Standard Dose Versus High Dose and Versus Extended Standard Dose Radium-223 Dichloride in Castration-resistant Prostate Cancer Metastatic to the Bone

Study Overview
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Brief Summary
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This study will assess different doses and regimens of radium-223 dichloride on the incidence of symptomatic skeletal events. Eligible subjects must have castration resistant prostate cancer with 2 or more skeletal metastases documented within 8 weeks of randomization. Subjects will be randomized to one of 3 treatment arms in a 1:1:1 fashion: a standard regimen of radium-223 dichloride of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 6 months, a high dose regimen of 80 kBq/kg (88 kBq/kg after implementation of NIST update)injections every month for 6 months or an extended duration regimen of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 12 months. Following the treatment phase, subjects will be followed up every 12 weeks for a minimum of 2 years, at which point they will enter a long term follow-up period during which they are seen every 6 months for up to 7 years after the last dose of radium dichloride. Symptomatic skeletal event and safety endpoints will be assessed at each clinic visit. Pain and analgesic use data will be collected every 4 weeks through Week 48. Additionally, radiological assessments including MRI/CT of the abdomen and pelvis and chest CT, as well as technetium-99 bone scans will be performed at Weeks 8, 16, and 24 and continue every 12 weeks thereafter until disease progression is documented in either the bone or in soft tissue. Radiological imaging will be evaluated by blinded central review.

Official Title
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A Three Arm Randomized, Open-label Phase II Study of Radium-223 Dichloride 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) Versus 80 kBq/kg (88 kBq/kg After Implementation of NIST Update), and Versus 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) in an Extended Dosing Schedule in Subjects With Castration-resistant Prostate Cancer Metastatic to the Bone

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Castration-resistant disease defined as: Serum testosterone level: ≤ 50 ng/dL (1.7 nmol/L) Bilateral orchiectomy or maintenance on androgen ablation therapy with luteinizing-hormone-releasing hormone (LHRH) agonist or antagonist, or polyestradiol phosphate Serum PSA (Prostate specific antigen) progression defined as 2 subsequent increases in PSA over a previous reference value (a minimum of 2 ng/mL [μg/L]) OR Radiographic evidence of disease progression in bone (according to Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) with or without PSA progression Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. In case of ECOG PS 2, the PS has to be due to metastatic prostate cancer to the bone. Two or more skeletal metastases (≥ 2 hot spots) on bone scintigraphy within 8 weeks of randomization Exclusion Criteria: History of visceral metastasis, or visceral metastases Lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter Central nervous system (CNS) metastases Treatment with cytotoxic chemotherapy for prostate cancer within the previous 4 weeks prior to randomization, or planned treatment with cytotoxic chemotherapy agents for prostate cancer during the treatment period or follow-up Chronic conditions associated with non-malignant abnormal bone growth (e.g. confirmed Paget's disease of bone) Prior treatment with radium-223 dichloride Prior systemic radiotherapy and hemibody external radiotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride (Standard dose)<br>One injection to be administered every 4 weeks up to 6 injections. The dose per injection is 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update). | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br> <br> |
| Experimental: Radium-223 dichloride (High dose)<br>One injection to be administered every 4 weeks up to 6 injections. The dose per injection is 80 kBq/kg body weight (88 kBq/kg after implementation of NIST update). | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br> <br> |
| Experimental: Radium-223 dichloride (Extended standard dose)<br>One injection to be administered every 4 weeks up to 12 injections. The dose per injection is 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update). | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose | Symptomatic skeletal event (SSE) free survival is based on the following events: the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); the occurrence of spinal cord compression; a tumor related orthopedic surgical intervention, and death. In this evaluation - comparison 1, SSE-FS following randomization is defined in ITT participants as the time from randomization to an SSE or death, whichever occurs first. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose | In this evaluation - comparison 1, SSE-FS following randomization is defined in ITT participants as the time from randomization to an SSE or death, whichever occurs first. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose | Symptomatic skeletal event (SSE) free survival is based on the following events: the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); the occurrence of spinal cord compression; a tumor related orthopedic surgical intervention, and death. In this evaluation - Comparison 2, SSE-FS from 6th dose is defined in W24 participants as the time from Week 24 baseline (the 6th dose date) to an SSE or death, whichever occurs first. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose | In this evaluation - Comparison 2, SSE-FS from 6th dose is defined in W24 participants as the time from Week 24 baseline (the 6th dose date) to an SSE or death, whichever occurs first. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized | Symptomatic skeletal event (SSE) free survival is based on the following events: the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); the occurrence of spinal cord compression; a tumor related orthopedic surgical intervention, and death. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized | Symptomatic skeletal event (SSE) is defined as follows: The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; The occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); The occurrence of spinal cord compression; A tumor related orthopedic surgical intervention. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Overall Survival - High Dose vs. Standard Dose | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Overall Survival - Extended Dose vs. Standard Dose | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With an Overall Survival - Three Dose Groups As Randomized | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Overall Survival Event - Three Dose Groups as Randomized | Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose | Symptomatic skeletal event (SSE) is defined as follows: The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; The occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); The occurrence of spinal cord compression; A tumor related orthopedic surgical intervention. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose | Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | Symptomatic skeletal event (SSE) is defined as follows: The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; The occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); The occurrence of spinal cord compression; A tumor related orthopedic surgical intervention. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized | Symptomatic skeletal event (SSE) is defined as follows: The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; The occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); The occurrence of spinal cord compression; A tumor related orthopedic surgical intervention. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized | Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose | Radiological progression of soft tissue disease is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Magnetic resonance imaging (MRI) or computed tomography (CT) scans. Radiological progression of osseous disease is determined according to adapted PCWG2 criteria based on whole body technetium-99 bone scans. Radiological bone progression is determined if at least one of the following criteria is met: The first bone scan with ≥2 new lesions compared to baseline is observed <12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); or The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from randomization and the new lesions are verified on the next bone scan ≥6 weeks later (a total of ≥2 new lesions compared to baseline). | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Radiological Progression Free Survival - High Dose vs. Standard Dose | Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose | Radiological progression of soft tissue disease is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Magnetic resonance imaging (MRI) or Computed tomography (CT) scans. Radiological progression of osseous disease is determined according to adapted PCWG2 criteria based on whole body technetium-99 bone scans. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Radiological Progression Free Survival - Extended Dose vs. Standard Dose | Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized | Radiological progression of soft tissue disease is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Magnetic resonance imaging (MRI) or Computed tomography (CT) scans. Radiological progression of osseous disease is determined according to adapted Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria based on whole body technetium-99 bone scans. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Radiological Progression Free Survival - Three Dose Groups as Randomized | Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose | Radiological progression of soft tissue disease is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Magnetic resonance imaging (MRI) or Computed tomography (CT) scans. Radiological progression of osseous disease is determined according to adapted Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria based on whole body technetium-99 bone scans. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Radiological Progression - High Dose vs. Standard Dose | Time to radiological progression is defined as the time in days from the applicable start date to the date of subsequent radiological progression. Participants without radiological progression as of database cut-off date, whether or not surviving, were censored at the last radiological progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose | Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Radiological Progression - Extended Dose vs. Standard Dose | Time to radiological progression is defined as the time in days from the applicable start date to the date of subsequent radiological progression. Participants without radiological progression as of database cut-off date, whether or not surviving, were censored at the last radiological progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized | Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Radiological Progression - Three Dose Groups as Randomized | Time to radiological progression is defined as the time in days from the applicable start date to the date of subsequent radiological progression. Participants without radiological progression as of database cut-off date, whether or not surviving, were censored at the last radiological progression assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Timepoint pain improvement rate is defined as the proportion of participants with a 30% and 2-point decrease in Worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart among participants with a WPS score ≥ 4 at baseline. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | Timepoint pain improvement rate is defined as the proportion of participants with a 30% and 2-point decrease in Worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart among participants with a WPS score ≥ 4 at baseline. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose | Participants were divided in 3 groups according to baseline pain evaluation: asymptomatic subjects (WPS 0 to < 1 at baseline); mildly symptomatic subjects (WPS 1-3 at baseline); and symptomatic subjects with WPS > 3 and ≤ 7 at baseline). Pain progression was defined as the occurrence of a pain increase of 2 or more points in the average (i.e., average of 7-day assessments) worst pain in 24 hours score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart. Participants with insufficient applicable baseline assessments or without adequate post-baseline assessments were to be censored at the applicable baseline date. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Pain Progression - High Dose vs. Standard Dose | The time to pain progression is defined for each applicable baseline for applicable participants as the time (in days) from the respective baseline until occurrence of the first post-baseline pain progression event. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose | Pain progression is defined for each baseline in participants evaluable for pain progression at the applicable baseline, i.e., participants with a WPS of ≤ 7 at the respective baseline assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Pain Progression - Extended Dose vs. Standard Dose | The time to pain progression is defined for each applicable baseline for applicable participants as the time (in days) from the respective baseline until occurrence of the first post-baseline pain progression event. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized | Pain progression is defined for each baseline in participants evaluable for pain progression at the applicable baseline, i.e., participants with a WPS of ≤ 7 at the respective baseline assessment. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Time to Pain Progression - Three Dose Groups as Randomized | The time to pain progression is defined for each applicable baseline for applicable participants as the time (in days) from the respective baseline until occurrence of the first post-baseline pain progression event. | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) | 
| Number of Participants With Treatment-Emergent Adverse Events | Treatment-emergent adverse events are events starting or worsening from the initiation of treatment until 30 days after the last administration of radium-223 dichloride. The intensity of an AE is classified according to the grades specified by the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE). | From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization) |