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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase 3 Trial Comparing Ipilimumab vs. Placebo Following Radiotherapy in Subjects with Castration Resistant Prostate Cancer That Have Received Prior Treatment with Docetaxel.

    Summary
    EudraCT number
    		 2008-003314-97
    Trial protocol
    		 DE   AT   NL   IT   CZ   DK   ES   IE   BE   GB   HU   FR   GR  
    Global end of trial date
    03 Jun 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA184-043
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00861614
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee 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
    03 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 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 OS of subjects with castration resistant prostate cancer (CRPC), that had progressed during or following docetaxel treatment, when randomized to treatment with bone-directed radiotherapy followed by ipilimumab versus bone-directed radiotherapy followed by placebo.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 24
    Country: Number of subjects enrolled
    Netherlands: 42
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Denmark: 46
    Country: Number of subjects enrolled
    France: 77
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 52
    Country: Number of subjects enrolled
    Argentina: 73
    Country: Number of subjects enrolled
    Australia: 33
    Country: Number of subjects enrolled
    Brazil: 79
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 32
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Mexico: 46
    Country: Number of subjects enrolled
    Peru: 19
    Country: Number of subjects enrolled
    Puerto Rico: 4
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    United States: 215
    Worldwide total number of subjects
    988
    EEA total number of subjects
    434
    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)
    327
    From 65 to 84 years
    655
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 153 sites in 27 countries.

    Pre-assignment
    Screening details
    		 988 enrolled, 799 randomized (399 ipilimumab, 400 placebo); 149 no longer met study criteria, 17 withdrew, 6 adverse events, 4 died, 1 lost to follow-up, 12 unspecified. 789 treated with radiotherapy (393 ipilimumab, 396 placebo); 2 no longer met study criteria, 3 withdrew consent, 1 died, 2 had adverse events, 2 had disease progression.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab + Radiotherapy
    Arm description
    		 Prior to receiving study drug, subjects receive radiotherapy at 8 Gray units (Gy) to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, 10 milligrams (mg) of ipilimumab per kilogram (kg) of body weight was administered intravenously (IV) over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    BMS-734016
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Subjects receive radiotherapy at 8 Gy to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, 10 milligrams (mg) of ipilimumab per kilogram (kg) of body weight was administered intravenously (IV) over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Arm title
    		 Placebo + Radiotherapy
    Arm description
    		 Subjects receive radiotherapy at 8 Gy to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium Chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Investigational medicinal product name
    Dextrose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Number of subjects in period 1 [1]
    		Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Started
    399
    400
    Completed
    22
    28
    Not completed
    377
    372
         Adverse event, serious fatal
    32
    19
         Consent withdrawn by subject
    35
    37
         Adverse event, non-fatal
    27
    23
         Unspecified
    21
    23
         Study Drug Toxicity
    79
    6
         Disease Progression
    183
    264
    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: 988 enrolled, 799 randomized (399 ipilimumab, 400 placebo); 149 no longer met study criteria, 17 withdrew, 6 adverse events, 4 died, 1 lost to follow-up,12 unspecified. 789 treated with radiotherapy (393 ipilimumab, 396 placebo); 2 no longer met study criteria, 3 withdrew consent, 1 died, 2 had adverse events, 2 had disease progression.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipilimumab + Radiotherapy
    Reporting group description
    		 Prior to receiving study drug, subjects receive radiotherapy at 8 Gray units (Gy) to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, 10 milligrams (mg) of ipilimumab per kilogram (kg) of body weight was administered intravenously (IV) over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Reporting group title
    Placebo + Radiotherapy
    Reporting group description
    		 Subjects receive radiotherapy at 8 Gy to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Reporting group values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy Total
    Number of subjects
    		 399 400 799
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        <70 years
    		 215 234 449
        >=70 years
    		 184 166 350
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.2 ± 7.53 67.1 ± 7.56 -
    Gender, Male/Female
    Units: subjects
        Female
    		 0 0 0
        Male
    		 399 400 799

    End points

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    End points reporting groups
    Reporting group title
    Ipilimumab + Radiotherapy
    Reporting group description
    		 Prior to receiving study drug, subjects receive radiotherapy at 8 Gray units (Gy) to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, 10 milligrams (mg) of ipilimumab per kilogram (kg) of body weight was administered intravenously (IV) over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Reporting group title
    Placebo + Radiotherapy
    Reporting group description
    		 Subjects receive radiotherapy at 8 Gy to at least 1, and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Subject analysis set title
    All Randomized Subjects Ipilimumab + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of ipilimumab.

    Subject analysis set title
    All Randomized Subjects in Placebo + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of placebo.

    Subject analysis set title
    Pain-Evaluable Subjects in Ipilimumab + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of ipilimumab with a baseline average daily worst pain score of 4 or higher for a 5 day period.

    Subject analysis set title
    Pain-Evaluable Subjects in Placebo + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of placebo with a baseline average daily worst pain score of 4 or higher for a 5 day period.

    Subject analysis set title
    Subjects with Pain Response in Ipilimumab + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of ipilimumab with a baseline average daily worst pain score of 4 or higher for a 5 day period.

    Subject analysis set title
    Subjects with pain response in Placebo + Radiotherapy Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received pretreatment bone-directed radiotherapy and at least 1 dose of placebo with a baseline average daily worst pain score of 4 or higher for a 5 day period.

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time in months from randomization date to date of death due to any cause in all randomized subjects. For subjects alive at the time of the database cutoff date, OS was censored at the last date the subject was known to be alive. The analysis population included all randomized subjects defined as all enrolled subjects that were randomized.
    End point type
    Primary
    End point timeframe
    Date of randomization to date of death, approximately 5 years
    End point values
    		 All Randomized Subjects Ipilimumab + Radiotherapy Arm All Randomized Subjects in Placebo + Radiotherapy Arm
    Number of subjects analysed
    399
    400
    Units: months
        median (confidence interval 95%)
    11.04 (9.46 to 12.48)
    10.02 (8.38 to 11.17)
    Statistical analysis title
    		 Overall Survival Comparison
    Comparison groups
    All Randomized Subjects Ipilimumab + Radiotherapy Arm v All Randomized Subjects in Placebo + Radiotherapy Arm
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0127
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.96

    Primary: Overall Survival Rate

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    End point title
    		 Overall Survival Rate [1]
    End point description
    The overall survival (OS) rate was a percentage, representing the fraction of all randomized subjects who were alive following one year of treatment. OS was defined as the time between the date of randomization and the date of death as a result of any cause. Survival rates were determined via Kaplan-Meier estimates. The analysis population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Date of randomization to date of death, approximately 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    End point values
    		 All Randomized Subjects Ipilimumab + Radiotherapy Arm All Randomized Subjects in Placebo + Radiotherapy Arm
    Number of subjects analysed
    399
    400
    Units: percentage of subjects
    number (confidence interval 95%)
        OS Rate at Year 1
    46.5 (41.6 to 51.4)
    40.8 (35.9 to 45.6)
        OS Rate at Year 2
    25.2 (20.9 to 29.6)
    16.6 (12.9 to 20.3)
        OS Rate at Year 3
    15.3 (15.3 to 18.9)
    7.9 (5.2 to 10.6)
        OS Rate at Year 4
    10.1 (6.9 to 13.3)
    3.3 (1.3 to 5.3)
        OS Rate at Year 5
    7.9 (4.4 to 11.4)
    2.7 (0.8 to 4.7)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    All PFS events were based on investigator’s assessment. Subjects who were alive and did not experience a PFS event were censored at the earlier of the latest prostate-specific antigen (PSA) or radiological tumor assessment date. Subjects who did not die, showed no clinical deterioration, and who had no recorded post-baseline PSA or radiological tumor assessment were censored at randomization date. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Date of randomization to earliest date of confirmed PSA or radiological progression, clinical deterioration or death, up to November 2012, approximately 3.5 years
    End point values
    		 All Randomized Subjects Ipilimumab + Radiotherapy Arm All Randomized Subjects in Placebo + Radiotherapy Arm
    Number of subjects analysed
    399
    400
    Units: months
        median (confidence interval 95%)
    4.01 (3.65 to 4.34)
    3.06 (2.86 to 3.42)
    Statistical analysis title
    		 Progression Free Survival Comparison
    Comparison groups
    All Randomized Subjects Ipilimumab + Radiotherapy Arm v All Randomized Subjects in Placebo + Radiotherapy Arm
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.82

    Secondary: Pain Response

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    End point title
    		 Pain Response
    End point description
    The percentage of subjects with a pain response assessed using the Brief Pain Inventory Short Form (BPI-SF) completed by subjects throughout the study in a daily diary log. Pain-evaluable subjects were defined as those with a decrease in the average daily worst pain intensity by at least 30% from baseline, maintained over 2 consecutive evaluations without the use of any rescue analgesic medication or increase in analgesic use in the same time period. The analysis population included all pain-evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Assessed at screening, weeks 12, 18, 24, and at the end of treatment visit
    End point values
    		 Pain-Evaluable Subjects in Ipilimumab + Radiotherapy Arm Pain-Evaluable Subjects in Placebo + Radiotherapy Arm
    Number of subjects analysed
    197
    186
    Units: percentage of subjects
        number (confidence interval 95%)
    3.55 (1.44 to 7.18)
    0.54 (0.01 to 2.96)
    No statistical analyses for this end point

    Secondary: Duration of Pain Response

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    End point title
    		 Duration of Pain Response
    End point description
    The time between the initial date of pain response and completion date of pain response. The initial date when the pain response criterion was achieved was considered the pain response date. The earlier of date of death, date of tumor resection surgery, or date when pain response criterion was no longer met was considered the completion date of the pain response. If none of these scenarios occurred, the completion of the pain response was set to the last known alive date. The analysis population included all pain-evaluable subjects with a pain response. Here -99999 to 99999 signifies that no confidence interval is applicable due to only one subject being analyzed.
    End point type
    Secondary
    End point timeframe
    Day of initial pain response to day of completion of pain response or date of death
    End point values
    		 Subjects with Pain Response in Ipilimumab + Radiotherapy Arm Subjects with pain response in Placebo + Radiotherapy Arm
    Number of subjects analysed
    7
    1
    Units: months
        median (confidence interval 95%)
    2.5 (1.5 to 3)
    1.5 (-99999 to 99999)
    Statistical analysis title
    		 Duration of Pain Response Comparison
    Comparison groups
    Subjects with pain response in Placebo + Radiotherapy Arm v Subjects with Pain Response in Ipilimumab + Radiotherapy Arm
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 4

    Secondary: Number of Subjects With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs, Immune-Related Adverse Events (irAE) and Immune-Mediated Adverse Reaction (imAR)

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    End point title
    		 Number of Subjects With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs, Immune-Related Adverse Events (irAE) and Immune-Mediated Adverse Reaction (imAR)
    End point description
    AE=new unfavorable symptom, sign, disease or worsening 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. Treatment-related=having certain, possible or missing relationship to study drug. Death=during study and up to 70 days after last dose. IrAEs=AEs potentially associated with inflammation, considered to be causally related to study drug and grouped into gastrointestinal (GI), hepatic, skin, endocrine and neurological. ImARs were collected prospectively and grouped into enterocolitis, hepatitis, dermatitis, neuropathies and endocrinopathies. Grading used Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Ver.3.0. The analysis population included all treated subjects
    End point type
    Secondary
    End point timeframe
    Randomization to date of death, up to approximately 5 years
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: subjects
    number (not applicable)
        SAE
    257
    164
        Treatment-Related AE
    296
    180
        Any Death
    346
    371
        Deaths Due to Study Drug Toxicity
    7
    1
        Discontinuation of Study Drug due to AEs
    137
    62
        Immune-Related AE (any grade)
    250
    86
        Immune-Mediated Adverse Reaction (Grade >=2)
    203
    40
    No statistical analyses for this end point

    Secondary: Time to Onset of Grade 3 or 4 Immune-Related Adverse Event (irAE)

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    End point title
    		 Time to Onset of Grade 3 or 4 Immune-Related Adverse Event (irAE)
    End point description
    The time between first dose of study drug and date of earliest Grade 3 or 4 irAE. These irAEs are AEs of unknown etiology, consistent with an immune phenomenon and considered as causally related to drug exposure. The five subcategories of irAE examined include gastrointestinal (GI), liver, skin, endocrine, and neurological and are graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. The analysis population included all treated subjects assessed for onset of adverse events. Here 99999 signifies that there were no subjects in this treatment arm who displayed irAEs of this type and -99999 to 99999 signifies that no confidence interval was applicable due to only one subject being analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: weeks
    median (confidence interval 95%)
        Gastrotintestinal (n= 71,3)
    5.71 (5 to 7)
    5.71 (0.57 to 31.86)
        Liver (n= 18,5)
    9.14 (8.29 to 10.43)
    6 (3.14 to 8.57)
        Skin (n=4,0)
    3.71 (2.57 to 6.43)
    99999 (-99999 to 99999)
        Endocrine (n=8,2)
    7.93 (4.14 to 11.14)
    5 (4.29 to 5.71)
        Neurological (n= 1,0)
    11.4 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Resolution of Grade 3 or 4 Immune-Related Adverse Event (irAE)

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    End point title
    		 Time to Resolution of Grade 3 or 4 Immune-Related Adverse Event (irAE)
    End point description
    Time between the date of onset of a Grade 3 or 4 irAE and the date of improvement to Grade 1 or less or the worst grade at baseline. The analysis population included all treated subjects assessed for onset of adverse events. Here 99999 signifies that there were no subjects in this treatment arm who displayed irAEs of this type and -99999 to 99999 signifies that no confidence interval was applicable due to only one subject being analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: weeks
    median (confidence interval 95%)
        Gastrointestinal (n=71,3)
    2.9 (1.6 to 4.7)
    0.9 (0.4 to 1.1)
        Liver (n=18,5)
    4.1 (3.6 to 8.1)
    6 (1.9 to 99999)
        Skin (n=4,0)
    3.6 (2.6 to 5.9)
    99999 (-99999 to 99999)
        Endocrine (n=8,2)
    11.1 (2.4 to 99999)
    5.9 (0.9 to 10.9)
        Neurological (n=1,0)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Onset of Grade 3 to 5 Immune-Mediated Adverse Reaction (imAR)

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    End point title
    		 Time to Onset of Grade 3 to 5 Immune-Mediated Adverse Reaction (imAR) [2]
    End point description
    The time between first dose of study drug and date of earliest Grade 3 or 4 imAR. ImARs were collected prospectively and grouped into enterocolitis, hepatitis, dermatitis, neuropathies and endocrinopathies and graded using Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Ver. 3.0. Only the Ipilimumab + Radiotherapy group of subjectss was included in the analysis because ipilimumab is associated with inflammatory events resulting from increased or excessive immune activity likely to be related to its mechanism of action. The analysis population included all treated subjects in the Ipilimumab + radiology arm.
    End point type
    Secondary
    End point timeframe
    Day 1 to time of onset of the imAR of interest
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arm receiving study drug was analyzed for this endpoint. Ipilimumab is associated with inflammatory events resulting from increased or excessive immune activity.
    End point values
    		 Ipilimumab + Radiotherapy
    Number of subjects analysed
    393
    Units: weeks
    median (full range (min-max))
        Enterocolitis (n=65)
    3.4 (0.3 to 16.6)
        Hepatitis (n=17)
    9 (1.7 to 16.9)
        Dermatitis (n=3)
    2.4 (0.1 to 3.1)
        Endocrinopathies (n=6)
    7.9 (1.7 to 10.7)
    No statistical analyses for this end point

    Secondary: Time to Resolution of Grade 3 to 5 to Grade 0 Immune-Mediated Adverse Reactions (imARs) to Grade 0

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    End point title
    		 Time to Resolution of Grade 3 to 5 to Grade 0 Immune-Mediated Adverse Reactions (imARs) to Grade 0 [3]
    End point description
    Time between the date of onset of an imAR to the date of resolution date of the event or the last known date subject was alive if an event did not resolve. Only the Ipilimumab + Radiotherapy group of subjects was included in the analysis because ipilimumab is associated with inflammatory events resulting from increased or excessive immune activity likely to be related to its mechanism of action. The analysis population included all treated subjects in the Ipilimumab + radiotherapy arm. Here 99999 signifies that there were no subjects in this treatment arm who displayed irAEs of this type and -99999 to 99999 signifies that no confidence interval was applicable due to only one subject being analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to 70 days after last dose of study drug
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arm receiving study drug was analyzed for this endpoint. Ipilimumab is associated with inflammatory events resulting from increased or excessive immune activity.
    End point values
    		 Ipilimumab + Radiotherapy
    Number of subjects analysed
    393
    Units: weeks
    median (full range (min-max))
        Enterocolitis (n=52)
    6 (0.1 to 40.1)
        Hepatitis (n=15)
    8.6 (1.1 to 19)
        Dermatitis (n=3)
    6.9 (4 to 12.1)
        Endocrinopathies (n=0)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Worst On-Study Hematology Common Toxicity Criteria (CTC) Grade and Shift from Baseline

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    End point title
    		 Number of Subjects with Worst On-Study Hematology Common Toxicity Criteria (CTC) Grade and Shift from Baseline
    End point description
    Comparison of baseline versus worst grade hematology laboratory tests as measured by white blood count (WBC), absolute neutrophil count (ANC), platelet count, hemoglobin and lymphocyte results. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Gr 0: within normal range. Abnormal values for WBC were based on Gr 1: 3.0 - < Lower Limit of Normal (LLN); Gr 2: 2.0 - < 3.0; Gr 3: 1.0 - < 2.0; Gr4: < 1.0. Abnormal values for Hemoglobin were based on Gr 1: 10.0 - < LLN; Gr 2: 8.0 - < 10.0; Gr 3: 6.5 - < 8.0; Gr 4: < 6.5. Abnormal values for Lymphocytes were based on Gr 1: 0.8 - < 1.5; Gr 2: 0.5 - < 0.8; Gr 3): 0.2 - < 0.5; Gr 4: < 0.2. Abnormal values for ANC were based on Gr 1: 1.5 - < 2.0; Gr 2: 1.0 - < 1.5; Gr 3: 0.5 - < 1.0; Gr 4: < 0.5. Abnormal values for Platelets were based on Gr 1: 75.0 - < LLN; Gr 2: 50.0 - < 75.0; Gr 3: 25.0 - < 50.0; Gr 4: < 25.0. Analysis population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    Day 2 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: subjects
    number (not applicable)
        WBC Gr 0 at Baseline to Gr 3-4
    3
    2
        WBC Gr 1 at Baseline to Gr 3-4
    0
    1
        WBC Gr 2 at Baseline to Gr 3-4
    0
    1
        WBC Gr 3 at Baseline to Gr 3-4
    0
    0
        WBC Gr 4 at Baseline to Gr 3-4
    0
    0
        WBC Not Reported at Baseline to Gr 3-4
    0
    0
        ANC Gr 0 at Baseline to Gr 3-4
    4
    6
        ANC Gr 1 at Baseline to Gr 3-4
    0
    0
        ANC Gr 2 at Baseline to Gr 3-4
    0
    0
        ANC Gr 3 at Baseline to Gr 3-4
    0
    0
        ANC Gr 4 at Baseline to Gr 3-4
    0
    0
        ANC Not Reported at Baseline to Gr 3-4
    1
    0
        Platelet Count Gr 0 at Baseline to Gr 3-4
    1
    6
        Platelet Count Gr 1 at Baseline to Gr 3-4
    1
    1
        Platelet Count Gr 2 at Baseline to Gr 3-4
    0
    0
        Platelet Count Gr 3 at Baseline to Gr 3-4
    0
    0
        Platelet Count Gr 4 at Baseline to Gr 3-4
    0
    0
        Platelet Count Not Reported at Baseline to Gr 3-4
    1
    1
        Hemoglobin Gr 0 at Baseline to Gr 3-4
    0
    3
        Hemoglobin Gr 1 at Baseline to Gr 3-4
    16
    25
        Hemoglobin Gr 2 at Baseline to Gr 3-4
    13
    11
        Hemoglobin Gr 3 at Baseline to Gr 3-4
    0
    1
        Hemoglobin Gr 4 at Baseline to Gr 3-4
    0
    0
        Hemoglobin Not Reported at Baseline to Gr 3-4
    0
    1
        Lymphocytes Gr 0 at Baseline to Gr 3-4
    4
    1
        Lymphocytes Gr 1 at Baseline to Gr 3-4
    6
    11
        Lymphocytes Gr 2 at Baseline to Gr 3-4
    11
    17
        Lymphocytes Gr 3 at Baseline to Gr 3-4
    8
    7
        Lymphocytes Gr 4 at Baseline to Gr 3-4
    0
    0
        Lymphocytes Not Reported at Baseline to Gr 3-4
    3
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Worst On-Study Liver Common Toxicity Criteria (CTC) Grade and Shift from Baseline

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    End point title
    		 Number of Subjects with Worst On-Study Liver Common Toxicity Criteria (CTC) Grade and Shift from Baseline
    End point description
    Comparison of baseline versus worst grade liver function as measured by alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and alkaline phosphatase (ALP). National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Gr 0: within normal range. Abnormal values for ALP, ALT and AST were based on grades; Gr 1: > 1.0 - 2.5 * upper limits of normal (ULN); Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Abnormal values for Total Bilirubin were based on Gr 1: > 1.0 - 1.5 * upper limits of normal (ULN); Gr 2: > 1.5 - 3.0 * ULN; Gr 3: > 3.0 - 10.0 * ULN; Gr 4: > 10.0 * ULN. Analysis population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    Day 2 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: subjects
    number (not applicable)
        ALT Gr 0 at Baseline to Gr 3-4
    16
    1
        ALT Gr 1 at Baseline to Gr 3-4
    1
    1
        ALT Gr 2 at Baseline to Gr 3-4
    0
    0
        ALT Gr 3 at Baseline to Gr 3-4
    0
    0
        ALT Gr 4 at Baseline to Gr 3-4
    0
    0
        ALT Not reported at Basline to Gr 3-4
    1
    0
        AST Gr 0 at Baseline to Gr 3-4
    15
    6
        AST Gr 1 at Baseline to Gr 3-4
    5
    1
        AST Gr 2 at Baseline to Gr 3-4
    1
    1
        AST Gr 3 at Baseline to Gr 3-4
    1
    0
        AST Gr 4 at Baseline to Gr 3-4
    0
    0
        AST Not Reported at Baseline to Gr 3-4
    1
    0
        Total Bilirubin Gr 0 at Baseline to Gr 3-4
    6
    2
        Total Bilirubin Gr 1 at Baseline to Gr 3-4
    1
    0
        Total Bilirubin Gr 2 at Baseline to Gr 3-4
    1
    0
        Total Bilirubin Gr 3 at Baseline to Gr 3-4
    0
    0
        Total Bilirubin Gr 4 at Baseline to Gr 3-4
    0
    0
        Total Bilirubin Not Reported at Baseline to Gr 3-4
    0
    0
        ALP Gr 0 at Baseline to Gr 3-4
    1
    1
        ALP Gr 1 at Baseline to Gr 3-4
    10
    17
        ALP Gr 2 at Baseline to Gr 3-4
    21
    29
        ALP Gr 3 at Baseline to Gr 3-4
    27
    42
        ALP Gr 4 at Baseline to Gr 3-4
    1
    0
        ALP Not Reported at Baseline to Gr 3-4
    0
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects with Worst On-Study Serum Chemistry Common Toxicity Criteria (CTC) Grade and Shift from Baseline

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    End point title
    		 Number of Subjects with Worst On-Study Serum Chemistry Common Toxicity Criteria (CTC) Grade and Shift from Baseline
    End point description
    Comparison of baseline versus worst grade serum chemistry as measured by lipase and amylase analysis. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Gr 0: within normal range. Abnormal values for lipase: Gr1: > 1.0 - 1.5 * ULN; Gr2: > 1.5 - 2.0 * ULN; Gr 3: > 2.0 - 5.0 * ULN; Gr4: > 5.0*ULN. Abnormal values for amylase: Gr1: > 1.0 - 1.5 * ULN; Gr 2: > 1.5 - 2.0 * ULN; Gr 3: > 2.0 - 5.0 * ULN; Gr4: > 5.0 * ULN. Analysis population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    Day 2 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: subjects
    number (not applicable)
        Lipase Gr 0 at Baseline to Gr 3-4
    21
    10
        Lipase Gr 1 at Baseline to Gr 3-4
    1
    1
        Lipase Gr 2 at Baseline to Gr 3-4
    1
    0
        Lipase Gr 3 at Baseline to Gr 3-4
    0
    1
        Lipase Gr 4 at Baseline to Gr 3-4
    0
    0
        Lipase Not reported at Basline to Gr 3-4
    0
    0
        Amylase Gr 0 at Baseline to Gr 3-4
    4
    4
        Amylase Gr 1 at Baseline to Gr 3-4
    1
    1
        Amylase Gr 2 at Baseline to Gr 3-4
    3
    1
        Amylase Gr 3 at Baseline to Gr 3-4
    1
    0
        Amylase Gr 4 at Baseline to Gr 3-4
    0
    0
        Amylase Not Reported at Baseline to Gr 3-4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Worst On-Study Renal Function Common Toxicity Criteria (CTC) Grade and Shift from Baseline

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    End point title
    		 Number of Subjects with Worst On-Study Renal Function Common Toxicity Criteria (CTC) Grade and Shift from Baseline
    End point description
    Comparison of baseline versus worst grade renal function as measured by creatinine analysis. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr).Gr 0: within normal range. Abnormal values for Creatinine were based on Gr 1: > 1.0 - 1.5*ULN; Gr 2: > 1.5 - 3.0*ULN; Gr 3: > 3.0 - 6.0*ULN; Gr 4: > 6.0*ULN. Analysis population included all treated subjects.
    End point type
    Secondary
    End point timeframe
    Day 2 to 70 days after last dose of study drug
    End point values
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Number of subjects analysed
    393
    396
    Units: subjects
    number (not applicable)
        Creatinine Gr 0 at Baseline to Gr 3-4
    3
    3
        Creatinine Gr 1 at Baseline to Gr 3-4
    0
    0
        Creatinine Gr 2 at Baseline to Gr 3-4
    0
    0
        Creatinine Gr 3 at Baseline to Gr 3-4
    0
    0
        Creatinine Gr 4 at Baseline to Gr 3-4
    0
    0
        Creatinine Not Reported at Baseline to Gr 3-4
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to 70 days following the last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Ipilimumab + Radiotherapy
    Reporting group description
    		 Prior to receiving study drug, subjects receive radiotherapy at 8 Gray units (Gy) to at least 1 and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, 10 milligrams (mg) of ipilimumab per kilogram (kg) of body weight was administered intravenously (IV) over 90 minutes. During the treatment phase, dosing was at weeks 1, 4,7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Reporting group title
    Placebo + Radiotherapy
    Reporting group description
    		 Subjects receive radiotherapy at 8 Gy to at least 1 and up to a maximum of 5, bone fields, all in one day. Within 2 days of radiotherapy, placebo solution (0.9% sodium chloride or 5% dextrose) infused IV over 90 minutes. During the treatment phase, dosing was at weeks 1, 4, 7 and 10. In the maintenance phase, dosing was a 12-week intervals, beginning at week 24. Dosing continued until confirmed progressive disease (PD), drug intolerance, clinical deterioration, death, withdrawal of consent or subject lost to follow-up.

    Serious adverse events
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    257 / 393 (65.39%)
    164 / 396 (41.41%)
         number of deaths (all causes)
    81
    62
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellopontine angle tumour
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm of spinal cord
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    36 / 393 (9.16%)
    31 / 396 (7.83%)
         occurrences causally related to treatment / all
    0 / 36
    0 / 31
         deaths causally related to treatment / all
    0 / 34
    0 / 29
    Metastases to bone
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral ischaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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
    9 / 393 (2.29%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    6 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Chest pain
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    13 / 393 (3.31%)
    10 / 396 (2.53%)
         occurrences causally related to treatment / all
    5 / 16
    2 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    16 / 393 (4.07%)
    8 / 396 (2.02%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 9
         deaths causally related to treatment / all
    0 / 8
    0 / 5
    Malaise
         subjects affected / exposed
    7 / 393 (1.78%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    9 / 10
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ failure
         subjects affected / exposed
    2 / 393 (0.51%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    1 / 4
    Oedema peripheral
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    6 / 393 (1.53%)
    10 / 396 (2.53%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Performance status decreased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    17 / 393 (4.33%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    8 / 19
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral swelling
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 393 (2.04%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 393 (1.02%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 393 (0.76%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    2 / 2
    0 / 2
    Pulmonary hypertension
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 393 (0.76%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self injurious behaviour
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 393 (1.53%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 393 (1.78%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase decreased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-Reactive protein increased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eastern cooperative oncology group performance status worsened
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoglobin decreased
         subjects affected / exposed
    13 / 393 (3.31%)
    7 / 396 (1.77%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General physical condition abnormal
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fissure
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Arrhythmia
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory arrest
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brachial plexopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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 / 393 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cerebral haematoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 393 (0.76%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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 / 393 (0.25%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paraparesis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paraplegia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    4 / 393 (1.02%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 396 (0.51%)
         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 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    4 / 393 (1.02%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tongue paralysis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 393 (3.82%)
    18 / 396 (4.55%)
         occurrences causally related to treatment / all
    0 / 17
    1 / 22
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 393 (0.25%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pupils unequal
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain
         subjects affected / exposed
    4 / 393 (1.02%)
    5 / 396 (1.26%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    21 / 393 (5.34%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    21 / 22
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    7 / 393 (1.78%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    59 / 393 (15.01%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    65 / 69
    4 / 6
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia incarcerated
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    11 / 393 (2.80%)
    8 / 396 (2.02%)
         occurrences causally related to treatment / all
    7 / 13
    4 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    11 / 393 (2.80%)
    10 / 396 (2.53%)
         occurrences causally related to treatment / all
    9 / 14
    4 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    4 / 393 (1.02%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder dilatation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    6 / 393 (1.53%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 393 (1.02%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    7 / 393 (1.78%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    4 / 393 (1.02%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    7 / 393 (1.78%)
    8 / 396 (2.02%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    4 / 393 (1.02%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         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
    5 / 393 (1.27%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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
    0 / 393 (0.00%)
    5 / 396 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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 / 393 (0.76%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 393 (0.00%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cavernous sinus thrombosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 396 (0.25%)
         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
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    18 / 393 (4.58%)
    5 / 396 (1.26%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 5
         deaths causally related to treatment / all
    0 / 11
    0 / 3
    Periorbital cellulitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (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
    2 / 393 (0.51%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 393 (1.53%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Septic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    12 / 393 (3.05%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Urosepsis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Viral infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 393 (0.76%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    18 / 393 (4.58%)
    10 / 396 (2.53%)
         occurrences causally related to treatment / all
    12 / 23
    0 / 11
         deaths causally related to treatment / all
    1 / 2
    0 / 4
    Failure to thrive
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipilimumab + Radiotherapy Placebo + Radiotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    350 / 393 (89.06%)
    333 / 396 (84.09%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 393 (6.62%)
    9 / 396 (2.27%)
         occurrences all number
    31
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    31 / 393 (7.89%)
    21 / 396 (5.30%)
         occurrences all number
    35
    24
    Haemoglobin decreased
         subjects affected / exposed
    26 / 393 (6.62%)
    20 / 396 (5.05%)
         occurrences all number
    34
    27
    Weight decreased
         subjects affected / exposed
    91 / 393 (23.16%)
    56 / 396 (14.14%)
         occurrences all number
    94
    56
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 393 (5.09%)
    13 / 396 (3.28%)
         occurrences all number
    22
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 393 (5.60%)
    18 / 396 (4.55%)
         occurrences all number
    22
    23
    Headache
         subjects affected / exposed
    38 / 393 (9.67%)
    31 / 396 (7.83%)
         occurrences all number
    48
    35
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    79 / 393 (20.10%)
    81 / 396 (20.45%)
         occurrences all number
    105
    99
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    80 / 393 (20.36%)
    64 / 396 (16.16%)
         occurrences all number
    95
    71
    Fatigue
         subjects affected / exposed
    144 / 393 (36.64%)
    120 / 396 (30.30%)
         occurrences all number
    156
    121
    Oedema peripheral
         subjects affected / exposed
    46 / 393 (11.70%)
    33 / 396 (8.33%)
         occurrences all number
    46
    34
    Pain
         subjects affected / exposed
    33 / 393 (8.40%)
    44 / 396 (11.11%)
         occurrences all number
    39
    43
    Pyrexia
         subjects affected / exposed
    81 / 393 (20.61%)
    50 / 396 (12.63%)
         occurrences all number
    97
    77
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    33 / 393 (8.40%)
    25 / 396 (6.31%)
         occurrences all number
    34
    27
    Constipation
         subjects affected / exposed
    66 / 393 (16.79%)
    82 / 396 (20.71%)
         occurrences all number
    70
    97
    Diarrhoea
         subjects affected / exposed
    186 / 393 (47.33%)
    94 / 396 (23.74%)
         occurrences all number
    281
    120
    Nausea
         subjects affected / exposed
    126 / 393 (32.06%)
    104 / 396 (26.26%)
         occurrences all number
    155
    122
    Vomiting
         subjects affected / exposed
    107 / 393 (27.23%)
    80 / 396 (20.20%)
         occurrences all number
    134
    102
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    36 / 393 (9.16%)
    27 / 396 (6.82%)
         occurrences all number
    36
    27
    Dyspnoea
         subjects affected / exposed
    47 / 393 (11.96%)
    32 / 396 (8.08%)
         occurrences all number
    49
    33
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    99 / 393 (25.19%)
    22 / 396 (5.56%)
         occurrences all number
    119
    23
    Rash
         subjects affected / exposed
    81 / 393 (20.61%)
    27 / 396 (6.82%)
         occurrences all number
    112
    31
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 393 (7.89%)
    34 / 396 (8.59%)
         occurrences all number
    31
    33
    Depression
         subjects affected / exposed
    10 / 393 (2.54%)
    20 / 396 (5.05%)
         occurrences all number
    10
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    44 / 393 (11.20%)
    57 / 396 (14.39%)
         occurrences all number
    45
    59
    Back pain
         subjects affected / exposed
    56 / 393 (14.25%)
    74 / 396 (18.69%)
         occurrences all number
    60
    77
    Bone pain
         subjects affected / exposed
    31 / 393 (7.89%)
    53 / 396 (13.38%)
         occurrences all number
    32
    53
    Pain in extremity
         subjects affected / exposed
    31 / 393 (7.89%)
    41 / 396 (10.35%)
         occurrences all number
    35
    46
    Musculoskeletal pain
         subjects affected / exposed
    32 / 393 (8.14%)
    44 / 396 (11.11%)
         occurrences all number
    30
    51
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    24 / 393 (6.11%)
    24 / 396 (6.06%)
         occurrences all number
    30
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    119 / 393 (30.28%)
    97 / 396 (24.49%)
         occurrences all number
    124
    99
    Dehydration
         subjects affected / exposed
    26 / 393 (6.62%)
    15 / 396 (3.79%)
         occurrences all number
    30
    18
    Hypokalaemia
         subjects affected / exposed
    20 / 393 (5.09%)
    10 / 396 (2.53%)
         occurrences all number
    22
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2009
    Clarified the following: pretreatment radiotherapy and use of standard-of-care radiotherapy while on study; discontinuation of anti-androgen therapy prior to randomization; weight measurement for dose calculation; exclusion of subjects with brain metastases; retreatment with docetaxel following progression after a prior docetaxel-containing regimen as a separate anti-cancer regimen
    27 Jan 2010
    Clarified inclusion/exclusion criteria pertaining to the allowable number of prior regimens and performance status in order to more accurately reflect evolving current clinical practice; Modified requirement for saline flush at end of study drug infusion; Updated Appendix 3 to contain complete patient pain diary and added Appendix 5 (SSQ).
    02 Sep 2010
    Removed requirement for disease progression during or within 6 months of receiving docetaxel treatment for metastatic CRPC prior to enrollment; Updated that for eligibility purposes, all docetaxel-containing regimens are counted as a single regimen; AEs were to be reported for 90 days after the last dose of study medication;
    17 Dec 2010
    Reinstated requirement that subjects were to have received a prior regimen of docetaxel that contained at least 2 cycles of docetaxel; Reinstated requirement that subjects were to have progressed while receiving, or within 6 months of receiving, a docetaxel-containing regimen, and clarified that subjects that have received additional anti-cancer therapy after docetaxel must also have demonstrated progression on that therapy.
    03 Jul 2012
    Removed interim analysis that was planned to occur at 435 events (deaths); Added Extension Phase to study design to allow for continued collection of survival and safety data after the database lock for the primary analysis.

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

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

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