ALSYMPCA: A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00699751
• Collaborator: (none)
• Enrollment: 921
• Locations: 135
• Arms: 2
• Duration (Months): 68
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

ALSYMPCA (ALpharadin in SYMPtomatic Prostate CAncer) is an international Phase III clinical study to evaluate the efficacy and safety of Radium-223 dichloride in patients with hormone refractory prostate cancer and skeletal metastases.

Condition or Disease	Intervention/Treatment	Phase
Hormone Refractory Prostate Cancer; Bone Metastases	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Placebo; Drug: Best standard of care (BSoC)	Phase 3

Detailed Description

The aim of the study was to compare, in patients with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care plus Radium-223 dichloride versus best standard of care plus placebo, with the primary efficacy endpoint being overall survival (OS).

Patients were randomised in a 2:1 allocation ratio (Radium-223 dichloride:Placebo). The study treatment consisted of 6 intravenous administrations of Radium-223 dichloride or placebo (saline) each separated by an interval of 4 weeks. The patient were followed until 3 years after first study drug administration.

Within the U.S., the trial was conducted under an IND sponsored by Bayer HealthCare Pharmaceuticals.

All patients received BSoC (Best Standard of Care).

This study has the original PCD as 14 October 2010, when a total of 316 deaths had been observed; this resulted in the Independent Data Monitoring Committee's (IDMC's) recommendation to stop the study as the primary efficacy analysis of overall survival had crossed the pre-specified boundary for efficacy. Later an updated analysis of primary endpoint in the first addendum was done with cut-off of 15 July 2011.

Study Design

• Study Type: Interventional
• Actual Enrollment: 921 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radium-223 dichloride (Xofigo, BAY88-8223) Participants received radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus Best Standard of Care (BSoC).	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Radium-223 dichloride 50 kBq/kg b.w., 6 IV administrations separated by 4 weeks intervals.; Other Names: Alpharadin ; Drug: Best standard of care (BSoC); Best standard of care is regarded as the routine standard of care at each center, for example local EBRT (External Beam Radiation Therapy), corticosteroids, antiandrogens, estrogens (e.g., stilboestrol), estramustine or ketoconazole.
Placebo Comparator: Placebo Participants received isotonic saline for 6 IV administrations separated by 4 weeks intervals plus Best Standard of Care (BSoC).	Drug: Placebo; Isotonic saline 6 IV administrations separated by 4 weeks intervals.; Drug: Best standard of care (BSoC); Best standard of care is regarded as the routine standard of care at each center, for example local EBRT (External Beam Radiation Therapy), corticosteroids, antiandrogens, estrogens (e.g., stilboestrol), estramustine or ketoconazole.

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization to death due to any cause until approximately 3 years after start of enrollment, the data was collected up to the second data analysis date (15 JUL 2011)]

   Overall survival was defined as the time from date of randomization to the date of death.

Secondary Outcome Measures

1. Time to Total Alkaline Phosphatase (ALP) Progression [From randomization to first ALP progression until approximately 3 years after start of enrollment]

   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% 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 ALP decline from baseline; the time from start of treatment to first ALP increase that is 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

2. Percentage of Participants With Total ALP Response at Week 12 [At Baseline and Week 12]

   ALP levels were measured in participants' 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.

3. Percentage of Participants With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) [At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)]

   ALP levels were measured in participants' 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.

4. Percentage of Participants With Total ALP Normalization at Week 12 [At Baseline and Week 12]

   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.

5. Percentage Change From Baseline in Total ALP at Week 12 [At Baseline and Week 12]

   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

6. Maximum Percentage Decrease From Baseline in Total ALP up to Week 12 [From baseline to Week 12]

   ALP level was measured in participant'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 participant, and set to zero if no decrease from baseline.

7. Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) [At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)]

   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

8. Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment [From baseline During the 24 Week Treatment]

   ALP level was measured in participant'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 participant, and set to zero if no decrease from baseline.

9. Time to Prostate Specific Antigen (PSA) Progression [From randomization to first PSA progression until approximately 3 years after start of enrollment]

   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 is 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

10. Percentage of Participants With PSA Response at Week 12 [At Baseline and Week 12]

    PSA levels were measured in participants' 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.

11. Percentage of Participants With PSA Response at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) [At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)]

    PSA levels were measured in participants' 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.

12. Percentage Change From Baseline in PSA at Week 12 [At Baseline and Week 12]

    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

13. Maximum Percentage Decrease From Baseline in PSA up to Week 12 [From baseline up to Week 12]

    PSA level was measured in participant'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 participant, and set to zero if no decrease from baseline.

14. Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) [At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)]

    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

15. Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period [From baseline to End of Treatment (Week 24; 4 weeks post last injection)]

    PSA level was measured in participant'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 participant, and set to zero if no decrease from baseline.

16. Time to First Skeletal Related Event (SRE) [From randomization to first first SRE until approximately 3 years after start of enrollment]

    A skeletal related event is 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 has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

17. Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms [From randomization to first EBRT until approximately 3 years after start of enrollment]

    The start date of therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

18. Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms [From randomization to first use of radioisotopes until approximately 3 years after start of enrollment]

    The start date of the radioisotopes was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

19. Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral [From randomization to occurrence of first new symptomatic pathological bone fractures until approximately 3 years after start of enrollment]

    The start date of the event was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

20. Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention [From randomization to occurrence of first tumor related orthopedic surgical intervention until approximately 3 years after start of enrollment]

    The start date of the intervention was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

21. Time to Occurrence of First Spinal Cord Compression [From randomization to first spinal cord compression until approximately 3 years after start of enrollment]

    The start date of the compression was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

22. Time to Occurrence of First Start of Any Other Anti-cancer Treatment [From randomization to first start of any other anti-cancer treatment until approximately 3 years after start of enrollment]

    The start date of the treatment was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

23. Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline [From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until approximately 3 years after start of enrollment]

    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 has not occurred at the time of the analysis or the participant was lost to follow-up, the time-to-event variables were censored at the last assessment date.

Other Outcome Measures

1. Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0. [Week 0]

   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.

2. Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8. [Week 8]

   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.

3. Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16. [Week 16]

   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.

4. Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24. [Week 24]

   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.

5. Absolute Scores for Functional Assessment of Cancer Therapy - Prostate (FACT-P) Trial Outcome Index (TOI) [Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)]

   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).

6. Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42) [Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)]

   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.

7. Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16 [At Week 16]

   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.

8. Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24 [At Week 24]

   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.

9. 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) [At Follow-up Visit 2 (Week 42)]

   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.

10. Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42) [At Week 16, Week 24, and Follow-up Visit 2 (Week 42)]

    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).

11. Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42) [Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)]

    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.

12. 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) [At Week 16, Week 24, and Follow-up Visit 2 (Week 42)]

    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).

13. Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42) [Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)]

    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.

14. Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16 [Week 16]

    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 participants 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').

15. Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24 [Week 24]

    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 participants 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').

16. Number of Participants 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) [Follow-up Visit 8 (Week 139)]

    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 participants 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').

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate

• Known hormone refractory disease

• Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy

• No intention to use cytotoxic chemotherapy within the next 6 months

• Either regular (not occasional) analgesic medication use for cancer related bone pain or treatment with EBRT (External Beam Radiation Therapy) for bone pain

Exclusion Criteria:

• Treatment with an investigational drug within previous 4 weeks, or planned during the treatment period

• Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and where docetaxel is available

• Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the treatment period, or failure to recover from adverse events due to cytotoxic chemotherapy administered more than 4 weeks ago

• Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within previous 24 weeks

• Other malignancy treated within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)

• History of visceral metastasis, or visceral metastases as assessed by abdominal/pelvic CT or chest x-ray within previous 8 weeks

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90048-0750
2		Roseville	California	United States	95661
3		Tampa	Florida	United States	33612
4		New Orleans	Louisiana	United States	70112
5		St. Louis	Missouri	United States	63110
6		Las Vegas	Nevada	United States	89169
7		Philadelphia	Pennsylvania	United States	19111-2497
8		Liverpool	New South Wales	Australia	2170
9		Randwick	New South Wales	Australia	2031
10		St Leonards	New South Wales	Australia	2065
11		Sydney	New South Wales	Australia	2010
12		Wahroonga	New South Wales	Australia	2076
13		Wollongong	New South Wales	Australia	2521
14		Brisbane	Queensland	Australia	4029
15		Toowoomba	Queensland	Australia	4350
16		Adelaide	South Australia	Australia	5000
17		Adelaide	South Australia	Australia	5011
18		Hobart	Tasmania	Australia	7000
19		Fitzroy	Victoria	Australia	3065
20		Nedlands	Western Australia	Australia	6009
21		Kortrijk		Belgium	8500
22		Ottignies		Belgium	1340
23		Salvador	Bahia	Brazil	41830-492
24		Belo Horizonte	Minas Gerais	Brazil	30110-090
25		Porto Alegre	Rio Grande do Sul	Brazil
26		Barretos	Sao Paulo	Brazil	14784400
27		Piracicaba	Sao Paulo	Brazil
28		Belo Horizonte		Brazil	30380490
29		Rio de Janeiro		Brazil	20551 030
30		Sao Paulo		Brazil	05403-900
31		Edmonton	Alberta	Canada	T6G 1Z2
32		London	Ontario	Canada	N6A 4G5
33		Ottawa	Ontario	Canada	K1H 8L6
34		Toronto	Ontario	Canada	M4N 3M5
35		Brno		Czech Republic	65653
36		Chomutov		Czech Republic	430 12
37		Olomouc		Czech Republic	775 20
38		Ostrava		Czech Republic	708 52
39		Plzen - Bory		Czech Republic	305 99
40		Praha 4		Czech Republic	140 59
41		Usti nad Labem		Czech Republic	401 13
42		La Roche Sur Yon		France	85925
43		Montbeliard		France	25209
44		Saint Cloud		France	92210
45		Ulm	Baden-Württemberg	Germany	89075
46		Frankfurt	Hessen	Germany	60590
47		Marburg	Hessen	Germany	35043
48		Göttingen	Niedersachsen	Germany	37099
49		Hannover	Niedersachsen	Germany	30625
50		Dortmund	Nordrhein-Westfalen	Germany	44137
51		Mainz	Rheinland-Pfalz	Germany	55131
52		Berlin		Germany	10967
53		Berlin		Germany	14197
54		Hamburg		Germany	20246
55		Chai Wan		Hong Kong
56		Hong Kong		Hong Kong
57		Hongkong		Hong Kong
58		Kowloon		Hong Kong
59		Beer Sheva		Israel	8410101
60		Kfar Saba		Israel	4428164
61		Tel Aviv		Israel	6423906
62		Zrifin		Israel	6093000
63		Meldola	Forlì	Italy	47014
64		Candiolo	Torino	Italy	10060
65		Bergamo		Italy	24128
66		Milano		Italy	20162
67		Reggio Emilia		Italy	42123
68		Alkmaar		Netherlands	1815 JD
69		Nijmegen		Netherlands	6532 SZ
70		Rotterdam		Netherlands	3015 CE
71		Bergen		Norway	5021
72		Bodø		Norway	8092
73		Kristiansand		Norway	N-4604
74		Oslo		Norway	0450
75		Oslo		Norway	N-0310
76		Tromsø		Norway	9038
77		Trondheim		Norway	7006
78		Ålesund		Norway	6026
79		Bydgoszcz		Poland	85-165
80		Gliwice		Poland	44-101
81		Kielce		Poland	25-734
82		Krakow		Poland	31-051
83		Luiblin		Poland	20-954
84		Warszawa		Poland	02-781
85		Wroclaw		Poland	50 - 556
86		Wroclaw		Poland	50-981
87		Singapore		Singapore	258499
88		Singapore		Singapore	308433
89		Banska Bystrica		Slovakia	97517
90		Bratislava		Slovakia	82606
91		Bratislava		Slovakia	83305
92		Martin		Slovakia	03659
93		Presov		Slovakia	08181
94		Trnava		Slovakia	917 01
95		Santiago de Compostela	A Coruña	Spain	15706
96		Alcorcón	Madrid	Spain	28922
97		Barakaldo	Vizcaya	Spain	48903
98		Barcelona		Spain	08025
99		Barcelona		Spain	08035
100		Barcelona		Spain	08036
101		Córdoba		Spain	14004
102		Pamplona		Spain	31008
103		Valencia		Spain	46026
104		Zaragoza		Spain	50009
105		Göteborg		Sweden	413 45
106		Jönköping		Sweden	551 85
107		Kalmar		Sweden	391 85
108		Malmö		Sweden	205 02
109		Sandviken		Sweden	80187
110		Stockholm		Sweden	171 76
111		Sundsvall		Sweden	851 86
112		Umeå		Sweden	901 85
113		Romford	Essex	United Kingdom	RM7 0AG
114		Leicester	Leicestershire	United Kingdom	LE1 5WW
115		Bebington	Merseyside	United Kingdom	CH63 4JY
116		Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
117		Taunton	Somerset	United Kingdom	TA1 5DA
118		Ipswich	Suffolk	United Kingdom	IP4 5PD
119		Guildford	Surrey	United Kingdom	GU2 7XX
120		Sutton	Surrey	United Kingdom	SM2 5PT
121		Coventry	Warwickshire	United Kingdom	CV2 2DX
122		Birmingham	West Midlands	United Kingdom	B15 2TH
123		Belfast		United Kingdom	BT9 7AB
124		Brighton		United Kingdom	BN2 5BD
125		Bristol		United Kingdom	BS2 8ED
126		Cardiff		United Kingdom
127		Derby		United Kingdom	DE22 3NE
128		Hull		United Kingdom	HU16 5JQ
129		Leeds		United Kingdom	LS9 7TF
130		Manchester		United Kingdom	M20 4BX
131		Northwood		United Kingdom	HA6 2RN
132		Plymouth		United Kingdom	PL6 8DH
133		Sheffield		United Kingdom	S10 2SJ
134		Southampton		United Kingdom	SO16 6YD
135		Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Bayer

Investigators

• Study Chair: Christopher Parker, MD, The Royal Marsden Hospital, UK

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00699751
• Other Study ID Numbers: 15245; BC1-06; 2007-006195-11
• First Posted: Jun 18, 2008
• Last Update Posted: May 27, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Bayer: Hormone Refractory Prostate Cancer; Bone Metastases; Radium-223
• Additional relevant MeSH terms: Prostatic Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Radium Ra 223 dichloride

Study Results

Participant Flow

Recruitment Details	Subjects with progressive symptomatic hormone refractory prostate cancer (HRPC), with at least 2 skeletal metastases on bone scan and no known visceral metastases, could participate in the study.
Pre-assignment Detail	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.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Participants received BSoC plus radium223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.	Participants received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals in double-blind phase; Participants received radium223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals after unblinding to the end of study.
Period Title: Period 1: Without/Before Drug Switch
STARTED	614	307
Participants Received Treatment	600	301
Entered 3-Year Follow-up Period	407	168
Completed 3-Year Follow-up Period	49	12
COMPLETED	389	145
NOT COMPLETED	225	162
Period Title: Period 1: Without/Before Drug Switch
STARTED	0	26
Participants Received Treatment	0	24
Entered 3-Year Follow-up Period	0	15
Completed 3-Year Follow-up Period	0	0
COMPLETED	0	17
NOT COMPLETED	0	9

Baseline Characteristics

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo	Total
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.	Total of all reporting groups
Overall Participants	614	307	921
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.2 (8.10)	70.8 (7.87)	70.4 (8.03)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	614 100%	307 100%	921 100%
Total Alkaline Phosphatase (ALP) (Number) [Number]
< 220 U/L	348 56.7%	169 55%	517 56.1%
≥ 220 U/L	266 43.3%	138 45%	404 43.9%
Current use of bisphosphonates (Number) [Number]
Yes	250 40.7%	124 40.4%	374 40.6%
No	364 59.3%	183 59.6%	547 59.4%
Any prior use of docetaxel (Number) [Number]
Yes	352 57.3%	174 56.7%	526 57.1%
No	262 42.7%	133 43.3%	395 42.9%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from date of randomization to the date of death.
Time Frame	From randomization to death due to any cause until approximately 3 years after start of enrollment, the data was collected up to the second data analysis date (15 JUL 2011)

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was defined as all randomized subjects.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	14.9	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of overall survival, and also for the secondary endpoints, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00005
	Comments
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.691
	Confidence Interval	(2-Sided) 95%; 0.578 to 0.827
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

2. Secondary Outcome

Title	Time to Total Alkaline Phosphatase (ALP) Progression
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% 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 ALP decline from baseline; the time from start of treatment to first ALP increase that is 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
Time Frame	From randomization to first ALP progression until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	7.4	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of time to total ALP progression, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.169
	Confidence Interval	(2-Sided) 95%; 0.131 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

3. Secondary Outcome

Title	Percentage of Participants With Total ALP Response at Week 12
Description	ALP levels were measured in participants' 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.
Time Frame	At Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	497	211
>=30% reduction of ALP in blood level	59.4 9.7%	6.2 2%
>=50% reduction of ALP in blood level	32.6 5.3%	1.4 0.5%
Confirmed Total ALP Response (>=30%)	47.1 7.7%	3.3 1.1%
Confirmed Total ALP Response (>=50%)	27.4 4.5%	0.9 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=30% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=30% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=50% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=50% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Confirmed Total ALP Response (>=30%), is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confirmed Total ALP Response (>=30%)
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Confirmed Total ALP Response (>=50%), is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confirmed Total ALP Response (>=50%)
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

4. Secondary Outcome

Title	Percentage of Participants With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
Description	ALP levels were measured in participants' 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.
Time Frame	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	589	288
>=30% reduction of ALP in blood level	59.9 9.8%	4.5 1.5%
>=50% reduction of ALP in blood level	34.6 5.6%	1.7 0.6%
Confirmed Total ALP Response (>=50%)	13.9 2.3%	1 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=30% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=30% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=50% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=50% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Confirmed Total ALP Response (>=50%), is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confirmed Total ALP Response (>=50%)
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

5. Secondary Outcome

Title	Percentage of Participants With Total ALP Normalization at Week 12
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.
Time Frame	At Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	321	140
Number [Percentage of participants]	34 5.5%	1.4 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Total ALP normalization, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Total ALP normalization
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

6. Secondary Outcome

Title	Percentage Change From Baseline in Total ALP at Week 12
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
Time Frame	At Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	497	211
Least Squares Mean (Standard Error) [Percentage change]	-32.2 (1.80)	37.2 (2.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Percentage change from baseline, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Percentage Change from Baseline
	Method	ANCOVA
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

7. Secondary Outcome

Title	Maximum Percentage Decrease From Baseline in Total ALP up to Week 12
Description	ALP level was measured in participant'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 participant, and set to zero if no decrease from baseline.
Time Frame	From baseline to Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	582	284
Least Squares Mean (Standard Error) [Percentage change]	-38.9 (0.76)	-5.9 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Maximum Percentage decrease from baseline to week 12, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Maximum Percentage decrease from baseline to week 12
	Method	ANCOVA
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

8. Secondary Outcome

Title	Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
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
Time Frame	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	589	288
Least Squares Mean (Standard Error) [Percent change]	-29.9 (3.13)	62.1 (4.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Percentage change from baseline, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Percentage change from baseline
	Method	ANCOVA
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

9. Secondary Outcome

Title	Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment
Description	ALP level was measured in participant'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 participant, and set to zero if no decrease from baseline.
Time Frame	From baseline During the 24 Week Treatment

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	589	288
Least Squares Mean (Standard Error) [Percentage change]	-44.4 (0.80)	-7.5 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Maximum Percentage decrease from baseline during the 24 week treatment, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Maximum Percentage decrease from baseline during the 24 week treatment
	Method	ANCOVA
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

10. Secondary Outcome

Title	Time to Prostate Specific Antigen (PSA) Progression
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 is 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
Time Frame	From randomization to first PSA progression until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	3.6	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to PSA progression, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	Time to Prostate Specific Antigen (PSA) progression
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.643
	Confidence Interval	(2-Sided) 95%; 0.539 to 0.768
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

11. Secondary Outcome

Title	Percentage of Participants With PSA Response at Week 12
Description	PSA levels were measured in participants' 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.
Time Frame	At Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	493	210
>=30% reduction of PSA in blood level	16.4 2.7%	6.2 2%
>=50% reduction of PSA in blood level	7.7 1.3%	4.3 1.4%
Confirmed PSA Response (>=50%)	5.7 0.9%	1.9 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=30% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=30% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=50% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments	>=50% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Confirmed PSA Response(>=50%), is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	Confirmed PSA Response(>=50%)
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

12. Secondary Outcome

Title	Percentage of Participants With PSA Response at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
Description	PSA levels were measured in participants' 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.
Time Frame	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	590	286
>=30% reduction in blood level	14.2 2.3%	4.5 1.5%
>=50% reduction in blood level	9 1.5%	3.1 1%
Confirmed PSA Response (>=50%)	6.1 1%	1.7 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=30% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	>=30% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of >=50% reduction in blood level, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	>=50% reduction in blood level
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Confirmed PSA Response(>=50%), is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	Confirmed PSA Response(>=50%)
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

13. Secondary Outcome

Title	Percentage Change From Baseline in PSA at Week 12
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
Time Frame	At Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	493	210
Least Squares Mean (Standard Error) [Percent change]	83.3 (152.48)	543.8 (233.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Percentage change from baseline in PSA at Week 12, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.160
	Comments	Percentage change from baseline in PSA at Week 12
	Method	ANCOVA
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

14. Secondary Outcome

Title	Maximum Percentage Decrease From Baseline in PSA up to Week 12
Description	PSA level was measured in participant'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 participant, and set to zero if no decrease from baseline.
Time Frame	From baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	581	283
Least Squares Mean (Standard Error) [Percentage change]	-13.0 (0.90)	-7.8 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline up to Week 12, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Maximum Percentage Decrease from Baseline up to Week 12
	Method	ANCOVA
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

15. Secondary Outcome

Title	Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
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
Time Frame	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	590	286
Least Squares Mean (Standard Error) [Percentage change]	144.3 (15.38)	191.1 (22.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Percentage change from baseline in PSA at EOT, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Percentage change from baseline in PSA at EOT
	Method	ANCOVA
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

16. Secondary Outcome

Title	Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period
Description	PSA level was measured in participant'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 participant, and set to zero if no decrease from baseline.
Time Frame	From baseline to End of Treatment (Week 24; 4 weeks post last injection)

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and had no missing values for this outcome measure

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	590	286
Least Squares Mean (Standard Error) [Percentage change]	-16.4 (1.01)	-9.3 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period
	Method	ANCOVA
	Comments	Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

17. Secondary Outcome

Title	Time to First Skeletal Related Event (SRE)
Description	A skeletal related event is 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 has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to first first SRE until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	16.4	8.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of time to first SRE, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00012
	Comments	Time to first Skeletal Related Event (SRE)
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.657
	Confidence Interval	(2-Sided) 95%; 0.529 to 0.814
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

18. Secondary Outcome

Title	Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms
Description	The start date of therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to first EBRT until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	18	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of time to EBRT, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00008
	Comments	Time to External Beam Radiotherapy
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.639
	Confidence Interval	(2-Sided) 95%; 0.511 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

19. Secondary Outcome

Title	Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms
Description	The start date of the radioisotopes was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to first use of radioisotopes until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Receiving Radio-isotope, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00191
	Comments	stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.344
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.695
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

20. Secondary Outcome

Title	Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral
Description	The start date of the event was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to occurrence of first new symptomatic pathological bone fractures until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Pathological Bone Fracture, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53277
	Comments	Time to Pathological Bone Fracture
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.847
	Confidence Interval	(2-Sided) 95%; 0.504 to 1.426
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

21. Secondary Outcome

Title	Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention
Description	The start date of the intervention was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to occurrence of first tumor related orthopedic surgical intervention until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Surgical Intervention, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.89567
	Comments	Time to Surgical Intervention
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.949
	Confidence Interval	(2-Sided) 95%; 0.435 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

22. Secondary Outcome

Title	Time to Occurrence of First Spinal Cord Compression
Description	The start date of the compression was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to first spinal cord compression until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Spinal Cord Compression, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14486
	Comments	Time to Spinal Cord Compression
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.404 to 1.145
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

23. Secondary Outcome

Title	Time to Occurrence of First Start of Any Other Anti-cancer Treatment
Description	The start date of the treatment was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
Time Frame	From randomization to first start of any other anti-cancer treatment until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	15.4	12.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Other Cancer Treatment, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00932
	Comments	Time to Other Cancer Treatment
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.727
	Confidence Interval	(2-Sided) 95%; 0.571 to 0.925
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

24. Secondary Outcome

Title	Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline
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 has not occurred at the time of the analysis or the participant was lost to follow-up, the time-to-event variables were censored at the last assessment date.
Time Frame	From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until approximately 3 years after start of enrollment

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Median (95% Confidence Interval) [Months]	23.4	18.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of Time to Marked Deterioration of ECOG PS, is that there is no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis is that a difference exists.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00187
	Comments	Time to Marked Deterioration of ECOG PS
	Method	Log Rank
	Comments	Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.546 to 0.873
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Alpharadin:Placebo) is from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

25. Other Pre-specified Outcome

Title	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0.
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.
Time Frame	Week 0

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and with ECOG analyzed

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	600	305
ECOG Grade 0	136 22.1%	72 23.5%
ECOG Grade 1	376 61.2%	191 62.2%
ECOG Grade 2	82 13.4%	40 13%
ECOG Grade 3	6 1%	1 0.3%
ECOG Grade 4	0 0%	0 0%
ECOG Grade 5	0 0%	0 0%
Missing	0 0%	1 0.3%

26. Other Pre-specified Outcome

Title	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8.
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.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and with ECOG analyzed

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	569	267
ECOG Grade 0	133 21.7%	49 16%
ECOG Grade 1	315 51.3%	142 46.3%
ECOG Grade 2	103 16.8%	53 17.3%
ECOG Grade 3	13 2.1%	15 4.9%
ECOG Grade 4	0 0%	3 1%
ECOG Grade 5	1 0.2%	1 0.3%
Missing	4 0.7%	4 1.3%

27. Other Pre-specified Outcome

Title	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16.
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.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and with ECOG analyzed

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	471	196
ECOG Grade 0	101 16.4%	29 9.4%
ECOG Grade 1	257 41.9%	113 36.8%
ECOG Grade 2	85 13.8%	42 13.7%
ECOG Grade 3	19 3.1%	11 3.6%
ECOG Grade 4	4 0.7%	0 0%
ECOG Grade 5	0 0%	0 0%
Missing	5 0.8%	1 0.3%

28. Other Pre-specified Outcome

Title	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24.
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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Participants in The ITT population and with ECOG analyzed

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	363	138
ECOG Grade 0	74 12.1%	22 7.2%
ECOG Grade 1	181 29.5%	66 21.5%
ECOG Grade 2	85 13.8%	36 11.7%
ECOG Grade 3	17 2.8%	10 3.3%
ECOG Grade 4	5 0.8%	4 1.3%
ECOG Grade 5	0 0%	0 0%
Missing	1 0.2%	0 0%

29. Other Pre-specified Outcome

Title	Absolute Scores for Functional Assessment of Cancer Therapy - Prostate (FACT-P) Trial Outcome Index (TOI)
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).
Time Frame	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
Week 0 (Baseline)	65.00	64.00
Week 16	65.00	61.31
Week 24	61.00	60.00
Follow-up Visit 2 (Week 42)	61.00	60.5

30. Other Pre-specified Outcome

Title	Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
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.
Time Frame	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
At Week 16	-1.55	-4.15
At Week 24	-4.00	-5.67
At Follow-up Visit 2 (Week 42)	-5.00	-5.5

31. Other Pre-specified Outcome

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
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.
Time Frame	At Week 16

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
physical well being	20.00	19.83
social/family well being	22.00	21.50
emotional well being	18.0	16.80
functional well being	16.0	15.0
the prostate cancer subscale	29.00	27.60

32. Other Pre-specified Outcome

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
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.
Time Frame	At Week 24

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
physical well being	19.00	18.67
social/family well being	21.00	21.00
emotional well being	17.00	16.00
functional well being	15.00	14.00
the prostate cancer subscale	28.00	27.64

33. Other Pre-specified Outcome

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)
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.
Time Frame	At Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
physical well being	19.00	18.00
social/family well being	22.00	22.00
emotional well being	17.00	16.00
functional well being	14.00	14.00
the prostate cancer subscale	28.00	29.00

34. Other Pre-specified Outcome

Title	Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
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).
Time Frame	At Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
At Week 16	100.68	99.90
At Week 24	98.00	97.5
At Follow-up Visit 2 (Week 42)	97.83	97.38

35. Other Pre-specified Outcome

Title	Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
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.
Time Frame	Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
At Week 16	-2.00	-5.67
At Week 24	-5.00	-9.40
At Follow-up Visit 2 (Week 42)	-6.17	-7.00

36. Other Pre-specified Outcome

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)
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).
Time Frame	At Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
At Week 16	73.00	72.00
At Week 24	71.00	69.00
At Follow-up Visit 2 (Week 42)	70.00	70.25

37. Other Pre-specified Outcome

Title	Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
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.
Time Frame	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	614	307
At Week 16	-1.00	-4.00
At Week 24	-4.08	-7.00
At Follow-up Visit 2 (Week 42)	-3.67	-6.00

38. Other Pre-specified Outcome

Title	Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16
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 participants 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').
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects with with EQ-5D analyzed.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	477	205
mobility - Grade 1	191 31.1%	64 20.8%
mobility - Grade 2	278 45.3%	129 42%
mobility - Grade 3	7 1.1%	10 3.3%
mobility - Missing	1 0.2%	2 0.7%
self-care - Grade 1	346 56.4%	140 45.6%
self-care - Grade 2	123 20%	54 17.6%
self-care - Grade 3	7 1.1%	10 3.3%
self-care - Missing	1 0.2%	1 0.3%
usual activities - Grade 1	199 32.4%	67 21.8%
usual activities - Grade 2	233 37.9%	105 34.2%
usual activities - Grade 3	44 7.2%	32 10.4%
usual activities - Missing	1 0.2%	1 0.3%
pain/discomfort - Grade 1	79 12.9%	23 7.5%
pain/discomfort - Grade 2	351 57.2%	159 51.8%
pain/discomfort - Grade 3	46 7.5%	22 7.2%
pain/discomfort - Missing	1 0.2%	1 0.3%
anxiety/depression - Grade 1	285 46.4%	104 33.9%
anxiety/depression - Grade 2	171 27.9%	95 30.9%
anxiety/depression - Grade 3	15 2.4%	4 1.3%
anxiety/depression - Missing	6 1%	2 0.7%

39. Other Pre-specified Outcome

Title	Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24
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 participants 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').
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects with with EQ-5D analyzed.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	368	140
mobility - Grade 1	129 21%	39 12.7%
mobility - Grade 2	225 36.6%	93 30.3%
mobility - Grade 3	11 1.8%	5 1.6%
mobility - Missing	3 0.5%	3 1%
self-care - Grade 1	256 41.7%	89 29%
self-care - Grade 2	102 16.6%	46 15%
self-care - Grade 3	6 1%	3 1%
self-care - Missing	4 0.7%	2 0.7%
usual activities - Grade 1	140 22.8%	38 12.4%
usual activities - Grade 2	187 30.5%	79 25.7%
usual activities - Grade 3	37 6%	20 6.5%
usual activities - Missing	4 0.7%	3 1%
pain/discomfort - Grade 1	56 9.1%	21 6.8%
pain/discomfort - Grade 2	270 44%	95 30.9%
pain/discomfort - Grade 3	39 6.4%	21 6.8%
pain/discomfort - Missing	3 0.5%	3 1%
anxiety/depression - Grade 1	195 31.8%	64 20.8%
anxiety/depression - Grade 2	159 25.9%	71 23.1%
anxiety/depression - Grade 3	10 1.6%	2 0.7%
anxiety/depression - Missing	4 0.7%	3 1%

40. Other Pre-specified Outcome

Title	Number of Participants 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)
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 participants 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').
Time Frame	Follow-up Visit 8 (Week 139)

Outcome Measure Data

Analysis Population Description

The ITT population was all randomized subjects with with EQ-5D analyzed.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo
Arm/Group Description	Radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.	Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.
Measure Participants	41	13
mobility - Grade 1	9 1.5%	2 0.7%
mobility - Grade 2	30 4.9%	10 3.3%
mobility - Grade 3	1 0.2%	1 0.3%
mobility - Missing	1 0.2%	0 0%
self-care - Grade 1	26 4.2%	7 2.3%
self-care - Grade 2	12 2%	3 1%
self-care - Grade 3	2 0.3%	3 1%
self-care - MIssing	1 0.2%	0 0%
usual activities - Grade 1	13 2.1%	2 0.7%
usual activities - Grade 2	19 3.1%	7 2.3%
usual activities - Grade 3	8 1.3%	4 1.3%
usual activities - Missing	1 0.2%	0 0%
pain/discomfort - Grade 1	5 0.8%	1 0.3%
pain/discomfort - Grade 2	32 5.2%	11 3.6%
pain/discomfort - Grade 3	3 0.5%	1 0.3%
pain/discomfort - Missing	1 0.2%	0 0%
anxiety/depression - Grade 1	24 3.9%	6 2%
anxiety/depression - Grade 2	15 2.4%	7 2.3%
anxiety/depression - Grade 3	1 0.2%	0 0%
anxiety/depression - Missing	1 0.2%	0 0%

Adverse Events

Time Frame	Treatment-emergent AEs (TEAEs) data were collected after the first injection of study treatment and within 12 weeks after the last injection of study treatment.
Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)		Placebo		Placebo Randomized, Then Switched to Radium-223 Dichloride
Arm/Group Description	Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.		Participants received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals in double-blind phase.		Participants received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals in double-blind phase; Participants received radium223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals after unblinding to the end of study.
All Cause Mortality
	Radium-223 Dichloride (Xofigo, BAY88-8223)		Placebo		Placebo Randomized, Then Switched to Radium-223 Dichloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Radium-223 Dichloride (Xofigo, BAY88-8223)		Placebo		Placebo Randomized, Then Switched to Radium-223 Dichloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	286/ (NaN)		185/ (NaN)		17/ (NaN)
Blood and lymphatic system disorders
Anaemia	50/600 (8.3%)	70	25/301 (8.3%)	35	1/24 (4.2%)	1
Aplastic anaemia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Disseminated intravascular coagulation	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Febrile neutropenia	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Leukopenia	3/600 (0.5%)	3	0/301 (0%)	0	0/24 (0%)	0
Neutropenia	3/600 (0.5%)	3	1/301 (0.3%)	1	0/24 (0%)	0
Pancytopenia	5/600 (0.8%)	6	0/301 (0%)	0	1/24 (4.2%)	1
Thrombocytopenia	14/600 (2.3%)	14	3/301 (1%)	3	1/24 (4.2%)	1
Bone marrow failure	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Cardiac disorders
Acute myocardial infarction	1/600 (0.2%)	1	3/301 (1%)	3	0/24 (0%)	0
Angina pectoris	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Arrhythmia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Atrial fibrillation	3/600 (0.5%)	3	4/301 (1.3%)	4	0/24 (0%)	0
Atrial flutter	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Atrioventricular block complete	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Cardiac arrest	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Cardiac failure	2/600 (0.3%)	2	4/301 (1.3%)	4	0/24 (0%)	0
Cardiac failure congestive	4/600 (0.7%)	4	2/301 (0.7%)	2	0/24 (0%)	0
Coronary artery disease	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Left ventricular failure	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Myocardial infarction	3/600 (0.5%)	3	3/301 (1%)	3	0/24 (0%)	0
Myocardial ischaemia	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Supraventricular tachycardia	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Left ventricular dysfunction	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Cardiopulmonary failure	1/600 (0.2%)	1	2/301 (0.7%)	2	0/24 (0%)	0
Acute coronary syndrome	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Eye disorders
Cataract	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Glaucoma	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Gastrointestinal disorders
Abdominal distension	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Abdominal pain	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Abdominal pain upper	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Ascites	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Constipation	8/600 (1.3%)	8	4/301 (1.3%)	4	0/24 (0%)	0
Diarrhoea	3/600 (0.5%)	4	4/301 (1.3%)	4	0/24 (0%)	0
Duodenal ulcer	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Dysphagia	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Faecal incontinence	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Food poisoning	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Gastritis	2/600 (0.3%)	2	1/301 (0.3%)	1	0/24 (0%)	0
Gastrointestinal haemorrhage	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Haematemesis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Intestinal obstruction	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Intestinal perforation	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Large intestine perforation	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Mouth haemorrhage	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Nausea	9/600 (1.5%)	10	5/301 (1.7%)	6	0/24 (0%)	0
Rectal haemorrhage	1/600 (0.2%)	1	1/301 (0.3%)	1	1/24 (4.2%)	1
Small intestinal obstruction	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Upper gastrointestinal haemorrhage	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Vomiting	11/600 (1.8%)	20	7/301 (2.3%)	7	0/24 (0%)	0
Subileus	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Erosive duodenitis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
General disorders
Asthenia	3/600 (0.5%)	3	1/301 (0.3%)	1	0/24 (0%)	0
Chest pain	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Death	4/600 (0.7%)	4	1/301 (0.3%)	1	0/24 (0%)	0
Fatigue	6/600 (1%)	7	9/301 (3%)	9	0/24 (0%)	0
Gait disturbance	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Malaise	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Mucosal inflammation	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Multi-organ failure	3/600 (0.5%)	3	0/301 (0%)	0	0/24 (0%)	0
Oedema	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Oedema peripheral	4/600 (0.7%)	5	2/301 (0.7%)	2	0/24 (0%)	0
Pyrexia	6/600 (1%)	9	6/301 (2%)	7	0/24 (0%)	0
Sudden death	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
General physical health deterioration	15/600 (2.5%)	15	8/301 (2.7%)	8	1/24 (4.2%)	1
Drug intolerance	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Cholestasis	1/600 (0.2%)	3	0/301 (0%)	0	0/24 (0%)	0
Hepatic failure	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Bile duct obstruction	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Infections and infestations
Bronchitis	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Bronchopneumonia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Catheter related infection	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Cellulitis	3/600 (0.5%)	3	1/301 (0.3%)	1	0/24 (0%)	0
Clostridium difficile colitis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Cystitis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Gastroenteritis	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Herpes zoster	2/600 (0.3%)	2	1/301 (0.3%)	1	0/24 (0%)	0
Infection	10/600 (1.7%)	12	3/301 (1%)	3	0/24 (0%)	0
Listeriosis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Lobar pneumonia	0/600 (0%)	0	2/301 (0.7%)	2	0/24 (0%)	0
Lower respiratory tract infection	8/600 (1.3%)	9	2/301 (0.7%)	2	0/24 (0%)	0
Oral candidiasis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Pneumonia	17/600 (2.8%)	18	7/301 (2.3%)	8	1/24 (4.2%)	1
Pneumonia primary atypical	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Postoperative wound infection	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Pyelonephritis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Pyonephrosis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Sepsis	7/600 (1.2%)	7	4/301 (1.3%)	4	0/24 (0%)	0
Upper respiratory tract infection	1/600 (0.2%)	1	0/301 (0%)	0	1/24 (4.2%)	1
Urinary tract infection	5/600 (0.8%)	5	6/301 (2%)	6	0/24 (0%)	0
Urosepsis	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Abscess jaw	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Bacterial sepsis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Staphylococcal infection	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Bursitis infective	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Lung infection	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Peritonitis bacterial	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Device related infection	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Post procedural infection	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Gastroenteritis norovirus	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Concussion	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Cystitis radiation	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Extradural haematoma	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Fall	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Femoral neck fracture	1/600 (0.2%)	1	1/301 (0.3%)	1	1/24 (4.2%)	1
Hip fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Injury	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Intentional overdose	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Patella fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Rib fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Spinal compression fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Sternal fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Therapeutic agent toxicity	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Stent occlusion	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Medical device complication	1/600 (0.2%)	1	0/301 (0%)	0	1/24 (4.2%)	1
Skin laceration	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Upper limb fracture	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Device dislocation	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Procedural pain	2/600 (0.3%)	2	1/301 (0.3%)	1	0/24 (0%)	0
Post-traumatic pain	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Investigations
Aspartate aminotransferase increased	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Liver function test abnormal	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Prostatic specific antigen increased	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Metabolism and nutrition disorders
Anorexia	5/600 (0.8%)	5	1/301 (0.3%)	1	0/24 (0%)	0
Cachexia	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Dehydration	12/600 (2%)	20	3/301 (1%)	3	0/24 (0%)	0
Hyperglycaemia	3/600 (0.5%)	3	1/301 (0.3%)	1	0/24 (0%)	0
Hypocalcaemia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Hypoglycaemia	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Hypophosphataemia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Malnutrition	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Back pain	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Bone pain	61/600 (10.2%)	76	50/301 (16.6%)	56	1/24 (4.2%)	1
Bursitis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Muscular weakness	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Musculoskeletal pain	5/600 (0.8%)	8	2/301 (0.7%)	2	0/24 (0%)	0
Myalgia	0/600 (0%)	0	2/301 (0.7%)	2	0/24 (0%)	0
Osteoporosis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Pathological fracture	14/600 (2.3%)	14	11/301 (3.7%)	11	1/24 (4.2%)	1
Spinal column stenosis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Mobility decreased	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Musculoskeletal chest pain	1/600 (0.2%)	3	0/301 (0%)	0	1/24 (4.2%)	1
Intervertebral disc degeneration	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of bladder	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Gastric cancer	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Metastases to bone	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Metastases to liver	4/600 (0.7%)	4	0/301 (0%)	0	0/24 (0%)	0
Metastases to lymph nodes	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Bone marrow tumour cell infiltration	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Malignant neoplasm progression	65/600 (10.8%)	67	38/301 (12.6%)	42	2/24 (8.3%)	2
Metastases to meninges	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Lymphangiosis carcinomatosa	1/600 (0.2%)	2	0/301 (0%)	0	0/24 (0%)	0
Metastases to central nervous system	5/600 (0.8%)	5	2/301 (0.7%)	2	0/24 (0%)	0
Benign urinary tract neoplasm	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Nervous system disorders
Aphasia	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Cerebral haemorrhage	3/600 (0.5%)	3	2/301 (0.7%)	2	0/24 (0%)	0
Cerebral ischaemia	1/600 (0.2%)	1	3/301 (1%)	3	0/24 (0%)	0
Cerebrovascular accident	3/600 (0.5%)	3	0/301 (0%)	0	0/24 (0%)	0
Convulsion	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Dementia	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Dementia Alzheimer's type	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Dizziness	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Dysarthria	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Epilepsy	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Facial palsy	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Haemorrhage intracranial	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Hydrocephalus	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Monoparesis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Neuralgia	0/600 (0%)	0	2/301 (0.7%)	3	0/24 (0%)	0
Paraesthesia	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Paraparesis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Paraplegia	0/600 (0%)	0	2/301 (0.7%)	2	0/24 (0%)	0
Peripheral motor neuropathy	1/600 (0.2%)	1	3/301 (1%)	3	0/24 (0%)	0
Polyneuropathy	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Somnolence	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Spinal cord compression	21/600 (3.5%)	21	16/301 (5.3%)	16	1/24 (4.2%)	1
Syncope	2/600 (0.3%)	2	1/301 (0.3%)	1	1/24 (4.2%)	1
Transient ischaemic attack	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Tremor	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Brain oedema	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Radicular syndrome	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Ischaemic stroke	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Nerve root compression	4/600 (0.7%)	4	0/301 (0%)	0	0/24 (0%)	0
Paresis cranial nerve	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Psychiatric disorders
Aggression	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Confusional state	6/600 (1%)	6	3/301 (1%)	3	0/24 (0%)	0
Depression	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Intentional self-injury	1/600 (0.2%)	2	0/301 (0%)	0	0/24 (0%)	0
Suicide attempt	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Renal and urinary disorders
Acute prerenal failure	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Calculus ureteric	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Haematuria	11/600 (1.8%)	13	7/301 (2.3%)	9	0/24 (0%)	0
Hydronephrosis	8/600 (1.3%)	10	2/301 (0.7%)	2	0/24 (0%)	0
Micturition urgency	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Renal failure	7/600 (1.2%)	7	2/301 (0.7%)	2	0/24 (0%)	0
Renal failure acute	4/600 (0.7%)	4	0/301 (0%)	0	0/24 (0%)	0
Renal pain	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Renal tubular necrosis	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Urinary bladder haemorrhage	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Urinary incontinence	2/600 (0.3%)	2	0/301 (0%)	0	0/24 (0%)	0
Urinary retention	10/600 (1.7%)	10	9/301 (3%)	9	0/24 (0%)	0
Haemorrhage urinary tract	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Reproductive system and breast disorders
Prostatic haemorrhage	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Scrotal oedema	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Chronic obstructive pulmonary disease	1/600 (0.2%)	1	3/301 (1%)	4	0/24 (0%)	0
Chronic respiratory failure	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Dyspnoea	6/600 (1%)	6	5/301 (1.7%)	5	0/24 (0%)	0
Emphysema	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Epistaxis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Pleural effusion	4/600 (0.7%)	8	3/301 (1%)	3	0/24 (0%)	0
Pleuritic pain	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Pneumonia aspiration	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Pulmonary embolism	7/600 (1.2%)	7	6/301 (2%)	6	0/24 (0%)	0
Pulmonary oedema	1/600 (0.2%)	1	1/301 (0.3%)	1	0/24 (0%)	0
Respiratory failure	0/600 (0%)	0	2/301 (0.7%)	2	0/24 (0%)	0
Vascular disorders
Circulatory collapse	1/600 (0.2%)	1	0/301 (0%)	0	0/24 (0%)	0
Orthostatic hypotension	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Peripheral ischaemia	0/600 (0%)	0	0/301 (0%)	0	1/24 (4.2%)	1
Venous thrombosis	0/600 (0%)	0	1/301 (0.3%)	1	0/24 (0%)	0
Deep vein thrombosis	4/600 (0.7%)	5	0/301 (0%)	0	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Radium-223 Dichloride (Xofigo, BAY88-8223)		Placebo		Placebo Randomized, Then Switched to Radium-223 Dichloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	524/ (NaN)		254/ (NaN)		23/ (NaN)
Blood and lymphatic system disorders
Anaemia	161/600 (26.8%)	247	81/301 (26.9%)	104	8/24 (33.3%)	10
Neutropenia	28/600 (4.7%)	37	3/301 (1%)	4	2/24 (8.3%)	3
Thrombocytopenia	59/600 (9.8%)	71	15/301 (5%)	16	2/24 (8.3%)	2
Gastrointestinal disorders
Abdominal pain	21/600 (3.5%)	21	13/301 (4.3%)	15	2/24 (8.3%)	2
Constipation	105/600 (17.5%)	111	60/301 (19.9%)	68	2/24 (8.3%)	2
Diarrhoea	153/600 (25.5%)	242	43/301 (14.3%)	60	7/24 (29.2%)	12
Nausea	210/600 (35%)	294	98/301 (32.6%)	126	11/24 (45.8%)	12
Vomiting	108/600 (18%)	151	34/301 (11.3%)	45	3/24 (12.5%)	3
General disorders
Asthenia	35/600 (5.8%)	43	17/301 (5.6%)	19	2/24 (8.3%)	2
Fatigue	157/600 (26.2%)	192	73/301 (24.3%)	86	9/24 (37.5%)	10
Oedema peripheral	76/600 (12.7%)	82	29/301 (9.6%)	34	2/24 (8.3%)	2
Pyrexia	38/600 (6.3%)	58	15/301 (5%)	24	0/24 (0%)	0
Infections and infestations
Nasopharyngitis	13/600 (2.2%)	13	8/301 (2.7%)	11	4/24 (16.7%)	4
Urinary tract infection	47/600 (7.8%)	55	22/301 (7.3%)	23	5/24 (20.8%)	8
Injury, poisoning and procedural complications
Contusion	12/600 (2%)	13	4/301 (1.3%)	4	3/24 (12.5%)	3
Investigations
Weight decreased	74/600 (12.3%)	74	44/301 (14.6%)	45	2/24 (8.3%)	2
Metabolism and nutrition disorders
Anorexia	104/600 (17.3%)	115	53/301 (17.6%)	57	4/24 (16.7%)	5
Hypokalaemia	14/600 (2.3%)	16	6/301 (2%)	7	2/24 (8.3%)	2
Hyponatraemia	2/600 (0.3%)	2	2/301 (0.7%)	2	3/24 (12.5%)	3
Decreased appetite	36/600 (6%)	39	13/301 (4.3%)	13	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Bone pain	287/600 (47.8%)	476	174/301 (57.8%)	321	11/24 (45.8%)	19
Joint swelling	2/600 (0.3%)	2	3/301 (1%)	3	2/24 (8.3%)	2
Muscular weakness	8/600 (1.3%)	8	15/301 (5%)	18	2/24 (8.3%)	2
Nervous system disorders
Dizziness	45/600 (7.5%)	53	26/301 (8.6%)	30	2/24 (8.3%)	2
Headache	25/600 (4.2%)	29	9/301 (3%)	9	2/24 (8.3%)	2
Paraesthesia	16/600 (2.7%)	16	4/301 (1.3%)	4	2/24 (8.3%)	2
Psychiatric disorders
Insomnia	31/600 (5.2%)	33	17/301 (5.6%)	17	0/24 (0%)	0
Renal and urinary disorders
Pollakiuria	14/600 (2.3%)	15	5/301 (1.7%)	6	2/24 (8.3%)	2
Urinary retention	20/600 (3.3%)	20	12/301 (4%)	13	3/24 (12.5%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea	47/600 (7.8%)	54	21/301 (7%)	22	0/24 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No PI may disclose or publish information from the trial before publication of the principal and first communication arising from the trial, unless 12 months has elapsed after completion of the trial. There is restriction on the PI that the sponsor can review results communication prior to public release and can embargo regarding trial results for a period that is less/or equal to 60 days from the time submitted to the sponsor for review. Sponsor cannot require changes or extend the embargo.