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    Clinical Trial Results:
    A Randomized Double-Blind Phase 3 Trial Comparing Docetaxel Combined with Dasatinib to Docetaxel Combined with Placebo in Castration-Resistant Prostate Cancer

    Summary
    EudraCT number
    		 2008-000701-11
    Trial protocol
    		 DE   IE   HU   FR   IT   GB   CZ   FI   SE   GR  
    Global end of trial date
    30 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2016
    First version publication date
    11 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA180-227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00744497
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Bristol-Myers Squibb International Corporation, Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, clinical.trials@bms.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
    30 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare overall survival for dasatinib plus docetaxel and prednisone versus placebo plus docetaxel and prednisone in subjects with metastatic castration-resistant prostate cancer.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Docetaxel and prednisolone were used as background therapy in this study.
    Evidence for comparator
    		 Docetaxel is used as a standard of care for the treatment of mCRPC and confers a survival advantage. If a subject discontinued docetaxel with no evidence of objective disease progression, then the subject was permitted to continue treatment with dasatinib/placebo until progression (with or without prednisone) at the investigator’s discretion.
    Actual start date of recruitment
    30 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 120
    Country: Number of subjects enrolled
    Australia: 104
    Country: Number of subjects enrolled
    Brazil: 107
    Country: Number of subjects enrolled
    Canada: 109
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 95
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Greece: 36
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    India: 74
    Country: Number of subjects enrolled
    Ireland: 54
    Country: Number of subjects enrolled
    Italy: 63
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Mexico: 108
    Country: Number of subjects enrolled
    Norway: 16
    Country: Number of subjects enrolled
    Peru: 48
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Russian Federation: 80
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Spain: 113
    Country: Number of subjects enrolled
    Sweden: 45
    Country: Number of subjects enrolled
    United Kingdom: 74
    Country: Number of subjects enrolled
    United States: 405
    Worldwide total number of subjects
    1930
    EEA total number of subjects
    698
    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)
    618
    From 65 to 84 years
    1293
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 187 sites worldwide.

    Pre-assignment
    Screening details
    		 1930 subjects were enrolled, and 1522 were randomised; 1518 received at least 1 dose of dasatinib (761) or placebo (757). Reason for 408 not randomised were: adverse event-7, subject withdrew consent-42, death-6, lost to follow-up-2, poor/non-compliance-3, subject did not met study criteria-332, administrative reason by sponsor-1, other reasons-15.

    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, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo, tablets, orally, once daily, plus docetaxel, 75 mg/m^2, intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with placebo tablets, orally once daily.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with Prednisone 5 mg tablet, orally twice daily to make the total daily dose of 10 mg up to disease progression or toxicity.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Docetaxel 75 mg/m^2 via intravenous infusion over 1 hour every 3 weeks up to disease progression or toxicity.

    Arm title
    		 Dasatinib
    Arm description
    		 Subjects received dasatinib, 100 mg, tablet, orally, once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    BMS-354825
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with dasatinib 20 mg/50 mg tablets orally once daily to make the total daily dose of 100 mg up to disease progression or toxicity.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with prednisone 5 mg tablet, orally twice daily to make the total daily dose of 10 mg up to disease progression or toxicity.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with docetaxel 75 mg/m^2 via intravenous infusion over 1 hour every 3 weeks up to disease progression or toxicity.

    Number of subjects in period 1 [1]
    		Placebo Dasatinib
    Started
    760
    762
    Received Treatment
    757
    761
    Completed
    0
    0
    Not completed
    760
    762
         Consent withdrawn by subject
    21
    18
         Disease progression
    312
    219
         Study drug toxicity
    68
    141
         Death
    11
    9
         Maximum clinical benefit
    141
    142
         Adverse event unrelated to study drug
    78
    122
         Other reasons
    19
    13
         Lost to follow-up
    4
    2
         Poor/non-compliance
    9
    5
         Subject no longer meets study criteria
    7
    3
         Subject requested to discontinue study treatment
    65
    80
         Administrative reason by sponsor
    25
    8
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 1930 subjects who were enrolled, 1522 subjects were randomised and 1518 subjects received at least 1 dose of dasatinib or placebo (761 in dasatinib group and 757 in placebo group).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, tablets, orally, once daily, plus docetaxel, 75 mg/m^2, intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Reporting group title
    Dasatinib
    Reporting group description
    		 Subjects received dasatinib, 100 mg, tablet, orally, once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Reporting group values
    		 Placebo Dasatinib Total
    Number of subjects
    		 760 762 1522
    Age categorical
    Units: Subjects
        <65 years
    		 263 251 514
        65 - <75 years
    		 323 333 656
        >=75 years
    		 174 178 352
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.9 ± 8.31 68.2 ± 8.15 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 760 762 1522
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 56 55 111
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        Black or African American
    		 34 23 57
        White
    		 645 656 1301
        Other
    		 24 27 51
    Type of metastatic disease
    Units: Subjects
        Bone disease only
    		 286 307 593
        Visceral/nodal disease only
    		 73 80 153
        Both bone and visceral/nodal disease
    		 399 373 772
        No evidence of metastatic disease
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, tablets, orally, once daily, plus docetaxel, 75 mg/m^2, intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Reporting group title
    Dasatinib
    Reporting group description
    		 Subjects received dasatinib, 100 mg, tablet, orally, once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Primary: Overall Survival: Time From Randomisation to Date of Death

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    End point title
    		 Overall Survival: Time From Randomisation to Date of Death
    End point description
    Overall survival was defined as time in months from the randomization date to the date of death due to any cause (in the randomised population). If the subject did not die, survival was censored on the last date he or she was known to be alive. The analysis was performed in all the subjects who were randomised to receive any treatment.
    End point type
    Primary
    End point timeframe
    From randomisation to death or date of last contact (maximum reached: 45 months)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    760
    762
    Units: Months
        median (confidence interval 95%)
    21.2 (20 to 23.4)
    21.5 (20.3 to 22.8)
    Statistical analysis title
    		 Overall Survival: Dasatinib vs Placebo
    Statistical analysis description
    Analysis compared survival in arms by 2-sided, alpha=0.05 level, log-rank test, stratified by bisphosphonate intake (yes/no) and urinary N-telopeptide category (<60 vs >=60 nmol/mmol creatinine) as defined at randomisation. Null hypothesis=survival was equal in both arms. Power calculations indicated that >=858 deaths would lead to >=90% power at 5% level for rejecting null hypothesis, given a true hazard ratio of 0.8.
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    1522
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9009 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.13
    Notes
    [1] - An interim analysis on survival was performed. Final analyses included a multiplicity correction.

    Secondary: Percentage of Subjects With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)

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    End point title
    		 Percentage of Subjects With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)
    End point description
    Objective tumor response rate=percentage of randomised subjects with a best tumor response of partial (PR) or complete response (CR), within 42 days of end of dosing, divided by total number of subjects who were evaluable. By RECIST: CR=disappearance of clinical and radiologic evidence of target and nontarget lesions confirmed by another evaluation at least 6 weeks later. PR=a >30% or greater decrease in the sum of longest diameter (LD) of target lesions in reference to the baseline sum LD confirmed by another evaluation at least 6 weeks later. Stable disease=neither sufficient increase to qualify for PD nor shrinkage to qualify for PR, and at least 8 weeks since start of study therapy. Progressive disease=a 20% or greater increase in sum of LD of all target lesions, taking as reference the smallest sum of LD at or following baseline, or unequivocal progression on existing nontarget lesions, or new lesions are present. Subjects with at least 1 target lesion at baseline were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, every 12 weeks thereafter to end of treatment, at end of treatment, and at follow-up (within 42 days of end of dosing)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    383
    381
    Units: Percentage of subjects
        number (confidence interval 95%)
    31.85 (27.21 to 36.78)
    30.45 (25.86 to 35.34)
    Statistical analysis title
    		 Objective Tumor Response:
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    764
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.935
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.688
         upper limit
    		 1.271
    Notes
    [2] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for experimental to control group.

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

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    End point title
    		 Time to First Skeletal-related Event (SRE)
    End point description
    Time to first SRE is defined as the time in months from the date of randomisation to the date of first SRE (unless SRE occurred while the subject was undergoing subsequent cancer therapy). Subjects with a first SRE while on subsequent cancer therapy, those who died without a reported SRE, and those who did not have an SRE were censored on the date of their last SRE assessment prior to start of subsequent cancer therapy, if any. Subjects who had no SRE assessments were censored on the day they were randomised. The analysis was performed in all the subjects who were randomised to receive any treatment. Here '99999' represents not estimable data.
    End point type
    Secondary
    End point timeframe
    From day of randomisation to date of first SRE or to last SRE assessment, if subsequent cancer therapy begun or no SRE (maximum reached: 42 months)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    760
    762
    Units: Months
        median (confidence interval 95%)
    31.1 (28.8 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Time to First SRE: Dasatinib vs Placebo
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    1522
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.02
    Notes
    [3] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.

    Secondary: Percentage of Subjects With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline

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    End point title
    		 Percentage of Subjects With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline
    End point description
    The percentage of Subjects who had an on-study uNTx value confirmed (at least 3 weeks later) within normal limits (or >=3 and <60 nmol/mmol creatinine, if normal limits were missing) or an on-study uNTx level reduction from baseline of >=35%, even when on-study uNTx value remained abnormal. Subjects who entered the study with baseline urinary N-telopeptide values higher than the upper limit of normal (ULN), or >=60 nmol/mmol creatinine, if ULN was missing were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, prior to each docetaxel infusion (every 3 weeks) to end of treatment, at end of treatment, and at follow-up (within 14 days of end of dosing)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    335
    321
    Units: Percentage of subjects
        number (confidence interval 95%)
    60.6 (55.14 to 65.86)
    66.04 (60.58 to 71.21)
    Statistical analysis title
    		 Reduction in uNTx Level from baseline
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.763
    Notes
    [4] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for experimental to control group.

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS is defined as the time from the randomisation date until the date of earliest evidence of disease progression or death, for subjects who progressed or died before subsequent cancer therapy. Those who progressed or died while on subsequent cancer therapy and those who did not die or progress were censored at their last radiologic bone scan/imaging, skeletal related-event, or tumor assessment or at measurement of prostate specific antigen levels, whichever occurred last prior to start of subsequent cancer therapy ,if any. Subjects with no assessments were censored on the day of randomisation. The analysis was performed in all the subjects who were randomised to receive any treatment.
    End point type
    Secondary
    End point timeframe
    From day of randomisation to disease progression or death (or to last clinical assessment, if subsequent cancer therapy started or no progression or death) (maximum reached: approximately 43 months)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    760
    762
    Units: Months
        median (confidence interval 95%)
    11.1 (10.8 to 11.7)
    11.8 (11.1 to 13.4)
    Statistical analysis title
    		 PFS: Dasatinib vs Placebo
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    1522
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.05
    Notes
    [5] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.

    Secondary: Time to Prostate Specific Antigen (PSA) Progression

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    End point title
    		 Time to Prostate Specific Antigen (PSA) Progression
    End point description
    PSA progression is defined as the time from randomisation to the date of the first PSA level measurement that led to confirmed PSA progression, for subjects who had not started subsequent cancer therapy. For subjects who did not progress or who progressed on cancer therapy, PSA progression is defined as the time from randomisation to the date of the last PSA level measurement before the start of cancer therapy, if any. Subjects who had no on-study PSA level measurements were censored on the day they were randomised. The analysis was performed in all subjects who were randomised to receive any treatment.
    End point type
    Secondary
    End point timeframe
    From randomisation to date of first PSA measurement leading to confirmed PSA progression (or to last bone scan assessment, if no progression or if cancer therapy started) (maximum reached: 30 months)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    760
    762
    Units: Months
        median (confidence interval 95%)
    6.9 (6.5 to 7.4)
    7.2 (6.6 to 7.9)
    Statistical analysis title
    		 Time to PSA Progression
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    1522
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.01
    Notes
    [6] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for of experimental to control group.

    Secondary: Percentage of Subjects With a Reduction in Pain Intensity From Baseline

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    End point title
    		 Percentage of Subjects With a Reduction in Pain Intensity From Baseline
    End point description
    The percentage of subjects with reduction in pain intensity from baseline was defined as the number of subjects who achieved a 30% or more decrease in pain intensity from baseline for at least 2 consecutive pain assessments (at least 14 days apart) within 14 days of end of dosing divided by the number of randomised subjects who had a baseline pain intensity of at least 2. Pain intensity was assessed based on question 3 of the brief pain inventory questionnaire. The analysis was performed in all the evaluable subjects with a baseline pain intensity of 2 or greater.
    End point type
    Secondary
    End point timeframe
    Baseline, prior to each docetaxel infusion (every 3 weeks), at end of treatment, and at follow-up (within 14 days of end of dosing)
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    467
    419
    Units: Percentage of subjects
        number (confidence interval 95%)
    71.52 (67.19 to 75.57)
    66.59 (61.85 to 71.09)
    Statistical analysis title
    		 Reduction from Baseline in Pain Intensity
    Comparison groups
    Placebo v Dasatinib
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.791
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.594
         upper limit
    		 1.052
    Notes
    [7] - Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for experimental to control group.

    Other pre-specified: Number of Subjects With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation

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    End point title
    		 Number of Subjects With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. The analysis was performed in all the subjects who received the treatment.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to >=30 days after last dose of study drug until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever shorter.
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        All Deaths
    505
    506
        Deaths on or within 30 days of treatment
    50
    79
        All SAEs
    317
    381
        Drug-related SAEs
    90
    150
        AEs leading to discontinuation
    186
    293
        Drug-related AEs leading to discontinuation
    76
    144
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Adverse Events (AEs) of Special Interest

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    End point title
    		 Number of Subjects With Adverse Events (AEs) of Special Interest
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. AEs of Special Interest=recognized events in other agents within this drug class or events for which safety data from nonclinical and clinical studies with dasatinib indicate that careful evaluation is warranted. AEs of Special Interest were identified by the medical and safety representatives of the sponsor based on MedDRA preferred terms or laboratory data. ANC=absolute neutrophil count. The analysis was performed in all the subjects who received the treatment.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to >=30 days after last dose of study drug until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever was shorter
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        Myelosuppression: Hemoglobin (n=746, 739)
    712
    720
        Myelosuppression: White blood cells (n=746, 738)
    128
    149
        Myelosuppression: ANC (n=745, 737)
    84
    161
        Myelosuppression: Platelets (n=746, 738)
    108
    100
        Hypocalcemia (n=739, 719)
    308
    377
        Hypophosphotemia (n=733, 720)
    189
    257
        Hypomagnesemia (n=734, 721)
    108
    98
        Diarrhea (n=757, 761)
    167
    229
        Nausea/vomiting (n=757, 761)
    127
    170
        Fatigue (n=757, 761)
    216
    236
        Myalgias/arthralgias (n=757, 761
    29
    29
        Rash (n=757, 761)
    46
    72
        Gastrointestinal tract bleeding (n=757, 761)
    6
    14
        Central nervous system bleeding (n=757, 761)
    1
    2
        Other hemorrhage (n=757, 761)
    14
    24
        Pulmonary arterial hypertension (n=757, 761)
    0
    0
        Fluid retention: Superficial edema (n=757, 761)
    77
    76
        Fluid retention: Pleural effusion (n=757, 761)
    13
    87
        Fluid retention: Other (n=757, 761)
    37
    52
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Abnormalities in Results of Clinical Laboratory Tests in Hematology

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    End point title
    		 Number of Subjects With Abnormalities in Results of Clinical Laboratory Tests in Hematology
    End point description
    Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening ). Grade 3 and 4 criteria are defined as follows: Absolute neutrophil count, Grade 3, neutrophils <1.0-0.5*10^9/L; Grade 4, <0.5*10^9/L. Hemoglobin, Grade 3, <4.9-4.0 mmol/L; Grade 4, <4.0 mmol/L. Platelets, Grade 3, <50.0-25.0*10^9/L; Grade 4, <25.0*10^9/L. Leukocytes, Grade 3, <2.0-1.0*10^9/L; Grade 4, <1.0*10^9/L. The analysis was performed in all the subjects who received treatment.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, within 3 days prior to each infusion of docetaxel (each cycle) and at end of treatment. If docetaxel is discontinued, every other cycle.
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        Absolute neutrophil count (All grades)
    84
    161
        Absolute neutrophil count (Grades 3 and 4)
    41
    46
        Hemoglobin (All grades)
    712
    720
        Hemoglobin (Grades 3 and 4)
    44
    59
        Platelets (All grades)
    108
    100
        Platelets (Grades 3 and 4)
    6
    3
        Leukocytes (All grades)
    128
    149
        Leukocytes (Grades 3 and 4)
    32
    30
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes

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    End point title
    		 Number of Subjects With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes
    End point description
    ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening). ALP, ALT, and AST, Grade 3, >5.0-20.0*ULN; Grade 4, >20.0*ULN. Total bilirubin, Grade 3, >3.0–10.0*ULN; Grade 4, >10.0*ULN. Creatinine, Grade 3, >3.0–6.0*ULN; Grade 4, >6.0*ULN. Hypercalcemia(serum calcium(SC), mmol/L), Grade 3, >3.1-3.4; Grade 4, >3.4. Hypocalcemia(SC, mmol/L), Grade 3, <1.75-1.5; Grade 4, <1.5. Hyperkalemia(SC, mmol/L), Grade 3, >6.0-7.0; Grade 4, >7.0. Hypokalemia(SC, mmol/L), Grade 3, <3.0-2.5; Grade 4, <2.5. Hypernatremia(SC, mmol/L), Grade 3, >155-160; Grade 4, >160. Hyponatremia(serum sodium(SS), mmol/L), Grade 3, <130-120; Grade 4, <120. Phosphorus (SS, mmol/L), Grade 3, <0.6-0.3; Grade 4, <0.3. The analysis was performed in all the subjects who received treatment.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        ALP (All grades)
    447
    375
        ALP (Grades 3 and 4)
    91
    68
        ALT (All grades)
    186
    256
        ALT (Grades 3 and 4)
    5
    6
        AST (All grades)
    212
    266
        AST (Grades 3 and 4)
    4
    5
        Total bilirubin (All grades)
    49
    41
        Total bilirubin (Grades 3 and 4)
    1
    3
        Creatinine (All grades)
    153
    184
        Creatinine (Grades 3 and 4)
    3
    5
        Hypercalcemia (All grades)
    56
    34
        Hypercalcemia (Grades 3 and 4)
    1
    1
        Hypocalcemia (All grades)
    308
    377
        Hypocalcemia (Grades 3 and 4)
    23
    25
        Hyperkalemia (All grades)
    164
    152
        Hyperkalemia (Grades 3 and 4)
    11
    14
        Hypokalemia (All grades)
    107
    152
        Hypokalemia (Grades 3 and 4)
    6
    16
        Hypernatremia (All grades)
    93
    101
        Hypernatremia (Grades 3 and 4)
    0
    0
        Hyponatremia (All grades)
    230
    241
        Hyponatremia (Grades 3 and 4)
    36
    43
        Phosporus (All grades)
    189
    257
        Phosphorus (Grades 3 and 4)
    43
    93
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Abnormal Results in Urinalysis

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    End point title
    		 Number of Subjects With Abnormal Results in Urinalysis
    End point description
    Abnormal=positive, defined as the presence of >=30 mg/dL of protein; a small, moderate, or large amount of blood; or >0 g/dL glucose in urine. BL=baseline; neg=negative. The analysis was performed in all the subjects who received the treatment.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        Protein, urine: positive
    246
    336
        Blood, urine: positive
    289
    307
        Glucose, urine: positive
    179
    154
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects by Maximal On-study Fridericia-corrected QTc Interval by Electrocardiogram

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    End point title
    		 Number of Subjects by Maximal On-study Fridericia-corrected QTc Interval by Electrocardiogram
    End point description
    The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval was corrected for heart rate using Fridericia's (QTcF) formula. QTc interval were measured in milliseconds (msec). The analysis was performed in all the subjects who received the treatment. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        <450 msecs (n=600, 548)
    550
    497
        450-500 msecs (n=600, 548)
    43
    48
        >500 msecs (n=600, 548)
    7
    3
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Changes From Baseline in Fridericia-corrected QTc Interval by Electrocardiogram

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    End point title
    		 Number of Subjects With Changes From Baseline in Fridericia-corrected QTc Interval by Electrocardiogram
    End point description
    The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval was corrected for heart rate using Fridericia's (QTcF) formula. QTc interval were measured in milliseconds (msec). A change from baseline QT and QTc (corrected for heart rate by Fridericia formula) were presented. The analysis was performed in all the subjects who received the treatment. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    757
    761
    Units: Subjects
        0 to 30 msecs increase (n=591, 540)
    203
    199
        >30 to 60 msecs increase (n=591, 540)
    52
    47
        >60 msecs increase (n=591, 540)
    32
    26
        Decrease (n=591, 540)
    304
    268
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study by Echocardiogram

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    End point title
    		 Number of Subjects With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study by Echocardiogram
    End point description
    BL=baseline; OS=on-study. Echocardiogram were performed at baseline and once during treatment. the analysis was done in all the subjects who were randomised to receive any treatment.
    End point type
    Other pre-specified
    End point timeframe
    At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated
    End point values
    		 Placebo Dasatinib
    Number of subjects analysed
    760
    762
    Units: Subjects
        Pericardial effusion at BL/absent OS
    3
    1
        Pericardial effusion at BL/present OS
    0
    1
        Pericardial effusion at BL/not reported OS
    1
    0
        Pericardial effusion absent at BL/ absent OS
    584
    545
        Pericardial effusion absent at BL/present OS
    24
    26
        Pericardial effusion absent at BL/not reported OS
    132
    184
        Pericardial not reported at BL
    16
    5
        LVEF OS <40%
    2
    2
        LVEF OS >=40%
    607
    566
        LVEF not reported OS
    151
    194
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On Study (i.e. events from 1st dose date through last dose date + 30 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, tablets, orally, once daily, plus docetaxel, 75 mg/m^2, intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Reporting group title
    Dasatinib
    Reporting group description
    		 Subjects received dasatinib, 100 mg, tablet, orally, once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily up to disease progression or toxicity.

    Serious adverse events
    		 Placebo Dasatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    317 / 757 (41.88%)
    381 / 761 (50.07%)
         number of deaths (all causes)
    50
    79
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenosquamous cell lung cancer
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Astrocytoma malignant
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer recurrent
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastasis
         subjects affected / exposed
    2 / 757 (0.26%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Small cell lung cancer
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 757 (0.40%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Prostate cancer metastatic
         subjects affected / exposed
    10 / 757 (1.32%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 8
    0 / 7
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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 skin
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    10 / 757 (1.32%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    5 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    8 / 757 (1.06%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    5 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vena cava thrombosis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Venous thrombosis limb
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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
    Asthenia
         subjects affected / exposed
    7 / 757 (0.92%)
    13 / 761 (1.71%)
         occurrences causally related to treatment / all
    6 / 8
    8 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Chest pain
         subjects affected / exposed
    8 / 757 (1.06%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    1 / 8
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    2 / 757 (0.26%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Device occlusion
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Face oedema
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    9 / 757 (1.19%)
    15 / 761 (1.97%)
         occurrences causally related to treatment / all
    3 / 9
    8 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 757 (0.13%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Generalised oedema
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ failure
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Oedema
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 757 (0.40%)
    6 / 761 (0.79%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    9 / 757 (1.19%)
    7 / 761 (0.92%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Performance status decreased
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    14 / 757 (1.85%)
    29 / 761 (3.81%)
         occurrences causally related to treatment / all
    5 / 15
    12 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    3 / 757 (0.40%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema genital
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile pain
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular mass
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Acute respiratory failure
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Alveolitis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 757 (1.32%)
    21 / 761 (2.76%)
         occurrences causally related to treatment / all
    3 / 11
    8 / 23
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 757 (0.13%)
    19 / 761 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    21 / 25
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pneumonitis
         subjects affected / exposed
    7 / 757 (0.92%)
    7 / 761 (0.92%)
         occurrences causally related to treatment / all
    2 / 8
    5 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Productive cough
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    17 / 757 (2.25%)
    5 / 761 (0.66%)
         occurrences causally related to treatment / all
    3 / 17
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary venous thrombosis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    2 / 757 (0.26%)
    7 / 761 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 757 (0.26%)
    6 / 761 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depression suicidal
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow myelogram abnormal
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    0 / 757 (0.00%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoglobin
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 757 (0.40%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 757 (0.26%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    6 / 757 (0.79%)
    11 / 761 (1.45%)
         occurrences causally related to treatment / all
    0 / 6
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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 / 757 (0.00%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal fracture
         subjects affected / exposed
    3 / 757 (0.40%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous injury
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 757 (0.00%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    8 / 757 (1.06%)
    8 / 761 (1.05%)
         occurrences causally related to treatment / all
    1 / 8
    3 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac disorder
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-Respiratory arrest
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 757 (0.26%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebral haematoma
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    0 / 757 (0.00%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    4 / 757 (0.53%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Coma
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iiird nerve disorder
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    4 / 757 (0.53%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Spinal cord compression
         subjects affected / exposed
    6 / 757 (0.79%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 757 (0.66%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    15 / 757 (1.98%)
    21 / 761 (2.76%)
         occurrences causally related to treatment / all
    4 / 16
    6 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    27 / 757 (3.57%)
    32 / 761 (4.20%)
         occurrences causally related to treatment / all
    13 / 30
    15 / 33
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    7 / 757 (0.92%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    3 / 12
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    18 / 757 (2.38%)
    19 / 761 (2.50%)
         occurrences causally related to treatment / all
    9 / 29
    6 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 757 (0.40%)
    6 / 761 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 757 (0.00%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    10 / 757 (1.32%)
    5 / 761 (0.66%)
         occurrences causally related to treatment / all
    1 / 10
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 757 (1.32%)
    44 / 761 (5.78%)
         occurrences causally related to treatment / all
    8 / 11
    33 / 51
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Diverticular perforation
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    3 / 757 (0.40%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    7 / 757 (0.92%)
    8 / 761 (1.05%)
         occurrences causally related to treatment / all
    1 / 8
    4 / 8
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-Abdominal haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 757 (0.92%)
    13 / 761 (1.71%)
         occurrences causally related to treatment / all
    2 / 8
    9 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    5 / 757 (0.66%)
    8 / 761 (1.05%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Volvulus
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 757 (1.32%)
    14 / 761 (1.84%)
         occurrences causally related to treatment / all
    4 / 11
    6 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic pain
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peau d'orange
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 757 (0.53%)
    8 / 761 (1.05%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 8
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Bladder neck obstruction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    3 / 757 (0.40%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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
    18 / 757 (2.38%)
    10 / 761 (1.31%)
         occurrences causally related to treatment / all
    0 / 19
    2 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobinuria
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    3 / 757 (0.40%)
    6 / 761 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 757 (0.66%)
    5 / 761 (0.66%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Renal impairment
         subjects affected / exposed
    3 / 757 (0.40%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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
    9 / 757 (1.19%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 757 (0.26%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital haemorrhage
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    12 / 757 (1.59%)
    7 / 761 (0.92%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    7 / 757 (0.92%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatinaemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    4 / 757 (0.53%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 757 (0.40%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 757 (0.13%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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
    Abscess intestinal
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 757 (0.26%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balanoposthitis infective
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Candida infection
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 757 (0.40%)
    9 / 761 (1.18%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis of male external genital organ
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 757 (0.40%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Erysipelas
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 757 (0.40%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 757 (0.13%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    4 / 757 (0.53%)
    8 / 761 (1.05%)
         occurrences causally related to treatment / all
    2 / 4
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 757 (0.00%)
    5 / 761 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung infection
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    3 / 757 (0.40%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal infection
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    2 / 757 (0.26%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    22 / 757 (2.91%)
    33 / 761 (4.34%)
         occurrences causally related to treatment / all
    3 / 23
    11 / 36
         deaths causally related to treatment / all
    1 / 5
    0 / 2
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis acute
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (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 / 757 (0.13%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Scrotal abscess
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 757 (0.79%)
    7 / 761 (0.92%)
         occurrences causally related to treatment / all
    2 / 6
    3 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    3 / 757 (0.40%)
    10 / 761 (1.31%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 10
         deaths causally related to treatment / all
    1 / 2
    1 / 5
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (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
    7 / 757 (0.92%)
    10 / 761 (1.31%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 757 (0.53%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 757 (0.53%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    11 / 757 (1.45%)
    21 / 761 (2.76%)
         occurrences causally related to treatment / all
    4 / 14
    10 / 22
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Fluid overload
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 757 (0.40%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    6 / 757 (0.79%)
    4 / 761 (0.53%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    4 / 757 (0.53%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 757 (0.26%)
    3 / 761 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 757 (0.40%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 757 (0.13%)
    0 / 761 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 757 (0.00%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 757 (0.00%)
    2 / 761 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 757 (0.13%)
    1 / 761 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Dasatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    701 / 757 (92.60%)
    716 / 761 (94.09%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    42 / 757 (5.55%)
    22 / 761 (2.89%)
         occurrences all number
    51
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    143 / 757 (18.89%)
    163 / 761 (21.42%)
         occurrences all number
    236
    258
    Chest pain
         subjects affected / exposed
    34 / 757 (4.49%)
    49 / 761 (6.44%)
         occurrences all number
    40
    60
    Fatigue
         subjects affected / exposed
    329 / 757 (43.46%)
    334 / 761 (43.89%)
         occurrences all number
    566
    572
    Mucosal inflammation
         subjects affected / exposed
    52 / 757 (6.87%)
    70 / 761 (9.20%)
         occurrences all number
    80
    106
    Oedema
         subjects affected / exposed
    47 / 757 (6.21%)
    36 / 761 (4.73%)
         occurrences all number
    50
    42
    Oedema peripheral
         subjects affected / exposed
    207 / 757 (27.34%)
    162 / 761 (21.29%)
         occurrences all number
    254
    213
    Pain
         subjects affected / exposed
    62 / 757 (8.19%)
    47 / 761 (6.18%)
         occurrences all number
    73
    55
    Pyrexia
         subjects affected / exposed
    71 / 757 (9.38%)
    132 / 761 (17.35%)
         occurrences all number
    88
    174
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    112 / 757 (14.80%)
    137 / 761 (18.00%)
         occurrences all number
    148
    181
    Dyspnoea
         subjects affected / exposed
    127 / 757 (16.78%)
    154 / 761 (20.24%)
         occurrences all number
    163
    205
    Epistaxis
         subjects affected / exposed
    41 / 757 (5.42%)
    33 / 761 (4.34%)
         occurrences all number
    57
    35
    Pleural effusion
         subjects affected / exposed
    28 / 757 (3.70%)
    117 / 761 (15.37%)
         occurrences all number
    29
    145
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    95 / 757 (12.55%)
    76 / 761 (9.99%)
         occurrences all number
    114
    84
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    27 / 757 (3.57%)
    49 / 761 (6.44%)
         occurrences all number
    31
    56
    Weight decreased
         subjects affected / exposed
    77 / 757 (10.17%)
    121 / 761 (15.90%)
         occurrences all number
    88
    130
    Weight increased
         subjects affected / exposed
    64 / 757 (8.45%)
    36 / 761 (4.73%)
         occurrences all number
    71
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    61 / 757 (8.06%)
    64 / 761 (8.41%)
         occurrences all number
    69
    77
    Dysgeusia
         subjects affected / exposed
    147 / 757 (19.42%)
    165 / 761 (21.68%)
         occurrences all number
    236
    254
    Headache
         subjects affected / exposed
    65 / 757 (8.59%)
    82 / 761 (10.78%)
         occurrences all number
    98
    111
    Neuropathy peripheral
         subjects affected / exposed
    109 / 757 (14.40%)
    83 / 761 (10.91%)
         occurrences all number
    132
    99
    Paraesthesia
         subjects affected / exposed
    59 / 757 (7.79%)
    44 / 761 (5.78%)
         occurrences all number
    70
    60
    Peripheral sensory neuropathy
         subjects affected / exposed
    106 / 757 (14.00%)
    98 / 761 (12.88%)
         occurrences all number
    132
    141
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    142 / 757 (18.76%)
    217 / 761 (28.52%)
         occurrences all number
    205
    285
    Neutropenia
         subjects affected / exposed
    67 / 757 (8.85%)
    79 / 761 (10.38%)
         occurrences all number
    89
    113
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    86 / 757 (11.36%)
    48 / 761 (6.31%)
         occurrences all number
    92
    53
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    67 / 757 (8.85%)
    66 / 761 (8.67%)
         occurrences all number
    79
    81
    Constipation
         subjects affected / exposed
    189 / 757 (24.97%)
    157 / 761 (20.63%)
         occurrences all number
    266
    230
    Diarrhoea
         subjects affected / exposed
    312 / 757 (41.22%)
    414 / 761 (54.40%)
         occurrences all number
    636
    975
    Dyspepsia
         subjects affected / exposed
    59 / 757 (7.79%)
    50 / 761 (6.57%)
         occurrences all number
    76
    60
    Nausea
         subjects affected / exposed
    231 / 757 (30.52%)
    288 / 761 (37.84%)
         occurrences all number
    389
    531
    Stomatitis
         subjects affected / exposed
    47 / 757 (6.21%)
    47 / 761 (6.18%)
         occurrences all number
    69
    83
    Vomiting
         subjects affected / exposed
    117 / 757 (15.46%)
    166 / 761 (21.81%)
         occurrences all number
    152
    245
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    326 / 757 (43.06%)
    311 / 761 (40.87%)
         occurrences all number
    336
    323
    Dry skin
         subjects affected / exposed
    46 / 757 (6.08%)
    54 / 761 (7.10%)
         occurrences all number
    49
    56
    Nail disorder
         subjects affected / exposed
    119 / 757 (15.72%)
    80 / 761 (10.51%)
         occurrences all number
    130
    84
    Rash
         subjects affected / exposed
    75 / 757 (9.91%)
    106 / 761 (13.93%)
         occurrences all number
    101
    133
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    44 / 757 (5.81%)
    46 / 761 (6.04%)
         occurrences all number
    59
    72
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    124 / 757 (16.38%)
    104 / 761 (13.67%)
         occurrences all number
    165
    129
    Back pain
         subjects affected / exposed
    194 / 757 (25.63%)
    148 / 761 (19.45%)
         occurrences all number
    248
    186
    Bone pain
         subjects affected / exposed
    70 / 757 (9.25%)
    61 / 761 (8.02%)
         occurrences all number
    93
    83
    Muscle spasms
         subjects affected / exposed
    42 / 757 (5.55%)
    15 / 761 (1.97%)
         occurrences all number
    53
    20
    Muscular weakness
         subjects affected / exposed
    51 / 757 (6.74%)
    38 / 761 (4.99%)
         occurrences all number
    56
    40
    Musculoskeletal chest pain
         subjects affected / exposed
    40 / 757 (5.28%)
    35 / 761 (4.60%)
         occurrences all number
    46
    49
    Musculoskeletal pain
         subjects affected / exposed
    55 / 757 (7.27%)
    62 / 761 (8.15%)
         occurrences all number
    67
    77
    Myalgia
         subjects affected / exposed
    54 / 757 (7.13%)
    50 / 761 (6.57%)
         occurrences all number
    61
    68
    Pain in extremity
         subjects affected / exposed
    128 / 757 (16.91%)
    115 / 761 (15.11%)
         occurrences all number
    176
    135
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    67 / 757 (8.85%)
    73 / 761 (9.59%)
         occurrences all number
    102
    111
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    151 / 757 (19.95%)
    207 / 761 (27.20%)
         occurrences all number
    207
    283
    Dehydration
         subjects affected / exposed
    23 / 757 (3.04%)
    44 / 761 (5.78%)
         occurrences all number
    24
    52
    Hyperglycaemia
         subjects affected / exposed
    55 / 757 (7.27%)
    41 / 761 (5.39%)
         occurrences all number
    68
    57
    Hypocalcaemia
         subjects affected / exposed
    24 / 757 (3.17%)
    40 / 761 (5.26%)
         occurrences all number
    42
    45

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2008
    The purpose of this amendment was to permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research studies.
    17 Apr 2009
    The Purpose of this amendment was to: • Expand number of allowable cycles of docetaxel, route and schedule of dexamethasone and exclude agents with known effect on bone turnover, • Set minimum period of time for definition of stable disease for Response Evaluation Criteria in Solid Tumor (RECIST) evaluable subjects and provide specification around timing and need for valuations such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, • Clarification of Subjective Significance Questionnaire, dose modifications, requirements for follow-up of toxicity and progression, • Change in requirement of collection of bone-specific alkaline phosphatase.
    22 Sep 2009
    The Purpose of this amendment was to: • Allow use of alternate imaging modalities (skeletal survey supported by CT/MRI) to evaluate bone if/when bone scan is unable to be conducted due to lack of Technetium 99, • Reclassify 2 objectives from Secondary to Exploratory (To estimate the objective tumor response rate, by modified RECIST criteria for subjects with measurable disease at baseline in each treatment arm; and to estimate the rate of stable disease by bone scan or other approved imaging modality at 24 weeks in each treatment arm), • Clarify Inclusion criteria timelines and dose modifications for toxicities, and modification of serious adverse event submission process.
    12 Jul 2011
    The Purpose of this amendment was to: • Address Regulatory feedback by reducing number of interim analyses for overall survival from two to one, • Remove radiological progression on bone scan/imaging from the Skeletal Related Event definition, to now be a “stand alone” progression event, • Add Progression Free Survival as a secondary objective/endpoint, • Move Objective Tumor Response Rate to Secondary objectives/endpoints, • Adjust hierarchy of Secondary objectives/endpoints, • Clarify terminology and correct typographical errors.

    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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