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

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

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.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Radium-223 dichloride (Xofigo, BAY88-8223)

• Study Type: Interventional
• Enrollment (Actual): 391
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
  • Darlinghurst, Australia, 2010
  • Westmead, Australia, 2145
  • South Australia
    • Adelaide, South Australia, Australia, 5000
  • Victoria
    • Melbourne, Victoria, Australia, 3052
• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Hospital de Clínicas de Porto Alegre
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90470 340
      • Irmandade Santa Casa de Misericordia de Porto Alegre
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01246-000
      • Instituto do Cancer do Estado de Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 03102 002
      • IBCC - Instituto Brasileiro de Controle do Câncer
    • São Paulo, Sao Paulo, Brazil, 05651-901
      • Hospital Israelita Albert Einstein
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4L6
    • Ottawa, Ontario, Canada, K1H 8L6
    • Toronto, Ontario, Canada, M5G 2M9
    • Toronto, Ontario, Canada, M4N 3M5
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
• Chile
  • Santiago, Chile, 7500921
• Czechia
  • Chomutov, Czechia, 430 12
  • Praha 5, Czechia, 150 06
• France
  • Nantes, France, 44805
  • Vandoeuvre les Nancy, France, 54500
  • Villejuif Cedex, France, 94805
• Germany
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
  • Bayern
    • München, Bayern, Germany, 81675
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
• Israel
  • Beer Sheva, Israel, 8410101
  • Haifa, Israel, 3109601
  • Jerusalem, Israel, 9112001
  • Kfar Saba, Israel, 4428164
  • Petah Tikva, Israel, 4941492
  • Ramat Gan, Israel, 5262000
• Italy
  • Emilia-Romagna
    • Meldola, Emilia-Romagna, Italy, 47014
  • Lazio
    • Roma, Lazio, Italy, 00152
  • Piemonte
    • Torino, Piemonte, Italy, 10043
  • Toscana
    • Arezzo, Toscana, Italy, 52100
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
  • Seoul, Korea, Republic of, 05505
  • Seoul, Korea, Republic of, 06591
  • Busan Gwang''yeogsi
    • Busan, Busan Gwang''yeogsi, Korea, Republic of, 49241
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06273
• Spain
  • Barcelona, Spain, 08025
  • Madrid, Spain, 28041
  • Pamplona, Spain, 31008
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
  • Illes Baleares
    • Palma de Mallorca, Illes Baleares, Spain, 07120
• Sweden
  • Göteborg, Sweden, 413 45
  • Karlstad, Sweden, 652 30
  • Sundsvalls, Sweden, 851 86
  • Umeå, Sweden, 901 85
• Taiwan
  • Kaohsiung, Taiwan, 81362
  • Taichung, Taiwan, 40705
  • Taipei, Taiwan, 100
  • Taipei
    • Taipei City, Taipei, Taiwan, 112
  • Taoyuan
    • Guishan Township, Taoyuan, Taiwan, 333
• United Kingdom
  • Northwood, United Kingdom, HA6 2RN
  • Merseyside
    • Bebington, Merseyside, United Kingdom, CH63 4JY
  • Somerset
    • Taunton, Somerset, United Kingdom, TA1 5DA
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85260
  • Connecticut
    • New Haven, Connecticut, United States, 06520
  • Florida
    • Fort Myers, Florida, United States, 33907
  • Maryland
    • Bethesda, Maryland, United States, 20889
    • Rockville, Maryland, United States, 20850
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0330
    • Detroit, Michigan, United States, 48201
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • Nebraska
    • Omaha, Nebraska, United States, 68130
  • New York
    • East Setauket, New York, United States, 11733
  • Oregon
    • Portland, Oregon, United States, 97239
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15215

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radium-223 dichloride (Standard dose); 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)
Experimental: Radium-223 dichloride (High dose); 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)
Experimental: Radium-223 dichloride (Extended standard dose); 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)

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline	Analgesic use in this study were captured via two methods: Analgesic concomitant medication case report form, where the physician records the analgesic medication prescribed to manage pain; 24 hour analgesic consumption case report form, in which all analgesic medication taken in the last 24 hours.	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)

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Sternberg CN, Saad F, Graff JN, Peer A, Vaishampayan UN, Leung E, Rosenbaum E, Gurney H, Epstein RJ, Davis ID, Wu B, Trandafir L, Wagner VJ, Hussain M. A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Ann Oncol. 2020 Feb;31(2):257-265. doi: 10.1016/j.annonc.2019.10.025. Epub 2019 Dec 23.

Helpful Links

• Click here to find results for studies related to Bayer Healthcare products.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2014
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): August 9, 2018

Study Registration Dates

• First Submitted: December 24, 2013
• First Submitted That Met QC Criteria: December 24, 2013
• First Posted (Estimate): December 30, 2013

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: June 30, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Antineoplastic Agents; Radium Ra 223 dichloride
• Other Study ID Numbers: 16507; 2013-003118-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No