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

• ClinicalTrials.gov Identifier: NCT00699751
• Recruitment Status: Completed
• First Posted: June 18, 2008
• Results First Posted: May 7, 2014
• Last Update Posted: May 27, 2016
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Hormone Refractory Prostate Cancer; Bone Metastases
• Interventions: Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Placebo; Drug: Best standard of care (BSoC)
• Enrollment: 921

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

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 [1]	168 [1]
Completed 3-Year Follow-up Period	49	12
Completed	389 [2]	145 [2]
Not Completed	225	162
Reason Not Completed
Investigator Request	27	27
Death	28	29
Subject Request	43	23
Other	30	20
Adverse Event	97	63
[1] Participants were not required to complete all 6 injections to enter to 3-year follow-up period.; [2] Completed all 6 injections
Period Title: Period 2:Switched From Placebo to Xofigo
Started	0	26 [1]
Participants Received Treatment	0	24
Entered 3-Year Follow-up Period	0	15
Completed 3-Year Follow-up Period	0	0
Completed	0	17 [2]
Not Completed	0	9
Reason Not Completed
Adverse Event	0	4
Investigator Request	0	1
Completion page not expected	0	4
[1] Participants in the placebo group switched to Xofigo treatment; [2] Completed all 6 injections

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 Number of Baseline Participants		614	307	921
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	614 participants	307 participants	921 participants
		70.2 (8.10)	70.8 (7.87)	70.4 (8.03)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	614 participants	307 participants	921 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	614 100.0%	307 100.0%	921 100.0%
Total Alkaline Phosphatase (ALP) [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	614 participants	307 participants	921 participants
< 220 U/L		348	169	517
≥ 220 U/L		266	138	404
		[1] Measure Description: The total amount of ALP in the blood was determined at baseline.
Current use of bisphosphonates [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	614 participants	307 participants	921 participants
Yes		250	124	374
No		364	183	547
		[1] Measure Description: Subjects may have been on bisphosphonate therapy during the study.
Any prior use of docetaxel; Measure Type: Number; Unit of measure: Participants	Number Analyzed	614 participants	307 participants	921 participants
Yes		352	174	526
No		262	133	395

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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	14.9; (13.9 to 16.1)	11.3; (10.1 to 12.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of 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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00005
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	7.4 [1]; (7.1 to NA)	3.8; (3.6 to 4.2)

[1]

95% Confidence Interval upper limit is not estimable due to insufficient number of participants with events.

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.00001
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	497	211
Measure Type: Number; Unit of Measure: Percentage of participants
>=30% reduction of ALP in blood level	59.4	6.2
>=50% reduction of ALP in blood level	32.6	1.4
Confirmed Total ALP Response (>=30%)	47.1	3.3
Confirmed Total ALP Response (>=50%)	27.4	0.9

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	[Not Specified]
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	[Not Specified]
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	[Not Specified]
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	[Not Specified]
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.
Overall Number of Participants Analyzed	589	288
Measure Type: Number; Unit of Measure: Percentage of participants
>=30% reduction of ALP in blood level	59.9	4.5
>=50% reduction of ALP in blood level	34.6	1.7
Confirmed Total ALP Response (>=50%)	13.9	1

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	[Not Specified]
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	[Not Specified]
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	[Not Specified]
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.
Overall Number of Participants Analyzed	321	140
Measure Type: Number; Unit of Measure: Percentage of participants
	34	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of 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	[Not Specified]
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.
Overall Number of Participants Analyzed	497	211
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	582	284
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	589	288
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	589	288
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	3.6; (3.5 to 3.8)	3.4; (3.3 to 3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of 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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	493	210
Measure Type: Number; Unit of Measure: Percentage of participants
>=30% reduction of PSA in blood level	16.4	6.2
>=50% reduction of PSA in blood level	7.7	4.3
Confirmed PSA Response (>=50%)	5.7	1.9

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	[Not Specified]
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	[Not Specified]
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	[Not Specified]
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.
Overall Number of Participants Analyzed	590	286
Measure Type: Number; Unit of Measure: Percentage of participants
>=30% reduction in blood level	14.2	4.5
>=50% reduction in blood level	9	3.1
Confirmed PSA Response (>=50%)	6.1	1.7

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	[Not Specified]
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	[Not Specified]
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	[Not Specified]
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.
Overall Number of Participants Analyzed	493	210
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	581	283
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	590	286
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	590	286
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	16.4; (14.3 to 18.3)	8.1; (6.7 to 11.9)

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	18; (15.9 to 20.6)	10.7; (7.6 to 18.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of 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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median survival time is not reached

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median survival time is not reached.

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median survival time is not reached

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median survival time is not reached

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	15.4; (12.6 to 17)	12.7; (11.0 to 14.7)

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	614	307
Median (95% Confidence Interval); Unit of Measure: Months
	23.4; (20.4 to 26.5)	18.4; (13.1 to 24.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride (Xofigo, BAY88-8223), Placebo
	Comments	The null hypothesis for the comparison of 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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	600	305
Measure Type: Number; Unit of Measure: Participants
ECOG Grade 0	136	72
ECOG Grade 1	376	191
ECOG Grade 2	82	40
ECOG Grade 3	6	1
ECOG Grade 4	0	0
ECOG Grade 5	0	0
Missing	0	1

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.
Overall Number of Participants Analyzed	569	267
Measure Type: Number; Unit of Measure: Participants
ECOG Grade 0	133	49
ECOG Grade 1	315	142
ECOG Grade 2	103	53
ECOG Grade 3	13	15
ECOG Grade 4	0	3
ECOG Grade 5	1	1
Missing	4	4

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.
Overall Number of Participants Analyzed	471	196
Measure Type: Number; Unit of Measure: Participants
ECOG Grade 0	101	29
ECOG Grade 1	257	113
ECOG Grade 2	85	42
ECOG Grade 3	19	11
ECOG Grade 4	4	0
ECOG Grade 5	0	0
Missing	5	1

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.
Overall Number of Participants Analyzed	363	138
Measure Type: Number; Unit of Measure: Participants
ECOG Grade 0	74	22
ECOG Grade 1	181	66
ECOG Grade 2	85	36
ECOG Grade 3	17	10
ECOG Grade 4	5	4
ECOG Grade 5	0	0
Missing	1	0

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
Week 0 (Baseline)	65.00; (17.0 to 104.0)	64.00; (23.0 to 96.0)
Week 16	65.00; (11.0 to 98.0)	61.31; (19.0 to 96.5)
Week 24	61.00; (17.0 to 102.0)	60.00; (17.0 to 97.0)
Follow-up Visit 2 (Week 42)	61.00; (10.0 to 95.0)	60.5; (16.7 to 97.0)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
At Week 16	-1.55; (-49.3 to 38.0)	-4.15; (-43.0 to 46.0)
At Week 24	-4.00; (-60.4 to 40.0)	-5.67; (-39.0 to 41.0)
At Follow-up Visit 2 (Week 42)	-5.00; (-89.0 to 44.5)	-5.5; (-47.4 to 25.0)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
physical well being	20.00; (3.0 to 28.0)	19.83; (1.0 to 28.0)
social/family well being	22.00; (0.0 to 28.0)	21.50; (0.0 to 28.0)
emotional well being	18.0; (0.0 to 24.0)	16.80; (2.0 to 24.0)
functional well being	16.0; (0.0 to 28.0)	15.0; (0.0 to 28.0)
the prostate cancer subscale	29.00; (1.0 to 46.9)	27.60; (9.0 to 42.5)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
physical well being	19.00; (3.0 to 28.0)	18.67; (3.0 to 28.0)
social/family well being	21.00; (0.0 to 28.0)	21.00; (9.0 to 28.0)
emotional well being	17.00; (4.0 to 24.0)	16.00; (1.2 to 24.0)
functional well being	15.00; (0.0 to 28.0)	14.00; (0.0 to 28.0)
the prostate cancer subscale	28.00; (3.6 to 46.0)	27.64; (5.0 to 43.0)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
physical well being	19.00; (0.0 to 28.0)	18.00; (1.0 to 28.0)
social/family well being	22.00; (0.0 to 28.0)	22.00; (9.0 to 33.8)
emotional well being	17.00; (0.0 to 24.0)	16.00; (3.0 to 24.0)
functional well being	14.00; (1.0 to 28.0)	14.00; (4.0 to 28.0)
the prostate cancer subscale	28.00; (3.0 to 42.0)	29.00; (6.5 to 43.0)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
At Week 16	100.68; (30.0 to 147.0)	99.90; (33.7 to 144.0)
At Week 24	98.00; (41.8 to 152.0)	97.5; (47.0 to 149.0)
At Follow-up Visit 2 (Week 42)	97.83; (41.0 to 145.0)	97.38; (40.9 to 147.8)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
At Week 16	-2.00; (-58.0 to 58.0)	-5.67; (-58.0 to 47)
At Week 24	-5.00; (-67.2 to 63.5)	-9.40; (-42.8 to 48.8)
At Follow-up Visit 2 (Week 42)	-6.17; (-97.0 to 63.5)	-7.00; (-54.7 to 23.7)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
At Week 16	73.00; (17.0 to 106.0)	72.00; (27.7 to 108.0)
At Week 24	71.00; (28.0 to 107.0)	69.00; (37.0 to 106.0)
At Follow-up Visit 2 (Week 42)	70.00; (22.0 to 107.0)	70.25; (32.2 to 104.8)

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.
Overall Number of Participants Analyzed	614	307
Median (Full Range); Unit of Measure: Scores on a scale
At Week 16	-1.00; (-38.3 to 40.0)	-4.00; (-53.0 to 32.8)
At Week 24	-4.08; (-49.0 to 49.5)	-7.00; (-35.8 to 41.8)
At Follow-up Visit 2 (Week 42)	-3.67; (-58.0 to 40.5)	-6.00; (-33.8 to 18.7)

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.
Overall Number of Participants Analyzed	477	205
Measure Type: Number; Unit of Measure: Participants
mobility - Grade 1	191	64
mobility - Grade 2	278	129
mobility - Grade 3	7	10
mobility - Missing	1	2
self-care - Grade 1	346	140
self-care - Grade 2	123	54
self-care - Grade 3	7	10
self-care - Missing	1	1
usual activities - Grade 1	199	67
usual activities - Grade 2	233	105
usual activities - Grade 3	44	32
usual activities - Missing	1	1
pain/discomfort - Grade 1	79	23
pain/discomfort - Grade 2	351	159
pain/discomfort - Grade 3	46	22
pain/discomfort - Missing	1	1
anxiety/depression - Grade 1	285	104
anxiety/depression - Grade 2	171	95
anxiety/depression - Grade 3	15	4
anxiety/depression - Missing	6	2

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.
Overall Number of Participants Analyzed	368	140
Measure Type: Number; Unit of Measure: Participants
mobility - Grade 1	129	39
mobility - Grade 2	225	93
mobility - Grade 3	11	5
mobility - Missing	3	3
self-care - Grade 1	256	89
self-care - Grade 2	102	46
self-care - Grade 3	6	3
self-care - Missing	4	2
usual activities - Grade 1	140	38
usual activities - Grade 2	187	79
usual activities - Grade 3	37	20
usual activities - Missing	4	3
pain/discomfort - Grade 1	56	21
pain/discomfort - Grade 2	270	95
pain/discomfort - Grade 3	39	21
pain/discomfort - Missing	3	3
anxiety/depression - Grade 1	195	64
anxiety/depression - Grade 2	159	71
anxiety/depression - Grade 3	10	2
anxiety/depression - Missing	4	3

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.
Overall Number of Participants Analyzed	41	13
Measure Type: Number; Unit of Measure: Participants
mobility - Grade 1	9	2
mobility - Grade 2	30	10
mobility - Grade 3	1	1
mobility - Missing	1	0
self-care - Grade 1	26	7
self-care - Grade 2	12	3
self-care - Grade 3	2	3
self-care - MIssing	1	0
usual activities - Grade 1	13	2
usual activities - Grade 2	19	7
usual activities - Grade 3	8	4
usual activities - Missing	1	0
pain/discomfort - Grade 1	5	1
pain/discomfort - Grade 2	32	11
pain/discomfort - Grade 3	3	1
pain/discomfort - Missing	1	0
anxiety/depression - Grade 1	24	6
anxiety/depression - Grade 2	15	7
anxiety/depression - Grade 3	1	0
anxiety/depression - Missing	1	0

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.
Adverse Event Reporting Description	[Not Specified]
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 (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
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		185		17
Blood and lymphatic system disorders
Anaemia * 1	50/600 (8.33%)	70	25/301 (8.31%)	35	1/24 (4.17%)	1
Aplastic anaemia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Disseminated intravascular coagulation * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Febrile neutropenia * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Leukopenia * 1	3/600 (0.50%)	3	0/301 (0.00%)	0	0/24 (0.00%)	0
Neutropenia * 1	3/600 (0.50%)	3	1/301 (0.33%)	1	0/24 (0.00%)	0
Pancytopenia * 1	5/600 (0.83%)	6	0/301 (0.00%)	0	1/24 (4.17%)	1
Thrombocytopenia * 1	14/600 (2.33%)	14	3/301 (1.00%)	3	1/24 (4.17%)	1
Bone marrow failure * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Cardiac disorders
Acute myocardial infarction * 1	1/600 (0.17%)	1	3/301 (1.00%)	3	0/24 (0.00%)	0
Angina pectoris * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Arrhythmia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Atrial fibrillation * 1	3/600 (0.50%)	3	4/301 (1.33%)	4	0/24 (0.00%)	0
Atrial flutter * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Atrioventricular block complete * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Cardiac arrest * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Cardiac failure * 1	2/600 (0.33%)	2	4/301 (1.33%)	4	0/24 (0.00%)	0
Cardiac failure congestive * 1	4/600 (0.67%)	4	2/301 (0.66%)	2	0/24 (0.00%)	0
Coronary artery disease * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Left ventricular failure * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Myocardial infarction * 1	3/600 (0.50%)	3	3/301 (1.00%)	3	0/24 (0.00%)	0
Myocardial ischaemia * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Supraventricular tachycardia * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Left ventricular dysfunction * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Cardiopulmonary failure * 1	1/600 (0.17%)	1	2/301 (0.66%)	2	0/24 (0.00%)	0
Acute coronary syndrome * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Eye disorders
Cataract * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Glaucoma * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Gastrointestinal disorders
Abdominal distension * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Abdominal pain * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Abdominal pain upper * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Ascites * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Constipation * 1	8/600 (1.33%)	8	4/301 (1.33%)	4	0/24 (0.00%)	0
Diarrhoea * 1	3/600 (0.50%)	4	4/301 (1.33%)	4	0/24 (0.00%)	0
Duodenal ulcer * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Dysphagia * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Faecal incontinence * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Food poisoning * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Gastritis * 1	2/600 (0.33%)	2	1/301 (0.33%)	1	0/24 (0.00%)	0
Gastrointestinal haemorrhage * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Haematemesis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Intestinal obstruction * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Intestinal perforation * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Large intestine perforation * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Mouth haemorrhage * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Nausea * 1	9/600 (1.50%)	10	5/301 (1.66%)	6	0/24 (0.00%)	0
Rectal haemorrhage * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	1/24 (4.17%)	1
Small intestinal obstruction * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Upper gastrointestinal haemorrhage * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Vomiting * 1	11/600 (1.83%)	20	7/301 (2.33%)	7	0/24 (0.00%)	0
Subileus * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Erosive duodenitis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
General disorders
Asthenia * 1	3/600 (0.50%)	3	1/301 (0.33%)	1	0/24 (0.00%)	0
Chest pain * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Death * 1	4/600 (0.67%)	4	1/301 (0.33%)	1	0/24 (0.00%)	0
Fatigue * 1	6/600 (1.00%)	7	9/301 (2.99%)	9	0/24 (0.00%)	0
Gait disturbance * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Malaise * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Mucosal inflammation * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Multi-organ failure * 1	3/600 (0.50%)	3	0/301 (0.00%)	0	0/24 (0.00%)	0
Oedema * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Oedema peripheral * 1	4/600 (0.67%)	5	2/301 (0.66%)	2	0/24 (0.00%)	0
Pyrexia * 1	6/600 (1.00%)	9	6/301 (1.99%)	7	0/24 (0.00%)	0
Sudden death * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
General physical health deterioration * 1	15/600 (2.50%)	15	8/301 (2.66%)	8	1/24 (4.17%)	1
Drug intolerance * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Hepatobiliary disorders
Cholecystitis * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Cholestasis * 1	1/600 (0.17%)	3	0/301 (0.00%)	0	0/24 (0.00%)	0
Hepatic failure * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Bile duct obstruction * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Infections and infestations
Bronchitis * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Bronchopneumonia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Catheter related infection * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Cellulitis * 1	3/600 (0.50%)	3	1/301 (0.33%)	1	0/24 (0.00%)	0
Clostridium difficile colitis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Cystitis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Gastroenteritis * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Herpes zoster * 1	2/600 (0.33%)	2	1/301 (0.33%)	1	0/24 (0.00%)	0
Infection * 1	10/600 (1.67%)	12	3/301 (1.00%)	3	0/24 (0.00%)	0
Listeriosis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Lobar pneumonia * 1	0/600 (0.00%)	0	2/301 (0.66%)	2	0/24 (0.00%)	0
Lower respiratory tract infection * 1	8/600 (1.33%)	9	2/301 (0.66%)	2	0/24 (0.00%)	0
Oral candidiasis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Pneumonia * 1	17/600 (2.83%)	18	7/301 (2.33%)	8	1/24 (4.17%)	1
Pneumonia primary atypical * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Postoperative wound infection * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Pyelonephritis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Pyonephrosis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Sepsis * 1	7/600 (1.17%)	7	4/301 (1.33%)	4	0/24 (0.00%)	0
Upper respiratory tract infection * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	1/24 (4.17%)	1
Urinary tract infection * 1	5/600 (0.83%)	5	6/301 (1.99%)	6	0/24 (0.00%)	0
Urosepsis * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Abscess jaw * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Bacterial sepsis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Staphylococcal infection * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Bursitis infective * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Lung infection * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Peritonitis bacterial * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Device related infection * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Post procedural infection * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Gastroenteritis norovirus * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Injury, poisoning and procedural complications
Accidental overdose * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Concussion * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Cystitis radiation * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Extradural haematoma * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Fall * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Femoral neck fracture * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	1/24 (4.17%)	1
Hip fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Injury * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Intentional overdose * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Patella fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Rib fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Spinal compression fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Sternal fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Therapeutic agent toxicity * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Stent occlusion * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Medical device complication * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	1/24 (4.17%)	1
Skin laceration * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Upper limb fracture * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Device dislocation * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Procedural pain * 1	2/600 (0.33%)	2	1/301 (0.33%)	1	0/24 (0.00%)	0
Post-traumatic pain * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Investigations
Aspartate aminotransferase increased * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Liver function test abnormal * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Prostatic specific antigen increased * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Metabolism and nutrition disorders
Anorexia * 1	5/600 (0.83%)	5	1/301 (0.33%)	1	0/24 (0.00%)	0
Cachexia * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Dehydration * 1	12/600 (2.00%)	20	3/301 (1.00%)	3	0/24 (0.00%)	0
Hyperglycaemia * 1	3/600 (0.50%)	3	1/301 (0.33%)	1	0/24 (0.00%)	0
Hypocalcaemia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Hypoglycaemia * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Hypophosphataemia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Malnutrition * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Back pain * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Bone pain * 1	61/600 (10.17%)	76	50/301 (16.61%)	56	1/24 (4.17%)	1
Bursitis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Muscular weakness * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Musculoskeletal pain * 1	5/600 (0.83%)	8	2/301 (0.66%)	2	0/24 (0.00%)	0
Myalgia * 1	0/600 (0.00%)	0	2/301 (0.66%)	2	0/24 (0.00%)	0
Osteoporosis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Pathological fracture * 1	14/600 (2.33%)	14	11/301 (3.65%)	11	1/24 (4.17%)	1
Spinal column stenosis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Mobility decreased * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Musculoskeletal chest pain * 1	1/600 (0.17%)	3	0/301 (0.00%)	0	1/24 (4.17%)	1
Intervertebral disc degeneration * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of bladder * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Gastric cancer * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Metastases to bone * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Metastases to liver * 1	4/600 (0.67%)	4	0/301 (0.00%)	0	0/24 (0.00%)	0
Metastases to lymph nodes * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Bone marrow tumour cell infiltration * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Malignant neoplasm progression * 1	65/600 (10.83%)	67	38/301 (12.62%)	42	2/24 (8.33%)	2
Metastases to meninges * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Lymphangiosis carcinomatosa * 1	1/600 (0.17%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Metastases to central nervous system * 1	5/600 (0.83%)	5	2/301 (0.66%)	2	0/24 (0.00%)	0
Benign urinary tract neoplasm * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Nervous system disorders
Aphasia * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Cerebral haemorrhage * 1	3/600 (0.50%)	3	2/301 (0.66%)	2	0/24 (0.00%)	0
Cerebral ischaemia * 1	1/600 (0.17%)	1	3/301 (1.00%)	3	0/24 (0.00%)	0
Cerebrovascular accident * 1	3/600 (0.50%)	3	0/301 (0.00%)	0	0/24 (0.00%)	0
Convulsion * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Dementia * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Dementia Alzheimer's type * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Dizziness * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Dysarthria * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Epilepsy * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Facial palsy * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Haemorrhage intracranial * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Hydrocephalus * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Monoparesis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Neuralgia * 1	0/600 (0.00%)	0	2/301 (0.66%)	3	0/24 (0.00%)	0
Paraesthesia * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Paraparesis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Paraplegia * 1	0/600 (0.00%)	0	2/301 (0.66%)	2	0/24 (0.00%)	0
Peripheral motor neuropathy * 1	1/600 (0.17%)	1	3/301 (1.00%)	3	0/24 (0.00%)	0
Polyneuropathy * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Somnolence * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Spinal cord compression * 1	21/600 (3.50%)	21	16/301 (5.32%)	16	1/24 (4.17%)	1
Syncope * 1	2/600 (0.33%)	2	1/301 (0.33%)	1	1/24 (4.17%)	1
Transient ischaemic attack * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Tremor * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Brain oedema * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Radicular syndrome * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Ischaemic stroke * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Nerve root compression * 1	4/600 (0.67%)	4	0/301 (0.00%)	0	0/24 (0.00%)	0
Paresis cranial nerve * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Psychiatric disorders
Aggression * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Confusional state * 1	6/600 (1.00%)	6	3/301 (1.00%)	3	0/24 (0.00%)	0
Depression * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Intentional self-injury * 1	1/600 (0.17%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Suicide attempt * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Renal and urinary disorders
Acute prerenal failure * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Calculus ureteric * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Haematuria * 1	11/600 (1.83%)	13	7/301 (2.33%)	9	0/24 (0.00%)	0
Hydronephrosis * 1	8/600 (1.33%)	10	2/301 (0.66%)	2	0/24 (0.00%)	0
Micturition urgency * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Renal failure * 1	7/600 (1.17%)	7	2/301 (0.66%)	2	0/24 (0.00%)	0
Renal failure acute * 1	4/600 (0.67%)	4	0/301 (0.00%)	0	0/24 (0.00%)	0
Renal pain * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Renal tubular necrosis * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Urinary bladder haemorrhage * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Urinary incontinence * 1	2/600 (0.33%)	2	0/301 (0.00%)	0	0/24 (0.00%)	0
Urinary retention * 1	10/600 (1.67%)	10	9/301 (2.99%)	9	0/24 (0.00%)	0
Haemorrhage urinary tract * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Reproductive system and breast disorders
Prostatic haemorrhage * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Scrotal oedema * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Chronic obstructive pulmonary disease * 1	1/600 (0.17%)	1	3/301 (1.00%)	4	0/24 (0.00%)	0
Chronic respiratory failure * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Dyspnoea * 1	6/600 (1.00%)	6	5/301 (1.66%)	5	0/24 (0.00%)	0
Emphysema * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Epistaxis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Pleural effusion * 1	4/600 (0.67%)	8	3/301 (1.00%)	3	0/24 (0.00%)	0
Pleuritic pain * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Pneumonia aspiration * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Pulmonary embolism * 1	7/600 (1.17%)	7	6/301 (1.99%)	6	0/24 (0.00%)	0
Pulmonary oedema * 1	1/600 (0.17%)	1	1/301 (0.33%)	1	0/24 (0.00%)	0
Respiratory failure * 1	0/600 (0.00%)	0	2/301 (0.66%)	2	0/24 (0.00%)	0
Vascular disorders
Circulatory collapse * 1	1/600 (0.17%)	1	0/301 (0.00%)	0	0/24 (0.00%)	0
Orthostatic hypotension * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Peripheral ischaemia * 1	0/600 (0.00%)	0	0/301 (0.00%)	0	1/24 (4.17%)	1
Venous thrombosis * 1	0/600 (0.00%)	0	1/301 (0.33%)	1	0/24 (0.00%)	0
Deep vein thrombosis * 1	4/600 (0.67%)	5	0/301 (0.00%)	0	0/24 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (11.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	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		254		23
Blood and lymphatic system disorders
Anaemia * 1	161/600 (26.83%)	247	81/301 (26.91%)	104	8/24 (33.33%)	10
Neutropenia * 1	28/600 (4.67%)	37	3/301 (1.00%)	4	2/24 (8.33%)	3
Thrombocytopenia * 1	59/600 (9.83%)	71	15/301 (4.98%)	16	2/24 (8.33%)	2
Gastrointestinal disorders
Abdominal pain * 1	21/600 (3.50%)	21	13/301 (4.32%)	15	2/24 (8.33%)	2
Constipation * 1	105/600 (17.50%)	111	60/301 (19.93%)	68	2/24 (8.33%)	2
Diarrhoea * 1	153/600 (25.50%)	242	43/301 (14.29%)	60	7/24 (29.17%)	12
Nausea * 1	210/600 (35.00%)	294	98/301 (32.56%)	126	11/24 (45.83%)	12
Vomiting * 1	108/600 (18.00%)	151	34/301 (11.30%)	45	3/24 (12.50%)	3
General disorders
Asthenia * 1	35/600 (5.83%)	43	17/301 (5.65%)	19	2/24 (8.33%)	2
Fatigue * 1	157/600 (26.17%)	192	73/301 (24.25%)	86	9/24 (37.50%)	10
Oedema peripheral * 1	76/600 (12.67%)	82	29/301 (9.63%)	34	2/24 (8.33%)	2
Pyrexia * 1	38/600 (6.33%)	58	15/301 (4.98%)	24	0/24 (0.00%)	0
Infections and infestations
Nasopharyngitis * 1	13/600 (2.17%)	13	8/301 (2.66%)	11	4/24 (16.67%)	4
Urinary tract infection * 1	47/600 (7.83%)	55	22/301 (7.31%)	23	5/24 (20.83%)	8
Injury, poisoning and procedural complications
Contusion * 1	12/600 (2.00%)	13	4/301 (1.33%)	4	3/24 (12.50%)	3
Investigations
Weight decreased * 1	74/600 (12.33%)	74	44/301 (14.62%)	45	2/24 (8.33%)	2
Metabolism and nutrition disorders
Anorexia * 1	104/600 (17.33%)	115	53/301 (17.61%)	57	4/24 (16.67%)	5
Hypokalaemia * 1	14/600 (2.33%)	16	6/301 (1.99%)	7	2/24 (8.33%)	2
Hyponatraemia * 1	2/600 (0.33%)	2	2/301 (0.66%)	2	3/24 (12.50%)	3
Decreased appetite * 1	36/600 (6.00%)	39	13/301 (4.32%)	13	1/24 (4.17%)	1
Musculoskeletal and connective tissue disorders
Bone pain * 1	287/600 (47.83%)	476	174/301 (57.81%)	321	11/24 (45.83%)	19
Joint swelling * 1	2/600 (0.33%)	2	3/301 (1.00%)	3	2/24 (8.33%)	2
Muscular weakness * 1	8/600 (1.33%)	8	15/301 (4.98%)	18	2/24 (8.33%)	2
Nervous system disorders
Dizziness * 1	45/600 (7.50%)	53	26/301 (8.64%)	30	2/24 (8.33%)	2
Headache * 1	25/600 (4.17%)	29	9/301 (2.99%)	9	2/24 (8.33%)	2
Paraesthesia * 1	16/600 (2.67%)	16	4/301 (1.33%)	4	2/24 (8.33%)	2
Psychiatric disorders
Insomnia * 1	31/600 (5.17%)	33	17/301 (5.65%)	17	0/24 (0.00%)	0
Renal and urinary disorders
Pollakiuria * 1	14/600 (2.33%)	15	5/301 (1.66%)	6	2/24 (8.33%)	2
Urinary retention * 1	20/600 (3.33%)	20	12/301 (3.99%)	13	3/24 (12.50%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	47/600 (7.83%)	54	21/301 (6.98%)	22	0/24 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (11.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: BAYER
• EMail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzen L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland OS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755.

Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. doi: 10.1016/S1470-2045(14)70474-7. Epub 2014 Oct 17.

Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland OS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. doi: 10.1016/S1470-2045(14)70183-4. Epub 2014 May 13.

Delacruz A, Arauz G, Curley T, Lindo A, Jensen T. Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment. Clin J Oncol Nurs. 2015 Apr;19(2):E31-5. doi: 10.1188/15.CJON.E31-E35.

Humm JL, Sartor O, Parker C, Bruland OS, Macklis R. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):898-906. doi: 10.1016/j.ijrobp.2014.12.061.

Nilsson S. Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. Am Soc Clin Oncol Educ Book. 2014:e132-9. doi: 10.14694/EdBook_AM.2014.34.e132.

Den RB, Doyle LA, Knudsen KE. Practical guide to the use of radium 223 dichloride. Can J Urol. 2014 Apr;21(2 Supp 1):70-6.

Shirley M, McCormack PL. Radium-223 dichloride: a review of its use in patients with castration-resistant prostate cancer with symptomatic bone metastases. Drugs. 2014 Apr;74(5):579-86. doi: 10.1007/s40265-014-0198-4.

Wissing MD, van Leeuwen FW, van der Pluijm G, Gelderblom H. Radium-223 chloride: Extending life in prostate cancer patients by treating bone metastases. Clin Cancer Res. 2013 Nov 1;19(21):5822-7. doi: 10.1158/1078-0432.CCR-13-1896. Epub 2013 Sep 19.

Joung JY, Ha YS, Kim IY. Radium Ra 223 dichloride in castration-resistant prostate cancer. Drugs Today (Barc). 2013 Aug;49(8):483-90. doi: 10.1358/dot.2013.49.8.1968670.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Parker C, Zhan L, Cislo P, Reuning-Scherer J, Vogelzang NJ, Nilsson S, Sartor O, O'Sullivan JM, Coleman RE. Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer. 2017 Jan;71:1-6. doi: 10.1016/j.ejca.2016.10.020. Epub 2016 Dec 6.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00699751
• Other Study ID Numbers: 15245; BC1-06 ( Other Identifier: Algeta ASA ); 2007-006195-11 ( EudraCT Number )
• First Submitted: June 17, 2008
• First Posted: June 18, 2008
• Results First Submitted: June 29, 2013
• Results First Posted: May 7, 2014
• Last Update Posted: May 27, 2016