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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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
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
Hide 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
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo Total
Hide 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
Hide 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
1.Primary Outcome
Title Overall Survival
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects.
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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.
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Show Statistical Analysis 1 Hide 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.
Show Statistical Analysis 2 Hide 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.
Show Statistical Analysis 3 Hide 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.
Show Statistical Analysis 4 Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Show Statistical Analysis 1 Hide 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.
Show Statistical Analysis 2 Hide 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.
Show Statistical Analysis 3 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Show Statistical Analysis 1 Hide 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.
Show Statistical Analysis 2 Hide 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.
Show Statistical Analysis 3 Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Show Statistical Analysis 1 Hide 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.
Show Statistical Analysis 2 Hide 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.
Show Statistical Analysis 3 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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.
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Show Statistical Analysis 1 Hide 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.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in The ITT population and with ECOG analyzed
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in The ITT population and with ECOG analyzed
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in The ITT population and with ECOG analyzed
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in The ITT population and with ECOG analyzed
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was all randomized subjects
Arm/Group Title Radium-223 Dichloride (Xofigo, BAY88-8223) Placebo
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
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
Hide 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   --/--      --/--      --/--    
Show Serious Adverse Events Hide 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