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    Clinical Trial Results:
    A Phase 4 long-term follow-up study to define the safety profile of radium-223 dichloride

    Summary
    EudraCT number
    		 2014-002407-25
    Trial protocol
    		 DE   SE   ES   FR   BE   CZ   GB   FI   PL  
    Global end of trial date
    31 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jan 2025
    First version publication date
    25 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY88-8223/16996
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02312960
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    ​Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area, Bayer AG, ​+49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area, Bayer AG, +49 30 300139003, clinica-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
    31 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives are to define the long-term safety profile of radium-223 dichloride (for up to 7 years after the last dose of radium-223 dichloride); to assess the incidence of leukemia, myelodysplastic syndrome, aplastic anemia, and primary bone cancer or any other new primary malignancy; to assess the incidence of bone fractures and bone associated events (e.g., osteoporosis); and, in subjects who receive cytotoxic chemotherapy, to assess the incidence of febrile neutropenia or hemorrhage during their chemotherapy treatment and for up to 6 months thereafter at a frequency based on local clinical practice.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects (or their legally authorized representative according to local legislation). Participating subjects (or their legally authorized representative according to local legislation) 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 85 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    255
    EEA total number of subjects
    105
    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)
    81
    From 65 to 84 years
    168
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at multiple centers in 22 countries between 18-Dec-2014 (first subject first visit) and 31-Jan-2024 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 257 participants were screened from the selected feeder studies into the 16996 study for long-term follow-up. Of these, 255 participants entered the study and 2 participants did not complete screening.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Feeder trials subjects enrolled into this long-term safety follow-up study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 From study 15396 Radium-223 dichloride+Abi/Pred group
    Arm description
    		 Safety follow up from feeder study 15396. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received prednisone/prednisolone in the selected feeder study.

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received abiraterone acetate in the selected feeder study.

    Arm title
    		 From study 15396 Placebo+Abi/Pred group
    Arm description
    		 Safety follow up from feeder study 15396. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received abiraterone acetate in the selected feeder study.

    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
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received at least 1 dose of placebo-matched radium-223 dichloride in the selected feeder study.

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received prednisone/prednisolone in the selected feeder study.

    Arm title
    		 From study 16216 Radium-223 dichloride group
    Arm description
    		 Safety follow up from feeder study 16216. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16298 Radium-223 dichloride+hormonal therapy group‌
    Arm description
    		 Safety follow up from feeder study 16298. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with single hormonal agent, for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16298 Placebo + hormonal therapy group
    Arm description
    		 Safety follow up from feeder study 16298. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with single hormonal agent for up to 6 cycles.
    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
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received at least 1 dose of placebo-matched radium-223 dichloride in the selected feeder study.

    Arm title
    		 From study 16506 Radium-223 dichloride group
    Arm description
    		 Safety follow up from feeder study 16506. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16507 Radium-223 dichloride treatment A group
    Arm description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16507 Radium-223 dichloride treatment B group
    Arm description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 88 kBg/kg at intervals of every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16507 Radium-223 dichloride treatment C group
    Arm description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16544 Radium-223 dichloride+Abi/Pred group
    Arm description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with Abi/Pred for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received prednisone/prednisolone in the selected feeder study.

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received abiraterone acetate in the selected feeder study.

    Arm title
    		 From study 16544 Radium-223 dichloride+enzalutamide group
    Arm description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with enzalutamide for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received enzalutamide in the selected feeder study.

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 16544 Radium-223 dichloride group
    Arm description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Arm title
    		 From study 17096 Radium-223 dichloride + EXE/EVE group‌
    Arm description
    		 Safety follow up from feeder study 17096. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) along with exemestane (EXE) + everolimus (EVE) once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride (BAY88-8223, Xofigo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received everolimus in the selected feeder study.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received exemestane in the selected feeder study.

    Arm title
    		 From study 17096 Placebo + EXE/EVEgroup
    Arm description
    		 Safety follow up from feeder study 17096. Participants received placebo matched to radium-223 dichloride along with exemestane (EXE) + everolimus (EVE) once daily.
    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
    No study treatment was provided in this long-term follow-up study. Eligible subjects had received at least 1 dose of radium-223 dichloride in the selected feeder trials.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received exemestane in the selected feeder study.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study treatment was provided in this long-term follow-up study. Subjects in this group had received everolimus in the selected feeder study.

    Number of subjects in period 1
    		From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup
    Started
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    Completed
    14
    15
    3
    3
    3
    0
    1
    1
    2
    2
    1
    2
    5
    9
    Not completed
    25
    34
    28
    11
    6
    5
    10
    8
    9
    7
    3
    1
    28
    19
         Consent withdrawn by subject
    1
    2
    -
    -
    1
    -
    1
    2
    2
    3
    -
    -
    2
    -
         Death
    24
    32
    25
    11
    5
    5
    8
    5
    7
    3
    3
    1
    25
    19
         Lost to follow-up
    -
    -
    1
    -
    -
    -
    1
    1
    -
    1
    -
    -
    1
    -
         Missing
    -
    -
    2
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    From study 15396 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 15396. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 15396 Placebo+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 15396. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 16216 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16216. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16298 Radium-223 dichloride+hormonal therapy group‌
    Reporting group description
    		 Safety follow up from feeder study 16298. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with single hormonal agent, for up to 6 cycles.

    Reporting group title
    From study 16298 Placebo + hormonal therapy group
    Reporting group description
    		 Safety follow up from feeder study 16298. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with single hormonal agent for up to 6 cycles.

    Reporting group title
    From study 16506 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16506. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment A group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment B group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 88 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment C group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 12 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with Abi/Pred for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+enzalutamide group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with enzalutamide for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 17096 Radium-223 dichloride + EXE/EVE group‌
    Reporting group description
    		 Safety follow up from feeder study 17096. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) along with exemestane (EXE) + everolimus (EVE) once daily.

    Reporting group title
    From study 17096 Placebo + EXE/EVEgroup
    Reporting group description
    		 Safety follow up from feeder study 17096. Participants received placebo matched to radium-223 dichloride along with exemestane (EXE) + everolimus (EVE) once daily.

    Reporting group values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Total
    Number of subjects
    		 39 49 31 14 9 5 11 9 11 9 4 3 33 28 255
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 3 3 9 5 2 1 2 5 1 1 1 26 16 81
        From 65-84 years
    		 32 44 28 5 4 3 9 7 6 7 3 2 6 12 168
        85 years and over
    		 1 2 0 0 0 0 1 0 0 1 0 0 1 0 6
    Age Continuous
    Units: years
        median (full range (min-max))
    		 73.0 (51 to 86) 75.0 (60 to 92) 73.0 (59 to 80) 57.5 (29 to 83) 57.0 (42 to 79) 66.0 (55 to 79) 75.0 (63 to 87) 69.0 (63 to 84) 65.0 (55 to 82) 72.0 (60 to 88) 75.0 (61 to 78) 68.0 (62 to 75) 59.0 (42 to 88) 59.0 (43 to 78) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0 0 14 9 0 0 0 0 0 0 0 33 28 84
        Male
    		 39 49 31 0 0 5 11 9 11 9 4 3 0 0 171
    Race
    Units: Subjects
        White
    		 29 30 31 9 7 5 7 4 7 7 3 3 21 20 183
        Black or African American
    		 1 0 0 0 0 0 0 0 1 2 0 0 0 0 4
        Asian
    		 6 13 0 4 2 0 4 5 2 0 0 0 10 7 53
        Not reported
    		 2 4 0 1 0 0 0 0 1 0 1 0 2 1 12
        Missing
    		 1 2 0 0 0 0 0 0 0 0 0 0 0 0 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 4 0 0 0 0 0 0 1 1 1 0 1 1 13
        Not Hispanic or Latino
    		 32 41 31 13 9 5 11 9 10 8 3 3 30 27 232
        Not reported
    		 3 4 0 1 0 0 0 0 0 0 0 0 2 0 10
    Subject analysis sets

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects received at least 1 dose of radium-223 dichloride or placebo in the feeder studies.

    Subject analysis sets values
    		 Safety analysis set (SAF)
    Number of subjects
    255
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    81
        From 65-84 years
    168
        85 years and over
    6
    Age Continuous
    Units: years
        median (full range (min-max))
    Gender Categorical
    Units: Subjects
        Female
        Male
    Race
    Units: Subjects
        White
        Black or African American
        Asian
        Not reported
        Missing
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Not reported

    End points

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    End points reporting groups
    Reporting group title
    From study 15396 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 15396. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 15396 Placebo+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 15396. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 16216 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16216. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16298 Radium-223 dichloride+hormonal therapy group‌
    Reporting group description
    		 Safety follow up from feeder study 16298. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with single hormonal agent, for up to 6 cycles.

    Reporting group title
    From study 16298 Placebo + hormonal therapy group
    Reporting group description
    		 Safety follow up from feeder study 16298. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with single hormonal agent for up to 6 cycles.

    Reporting group title
    From study 16506 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16506. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment A group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment B group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 88 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment C group
    Reporting group description
    		 Safety follow up from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 12 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with Abi/Pred for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+enzalutamide group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with enzalutamide for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride group
    Reporting group description
    		 Safety follow up from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 17096 Radium-223 dichloride + EXE/EVE group‌
    Reporting group description
    		 Safety follow up from feeder study 17096. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) along with exemestane (EXE) + everolimus (EVE) once daily.

    Reporting group title
    From study 17096 Placebo + EXE/EVEgroup
    Reporting group description
    		 Safety follow up from feeder study 17096. Participants received placebo matched to radium-223 dichloride along with exemestane (EXE) + everolimus (EVE) once daily.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects received at least 1 dose of radium-223 dichloride or placebo in the feeder studies.

    Primary: Number of subjects and severity of radium-223 dichloride-/placebo-related Adverse Events (AEs)

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    End point title
    		 Number of subjects and severity of radium-223 dichloride-/placebo-related Adverse Events (AEs) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 7 years after the last dose of radium-223 dichloride or placebo in the feeder studies.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of serious and high-grade long-term AEs was too limited to support statistical analysis. Accordingly, only descriptive summaries are included in the results.
    End point values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Safety analysis set (SAF)
    Number of subjects analysed
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    255
    Units: Subjects
        Radium-223/Placebo-related AE
    0
    1
    1
    0
    0
    0
    1
    0
    3
    0
    0
    1
    3
    0
    10
        Grade 1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
        Grade 2
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    1
    0
    3
        Grade 3
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    2
    0
    4
        Grade 4
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
        Grade 5
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of subjects with radium-223 dichloride-/placebo-related Serious Adverse Events (SAEs)

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    End point title
    		 Number of subjects with radium-223 dichloride-/placebo-related Serious Adverse Events (SAEs) [2]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 7 years after the last dose of radium-223 dichloride or placebo in the feeder studies.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of serious and high-grade long-term AEs was too limited to support statistical analysis. Accordingly, only descriptive summaries are included in the results.
    End point values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Safety analysis set (SAF)
    Number of subjects analysed
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    255
    Units: Subjects
        Radium-223/Placebo-related SAE
    0
    0
    1
    0
    0
    0
    1
    0
    2
    0
    0
    0
    1
    0
    5
    No statistical analyses for this end point

    Primary: Number of subjects with leukemia, myelodysplastic syndrome, aplastic anemia, and primary bone cancer or any other new primary malignancy

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    End point title
    		 Number of subjects with leukemia, myelodysplastic syndrome, aplastic anemia, and primary bone cancer or any other new primary malignancy [3]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 7 years after the last dose of radium-223 dichloride or placebo in the feeder studies.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of serious and high-grade long-term AEs was too limited to support statistical analysis. Accordingly, only descriptive summaries are included in the results.
    End point values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Safety analysis set (SAF)
    Number of subjects analysed
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    255
    Units: Subjects
        Leukemia
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
        Myelodysplastic syndrome
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Aplastic anemia
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
        Primary bone cancer
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Any other new primary malignancy
    1
    1
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    4
    No statistical analyses for this end point

    Primary: Number of subjects with bone fractures and bone associated events

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    End point title
    		 Number of subjects with bone fractures and bone associated events [4]
    End point description
    Bone fractures and Bone associated events (e.g., osteoporosis), regardless of investigator assessment of causality.
    End point type
    Primary
    End point timeframe
    Up to 7 years after the last dose of radium-223 dichloride or placebo in the feeder studies.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of serious and high-grade long-term AEs was too limited to support statistical analysis. Accordingly, only descriptive summaries are included in the results.
    End point values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Safety analysis set (SAF)
    Number of subjects analysed
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    255
    Units: Subjects
        Bone fractures
    3
    6
    1
    1
    3
    0
    1
    2
    3
    1
    2
    0
    6
    7
    36
        Bone associated events
    1
    2
    1
    2
    0
    0
    0
    1
    4
    2
    0
    1
    3
    0
    17
    No statistical analyses for this end point

    Primary: Number of subjects with febrile neutropenia or hemorrhage

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    End point title
    		 Number of subjects with febrile neutropenia or hemorrhage [5]
    End point description
    Only for subjects who received cytotoxic chemotherapy in feeder studies.
    End point type
    Primary
    End point timeframe
    During chemotherapy treatment and for up to 6 months thereafter
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of serious and high-grade long-term AEs was too limited to support statistical analysis. Accordingly, only descriptive summaries are included in the results.
    End point values
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 15396 Placebo+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group‌ From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 16507 Radium-223 dichloride treatment A group From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group‌ From study 17096 Placebo + EXE/EVEgroup Safety analysis set (SAF)
    Number of subjects analysed
    39
    49
    31
    14
    9
    5
    11
    9
    11
    9
    4
    3
    33
    28
    255
    Units: Subjects
        Febrile neutropenia
    0
    0
    0
    1
    0
    0
    1
    1
    0
    0
    0
    0
    1
    0
    4
        Hemorrhage
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 7 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    From study 15396 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety FU from feeder study 15396. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 16216 Radium-223 dichloride group
    Reporting group description
    		 Safety FU from feeder study 16216. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16298 Radium-223 dichloride+hormonal therapy group
    Reporting group description
    		 Safety FU from feeder study 16298. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with single hormonal agent, for up to 6 cycles.

    Reporting group title
    From study 16298 Placebo + hormonal therapy group
    Reporting group description
    		 Safety FU from feeder study 16298. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with single hormonal agent for up to 6 cycles.

    Reporting group title
    From study 16506 Radium-223 dichloride group
    Reporting group description
    		 Safety FU from feeder study 16506. Participants received radium-223 dichloride 50 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 17096 Placebo + EXE/EVEgroup
    Reporting group description
    		 Safety FU from feeder study 17096. Participants received placebo matched to radium-223 dichloride along with exemestane (EXE) + everolimus (EVE) once daily.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment B group
    Reporting group description
    		 Safety FU from feeder study 16507. Participants received radium-223 dichloride 88 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment C group
    Reporting group description
    		 Safety FU from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 12 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+Abi/Pred group
    Reporting group description
    		 Safety FU from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with Abi/Pred for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride+enzalutamide group
    Reporting group description
    		 Safety FU from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks, along with enzalutamide for up to 6 cycles.

    Reporting group title
    From study 16544 Radium-223 dichloride group
    Reporting group description
    		 Safety FU from feeder study 16544. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) at intervals of every 4 weeks for up to 6 cycles.

    Reporting group title
    From study 17096 Radium-223 dichloride + EXE/EVE group
    Reporting group description
    		 Safety FU from feeder study 17096. Participants received radium-223 dichloride 50 kBg/kg (55 kBq/kg after implementation of NIST update) along with exemestane (EXE) + everolimus (EVE) once daily.

    Reporting group title
    From study 15396 Placebo+Abi/Pred group
    Reporting group description
    		 Safety FU from feeder study 15396. Participants received placebo matched to radium-223 dichloride at intervals of every 4 weeks, along with abiraterone acetate plus prednisone/prednisolone (abi/pred) for up to 6 cycles.

    Reporting group title
    From study 16507 Radium-223 dichloride treatment A group
    Reporting group description
    		 Safety FU from feeder study 16507. Participants received radium-223 dichloride 55 kBg/kg at intervals of every 4 weeks for up to 6 cycles.

    Serious adverse events
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 17096 Placebo + EXE/EVEgroup From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group From study 15396 Placebo+Abi/Pred group From study 16507 Radium-223 dichloride treatment A group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 31 (12.90%)
    1 / 14 (7.14%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    6 / 28 (21.43%)
    3 / 9 (33.33%)
    3 / 11 (27.27%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    4 / 33 (12.12%)
    4 / 49 (8.16%)
    2 / 11 (18.18%)
         number of deaths (all causes)
    24
    25
    11
    5
    5
    19
    5
    7
    3
    3
    1
    25
    32
    8
         number of deaths resulting from adverse events
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 31 (3.23%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 31 (3.23%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 31 (3.23%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aplastic anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoporotic fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    3 / 28 (10.71%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    2 / 49 (4.08%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 5
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 31 (3.23%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 From study 15396 Radium-223 dichloride+Abi/Pred group From study 16216 Radium-223 dichloride group From study 16298 Radium-223 dichloride+hormonal therapy group From study 16298 Placebo + hormonal therapy group From study 16506 Radium-223 dichloride group From study 17096 Placebo + EXE/EVEgroup From study 16507 Radium-223 dichloride treatment B group From study 16507 Radium-223 dichloride treatment C group From study 16544 Radium-223 dichloride+Abi/Pred group From study 16544 Radium-223 dichloride+enzalutamide group From study 16544 Radium-223 dichloride group From study 17096 Radium-223 dichloride + EXE/EVE group From study 15396 Placebo+Abi/Pred group From study 16507 Radium-223 dichloride treatment A group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 31 (0.00%)
    3 / 14 (21.43%)
    3 / 9 (33.33%)
    0 / 5 (0.00%)
    3 / 28 (10.71%)
    1 / 9 (11.11%)
    3 / 11 (27.27%)
    3 / 9 (33.33%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    8 / 33 (24.24%)
    6 / 49 (12.24%)
    1 / 11 (9.09%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Craniofacial fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 33 (3.03%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Genital haemorrhage
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    1 / 49 (2.04%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    2
    1
    Pathological fracture
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    3 / 9 (33.33%)
    0 / 5 (0.00%)
    1 / 28 (3.57%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    5 / 33 (15.15%)
    3 / 49 (6.12%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    2
    0
    0
    1
    0
    0
    10
    3
    0
    Osteopenia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Spondylitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Spondylolisthesis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Spinal stenosis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 33 (9.09%)
    1 / 49 (2.04%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    3
    1
    0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    1 / 14 (7.14%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Product issues
    Device failure
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 31 (0.00%)
    0 / 14 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 28 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 33 (0.00%)
    0 / 49 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2016
    Global amendment 01 forming integrated protocol Version 2.0 introduced the following changes: Clarified that all cytotoxic chemotherapy and radiotherapy received by participants was to be recorded for this study; removed overall survival as secondary objective and removed reference to an interim analysis; clarified the selected safety variables collected in the 16996 study and detailed the plan for pooling and presenting feeder study data. Added an option for the study site to obtain information directly from the participant’s primary health care professional or caregiver. Removed references to collection of medical history.
    11 Apr 2018
    Global amendment 02 forming integrated protocol Version 3.0 introduced the following changes: Updated indications to include breast cancer and multiple myeloma. Added request that bone fractures and bone-associated events (e.g., osteoporosis) need to be reported as (S)AEs, including during long-term follow-up, regardless of investigator’s causality assessment. Added that radium-223 dichloride should not be given with abiraterone plus prednisone/prednisolone. Added statement that initiation of a bone health agent (BHA), including bisphosphonates or denosumab, should be considered taking into consideration applicable guidelines. Any BHA treatment taken during the study period must be recorded. Clarified that participants are permitted to take concomitant medications as part of a clinical trial while participating in the current study. Clarified reporting of related SAEs.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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