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    Clinical Trial Results:
    A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2007-006195-11
    Trial protocol
    SE   FR   GB   BE   SK   ES   CZ   NL   IT   DE  
    Global end of trial date
    13 Feb 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    24 Jul 2016
    First version publication date
    30 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    NA

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BAY88-8223/15245
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00699751
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Other: BC1-06
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    13 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare, in subjects with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care (BSoC) plus radium-223 dichloride versus BSoC plus placebo, with the primary efficacy endpoint being overall survival.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug. The formal interim analysis (IA) was performed using the data cut-off date of 14 October 2010 when a total of 316 deaths had been observed; this resulted in the Independent data monitoring committee's (IDMC) recommendation to unblind the study, to stop further placebo treatment, and to offer radium-223 dichloride to placebo subjects who were still participating in the study (who had not withdrawn from the study) and who fulfilled the eligibility criteria as defined in amendment 6 to the Protocol BC1-06, as the primary efficacy analysis of overall survival had crossed the prespecified boundary for efficacy.
    Background therapy
    BSoC was regarded as the routine standard of care at each center, for example local external beam radiation therapy (EBRT), corticosteroids, antiandrogens, estrogens (example: stilboestrol), estramustine or ketoconazole.
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jun 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 138
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Brazil: 39
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Czech Republic: 52
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Hong Kong: 21
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    Slovakia: 22
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Sweden: 90
    Country: Number of subjects enrolled
    United Kingdom: 258
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    921
    EEA total number of subjects
    775
    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)
    231
    From 65 to 84 years
    673
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with progressive symptomatic HRPC, with at least 2 skeletal metastases on bone scan and no known visceral metastases, could participate in the study.

    Pre-assignment
    Screening details
    Subjects were to be randomized in a 2:1, a total of 921 subjects were enrolled in the study and were randomized to receive either Alpharadin [Radium-223 dichloride (Xofigo, BAY88-8223)] or placebo study treatment, which resulted in 614 subjects enrolled in the Alpharadin group and 307 enrolled in the placebo group.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Radium-223 dichloride (Xofigo, BAY88-8223)
    Arm description
    Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.
    Arm type
    Experimental

    Investigational medicinal product name
    Radium-223 dichloride
    Investigational medicinal product code
    BAY88-8223
    Other name
    Xofigo
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Arm title
    Placebo
    Arm description
    Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Number of subjects in period 1
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Started
    614
    307
    Completed
    614
    307
    Period 2
    Period 2 title
    Overall study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Radium-223 Dichloride (Xofigo, BAY88-8223)
    Arm description
    Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.
    Arm type
    Experimental

    Investigational medicinal product name
    Radium-223 dichloride
    Investigational medicinal product code
    BAY88-8223
    Other name
    Xofigo
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Arm title
    Placebo
    Arm description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Arm title
    Placebo Randomized, Then Switched to Radium-223 Dichloride
    Arm description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals from randomization to data cut-off date of 15 July 2011; subjects received radium-223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals from 15 July 2011 to the end of study.
    Arm type
    Experimental

    Investigational medicinal product name
    Radium-223 dichloride
    Investigational medicinal product code
    BAY88-8223
    Other name
    Xofigo
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Number of subjects in period 2
    Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo Placebo Randomized, Then Switched to Radium-223 Dichloride
    Started
    614
    307
    26
    Completed all 6 Injections
    389
    145
    17
    Entered 3-Year Follow-up Period
    407
    168
    15 [1]
    Completed 3-Year Follow-up Period
    49 [2]
    12 [3]
    0 [4]
    Completed
    389
    145
    17
    Not completed
    225
    162
    9
         Death
             28
             29
             -
         Investigator Request
             27
             27
             1
         Subject Request
             43
             23
             -
         Unspecified
             30
             20
             -
         Treatment Completion Page not expected
             -
             -
             4
         Adverse Event
             97
             63
             4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of subjects who completed treatment of all 6 injections, only a few subjects entered the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radium-223 dichloride (Xofigo, BAY88-8223)
    Reporting group description
    Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Reporting group title
    Placebo
    Reporting group description
    Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.

    Reporting group values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo Total
    Number of subjects
    614 307 307
    Age categorical
    Units: Subjects
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    70.2 ± 8.1 70.8 ± 7.87 -
    Gender categorical
    Units: Subjects
        Male
    614 307 921
    Total Alkaline Phosphatase (ALP)
    The total amount of ALP in the blood was determined at baseline.
    Units: Subjects
        < 220 Units/Liter (U/L)
    348 169 517
        >= 220 U/L
    266 138 404
    Current use of bisphosphonates
    Subjects may have been on bisphosphonate therapy during the study.
    Units: Subjects
        Yes
    250 124 374
        No
    364 183 547
    Any prior use of docetaxel
    Units: Subjects
        Yes
    352 174 526
        No
    262 133 395

    End points

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    End points reporting groups
    Reporting group title
    Radium-223 dichloride (Xofigo, BAY88-8223)
    Reporting group description
    Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

    Reporting group title
    Placebo
    Reporting group description
    Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.
    Reporting group title
    Radium-223 Dichloride (Xofigo, BAY88-8223)
    Reporting group description
    Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.

    Reporting group title
    Placebo Randomized, Then Switched to Radium-223 Dichloride
    Reporting group description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals from randomization to data cut-off date of 15 July 2011; subjects received radium-223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals from 15 July 2011 to the end of study.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT population (N=921) was defined as all randomized subjects.

    Primary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as the time from date of randomization to the date of death.
    End point type
    Primary
    End point timeframe
    From randomization to death due to any cause until the data cut-off date (15JUL2011) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [1]
    307 [2]
    Units: Months
        median (confidence interval 95%)
    14.9 (13.9 to 16.1)
    11.3 (10.1 to 12.8)
    Notes
    [1] - ITT population.
    [2] - ITT population.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of overall survival, and also for the secondary endpoints, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.00005 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.691
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.578
         upper limit
    0.827
    Notes
    [3] - Comparison with placebo
    [4] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Total Alkaline Phosphatase (ALP) Progression

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    End point title
    Time to Total Alkaline Phosphatase (ALP) Progression
    End point description
    The time from the first study drug administration to when ALP progression was observed, defined as: 1) In subjects with no ALP decline from baseline; a greater than or equal to 25 percent (%) increase from baseline value and an increase in absolute value of greater than or equal to 2 nanogram (ng)/milliliter (mL), at least 12 weeks from baseline; 2) In subjects with initial ALP decline from baseline; the time from start of treatment to first ALP increase that was greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later. '99999" indicates 95% confidence interval upper limit was not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From randomization to first ALP progression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [5]
    307 [6]
    Units: Months
        median (confidence interval 95%)
    7.4 (7.1 to 99999)
    3.8 (3.6 to 4.2)
    Notes
    [5] - The ITT population was all randomized subjects.
    [6] - The ITT population was all randomized subjects.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of time to total ALP progression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    < 0.00001 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.169
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.131
         upper limit
    0.22
    Notes
    [7] - Comparison with placebo
    [8] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage of Subjects With Total ALP Response at Week 12

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    End point title
    Percentage of Subjects With Total ALP Response at Week 12
    End point description
    ALP levels were measured in subjects' blood at Week 12 and compared to baseline values. A confirmed total ALP response (either >=30% or 50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 12 based of 10 Oct 2014 cutoff date
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    497 [9]
    211 [10]
    Units: Percentage of subjects
    number (not applicable)
        >=30% reduction of ALP in blood level
    59.4
    6.2
        >=50% reduction of ALP in blood level
    32.6
    1.4
        Confirmed Total ALP Response (>=30%)
    47.1
    3.3
        Confirmed Total ALP Response (>=50%)
    27.4
    0.9
    Notes
    [9] - Subjects in the ITT population and had no missing values for this endpoint.
    [10] - Subjects in the ITT population and had no missing values for this endpoint.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of >=30% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    708
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    < 0.001 [12]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [11] - Comparison with placebo
    [12] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. >=30% reduction in blood level.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis for the comparison of >=50% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    708
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    < 0.001 [14]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [13] - Comparison with placebo
    [14] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. >=50% reduction in blood level.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis for the comparison of Confirmed Total ALP Response (>=30%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    708
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    < 0.001 [16]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [15] - Comparison with placebo
    [16] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Confirmed Total ALP Response (>=30%).
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The null hypothesis for the comparison of Confirmed Total ALP Response (>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    708
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    P-value
    < 0.001 [18]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [17] - Comparison with placebo
    [18] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Confirmed Total ALP Response (>=50%).

    Secondary: Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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    End point title
    Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)
    End point description
    ALP levels were measured in subjects' blood at EOT (Week 24) and compared to baseline values. A confirmed total ALP response (>=50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.
    End point type
    Secondary
    End point timeframe
    At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase) based on 10 Oct 2014 cutoff date
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    589 [19]
    288 [20]
    Units: Percentage of subjects
    number (not applicable)
        >=30% reduction of ALP in blood level
    59.9
    4.5
        >=50% reduction of ALP in blood level
    34.6
    1.7
        Confirmed Total ALP Response (>=50%)
    13.9
    1
    Notes
    [19] - Subjects in the ITT population and had no missing values for this endpoint
    [20] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of >=30% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    < 0.001 [22]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [21] - Comparison with placebo
    [22] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis for the comparison of Confirmed Total ALP Response (>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    < 0.001 [24]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [23] - Comparison with placebo
    [24] - Confirmed Total ALP Response (>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis for the comparison of >=50% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    P-value
    < 0.001 [26]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [25] - Comparison with placebo
    [26] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage of Subjects With Total ALP Normalization at Week 12

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    End point title
    Percentage of Subjects With Total ALP Normalization at Week 12
    End point description
    The return of total ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in subjects who had ALP above the upper limit of normal (ULN) at baseline.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    321 [27]
    140 [28]
    Units: Percentage of subjects
        number (not applicable)
    34
    1.4
    Notes
    [27] - Subjects in the ITT population and had no missing values for this endpoint.
    [28] - Subjects in the ITT population and had no missing values for this endpoint.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Total ALP normalization, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    other [29]
    P-value
    < 0.001 [30]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [29] - comparison with placebo
    [30] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Total ALP normalization.

    Secondary: Percentage Change From Baseline in Total ALP at Week 12

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    End point title
    Percentage Change From Baseline in Total ALP at Week 12
    End point description
    ALP level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (ALP level at week 12 minus ALP level at baseline)/(ALP level at baseline)*100.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    497 [31]
    211 [32]
    Units: Percentage change
        least squares mean (standard error)
    -32.2 ± 1.8
    37.2 ± 2.77
    Notes
    [31] - Subjects in the ITT population and had no missing values for this endpoint
    [32] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Percentage change from baseline, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    708
    Analysis specification
    Pre-specified
    Analysis type
    other [33]
    P-value
    < 0.001 [34]
    Method
    ANCOVA
    Confidence interval
    Notes
    [33] - comparison with placebo
    [34] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Percentage change from Baseline.

    Secondary: Maximum Percentage Decrease From Baseline in Total ALP up to Week 12

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    End point title
    Maximum Percentage Decrease From Baseline in Total ALP up to Week 12
    End point description
    ALP level was measured in subject's blood up to week 12 and the maximum percent decrease from the baseline up to Week 12 value was calculated as the minimum value of [(ALP level up to week 12 minus ALP level at baseline)/(ALP level at baseline)*100] by subject, and set to zero if no decrease from baseline.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    582 [35]
    284 [36]
    Units: Percentage change
        least squares mean (standard error)
    -38.9 ± 0.76
    -5.9 ± 1.09
    Notes
    [35] - Subjects in the ITT population and had no missing values for this endpoint
    [36] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Maximum Percentage decrease from baseline to week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    866
    Analysis specification
    Pre-specified
    Analysis type
    other [37]
    P-value
    < 0.001 [38]
    Method
    ANCOVA
    Confidence interval
    Notes
    [37] - Comparison with placebo
    [38] - Maximum percentage decrease from baseline to week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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    End point title
    Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)
    End point description
    ALP level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (ALP level at EOT minus ALP level at baseline)/(ALP level at baseline)*100.
    End point type
    Secondary
    End point timeframe
    At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase) based on 10 Oct 2014 cutoff date
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    589 [39]
    288 [40]
    Units: Percent change
        least squares mean (standard error)
    -29.9 ± 3.13
    62.1 ± 4.48
    Notes
    [39] - Subjects in the ITT population and had no missing values for this endpoint.
    [40] - Subjects in the ITT population and had no missing values for this endpoint.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Percentage change from baseline, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    other [41]
    P-value
    < 0.001 [42]
    Method
    ANCOVA
    Confidence interval
    Notes
    [41] - Comparison with placebo.
    [42] - Percentage change from baseline. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment

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    End point title
    Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment
    End point description
    ALP level was measured in subject's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 week treatment value was calculated as the minimum value of [(ALP level up to week 24 minus ALP level at baseline)/(ALP level at baseline)*100] by subject, and set to zero if no decrease from baseline.
    End point type
    Secondary
    End point timeframe
    From baseline During the 24 Week Treatment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    589 [43]
    288 [44]
    Units: Percentage change
        least squares mean (standard error)
    -44.4 ± 0.8
    -7.5 ± 1.14
    Notes
    [43] - Subjects in the ITT population and had no missing values for this endpoint
    [44] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Maximum Percentage decrease from baseline during the 24 week treatment, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    other [45]
    P-value
    < 0.001 [46]
    Method
    ANCOVA
    Confidence interval
    Notes
    [45] - Comparison with placebo
    [46] - Maximum Percentage decrease from baseline. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Prostate Specific Antigen (PSA) Progression

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    End point title
    Time to Prostate Specific Antigen (PSA) Progression
    End point description
    The time from the first study drug administration to when PSA progression was observed, defined as: 1) In subjects with no PSA decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial PSA decline from baseline; the time from start of treatment to first PSA increase that was greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later.
    End point type
    Secondary
    End point timeframe
    From randomization to first PSA progression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [47]
    307 [48]
    Units: Months
        median (confidence interval 95%)
    3.6 (3.5 to 3.8)
    3.4 (3.3 to 3.5)
    Notes
    [47] - The ITT population was all randomized subjects
    [48] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to PSA progression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [49]
    P-value
    < 0.00001 [50]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.643
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.539
         upper limit
    0.768
    Notes
    [49] - Comparison with placebo
    [50] - Time to PSA progression. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage of Subjects With PSA Response at Week 12

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    End point title
    Percentage of Subjects With PSA Response at Week 12
    End point description
    PSA levels were measured in subjects' blood at Week 12 and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    493 [51]
    210 [52]
    Units: Percentage of subjects
    number (not applicable)
        >=30% reduction of PSA in blood level
    16.4
    6.2
        >=50% reduction of PSA in blood level
    7.7
    4.3
        Confirmed PSA Response (>=50%)
    5.7
    1.9
    Notes
    [51] - Subjects in the ITT population and had no missing values for this endpoint
    [52] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of >=30% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Placebo v Radium-223 dichloride (Xofigo, BAY88-8223)
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    other [53]
    P-value
    < 0.001 [54]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [53] - Comparison with placebo
    [54] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis for the comparison of >=50% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    other [55]
    P-value
    = 0.106 [56]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [55] - Comparison with placebo
    [56] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis for the comparison of Confirmed PSA Response(>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    other [57]
    P-value
    = 0.032 [58]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [57] - Comparison with placebo
    [58] - Confirmed PSA Response(>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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    End point title
    Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)
    End point description
    PSA levels were measured in subjects' blood at EOT (Week 24) and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.
    End point type
    Secondary
    End point timeframe
    At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    590 [59]
    286 [60]
    Units: Percentage of subjects
    number (not applicable)
        >=30% reduction in blood level
    14.2
    4.5
        >=50% reduction in blood level
    9
    3.1
        Confirmed PSA Response (>=50%)
    6.1
    1.7
    Notes
    [59] - Subjects in the ITT population and had no missing values for this endpoint
    [60] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of >=30% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    other [61]
    P-value
    < 0.001 [62]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [61] - Comparison with placebo
    [62] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis for the comparison of >=50% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    other [63]
    P-value
    = 0.002 [64]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [63] - Comparison with placebo
    [64] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis for the comparison of Confirmed PSA Response(>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    other [65]
    P-value
    = 0.005 [66]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [65] - Comparison with placebo
    [66] - Confirmed PSA Response(>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage Change From Baseline in PSA at Week 12

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    End point title
    Percentage Change From Baseline in PSA at Week 12
    End point description
    PSA level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (PSA level at week 12 minus PSA level at baseline)/(PSA level at baseline)*100.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    493 [67]
    210 [68]
    Units: Percent change
        least squares mean (standard error)
    83.3 ± 152.48
    543.8 ± 233.69
    Notes
    [67] - Subjects in the ITT population and had no missing values for this endpoint
    [68] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Percentage change from baseline in PSA at Week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    other [69]
    P-value
    = 0.16 [70]
    Method
    ANCOVA
    Confidence interval
    Notes
    [69] - Comparison with placebo
    [70] - Percentage change from baseline in PSA at Week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Maximum Percentage Decrease From Baseline in PSA up to Week 12

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    End point title
    Maximum Percentage Decrease From Baseline in PSA up to Week 12
    End point description
    PSA level was measured in subject's blood up to Week 12 and the maximum percent decrease from the baseline up to week 12 value was calculated as the minimum value of [(PSA level up to week 12 minus PSA level at baseline)/(PSA level at baseline)*100] by subject, and set to zero if no decrease from baseline.
    End point type
    Secondary
    End point timeframe
    From baseline up to Week 12
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    581 [71]
    283 [72]
    Units: Percentage change
        least squares mean (standard error)
    -13 ± 0.9
    -7.8 ± 1.28
    Notes
    [71] - Subjects in the ITT population and had no missing values for this endpoint
    [72] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline up to Week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    864
    Analysis specification
    Pre-specified
    Analysis type
    other [73]
    P-value
    = 0.004 [74]
    Method
    ANCOVA
    Confidence interval
    Notes
    [73] - Comparison with placebo
    [74] - Maximum Percentage Decrease from Baseline up to Week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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    End point title
    Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)
    End point description
    PSA level was measured in subject’s blood at EOT (Week 24) and the percent change from the baseline value was calculated (PSA level at EOT minus PSA level at baseline)/(PSA level at baseline)*100.
    End point type
    Secondary
    End point timeframe
    At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    590 [75]
    286 [76]
    Units: Percentage change
        least squares mean (standard error)
    144.3 ± 15.38
    191.1 ± 22.1
    Notes
    [75] - Subjects in the ITT population and had no missing values for this endpoint
    [76] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Percentage change from baseline in PSA at EOT, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    other [77]
    P-value
    = 0.009 [78]
    Method
    ANCOVA
    Confidence interval
    Notes
    [77] - Comparison with placebo
    [78] - Percentage change from baseline in PSA at EOT. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period

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    End point title
    Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period
    End point description
    PSA level was measured in subject's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 Week treatment value was calculated as the minimum value of [(PSA level up to week 24 minus PSA level at baseline)/(PSA level at baseline)*100] by subject, and set to zero if no decrease from baseline.
    End point type
    Secondary
    End point timeframe
    From baseline to End of Treatment (Week 24; 4 weeks post last injection)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    590 [79]
    286 [80]
    Units: Percentage change
        least squares mean (standard error)
    -16.4 ± 1.01
    -9.3 ± 1.45
    Notes
    [79] - Subjects in the ITT population and had no missing values for this endpoint
    [80] - Subjects in the ITT population and had no missing values for this endpoint
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    876
    Analysis specification
    Pre-specified
    Analysis type
    other [81]
    P-value
    < 0.001 [82]
    Method
    ANCOVA
    Confidence interval
    Notes
    [81] - Comparison with placebo
    [82] - Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

    Secondary: Time to First Skeletal Related Event (SRE)

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    End point title
    Time to First Skeletal Related Event (SRE)
    End point description
    A skeletal related event was the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention. For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization to first SRE until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [83]
    307 [84]
    Units: Months
        median (confidence interval 95%)
    16.4 (14.3 to 18.3)
    8.1 (6.7 to 11.9)
    Notes
    [83] - The ITT population was all randomized subjects
    [84] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of time to first SRE, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [85]
    P-value
    = 0.00012 [86]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.529
         upper limit
    0.814
    Notes
    [85] - Comparison with placebo
    [86] - Time to first Skeletal Related Event (SRE). Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms

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    End point title
    Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms
    End point description
    The start date of therapy was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization to first EBRT until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [87]
    307 [88]
    Units: Months
        median (confidence interval 95%)
    18 (15.9 to 20.6)
    10.7 (7.6 to 18.5)
    Notes
    [87] - The ITT population was all randomized subjects
    [88] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of time to EBRT, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [89]
    P-value
    = 0.00008 [90]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.639
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.511
         upper limit
    0.8
    Notes
    [89] - Comparison with placebo
    [90] - Time to External Beam Radiotherapy. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms

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    End point title
    Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms
    End point description
    The start date of the radioisotopes was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization to first use of radioisotopes until the data cut-off date (10 Oct 2014)approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [91]
    307 [92]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [91] - The ITT population was all randomized subjects.
    [92] - The ITT population was all randomized subjects.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Receiving Radio-isotope, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [93]
    P-value
    = 0.00191 [94]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.344
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.695
    Notes
    [93] - Comparison with placebo
    [94] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral

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    End point title
    Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral
    End point description
    The start date of the event was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization to occurrence of first new symptomatic pathological bone fractures until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [95]
    307 [96]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [95] - The ITT population was all randomized subjects
    [96] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Pathological Bone Fracture, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [97]
    P-value
    = 0.53277 [98]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.847
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.504
         upper limit
    1.426
    Notes
    [97] - Comparison with placebo.
    [98] - Time to Pathological Bone Fracture. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention

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    End point title
    Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention
    End point description
    The start date of the intervention was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization to occurrence of first tumor related orthopedic surgical intervention until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [99]
    307 [100]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [99] - The ITT population was all randomized subjects
    [100] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Surgical Intervention, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [101]
    P-value
    = 0.89567 [102]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.949
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.435
         upper limit
    2.07
    Notes
    [101] - Comparison with placebo
    [102] - Time to Surgical Intervention. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Spinal Cord Compression

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    End point title
    Time to Occurrence of First Spinal Cord Compression
    End point description
    The start date of the compression was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization to first spinal cord compression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [103]
    307 [104]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [103] - The ITT population was all randomized subjects
    [104] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Spinal Cord Compression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [105]
    P-value
    = 0.14486 [106]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.404
         upper limit
    1.145
    Notes
    [105] - Comparison with placebo
    [106] - Time to Spinal Cord Compression. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Start of any Other Anti-cancer Treatment

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    End point title
    Time to Occurrence of First Start of any Other Anti-cancer Treatment
    End point description
    The start date of the treatment was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization to first start of any other anti-cancer treatment until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [107]
    307 [108]
    Units: Months
        median (confidence interval 95%)
    15.4 (12.6 to 17)
    12.7 (11 to 14.7)
    Notes
    [107] - The ITT population was all randomized subjects
    [108] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Other Cancer Treatment, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [109]
    P-value
    = 0.00932 [110]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.727
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.571
         upper limit
    0.925
    Notes
    [109] - comparison with placebo
    [110] - Time to Other Cancer Treatment. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Secondary: Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline

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    End point title
    Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline
    End point description
    ECOG scores were: 0 = fully active; 1 = restricted in physically strenuous activity; 2 = ambulatory and capable of all self-care but unable to work; 3 = capable of only limited self-care; 4 = completely disabled; 5 = death. The visit at which a 2-point or more deterioration in PS was observed was the time of the event. ECOG was assessed at every visit. If a marked deterioration in PS had not occurred at the time of the analysis or the subject was lost to follow-up, the time-to-event variables were censored at the last assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [111]
    307 [112]
    Units: Months
        median (confidence interval 95%)
    23.4 (20.4 to 26.5)
    18.4 (13.1 to 24.5)
    Notes
    [111] - The ITT population was all randomized subjects
    [112] - The ITT population was all randomized subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the comparison of Time to Marked Deterioration of ECOG PS, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
    Comparison groups
    Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    other [113]
    P-value
    = 0.00187 [114]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.546
         upper limit
    0.873
    Notes
    [113] - Comparison with placebo
    [114] - Time to Marked Deterioration of ECOG PS. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

    Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0

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    End point title
    Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0
    End point description
    ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.
    End point type
    Other pre-specified
    End point timeframe
    Week 0
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    600 [115]
    305 [116]
    Units: Subjects
    number (not applicable)
        ECOG Grade 0
    136
    72
        ECOG Grade 1
    376
    191
        ECOG Grade 2
    82
    40
        ECOG Grade 3
    6
    1
        ECOG Grade 4
    0
    0
        ECOG Grade 5
    0
    0
        Missing
    0
    1
    Notes
    [115] - Subjects in the ITT population and with ECOG analyzed
    [116] - Subjects in the ITT population and with ECOG analyzed
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8

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    End point title
    Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8
    End point description
    ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.
    End point type
    Other pre-specified
    End point timeframe
    Week 8
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    569 [117]
    267 [118]
    Units: Subjects
    number (not applicable)
        ECOG Grade 0
    133
    49
        ECOG Grade 1
    315
    142
        ECOG Grade 2
    103
    53
        ECOG Grade 3
    13
    15
        ECOG Grade 4
    0
    3
        ECOG Grade 5
    1
    1
        Missing
    4
    4
    Notes
    [117] - Subjects in the ITT population and with ECOG analyzed
    [118] - Subjects in the ITT population and with ECOG analyzed
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16

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    End point title
    Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16
    End point description
    ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.
    End point type
    Other pre-specified
    End point timeframe
    Week 16
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    471 [119]
    196 [120]
    Units: Subjects
    number (not applicable)
        ECOG Grade 0
    101
    29
        ECOG Grade 1
    257
    113
        ECOG Grade 2
    85
    42
        ECOG Grade 3
    19
    11
        ECOG Grade 4
    4
    0
        ECOG Grade 5
    0
    0
        Missing
    5
    1
    Notes
    [119] - Subjects in the ITT population and with ECOG analyzed
    [120] - Subjects in the ITT population and with ECOG analyzed
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24

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    End point title
    Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24
    End point description
    ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.
    End point type
    Other pre-specified
    End point timeframe
    Week 24
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    363 [121]
    138 [122]
    Units: Subjects
    number (not applicable)
        ECOG Grade 0
    74
    22
        ECOG Grade 1
    181
    66
        ECOG Grade 2
    85
    36
        ECOG Grade 3
    17
    10
        ECOG Grade 4
    5
    4
        ECOG Grade 5
    0
    0
        Missing
    1
    0
    Notes
    [121] - Subjects in the ITT population and with ECOG analyzed
    [122] - Subjects`in the ITT population and with ECOG analyzed
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)

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    End point title
    Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Prostate Cancer Trial Outcome Index (TOI): Physical Well-being (PWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 104 (best).
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [123]
    307 [124]
    Units: Scores on a scale
    median (full range (min-max))
        Week 0 (Baseline)
    65 (17 to 104)
    64 (23 to 96)
        Week 16
    65 (11 to 98)
    61.31 (19 to 96.5)
        Week 24
    61 (17 to 102)
    60 (17 to 97)
        Follow-up Visit 2 (Week 42)
    61 (10 to 95)
    60.5 (16.7 to 97)
    Notes
    [123] - The ITT population was all randomized subjects
    [124] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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    End point title
    Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Possible scores were 0 to 104; the higher the score, the better the quality of life. The changes from baseline (range -104 to 104) in the domain FACT-P TOI were summarized using descriptive statistics at Week 16, Week 24, and Follow-up Visit 2.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [125]
    307 [126]
    Units: Scores on a scale
    median (full range (min-max))
        At Week 16
    -1.55 (-49.3 to 38)
    -4.15 (-43 to 46)
        At Week 24
    -4 (-60.4 to 40)
    -5.67 (-39 to 41)
        At Follow-up Visit 2 (Week 42)
    -5 (-89 to 44.5)
    -5.5 (-47.4 to 25)
    Notes
    [125] - The ITT population was all randomized subjects
    [126] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16

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    End point title
    Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 – Not at all; 4 – Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Week 16.
    End point type
    Other pre-specified
    End point timeframe
    At Week 16
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [127]
    307 [128]
    Units: Scores on a scale
    median (full range (min-max))
        physical well being
    20 (3 to 28)
    19.83 (1 to 28)
        social/family well being
    22 (0 to 28)
    21.5 (0 to 28)
        emotional well being
    18 (0 to 24)
    16.8 (2 to 24)
        functional well being
    16 (0 to 28)
    15 (0 to 28)
        the prostate cancer subscale
    29 (1 to 46.9)
    27.6 (9 to 42.5)
    Notes
    [127] - The ITT population was all randomized subjects
    [128] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24

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    End point title
    Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 – Not at all; 4 – Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Week 24.
    End point type
    Other pre-specified
    End point timeframe
    At Week 24
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [129]
    307 [130]
    Units: Scores on a scale
    median (full range (min-max))
        physical well being
    19 (3 to 28)
    18.67 (3 to 28)
        social/family well being
    21 (0 to 28)
    21 (9 to 28)
        emotional well being
    17 (4 to 24)
    16 (1.2 to 24)
        functional well being
    15 (0 to 28)
    14 (0 to 28)
        the prostate cancer subscale
    28 (3.6 to 46)
    27.64 (5 to 43)
    Notes
    [129] - The ITT population was all randomized subjects
    [130] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)

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    End point title
    Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 – Not at all; 4 – Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Follow-up Visit 2.
    End point type
    Other pre-specified
    End point timeframe
    At Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [131]
    307 [132]
    Units: Scores on a scale
    median (full range (min-max))
        physical well being
    19 (0 to 28)
    18 (1 to 28)
        social/family well being
    22 (0 to 28)
    22 (9 to 33.8)
        emotional well being
    17 (0 to 24)
    16 (3 to 24)
        functional well being
    14 (1 to 28)
    14 (4 to 28)
        the prostate cancer subscale
    28 (3 to 42)
    29 (6.5 to 43)
    Notes
    [131] - The ITT population was all randomized subjects
    [132] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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    End point title
    Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score of the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) was calculated at Week 16, Week 24, and Follow-up Visit 2.FACT-P Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 156 (best).
    End point type
    Other pre-specified
    End point timeframe
    At Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [133]
    307 [134]
    Units: Scores on a scale
    median (full range (min-max))
        At Week 16
    100.68 (30 to 147)
    99.9 (33.7 to 144)
        At Week 24
    98 (41.8 to 152)
    97.5 (47 to 149)
        At Follow-up Visit 2 (Week 42)
    97.83 (41 to 145)
    97.38 (40.9 to 147.8)
    Notes
    [133] - The ITT population was all randomized subjects
    [134] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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    End point title
    Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point description
    The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. Total possible score was 156; a higher score indicates a better quality of life. The changes from baseline in the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -156 to 156.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [135]
    307 [136]
    Units: Scores on a scale
    median (full range (min-max))
        At Week 16
    -2 (-58 to 58)
    -5.67 (-58 to 47)
        At Week 24
    -5 (-67.2 to 63.5)
    -9.4 (-42.8 to 48.8)
        At Follow-up Visit 2 (Week 42)
    -6.17 (-97 to 63.5)
    -7 (-54.7 to 23.7)
    Notes
    [135] - The ITT population was all randomized subjects
    [136] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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    End point title
    Absolute Scores for Functional Assessment of Cancer Therapy – General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point description
    The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. The FACT-G absolute total score (physical, social/family, emotional, and functional well-being) was calculated at Week 16, Week 24, and Follow-up Visit 2. FACT-G Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB). Score ranges from 0 (worst) to 108 (best).
    End point type
    Other pre-specified
    End point timeframe
    At Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [137]
    307 [138]
    Units: Scores on a scale
    median (full range (min-max))
        At Week 16
    73 (17 to 106)
    72 (27.7 to 108)
        At Week 24
    71 (28 to 107)
    69 (37 to 106)
        At Follow-up Visit 2 (Week 42)
    70 (22 to 107)
    70.25 (32.2 to 104.8)
    Notes
    [137] - The ITT population was all randomized subjects
    [138] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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    End point title
    Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point description
    The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. Total possible score was 108; a higher score indicates a better quality of life. The changes from baseline in the FACT-G total score (physical, social/family, emotional, and functional well-being) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -108 to 108.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    614 [139]
    307 [140]
    Units: Scores on a scale
    median (full range (min-max))
        At Week 16
    -1 (-38.3 to 40)
    -4 (-53 to 32.8)
        At Week 24
    -4.08 (-49 to 49.5)
    -7 (-35.8 to 41.8)
        At Follow-up Visit 2 (Week 42)
    -3.67 (-58 to 40.5)
    -6 (-33.8 to 18.7)
    Notes
    [139] - The ITT population was all randomized subjects
    [140] - The ITT population was all randomized subjects
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16

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    End point title
    Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16
    End point description
    The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at Week 16, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).
    End point type
    Other pre-specified
    End point timeframe
    Week 16
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    477 [141]
    205 [142]
    Units: Subjects
    number (not applicable)
        mobility - Grade 1
    191
    64
        mobility - Grade 2
    278
    129
        mobility - Grade 3
    7
    10
        mobility - Missing
    1
    2
        self-care - Grade 1
    346
    140
        self-care - Grade 2
    123
    54
        self-care - Grade 3
    7
    10
        self-care - Missing
    1
    1
        usual activities - Grade 1
    199
    67
        usual activities - Grade 2
    233
    105
        usual activities - Grade 3
    44
    32
        usual activities - Missing
    1
    1
        pain/discomfort - Grade 1
    79
    23
        pain/discomfort - Grade 2
    351
    159
        pain/discomfort - Grade 3
    46
    22
        pain/discomfort - Missing
    1
    1
        anxiety/depression - Grade 1
    285
    104
        anxiety/depression - Grade 2
    171
    95
        anxiety/depression - Grade 3
    15
    4
        anxiety/depression - Missing
    6
    2
    Notes
    [141] - The ITT population was all randomized subjects with with EQ-5D analyzed.
    [142] - The ITT population was all randomized subjects with with EQ5D analysed.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24

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    End point title
    Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24
    End point description
    The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at Week 24, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).
    End point type
    Other pre-specified
    End point timeframe
    Week 24
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    368 [143]
    140 [144]
    Units: Subjects
    number (not applicable)
        mobility - Grade 1
    129
    39
        mobility - Grade 2
    225
    93
        mobility - Grade 3
    11
    5
        mobility - Missing
    3
    3
        self-care - Grade 1
    256
    89
        self-care - Grade 2
    102
    46
        self-care - Grade 3
    6
    3
        self-care - Missing
    4
    2
        usual activities - Grade 1
    140
    38
        usual activities - Grade 2
    187
    79
        usual activities - Grade 3
    37
    20
        usual activities - Missing
    4
    3
        pain/discomfort - Grade 1
    56
    21
        pain/discomfort - Grade 2
    270
    95
        pain/discomfort - Grade 3
    39
    21
        pain/discomfort - Missing
    3
    3
        anxiety/depression - Grade 1
    195
    64
        anxiety/depression - Grade 2
    159
    71
        anxiety/depression - Grade 3
    10
    2
        anxiety/depression - Missing
    4
    3
    Notes
    [143] - The ITT population was all randomized subjects with with EQ-5D analyzed.
    [144] - The ITT population was all randomized subjects with with EQ5D analysed.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)

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    End point title
    Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)
    End point description
    The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at follow-up visit 8, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).
    End point type
    Other pre-specified
    End point timeframe
    Follow-up Visit 8 (Week 139)
    End point values
    Radium-223 dichloride (Xofigo, BAY88-8223) Placebo
    Number of subjects analysed
    41 [145]
    13 [146]
    Units: Subjects
    number (not applicable)
        mobility - Grade 1
    9
    2
        mobility - Grade 2
    30
    10
        mobility - Grade 3
    1
    1
        mobility - Missing
    1
    0
        self-care - Grade 1
    26
    7
        self-care - Grade 2
    12
    3
        self-care - Grade 3
    2
    3
        self-care - Missing
    1
    0
        usual activities - Grade 1
    13
    2
        usual activities - Grade 2
    19
    7
        usual activities - Grade 3
    8
    4
        usual activities - Missing
    1
    0
        pain/discomfort - Grade 1
    5
    1
        pain/discomfort - Grade 2
    32
    11
        pain/discomfort - Grade 3
    3
    1
        pain/discomfort - Missing
    1
    0
        anxiety/depression - Grade 1
    24
    6
        anxiety/depression - Grade 2
    15
    7
        anxiety/depression - Grade 3
    1
    0
        anxiety/depression - Missing
    1
    0
    Notes
    [145] - The ITT population was all randomized subjects with with EQ-5D analyzed.
    [146] - The ITT population was all randomized subjects with with EQ-5D analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from first dose of study drug to the final data as of 10OCT2014
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Radium-223 Dichloride (Xofigo, BAY88-8223)
    Reporting group description
    Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.

    Reporting group title
    Placebo Randomized, Then Switched to Radium-223 Dichloride
    Reporting group description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals from first dose of study drug to data cut-off date of 15 July 2011; Subjects received radium-223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals from 15 July 2011 to the end of study.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.

    Serious adverse events
    Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo Randomized, Then Switched to Radium-223 Dichloride Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    286 / 600 (47.67%)
    17 / 24 (70.83%)
    185 / 301 (61.46%)
         number of deaths (all causes)
    520
    18
    251
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of bladder
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    65 / 600 (10.83%)
    2 / 24 (8.33%)
    38 / 301 (12.62%)
         occurrences causally related to treatment / all
    0 / 67
    0 / 2
    0 / 42
         deaths causally related to treatment / all
    0 / 53
    0 / 2
    0 / 35
    Metastases to meninges
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bone marrow tumour cell infiltration
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Benign urinary tract neoplasm
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    5 / 600 (0.83%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    6 / 600 (1.00%)
    0 / 24 (0.00%)
    9 / 301 (2.99%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 600 (1.00%)
    0 / 24 (0.00%)
    6 / 301 (1.99%)
         occurrences causally related to treatment / all
    6 / 9
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    15 / 600 (2.50%)
    1 / 24 (4.17%)
    8 / 301 (2.66%)
         occurrences causally related to treatment / all
    3 / 15
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
    Sudden death
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Drug intolerance
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    6 / 600 (1.00%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic haemorrhage
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    1 / 24 (4.17%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Therapeutic agent toxicity
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stent occlusion
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 600 (0.17%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    4 / 301 (1.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    4 / 301 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Atrioventricular block complete
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    Acute coronary syndrome
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 600 (1.00%)
    0 / 24 (0.00%)
    5 / 301 (1.66%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    Epistaxis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pleuritic pain
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 600 (1.17%)
    0 / 24 (0.00%)
    6 / 301 (1.99%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 3
    Pneumonia aspiration
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 600 (8.33%)
    1 / 24 (4.17%)
    25 / 301 (8.31%)
         occurrences causally related to treatment / all
    49 / 70
    1 / 1
    15 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aplastic anaemia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    5 / 600 (0.83%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    14 / 600 (2.33%)
    1 / 24 (4.17%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    11 / 14
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aphasia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hydrocephalus
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial palsy
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 600 (0.33%)
    1 / 24 (4.17%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    21 / 600 (3.50%)
    1 / 24 (4.17%)
    16 / 301 (5.32%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 1
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paresis cranial nerve
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    8 / 600 (1.33%)
    0 / 24 (0.00%)
    4 / 301 (1.33%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    4 / 301 (1.33%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 600 (1.50%)
    0 / 24 (0.00%)
    5 / 301 (1.66%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 600 (0.17%)
    1 / 24 (4.17%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    11 / 600 (1.83%)
    0 / 24 (0.00%)
    7 / 301 (2.33%)
         occurrences causally related to treatment / all
    6 / 20
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    11 / 600 (1.83%)
    0 / 24 (0.00%)
    7 / 301 (2.33%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    8 / 600 (1.33%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    4 / 600 (0.67%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Micturition urgency
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    7 / 600 (1.17%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Urinary incontinence
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    10 / 600 (1.67%)
    0 / 24 (0.00%)
    9 / 301 (2.99%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    61 / 600 (10.17%)
    1 / 24 (4.17%)
    50 / 301 (16.61%)
         occurrences causally related to treatment / all
    6 / 76
    0 / 1
    6 / 56
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    5 / 600 (0.83%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 600 (0.17%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    14 / 600 (2.33%)
    1 / 24 (4.17%)
    11 / 301 (3.65%)
         occurrences causally related to treatment / all
    1 / 14
    1 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 600 (0.83%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    12 / 600 (2.00%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    10 / 20
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 600 (0.00%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 600 (0.50%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 600 (0.33%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    10 / 600 (1.67%)
    0 / 24 (0.00%)
    3 / 301 (1.00%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    8 / 600 (1.33%)
    0 / 24 (0.00%)
    2 / 301 (0.66%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 600 (2.83%)
    1 / 24 (4.17%)
    7 / 301 (2.33%)
         occurrences causally related to treatment / all
    1 / 18
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    Pneumonia primary atypical
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 600 (1.17%)
    0 / 24 (0.00%)
    4 / 301 (1.33%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 600 (0.17%)
    1 / 24 (4.17%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    5 / 600 (0.83%)
    0 / 24 (0.00%)
    6 / 301 (1.99%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 600 (0.17%)
    0 / 24 (0.00%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 600 (0.00%)
    0 / 24 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo Randomized, Then Switched to Radium-223 Dichloride Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    524 / 600 (87.33%)
    23 / 24 (95.83%)
    254 / 301 (84.39%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    12 / 600 (2.00%)
    3 / 24 (12.50%)
    4 / 301 (1.33%)
         occurrences all number
    13
    3
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    74 / 600 (12.33%)
    2 / 24 (8.33%)
    44 / 301 (14.62%)
         occurrences all number
    74
    2
    45
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    47 / 600 (7.83%)
    0 / 24 (0.00%)
    21 / 301 (6.98%)
         occurrences all number
    54
    0
    22
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    161 / 600 (26.83%)
    8 / 24 (33.33%)
    81 / 301 (26.91%)
         occurrences all number
    247
    10
    104
    Thrombocytopenia
         subjects affected / exposed
    59 / 600 (9.83%)
    2 / 24 (8.33%)
    15 / 301 (4.98%)
         occurrences all number
    71
    2
    16
    Neutropenia
         subjects affected / exposed
    28 / 600 (4.67%)
    2 / 24 (8.33%)
    3 / 301 (1.00%)
         occurrences all number
    37
    3
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    45 / 600 (7.50%)
    2 / 24 (8.33%)
    26 / 301 (8.64%)
         occurrences all number
    53
    2
    30
    Headache
         subjects affected / exposed
    25 / 600 (4.17%)
    2 / 24 (8.33%)
    9 / 301 (2.99%)
         occurrences all number
    29
    2
    9
    Paraesthesia
         subjects affected / exposed
    16 / 600 (2.67%)
    2 / 24 (8.33%)
    4 / 301 (1.33%)
         occurrences all number
    16
    2
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    157 / 600 (26.17%)
    9 / 24 (37.50%)
    73 / 301 (24.25%)
         occurrences all number
    192
    10
    86
    Asthenia
         subjects affected / exposed
    35 / 600 (5.83%)
    2 / 24 (8.33%)
    17 / 301 (5.65%)
         occurrences all number
    43
    2
    19
    Oedema peripheral
         subjects affected / exposed
    76 / 600 (12.67%)
    2 / 24 (8.33%)
    29 / 301 (9.63%)
         occurrences all number
    82
    2
    34
    Pyrexia
         subjects affected / exposed
    38 / 600 (6.33%)
    0 / 24 (0.00%)
    15 / 301 (4.98%)
         occurrences all number
    58
    0
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 600 (5.17%)
    0 / 24 (0.00%)
    17 / 301 (5.65%)
         occurrences all number
    33
    0
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    105 / 600 (17.50%)
    2 / 24 (8.33%)
    60 / 301 (19.93%)
         occurrences all number
    111
    2
    68
    Abdominal pain
         subjects affected / exposed
    21 / 600 (3.50%)
    2 / 24 (8.33%)
    13 / 301 (4.32%)
         occurrences all number
    21
    2
    15
    Diarrhoea
         subjects affected / exposed
    153 / 600 (25.50%)
    7 / 24 (29.17%)
    43 / 301 (14.29%)
         occurrences all number
    242
    12
    60
    Nausea
         subjects affected / exposed
    210 / 600 (35.00%)
    11 / 24 (45.83%)
    98 / 301 (32.56%)
         occurrences all number
    294
    12
    126
    Vomiting
         subjects affected / exposed
    108 / 600 (18.00%)
    3 / 24 (12.50%)
    34 / 301 (11.30%)
         occurrences all number
    151
    3
    45
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    14 / 600 (2.33%)
    2 / 24 (8.33%)
    5 / 301 (1.66%)
         occurrences all number
    15
    2
    6
    Urinary retention
         subjects affected / exposed
    20 / 600 (3.33%)
    3 / 24 (12.50%)
    12 / 301 (3.99%)
         occurrences all number
    20
    3
    13
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    2 / 600 (0.33%)
    2 / 24 (8.33%)
    3 / 301 (1.00%)
         occurrences all number
    2
    2
    3
    Bone pain
         subjects affected / exposed
    287 / 600 (47.83%)
    11 / 24 (45.83%)
    174 / 301 (57.81%)
         occurrences all number
    476
    19
    321
    Muscular weakness
         subjects affected / exposed
    8 / 600 (1.33%)
    2 / 24 (8.33%)
    15 / 301 (4.98%)
         occurrences all number
    8
    2
    18
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    104 / 600 (17.33%)
    4 / 24 (16.67%)
    53 / 301 (17.61%)
         occurrences all number
    115
    5
    57
    Hypokalaemia
         subjects affected / exposed
    14 / 600 (2.33%)
    2 / 24 (8.33%)
    6 / 301 (1.99%)
         occurrences all number
    16
    2
    7
    Hyponatraemia
         subjects affected / exposed
    2 / 600 (0.33%)
    3 / 24 (12.50%)
    2 / 301 (0.66%)
         occurrences all number
    2
    3
    2
    Decreased appetite
         subjects affected / exposed
    36 / 600 (6.00%)
    1 / 24 (4.17%)
    13 / 301 (4.32%)
         occurrences all number
    39
    1
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 600 (2.17%)
    4 / 24 (16.67%)
    8 / 301 (2.66%)
         occurrences all number
    13
    4
    11
    Urinary tract infection
         subjects affected / exposed
    47 / 600 (7.83%)
    5 / 24 (20.83%)
    22 / 301 (7.31%)
         occurrences all number
    55
    8
    23

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2008
    The main rationale for this amendment was to make sure that the most important baseline parameters which might have an impact on the primary and secondary efficacy endpoints were well balanced between the two study groups. Changes were: 1. Removed stratification factors for ECOG and any prior cytotoxic therapy 2. Added stratification factors for current use of bisphosphonates (yes or no) and prior use of docetaxel (yes or no).
    09 Jul 2008
    The main rationale for this amendment was to ensure that the study meets its stated objectives and yields robust conclusions, with adequate monitoring of data to detect emerging risk/benefit trends. The key changes were: 1. Changed the sample size requirements for the study, from 450 subjects to 750 subjects randomized to account for the introduction of prior docetaxel use (yes/no) as a stratification factor during randomization 2. Planned for an unblinded IA of overall survival, to be reviewed by the IDMC 3. Changed PSA outcome and reporting to adhere to the Prostate Cancer Clinical Trials Working Group 2, published March, 2008.
    10 Jul 2009
    The main rationale for this amendment was to add clarifications to various sections in the protocol. The key changes were: 1. Recommended that the screening hematology values were measured at a maximum of 1 week prior to randomization, and that the first injection was to be done as soon as possible after randomization 2. Clarified that while screening hemoglobin (Hb) was required to be 10 gram per deciliter (g/dL), the Hb level should not have been lower than 8 g/dL within 24 hours before any injection. If, prior to first injection, the subject had a Hb level of <8 g/dL, the subject should not have received study drug and would directly go into the follow-up phase 3. Clarified that it was accepted that after documented PSA progression, the PSA could decline pre-randomization, provided that the screening value was at least 5 ng/mL 4. Clarified that for traumatic fractures in weight-bearing bones during treatment phase, the study drug administration was to be delayed 2-4 weeks from the occurrence of the fracture 5. Changed the collection of date of death: To collect date of death for all subjects until the last subject had been followed for 3 years 6. Changedthe interval between injection of bisphosphonates and injection of study drug: Injection of bisphosphonates was to be done at least 2 hours before or after study drug administration 7. Changed the analysis of the primary efficacy endpoint from Cox proportional hazards regression to a stratified log-rank test 8. Changed the timing of sample size re-estimation, from approximately 350 subjects to 500-600 subjects enrolled 9. Changed the definition of the Safety population from all randomized subjects to all randomized subjects who had received at least 1 study drug treatment 10. Added sub-group analyses for safety and secondary efficacy variables in order to examine relationships between exposure and response.
    23 Jun 2010
    The main rationale for this amendment was to increase the sample size of the study due to an increase in the statistical power from 80% to 90%. The rationale for the increase in power was to 1. Reduce the risk of false negative results 2. Get a better estimate of the primary efficacy endpoint 3. Get a better estimate of the secondary endpoints and subgroup analyses 4. Increase the body of safety data. The same assumptions as in the original sample size calculation have been used for the calculation. Changes: 1. Increased statistical power from 80% to 90% and increased the sample size from 750 to 900 with an increase in the accrual period from 24 to 30 months 2. Changed time of IA to be after approximately 320 events were observed 3. Made various minor clarifications and administrative changes.
    20 Jan 2011
    The main rationale for this amendment was to control for overall false positive rate (type I error rate) for the analysis of the secondary endpoints by using a gatekeeping procedure. Five secondary endpoints have been identified as main secondary endpoints and have been ordered hierarchically according to their clinical importance. Changes were: 1. Defined 5 main secondary endpoints: including creating a composite endpoint for the time to occurrence of first SRE based on disease events already being collected and adding total ALP normalization, 2. Provided IDMC members with the opportunity to request analysis results for the main secondary endpoints provided that the IA met the efficacy criterion for overall survival; additionally, if the study was stopped based on the recommendation of the IDMC, then all remaining planned analyses were to be performed according to what was described in the final analysis in the protocol and the statistical analysis plan.
    24 Jun 2011
    The main rationale for this amendment was to offer placebo subjects who are still participating in the study (that is, have not withdrawn from the study) and who fulfil the eligibility criteria as defined in this protocol addendum, a full course of Alpharadin treatment (50 kBq/kg body weight administered 6 times, at intervals of 4 weeks). 1. Changes to study design and reference therapy (placebo) due to IDMC approval to unblind the study, allowing a