ventricular failure
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 687 (1.16%)
    1 / 135 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 687 (1.31%)
    2 / 135 (1.48%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    6 / 17
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 687 (0.15%)
    15 / 135 (11.11%)
    10 / 136 (7.35%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 17
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 687 (0.00%)
    5 / 135 (3.70%)
    11 / 136 (8.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 12
    1 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain compression
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 687 (0.58%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    6 / 687 (0.87%)
    1 / 135 (0.74%)
    5 / 136 (3.68%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 687 (0.73%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exfoliation glaucoma
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 687 (0.29%)
    2 / 135 (1.48%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 687 (0.29%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 687 (0.15%)
    3 / 135 (2.22%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    5 / 687 (0.73%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 687 (0.15%)
    2 / 135 (1.48%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 687 (0.29%)
    1 / 135 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    6 / 687 (0.87%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    12 / 687 (1.75%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bladder tamponade
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    7 / 687 (1.02%)
    2 / 135 (1.48%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    7 / 687 (1.02%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    3 / 687 (0.44%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    2 / 687 (0.29%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    12 / 687 (1.75%)
    3 / 135 (2.22%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 687 (0.29%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    5 / 687 (0.73%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis bacterial
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter bacteraemia
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryocystitis
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective aneurysm
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    4 / 687 (0.58%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 687 (0.15%)
    3 / 135 (2.22%)
    5 / 136 (3.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 687 (0.58%)
    3 / 135 (2.22%)
    4 / 136 (2.94%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory tract infection fungal
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 687 (0.73%)
    0 / 135 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 687 (0.00%)
    0 / 135 (0.00%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Streptococcal urinary tract infection
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 687 (0.29%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 135 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    6 / 687 (0.87%)
    0 / 135 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Period 1: Enzalutamide Period 2: Placebo Period 2: Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    521 / 687 (75.84%)
    123 / 135 (91.11%)
    125 / 136 (91.91%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    73 / 687 (10.63%)
    1 / 135 (0.74%)
    1 / 136 (0.74%)
         occurrences all number
    89
    1
    1
    Hypertension
         subjects affected / exposed
    90 / 687 (13.10%)
    2 / 135 (1.48%)
    3 / 136 (2.21%)
         occurrences all number
    102
    2
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    22 / 687 (3.20%)
    11 / 135 (8.15%)
    8 / 136 (5.88%)
         occurrences all number
    25
    14
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    109 / 687 (15.87%)
    35 / 135 (25.93%)
    46 / 136 (33.82%)
         occurrences all number
    175
    64
    92
    Mucosal inflammation
         subjects affected / exposed
    3 / 687 (0.44%)
    17 / 135 (12.59%)
    10 / 136 (7.35%)
         occurrences all number
    3
    19
    14
    Oedema peripheral
         subjects affected / exposed
    26 / 687 (3.78%)
    20 / 135 (14.81%)
    16 / 136 (11.76%)
         occurrences all number
    31
    23
    18
    Pyrexia
         subjects affected / exposed
    17 / 687 (2.47%)
    7 / 135 (5.19%)
    9 / 136 (6.62%)
         occurrences all number
    18
    9
    11
    Fatigue
         subjects affected / exposed
    158 / 687 (23.00%)
    28 / 135 (20.74%)
    40 / 136 (29.41%)
         occurrences all number
    193
    41
    65
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    45 / 687 (6.55%)
    4 / 135 (2.96%)
    6 / 136 (4.41%)
         occurrences all number
    61
    4
    7
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    9 / 687 (1.31%)
    7 / 135 (5.19%)
    5 / 136 (3.68%)
         occurrences all number
    12
    24
    17
    Weight decreased
         subjects affected / exposed
    30 / 687 (4.37%)
    2 / 135 (1.48%)
    11 / 136 (8.09%)
         occurrences all number
    36
    2
    11
    Neutrophil count decreased
         subjects affected / exposed
    3 / 687 (0.44%)
    7 / 135 (5.19%)
    7 / 136 (5.15%)
         occurrences all number
    4
    27
    14
    Haemoglobin decreased
         subjects affected / exposed
    15 / 687 (2.18%)
    7 / 135 (5.19%)
    2 / 136 (1.47%)
         occurrences all number
    17
    7
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    49 / 687 (7.13%)
    15 / 135 (11.11%)
    27 / 136 (19.85%)
         occurrences all number
    63
    32
    47
    Neutropenia
         subjects affected / exposed
    5 / 687 (0.73%)
    43 / 135 (31.85%)
    41 / 136 (30.15%)
         occurrences all number
    5
    129
    124
    Leukopenia
         subjects affected / exposed
    1 / 687 (0.15%)
    16 / 135 (11.85%)
    11 / 136 (8.09%)
         occurrences all number
    1
    48
    37
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    28 / 687 (4.08%)
    4 / 135 (2.96%)
    11 / 136 (8.09%)
         occurrences all number
    31
    4
    13
    Cough
         subjects affected / exposed
    26 / 687 (3.78%)
    10 / 135 (7.41%)
    11 / 136 (8.09%)
         occurrences all number
    30
    11
    15
    Epistaxis
         subjects affected / exposed
    10 / 687 (1.46%)
    7 / 135 (5.19%)
    13 / 136 (9.56%)
         occurrences all number
    11
    9
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    45 / 687 (6.55%)
    6 / 135 (4.44%)
    5 / 136 (3.68%)
         occurrences all number
    49
    6
    5
    Neuropathy peripheral
         subjects affected / exposed
    2 / 687 (0.29%)
    12 / 135 (8.89%)
    22 / 136 (16.18%)
         occurrences all number
    2
    21
    29
    Headache
         subjects affected / exposed
    44 / 687 (6.40%)
    8 / 135 (5.93%)
    5 / 136 (3.68%)
         occurrences all number
    56
    10
    6
    Dysgeusia
         subjects affected / exposed
    10 / 687 (1.46%)
    9 / 135 (6.67%)
    18 / 136 (13.24%)
         occurrences all number
    12
    9
    22
    Taste disorder
         subjects affected / exposed
    7 / 687 (1.02%)
    9 / 135 (6.67%)
    6 / 136 (4.41%)
         occurrences all number
    7
    11
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 687 (0.15%)
    14 / 135 (10.37%)
    12 / 136 (8.82%)
         occurrences all number
    1
    25
    16
    Paraesthesia
         subjects affected / exposed
    22 / 687 (3.20%)
    10 / 135 (7.41%)
    8 / 136 (5.88%)
         occurrences all number
    24
    21
    10
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    2 / 687 (0.29%)
    6 / 135 (4.44%)
    25 / 136 (18.38%)
         occurrences all number
    3
    7
    28
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    63 / 687 (9.17%)
    42 / 135 (31.11%)
    37 / 136 (27.21%)
         occurrences all number
    76
    67
    51
    Constipation
         subjects affected / exposed
    60 / 687 (8.73%)
    15 / 135 (11.11%)
    12 / 136 (8.82%)
         occurrences all number
    64
    17
    21
    Nausea
         subjects affected / exposed
    69 / 687 (10.04%)
    25 / 135 (18.52%)
    26 / 136 (19.12%)
         occurrences all number
    79
    31
    33
    Stomatitis
         subjects affected / exposed
    2 / 687 (0.29%)
    8 / 135 (5.93%)
    5 / 136 (3.68%)
         occurrences all number
    2
    9
    5
    Vomiting
         subjects affected / exposed
    22 / 687 (3.20%)
    6 / 135 (4.44%)
    8 / 136 (5.88%)
         occurrences all number
    25
    6
    8
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    39 / 687 (5.68%)
    7 / 135 (5.19%)
    4 / 136 (2.94%)
         occurrences all number
    48
    8
    5
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    14 / 687 (2.04%)
    5 / 135 (3.70%)
    12 / 136 (8.82%)
         occurrences all number
    14
    5
    12
    Nail toxicity
         subjects affected / exposed
    0 / 687 (0.00%)
    5 / 135 (3.70%)
    11 / 136 (8.09%)
         occurrences all number
    0
    7
    16
    Nail dystrophy
         subjects affected / exposed
    0 / 687 (0.00%)
    2 / 135 (1.48%)
    7 / 136 (5.15%)
         occurrences all number
    0
    3
    9
    Alopecia
         subjects affected / exposed
    2 / 687 (0.29%)
    37 / 135 (27.41%)
    44 / 136 (32.35%)
         occurrences all number
    2
    48
    56
    Nail disorder
         subjects affected / exposed
    0 / 687 (0.00%)
    7 / 135 (5.19%)
    13 / 136 (9.56%)
         occurrences all number
    0
    8
    13
    Onycholysis
         subjects affected / exposed
    0 / 687 (0.00%)
    12 / 135 (8.89%)
    13 / 136 (9.56%)
         occurrences all number
    0
    16
    14
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 135 (0.74%)
    10 / 136 (7.35%)
         occurrences all number
    0
    1
    15
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    32 / 687 (4.66%)
    7 / 135 (5.19%)
    5 / 136 (3.68%)
         occurrences all number
    37
    12
    7
    Bone pain
         subjects affected / exposed
    64 / 687 (9.32%)
    14 / 135 (10.37%)
    12 / 136 (8.82%)
         occurrences all number
    79
    16
    14
    Back pain
         subjects affected / exposed
    116 / 687 (16.89%)
    14 / 135 (10.37%)
    13 / 136 (9.56%)
         occurrences all number
    152
    15
    15
    Arthralgia
         subjects affected / exposed
    70 / 687 (10.19%)
    10 / 135 (7.41%)
    25 / 136 (18.38%)
         occurrences all number
    85
    10
    27
    Myalgia
         subjects affected / exposed
    22 / 687 (3.20%)
    7 / 135 (5.19%)
    9 / 136 (6.62%)
         occurrences all number
    23
    9
    9
    Pain in extremity
         subjects affected / exposed
    43 / 687 (6.26%)
    7 / 135 (5.19%)
    7 / 136 (5.15%)
         occurrences all number
    54
    7
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    69 / 687 (10.04%)
    17 / 135 (12.59%)
    23 / 136 (16.91%)
         occurrences all number
    86
    18
    28
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    28 / 687 (4.08%)
    8 / 135 (5.93%)
    4 / 136 (2.94%)
         occurrences all number
    33
    8
    5

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2014
    The changes included: ● Extended the contraception/sperm donation requirements in period 2 from 3 months after last IMP to 6 months after last dose of docetaxel. ● Reduced threshold for excluding patients based on elevated bilirubin levels in periods 1 and 2. Introduced additional biochemistry testing of patients with elevated liver function tests (LFTs) in period 2 prior to each docetaxel cycle. ● Removed docetaxel brand name and allowed local provision of docetaxel. ● Deleted requirement that site contact sponsor to assess necessity of breaking blind.
    19 Jun 2015
    The changes included: ● Added the collection of blood samples to analyze candidate biomarkers in circulation for association with response or progression and for identifying mechanisms of resistance. ● Clarified that any patients who were enrolled in a noninterventional control arm of an interventional study could be enrolled, provided they met all other inclusion and exclusion criteria.
    13 Jun 2016
    The changes included: ● Added an extension period to period 1 to allow treatment continuation for patients still in period 1 after enrollment to period 2 is completed. Added an extension period to period 2 to allow treatment continuation for patients still in period 2 after the cutoff for data analysis was reached. ● Removed the per protocol set.

    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
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA