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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Chemotherapy Naïve Metastatic Castration-Resistant Prostate Cancer

    Summary
    EudraCT number
    		 2010-018661-35
    Trial protocol
    		 FR   HU   EE   BE   SK   LV   FI   NL   ES   LT   CZ   AT   GB   PT   SE   IE   DE   PL   IT   BG   GR   RO  
    Global end of trial date
    07 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2017
    First version publication date
    23 Apr 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C21004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01193244
    WHO universal trial number (UTN)
    		 U1111-1181-0387
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Study Manager, Millennium Medical and Drug Information Center, 001 866-835-2233, trialdisclosures@takeda.com
    Scientific contact
    Study Manager, Millennium Medical and Drug Information Center, 001 866-835-2233, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to determine if orteronel plus prednisone improved radiographic progression-free survival (rPFS) and to determine if orteronel plus prednisone improved overall survival (OS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Oct 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 44
    Country: Number of subjects enrolled
    United States: 295
    Country: Number of subjects enrolled
    Austria: 24
    Country: Number of subjects enrolled
    Belarus: 16
    Country: Number of subjects enrolled
    Belgium: 39
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Czech Republic: 31
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    Estonia: 6
    Country: Number of subjects enrolled
    France: 121
    Country: Number of subjects enrolled
    Germany: 69
    Country: Number of subjects enrolled
    Greece: 39
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Ireland: 24
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Latvia: 26
    Country: Number of subjects enrolled
    Lithuania: 37
    Country: Number of subjects enrolled
    Netherlands: 73
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Romania: 33
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    United Kingdom: 95
    Country: Number of subjects enrolled
    Australia: 54
    Country: Number of subjects enrolled
    Brazil: 91
    Country: Number of subjects enrolled
    Chile: 40
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    New Zealand: 51
    Country: Number of subjects enrolled
    Peru: 16
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    1560
    EEA total number of subjects
    748
    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)
    354
    From 65 to 84 years
    1144
    85 years and over
    62

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 324 investigative sites in North America, Europe, Australia, Brazil, Chile, Colombia, Hong Kong, Peru, Puerto Rico, Israel, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan from 19 October 2010 to 7 April 2016.

    Pre-assignment
    Screening details
    		 Subjects who were chemotherapy-naïve, had metastatic castration-resistant prostate cancer (mCRPC) with documented progressive metastatic disease were enrolled to receive: Orteronel 400 milligram (mg) + Prednisone 5 mg or Placebo + Prednisone 5 mg. After unblinding, 7 subjects who received placebo crossed over to receive Orteronel.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Prednisone 5 mg
    Arm description
    		 Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel placebo-matching tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Arm title
    		 Orteronel 400 mg + Prednisone 5 mg
    Arm description
    		 Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel 400 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Number of subjects in period 1
    		Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Started
    779
    781
    Completed
    391
    391
    Not completed
    388
    390
         Consent withdrawn by subject
    79
    97
         Other
    303
    278
         Lost to follow-up
    6
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Prednisone 5 mg
    Reporting group description
    		 Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Reporting group title
    Orteronel 400 mg + Prednisone 5 mg
    Reporting group description
    		 Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Reporting group values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg Total
    Number of subjects
    		 779 781 1560
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 176 178 354
        From 65-84 years
    		 573 571 1144
        85 years and over
    		 30 32 62
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.1 ( 8.19 ) 70.9 ( 8.26 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 779 781 1560
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 10 12 22
        Asian
    		 51 38 89
        Native Hawaiian or Other Pacific Islander
    		 2 1 3
        Black or African American
    		 19 25 44
        White
    		 670 685 1355
        Unknown or Not Reported
    		 12 3 15
        Other
    		 15 17 32
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 90 107 197
        Not Hispanic or Latino
    		 672 669 1341
        Unknown or Not Reported
    		 17 5 22
    Region of Enrollment
    Units: Subjects
        Canada
    		 22 22 44
        United States
    		 147 148 295
        Austria
    		 12 12 24
        Belarus
    		 6 10 16
        Belgium
    		 18 21 39
        Bulgaria
    		 6 6 12
        Croatia
    		 5 1 6
        Czech Republic
    		 13 18 31
        Estonia
    		 2 4 6
        Finland
    		 9 4 13
        France
    		 66 55 121
        Germany
    		 29 40 69
        Greece
    		 23 16 39
        Hungary
    		 3 4 7
        Ireland
    		 11 13 24
        Italy
    		 10 8 18
        Latvia
    		 12 14 26
        Lithuania
    		 19 18 37
        Netherlands
    		 35 38 73
        Poland
    		 0 4 4
        Portugal
    		 4 4 8
        Romania
    		 20 13 33
        Slovakia
    		 9 11 20
        Spain
    		 14 12 26
        Sweden
    		 11 6 17
        Switzerland
    		 10 8 18
        Ukraine
    		 25 23 48
        United Kingdom
    		 42 53 95
        Australia
    		 27 27 54
        Brazil
    		 41 50 91
        Chile
    		 20 20 40
        Colombia
    		 3 6 9
        Hong Kong
    		 1 3 4
        Israel
    		 14 4 18
        Japan
    		 22 18 40
        Mexico
    		 7 9 16
        New Zealand
    		 25 26 51
        Peru
    		 6 10 16
        Puerto Rico
    		 1 1 2
        Singapore
    		 5 2 7
        South Africa
    		 6 4 10
        Taiwan, Province Of China
    		 12 10 22
        Russia
    		 6 5 11
    Study Specific Characteristic | Height
    Height data was available for 1558 subjects as follows: n= 778, 780.
    Units: centimeter
        arithmetic mean (standard deviation)
    		 172.77 ( 7.485 ) 173.26 ( 7.858 ) -
    Study Specific Characteristic | Weight
    Weight data was available for 1559 subjects as follows: n= 778, 781.
    Units: kilogram
        arithmetic mean (standard deviation)
    		 84.04 ( 15.846 ) 85.09 ( 16.286 ) -
    Study Specific Characteristic | Body Mass Index (BMI)
    BMI data was available for 1557 subjects as follows: n= 777, 780.
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    		 28.09 ( 4.651 ) 28.28 ( 4.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Prednisone 5 mg
    Reporting group description
    		 Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Reporting group title
    Orteronel 400 mg + Prednisone 5 mg
    Reporting group description
    		 Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Subject analysis set title
    Orteronel 400 mg + Prednisone 5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Primary: Radiographic Progression-free Survival (rPFS)

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    End point title
    		 Radiographic Progression-free Survival (rPFS)
    End point description
    rPFS was defined as the time from randomization to the first objective evidence of radiographic disease progression assessed by independent central radiology review or death due to any cause, whichever occurred first. Radiographic disease progression was evaluated by computerized tomography (CT) scan or magnetic resonance imaging (MRI) and radionuclide bone scans at regularly scheduled visits. Radiographic disease progression in bone required a confirmatory scan. Radiographic disease progression in soft tissue did not require a confirmatory scan for purposes of analysis. Radiographic disease progression was evaluated by independent central radiology review using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for soft tissue disease and Prostate Cancer Working Group (PCWG2) guidelines for bone disease. Subjects who did not reach the endpoint were censored at their last assessment. Intent-to-treat (ITT) population included all subjects who were randomized.
    End point type
    Primary
    End point timeframe
    Baseline until radiographic disease progression or death, whichever occurred first (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    8.7 (8.32 to 10.91)
    13.8 (13.05 to 14.92)
    Statistical analysis title
    		 Orteronel vs Placebo
    Statistical analysis description
    Hazard ratio is based on a stratified Cox’s proportional hazard regression model with stratification factors of region and radiographic disease progression at baseline with treatment as a factor in the model. A hazard ratio less than (<) 1 indicated better prevention of death in the orteronel group compared to the placebo group. From log-rank test stratified by region and radiographic disease progression at Baseline.
    Comparison groups
    Placebo + Prednisone 5 mg v Orteronel 400 mg + Prednisone 5 mg
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.707
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.626
         upper limit
    		 0.799

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was calculated from the date of subject randomization to the date of subject death due to any cause. Subjects without documentation of death at time of the analysis were censored as of the date the subject was last known to be alive, or the data cutoff date, whichever was earlier. ITT population included all subjects who were randomized.
    End point type
    Primary
    End point timeframe
    Baseline until death (up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    29.5 (27.28 to 32.38)
    29.9 (27.88 to 33.04)
    Statistical analysis title
    		 Orteronel vs Placebo
    Statistical analysis description
    Hazard ratio is based on a stratified Cox’s proportional hazard regression model with stratification factors of region and radiographic disease progression at baseline with treatment as a factor in the model. A hazard ratio <1 indicated better prevention of death in the orteronel group compared to the placebo group. From log-rank test stratified by region and radiographic disease progression at baseline.
    Comparison groups
    Placebo + Prednisone 5 mg v Orteronel 400 mg + Prednisone 5 mg
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59755
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.963
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.838
         upper limit
    		 1.107

    Secondary: Percentage of Subjects Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50) Response at Week 12

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    End point title
    		 Percentage of Subjects Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50) Response at Week 12
    End point description
    The PSA50 is defined as a decline of at least 50 percent (%) from baseline. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
        number (confidence interval 95%)
    24.6 (21.7 to 27.8)
    42.6 (39.1 to 46.2)
    Statistical analysis title
    		 Orteronel vs Placebo
    Statistical analysis description
    Logistic regression model with prognostic factors: region; radiographic disease progression at baseline; age; race; baseline Eastern Cooperative Oncology Group (ECOG) score; Gleason score at initial diagnosis; baseline PSA, natural log scale; presence of visceral disease; alkaline phosphatase; lactate dehydrogenase; and hemoglobin. Odds ratio greater than (>)1 favored orteronel. P-values tested for odds ratio equal to 1.
    Comparison groups
    Placebo + Prednisone 5 mg v Orteronel 400 mg + Prednisone 5 mg
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.166
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.724
         upper limit
    		 2.721

    Secondary: Percentage of Subjects With Favorable Circulating Tumor Cell Count (CTC) Levels at Week 12

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    End point title
    		 Percentage of Subjects With Favorable Circulating Tumor Cell Count (CTC) Levels at Week 12
    End point description
    A favorable CTC count was defined as <5 counts per 7.5 milliliter (mL) in whole blood. An unfavorable CTC count was defined as greater than or equal to (>=) 5 counts/7.5 mL in whole blood. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
        number (confidence interval 95%)
    9.1 (7.2 to 11.4)
    15.4 (12.9 to 18.1)
    Statistical analysis title
    		 Orteronel vs Placebo
    Statistical analysis description
    Logistic regression model with prognostic factors: region; radiographic disease progression at baseline; age; race; baseline ECOG score; Gleason score at initial diagnosis; baseline PSA, natural log scale; presence of visceral disease; alkaline phosphatase; lactate dehydrogenase; and hemoglobin. Odds ratio > 1 favored orteronel. P-values tested for odds ratio equal to 1.
    Comparison groups
    Placebo + Prednisone 5 mg v Orteronel 400 mg + Prednisone 5 mg
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.712
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.235
         upper limit
    		 2.373

    Secondary: Time to Pain Progression

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    End point title
    		 Time to Pain Progression
    End point description
    Time to pain progression defined as time from subject randomization to first assessment date of pain progression. Pain progression defined as occurrence of 1 of the following, confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: The brief pain inventory-short form(BPI-SF) worst pain score>=4 with a >=2 point increase over baseline in BPI-SF worst pain score with stable/increased analgesic use; The BPI-SF worst pain score>=4 but not less than baseline with new/increased (relative to baseline) Step II or Step III analgesic use; The BPI-SF worst pain score<=3 but not less than baseline with new/increased (relative to baseline) Step III analgesic use. BPI-SF(11-item questionnaire), designed to assess severity and impact of pain on daily functions. Total score ranged from 0 to 100; lower scores indicative of less pain. ITT population. Here, 99999 in median and confidence interval (CI) signifies "not estimable due to low number of events in arm".
    End point type
    Secondary
    End point timeframe
    Baseline until End of treatment (EOT) (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (28.57 to 99999)
    Statistical analysis title
    		 Orteronel vs Placebo
    Statistical analysis description
    Hazard ratio is based on a stratified Cox’s proportional hazard regression model with stratification factors of region and radiographic disease progression at baseline with treatment as a factor in the model. A hazard ratio <1 indicated better prevention of death in the orteronel group compared to the placebo group. From log-rank test stratified by region and radiographic disease progression at baseline.
    Comparison groups
    Placebo + Prednisone 5 mg v Orteronel 400 mg + Prednisone 5 mg
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33906
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.885
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.688
         upper limit
    		 1.138

    Secondary: Number of Subjects Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
        TEAE
    733
    769
        Serious Adverse Events (SAE)
    321
    380
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events Greater Than or Equal to (>=) Grade 3

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events Greater Than or Equal to (>=) Grade 3 [2]
    End point description
    Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused subject to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
        Grade 3 or higher TEAE
    405
    537
        Grade 5 (Death)
    78
    77
    No statistical analyses for this end point

    Secondary: Number of Subjects With TEAEs Related to Vital Signs

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    End point title
    		 Number of Subjects With TEAEs Related to Vital Signs [3]
    End point description
    Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
        Hypertension
    76
    98
        Pyrexia
    26
    41
        Hypotension
    12
    26
    No statistical analyses for this end point

    Secondary: Number of Subjects With TEAEs Related to Weight

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    End point title
    		 Number of Subjects With TEAEs Related to Weight [4]
    End point description
    Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
        Weight decreased
    47
    119
        Weight increased
    36
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status

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    End point title
    		 Number of Subjects With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status
    End point description
    ECOG assessed subject's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50 percent of waking hours [hrs]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50 percent of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Worst change was defined as the worst overall change that occurred in ECOG status at any measured time point during the treatment period. Safety population where baseline and post-baseline assessments were available. Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline until EOT (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    760
    771
    Units: subjects
        Baseline: 0; Overall: 0
    251
    200
        Baseline: 0; Overall: 1
    177
    237
        Baseline: 0; Overall: 2
    47
    66
        Baseline: 0; Overall: 3
    22
    15
        Baseline: 0; Overall: 4
    7
    7
        Baseline: 1; Overall: 0
    6
    6
        Baseline: 1; Overall: 1
    162
    147
        Baseline: 1; Overall: 2
    57
    60
        Baseline: 1; Overall: 3
    28
    26
        Baseline: 1; Overall: 4
    2
    6
        Baseline: 2; Overall: 2
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Findings [5]
    End point description
    Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (Cycle 61 Day 58)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
    130
    163
    No statistical analyses for this end point

    Secondary: Worst Change From Baseline Over Time in Cardiac Ejection Fraction

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    End point title
    		 Worst Change From Baseline Over Time in Cardiac Ejection Fraction
    End point description
    Worst change was defined as the worst overall change that occurred in cardiac ejection fraction at any measured time point. Safety population where baseline and post-baseline assessments were available. Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    676
    670
    Units: percent ejection fraction
        arithmetic mean (standard deviation)
    -3.8 ( 6.93 )
    -4.8 ( 7 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation

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    End point title
    		 Number of Subjects With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation [6]
    End point description
    Safety population included all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analysed in safety analysis set. Orteronel 400 mg + Prednisone 5 mg safety analysis set included subjects who received placebo crossed over to receive Orteronel after unblinding.
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    770
    784
    Units: subjects
        Investigations
    215
    399
        Blood and lymphatic system disorders
    114
    107
        Metabolism and nutrition disorders
    204
    336
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Skeletal Related Events (SRE)

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    End point title
    		 Percentage of Subjects With Skeletal Related Events (SRE)
    End point description
    Skeletal related (SRE) event is defined as a fracture or spinal cord compression or the need for radiation or surgery at the site of a prostate cancer metastatic lesion that is substantiated by radiographic or pathologic evidence. The ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
        number (confidence interval 95%)
    10.9 (8.8 to 13.3)
    8.6 (6.7 to 10.8)
    No statistical analyses for this end point

    Secondary: Time to SRE

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    End point title
    		 Time to SRE
    End point description
    Time to SRE is defined as the time from randomization to SRE, or death due to any cause, whichever comes first. SRE is defined as a fracture or spinal cord compression or the need for radiation or surgery at the site of a prostate cancer metastatic lesion that is substantiated by radiographic or pathologic evidence. The ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (Cycle 61 Day 58)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    9 (8.32 to 10.98)
    13.9 (13.68 to 16.57)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving PSA50 Response at any Time During the Study

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    End point title
    		 Percentage of Subjects Achieving PSA50 Response at any Time During the Study
    End point description
    The PSA50 is defined as a decline of PSA by 50 percent from baseline. ITT population where baseline and post-baseline assessments were available. The ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
    number (confidence interval 95%)
        Cycle 4 (n= 687, 672)
    28.09 (24.76 to 31.62)
    49.7 (45.86 to 53.55)
        Cycle 7 (n= 541, 540)
    34.94 (30.92 to 39.12)
    54.81 (50.51 to 59.07)
        Cycle 10 (n= 438, 450)
    36.99 (32.45 to 41.7)
    56 (51.28 to 60.64)
        Cycle 13 (n= 344, 382)
    37.21 (32.09 to 42.56)
    53.14 (48 to 58.24)
        Cycle 16 (n= 286, 303)
    34.27 (28.78 to 40.08)
    54.13 (48.33 to 59.84)
        Cycle 19 (n= 228, 272)
    37.72 (31.41 to 44.36)
    52.94 (46.82 to 59)
        Cycle 22 (n= 184, 211)
    33.15 (26.4 to 40.46)
    54.03 (47.05 to 60.89)
        Cycle 25 (n= 109, 119)
    35.78 (26.83 to 45.53)
    46.22 (37.04 to 55.59)
        Cycle 28 (n= 67, 77)
    44.78 (32.6 to 57.42)
    48.05 (36.52 to 59.74)
        Cycle 31 (n= 35, 39)
    34.29 (19.13 to 52.21)
    48.72 (32.42 to 65.22)
        Cycle 34 (n= 22, 18)
    36.36 (17.2 to 59.34)
    38.89 (17.3 to 64.25)
        Cycle 37 (n= 7, 5)
    71.43 (29.04 to 96.33)
    40 (5.27 to 85.34)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12

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    End point title
    		 Percentage of Subjects Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12
    End point description
    The PSA90 is defined as a decline of PSA by 90 percent from baseline. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
        number (not applicable)
    5.4
    16.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving PSA90 Response at any Time During the Study

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    End point title
    		 Percentage of Subjects Achieving PSA90 Response at any Time During the Study
    End point description
    The PSA90 is defined as a decline of PSA by 90 percent from baseline. ITT population where baseline and post-baseline assessments were available. The ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: percentage of subjects
    number (confidence interval 95%)
        Cycle 4 (n= 687, 672)
    5.39 (3.82 to 7.35)
    16.67 (13.93 to 19.7)
        Cycle 7 (n= 541, 540)
    8.69 (6.45 to 11.39)
    22.22 (18.78 to 25.97)
        Cycle 10 (n= 438, 450)
    11.64 (8.79 to 15.02)
    26.44 (22.42 to 30.78)
        Cycle 13 (n= 344, 382)
    12.79 (9.45 to 16.79)
    26.18 (21.84 to 30.89)
        Cycle 16 (n= 286, 303)
    12.24 (8.67 to 16.61)
    25.74 (20.91 to 31.05)
        Cycle 19 (n= 228, 272)
    12.72 (8.69 to 17.75)
    26.1 (20.99 to 31.75)
        Cycle 22 (n= 184, 211)
    10.87 (6.77 to 16.29)
    28.44 (22.45 to 35.03)
        Cycle 25 (n= 109, 119)
    11.01 (5.82 to 18.44)
    21.01 (14.08 to 29.43)
        Cycle 28 (n= 67, 77)
    16.42 (8.49 to 27.48)
    27.27 (17.74 to 38.62)
        Cycle 31 (n= 35, 39)
    8.57 (1.8 to 23.06)
    12.82 (4.3 to 27.43)
        Cycle 34 (n= 22, 18)
    4.55 (0.12 to 22.84)
    22.22 (6.41 to 47.64)
        Cycle 37 (n= 7, 5)
    14.29 (0.36 to 57.87)
    20 (0.51 to 71.64)
    No statistical analyses for this end point

    Secondary: Time to PSA Progression

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    End point title
    		 Time to PSA Progression
    End point description
    Time to PSA progression was defined as time from randomization to a PSA increase of 25 percent and PSA rise of at least 2 nanogram per milliliter (ng/mL) above the lowest value observed post baseline or, if no PSA decline occurred post baseline, compared to baseline PSA.
    End point type
    Secondary
    End point timeframe
    Baseline until the final on treatment assessment or until end of short term follow-up following discontinuation of treatment, whichever occurred later (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    5.59 (5.56 to 5.59)
    8.3 (8.28 to 8.35)
    No statistical analyses for this end point

    Secondary: Time to Docetaxel Chemotherapy

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    End point title
    		 Time to Docetaxel Chemotherapy
    End point description
    Time to docetaxel based chemotherapy is defined as the time from randomization to the start of docetaxel based chemotherapy for prostate cancer, regardless of whether the subject received concurrent orteronel or not. Deaths due to disease progression prior to Docetaxel based chemotherapy were considered as events. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline until start of docetaxel chemotherapy (up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    19 (16.44 to 21.43)
    23 (20.71 to 24.65)
    No statistical analyses for this end point

    Secondary: Time to Subsequent Antineoplastic Therapy

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    End point title
    		 Time to Subsequent Antineoplastic Therapy
    End point description
    Time to subsequent antineoplastic therapy is defined as the time from randomization to the start of any alternate antineoplastic therapy for prostate cancer. Deaths due to disease progression prior to antineoplastic therapy for prostate cancer are considered as events. Otherwise, time to next therapy is censored at the date of death or the last date the subject was known to be alive or the data cutoff date, whichever is earlier. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline until start of subsequent antineoplastic therapy (up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    13.9 (12.16 to 14.86)
    17.2 (15.09 to 18.97)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response

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    End point title
    		 Percentage of Subjects With Objective Response
    End point description
    Percentage of subjects with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. A CR was defined as the disappearance of all target lesions determined by computerized tomography (CT) or MRI. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 millimetre (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter or short axis of lymph nodes. The Response Evaluation Criteria in Solid Tumors (RECIST) evaluable population included all subjects who had measurable disease by RECIST 1.1 at the baseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death, whichever occurred first (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    243
    236
    Units: percentage of subjects
        number (confidence interval 95%)
    15.2 (11 to 20.4)
    34.7 (28.7 to 41.2)
    No statistical analyses for this end point

    Secondary: Time to Deterioration in Global Health Status

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    End point title
    		 Time to Deterioration in Global Health Status
    End point description
    Global health status deterioration is defined as a drop greater than 16 points from the baseline assessment, confirmed at least 3 weeks later, on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module 30 (EORTC QLQ-C30) index after the score has been linearly transformed to a 0 to 100 scale. EORTC QLQ-C30 consists of 30 questions, where question 1 to 28 can be answered with 1: Not at all, 2: A little, 3: Quite a bit, 4: Very much and question 29 to 30 with 1: Very poor to 7: Excellent. For subscales a high score from 0-100 indicates: high global quality of life, high level of functioning (physical, role, emotional, cognitive, social) or a high level of symptoms (fatigue, nausea, pain, dyspnea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties).
    End point type
    Secondary
    End point timeframe
    Baseline until EOT (approximately up to 4.7 years)
    End point values
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Number of subjects analysed
    779
    781
    Units: months
        median (confidence interval 95%)
    10.7 (8.97 to 11.11)
    8.3 (7.36 to 10.16)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (up to Cycle 61 Day 58).
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo + Prednisone 5 mg
    Reporting group description
    		 Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Reporting group title
    Orteronel 400 mg + Prednisone 5 mg
    Reporting group description
    		 Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, subjects were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.

    Serious adverse events
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    321 / 770 (41.69%)
    380 / 784 (48.47%)
         number of deaths (all causes)
    76
    75
         number of deaths resulting from adverse events
    9
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    25 / 770 (3.25%)
    24 / 784 (3.06%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 28
         deaths causally related to treatment / all
    0 / 19
    0 / 19
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 770 (0.13%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Metastatic pain
         subjects affected / exposed
    7 / 770 (0.91%)
    12 / 784 (1.53%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    4 / 770 (0.52%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to biliary tract
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bladder
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to small intestine
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to rectum
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to urinary tract
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    3 / 770 (0.39%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Throat cancer
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromatosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    5 / 770 (0.65%)
    9 / 784 (1.15%)
         occurrences causally related to treatment / all
    2 / 6
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 770 (0.13%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 770 (0.00%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Shock
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphoedema
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 770 (0.26%)
    11 / 784 (1.40%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 770 (0.13%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 770 (0.78%)
    9 / 784 (1.15%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    3 / 770 (0.39%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 5
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Multi-organ disorder
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 770 (0.39%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 770 (0.13%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abasia
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic obstruction
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    23 / 770 (2.99%)
    27 / 784 (3.44%)
         occurrences causally related to treatment / all
    11 / 24
    11 / 27
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dyspnoea
         subjects affected / exposed
    5 / 770 (0.65%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 770 (0.39%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 770 (0.26%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pharyngeal pouch
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lipase increased
         subjects affected / exposed
    5 / 770 (0.65%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    5 / 5
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 770 (0.00%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 770 (0.39%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post procedural haematoma
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    6 / 770 (0.78%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 770 (0.13%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural pulmonary embolism
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stricture postoperative
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 770 (0.39%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    5 / 770 (0.65%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Angina pectoris
         subjects affected / exposed
    4 / 770 (0.52%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    18 / 770 (2.34%)
    14 / 784 (1.79%)
         occurrences causally related to treatment / all
    6 / 20
    3 / 15
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 770 (0.39%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    7 / 770 (0.91%)
    8 / 784 (1.02%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Cardiac failure acute
         subjects affected / exposed
    3 / 770 (0.39%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    3 / 770 (0.39%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Arrhythmia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 770 (0.39%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomegaly
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular hypertrophy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiotoxicity
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    8 / 770 (1.04%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    3 / 12
    0 / 6
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 770 (0.65%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    11 / 770 (1.43%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular pain
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nystagmus
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve disorder
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 770 (2.34%)
    18 / 784 (2.30%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphadenopathy
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 770 (0.52%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 770 (0.78%)
    9 / 784 (1.15%)
         occurrences causally related to treatment / all
    0 / 6
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 770 (0.39%)
    9 / 784 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 770 (0.65%)
    12 / 784 (1.53%)
         occurrences causally related to treatment / all
    1 / 5
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 770 (0.26%)
    8 / 784 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 770 (0.00%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 770 (0.00%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 770 (0.52%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    0 / 5
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 770 (0.39%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallstone ileus
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    3 / 770 (0.39%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastric haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 770 (0.52%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal stenosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 770 (0.78%)
    9 / 784 (1.15%)
         occurrences causally related to treatment / all
    1 / 7
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 770 (0.39%)
    7 / 784 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    20 / 770 (2.60%)
    13 / 784 (1.66%)
         occurrences causally related to treatment / all
    1 / 22
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary hesitation
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    16 / 770 (2.08%)
    8 / 784 (1.02%)
         occurrences causally related to treatment / all
    2 / 21
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    6 / 770 (0.78%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    3 / 770 (0.39%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydroureter
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder rupture
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery thrombosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 770 (0.00%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyrotoxic crisis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 770 (1.04%)
    12 / 784 (1.53%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 770 (0.39%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    4 / 770 (0.52%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 770 (0.26%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    8 / 770 (1.04%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 770 (0.26%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 770 (0.52%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint destruction
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    9 / 770 (1.17%)
    30 / 784 (3.83%)
         occurrences causally related to treatment / all
    2 / 9
    5 / 35
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    Lobar pneumonia
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 770 (0.13%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 770 (0.39%)
    12 / 784 (1.53%)
         occurrences causally related to treatment / all
    0 / 3
    5 / 17
         deaths causally related to treatment / all
    0 / 2
    2 / 6
    Urosepsis
         subjects affected / exposed
    4 / 770 (0.52%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 770 (0.26%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Bacteraemia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    9 / 770 (1.17%)
    13 / 784 (1.66%)
         occurrences causally related to treatment / all
    2 / 11
    2 / 21
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 770 (0.52%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 770 (0.26%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abscess limb
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 770 (0.26%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 770 (0.13%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 770 (0.26%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Borrelia infection
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue abscess
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 770 (0.13%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    8 / 770 (1.04%)
    11 / 784 (1.40%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypovolaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 770 (0.26%)
    8 / 784 (1.02%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 770 (0.00%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    5 / 784 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 770 (0.13%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    6 / 784 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 770 (0.00%)
    4 / 784 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 770 (0.00%)
    3 / 784 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    5 / 770 (0.65%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 770 (0.39%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 770 (0.00%)
    2 / 784 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    2 / 770 (0.26%)
    1 / 784 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Failure to thrive
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 770 (0.26%)
    0 / 784 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Prednisone 5 mg Orteronel 400 mg + Prednisone 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    721 / 770 (93.64%)
    757 / 784 (96.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    80 / 770 (10.39%)
    98 / 784 (12.50%)
         occurrences all number
    92
    110
    Hot flush
         subjects affected / exposed
    77 / 770 (10.00%)
    81 / 784 (10.33%)
         occurrences all number
    85
    87
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    173 / 770 (22.47%)
    269 / 784 (34.31%)
         occurrences all number
    207
    360
    Asthenia
         subjects affected / exposed
    70 / 770 (9.09%)
    106 / 784 (13.52%)
         occurrences all number
    93
    138
    Oedema peripheral
         subjects affected / exposed
    85 / 770 (11.04%)
    86 / 784 (10.97%)
         occurrences all number
    97
    109
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    41 / 770 (5.32%)
    84 / 784 (10.71%)
         occurrences all number
    49
    106
    Cough
         subjects affected / exposed
    58 / 770 (7.53%)
    62 / 784 (7.91%)
         occurrences all number
    66
    71
    Dyspnoea exertional
         subjects affected / exposed
    22 / 770 (2.86%)
    41 / 784 (5.23%)
         occurrences all number
    24
    46
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    65 / 770 (8.44%)
    84 / 784 (10.71%)
         occurrences all number
    70
    90
    Depression
         subjects affected / exposed
    23 / 770 (2.99%)
    56 / 784 (7.14%)
         occurrences all number
    23
    57
    Investigations
    Lipase increased
         subjects affected / exposed
    35 / 770 (4.55%)
    179 / 784 (22.83%)
         occurrences all number
    53
    243
    Weight decreased
         subjects affected / exposed
    54 / 770 (7.01%)
    124 / 784 (15.82%)
         occurrences all number
    64
    153
    Amylase increased
         subjects affected / exposed
    27 / 770 (3.51%)
    146 / 784 (18.62%)
         occurrences all number
    41
    199
    Blood creatinine increased
         subjects affected / exposed
    21 / 770 (2.73%)
    78 / 784 (9.95%)
         occurrences all number
    25
    97
    Alanine aminotransferase increased
         subjects affected / exposed
    14 / 770 (1.82%)
    49 / 784 (6.25%)
         occurrences all number
    14
    63
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    47 / 770 (6.10%)
    57 / 784 (7.27%)
         occurrences all number
    57
    70
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    50 / 770 (6.49%)
    105 / 784 (13.39%)
         occurrences all number
    57
    140
    Headache
         subjects affected / exposed
    50 / 770 (6.49%)
    70 / 784 (8.93%)
         occurrences all number
    71
    83
    Dysgeusia
         subjects affected / exposed
    15 / 770 (1.95%)
    46 / 784 (5.87%)
         occurrences all number
    16
    49
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    90 / 770 (11.69%)
    75 / 784 (9.57%)
         occurrences all number
    113
    92
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    130 / 770 (16.88%)
    281 / 784 (35.84%)
         occurrences all number
    162
    439
    Constipation
         subjects affected / exposed
    129 / 770 (16.75%)
    261 / 784 (33.29%)
         occurrences all number
    159
    332
    Diarrhoea
         subjects affected / exposed
    110 / 770 (14.29%)
    221 / 784 (28.19%)
         occurrences all number
    149
    341
    Vomiting
         subjects affected / exposed
    115 / 770 (14.94%)
    174 / 784 (22.19%)
         occurrences all number
    166
    317
    Abdominal pain
         subjects affected / exposed
    40 / 770 (5.19%)
    72 / 784 (9.18%)
         occurrences all number
    48
    82
    Dyspepsia
         subjects affected / exposed
    33 / 770 (4.29%)
    60 / 784 (7.65%)
         occurrences all number
    36
    65
    Abdominal pain upper
         subjects affected / exposed
    39 / 770 (5.06%)
    51 / 784 (6.51%)
         occurrences all number
    48
    65
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    45 / 770 (5.84%)
    43 / 784 (5.48%)
         occurrences all number
    55
    57
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    196 / 770 (25.45%)
    158 / 784 (20.15%)
         occurrences all number
    260
    207
    Muscle spasms
         subjects affected / exposed
    118 / 770 (15.32%)
    171 / 784 (21.81%)
         occurrences all number
    171
    269
    Arthralgia
         subjects affected / exposed
    122 / 770 (15.84%)
    123 / 784 (15.69%)
         occurrences all number
    155
    207
    Pain in extremity
         subjects affected / exposed
    93 / 770 (12.08%)
    79 / 784 (10.08%)
         occurrences all number
    111
    99
    Bone pain
         subjects affected / exposed
    75 / 770 (9.74%)
    65 / 784 (8.29%)
         occurrences all number
    92
    82
    Musculoskeletal pain
         subjects affected / exposed
    64 / 770 (8.31%)
    55 / 784 (7.02%)
         occurrences all number
    74
    66
    Musculoskeletal chest pain
         subjects affected / exposed
    42 / 770 (5.45%)
    51 / 784 (6.51%)
         occurrences all number
    51
    59
    Muscular weakness
         subjects affected / exposed
    42 / 770 (5.45%)
    42 / 784 (5.36%)
         occurrences all number
    49
    47
    Myalgia
         subjects affected / exposed
    39 / 770 (5.06%)
    45 / 784 (5.74%)
         occurrences all number
    43
    59
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    60 / 770 (7.79%)
    58 / 784 (7.40%)
         occurrences all number
    90
    73
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    86 / 770 (11.17%)
    170 / 784 (21.68%)
         occurrences all number
    98
    206
    Diabetes mellitus
         subjects affected / exposed
    23 / 770 (2.99%)
    45 / 784 (5.74%)
         occurrences all number
    30
    50
    Hyperkalaemia
         subjects affected / exposed
    15 / 770 (1.95%)
    47 / 784 (5.99%)
         occurrences all number
    20
    63
    Dehydration
         subjects affected / exposed
    18 / 770 (2.34%)
    42 / 784 (5.36%)
         occurrences all number
    24
    53

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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