Prostatic Neoplasms
Conditions
Brief summary
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.
Interventions
DRUGRadium-223 dichloride (Xofigo, BAY88-8223)
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized | 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 (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. |
| Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose | 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 (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. |
| Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose | 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) | 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. |
| Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose | 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 (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. |
| Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose | 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) | 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. |
| Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized | 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 (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Event - Three Dose Groups as Randomized | 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 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. |
| Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 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 (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. |
| Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 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 SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. |
| Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | 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 (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. |
| Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | 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 SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. |
| Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 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 (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. |
| Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 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 SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date. |
| Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose | 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 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). |
| Radiological Progression Free Survival - High Dose vs. Standard Dose | 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 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. |
| Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose | 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 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 Progression Free Survival - Extended Dose vs. Standard Dose | 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 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. |
| Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized | 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 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. |
| Radiological Progression Free Survival - Three Dose Groups as Randomized | 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 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. |
| Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose | 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 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. |
| Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose | 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 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. |
| Time to Radiological Progression - Extended Dose vs. Standard Dose | 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 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. |
| Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized | 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 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. |
| Time to Radiological Progression - Three Dose Groups as Randomized | 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 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. |
| Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | 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 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. |
| Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | 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 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. |
| Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose | 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) | 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. |
| Time to Pain Progression - High Dose vs. Standard Dose | 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) | 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. |
| Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose | 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) | 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. |
| Time to Pain Progression - Extended Dose vs. Standard Dose | 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) | 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. |
| Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized | 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) | 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. |
| Time to Pain Progression - Three Dose Groups as Randomized | 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) | 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. |
| Number of Participants With Treatment-Emergent Adverse Events | 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) | 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). |
| Time to Radiological Progression - High Dose vs. Standard Dose | 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 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. |
| Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose | 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 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. |
| Overall Survival - High Dose vs. Standard Dose | 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 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. |
| Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose | 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 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. |
| Overall Survival - Extended Dose vs. Standard Dose | 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 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. |
| Number of Participants With an Overall Survival - Three Dose Groups As Randomized | 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 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-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) | 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. |
Countries
Australia, Brazil, Canada, Chile, Czechia, France, Germany, Israel, Italy, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Of the 391 participants assigned to treatment in the intention to treatment (ITT) analysis set, 370 participants (94.6%) received at least one dose of radium-223 dichloride, and a total of 21 participants (5.4%) never received treatment
Participants by arm
| Arm | Count |
|---|---|
| Radium-223 Dichloride 55 kBq/kg, 6 Doses (Arm A) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses (standard dose). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years. | 130 |
| Radium-223 Dichloride 88 kBq/kg, 6 Doses (Arm B) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 88 kBq/kg IV every 28 days for up to 6 doses (high dose). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years. | 130 |
| Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg IV every 28 days for up to 12 doses (extended dose). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years. | 131 |
| Total | 391 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Active Follow-up Period | Clinical progression | 0 | 2 | 1 |
| Active Follow-up Period | Death | 83 | 82 | 87 |
| Active Follow-up Period | Deterioration of general condition | 1 | 1 | 1 |
| Active Follow-up Period | Lost to Follow-up | 1 | 1 | 1 |
| Active Follow-up Period | Other unspecified | 2 | 0 | 1 |
| Active Follow-up Period | Radiological progression | 0 | 0 | 1 |
| Active Follow-up Period | Withdrawal by Subject | 5 | 13 | 7 |
| Long-term Follow-up Period | Death | 9 | 6 | 4 |
| Long-term Follow-up Period | Entered the long-term follow-up study | 6 | 9 | 6 |
| Long-term Follow-up Period | Lost to Follow-up | 1 | 0 | 1 |
| Long-term Follow-up Period | Other unspecified | 6 | 3 | 5 |
| Long-term Follow-up Period | Technical problems | 0 | 0 | 1 |
| Long-term Follow-up Period | Withdrawal by Subject | 6 | 3 | 0 |
| Treatment Period | Adverse Event | 13 | 25 | 23 |
| Treatment Period | Clinical progression | 10 | 8 | 28 |
| Treatment Period | Logistical difficulties | 1 | 1 | 1 |
| Treatment Period | Never Treated | 5 | 6 | 10 |
| Treatment Period | Physician Decision | 0 | 0 | 1 |
| Treatment Period | Radiological progression | 13 | 17 | 26 |
| Treatment Period | Safety outcome reached | 0 | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 4 | 5 | 13 |
Baseline characteristics
| Characteristic | Radium-223 Dichloride 55 kBq/kg, 6 Doses (Arm A) | Radium-223 Dichloride 88 kBq/kg, 6 Doses (Arm B) | Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) | Total |
|---|---|---|---|---|
| Age, Continuous | 70.6 years STANDARD_DEVIATION 8.6 | 70.9 years STANDARD_DEVIATION 8.3 | 70.0 years STANDARD_DEVIATION 8.1 | 70.5 years STANDARD_DEVIATION 8.3 |
| Average Worst Pain Score (WPS) | 3.6 scores on a scale STANDARD_DEVIATION 2.6 | 3.3 scores on a scale STANDARD_DEVIATION 2.5 | 3.4 scores on a scale STANDARD_DEVIATION 2.6 | 3.4 scores on a scale STANDARD_DEVIATION 2.5 |
| Body Mass Index | 28.4 kg/m^2 STANDARD_DEVIATION 5.2 | 28.0 kg/m^2 STANDARD_DEVIATION 5.2 | 29.1 kg/m^2 STANDARD_DEVIATION 5.4 | 28.5 kg/m^2 STANDARD_DEVIATION 5.3 |
| ECOG PS 0 | 48 Participants | 59 Participants | 49 Participants | 156 Participants |
| ECOG PS 1 | 78 Participants | 67 Participants | 77 Participants | 222 Participants |
| ECOG PS 2 | 4 Participants | 4 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 124 Participants | 120 Participants | 369 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 5 Participants | 12 Participants |
| Extent of disease >20 lesions but not a superscan | 47 Participants | 48 Participants | 54 Participants | 149 Participants |
| Extent of disease 6-20 metastases | 52 Participants | 53 Participants | 52 Participants | 157 Participants |
| Extent of disease <6 metastases | 19 Participants | 22 Participants | 19 Participants | 60 Participants |
| Extent of disease Normal or abnormal because of benign bone disease | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Extent of disease Superscan | 12 Participants | 6 Participants | 6 Participants | 24 Participants |
| Race/Ethnicity, Customized Asian | 17 Participants | 17 Participants | 13 Participants | 47 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 5 Participants | 5 Participants | 13 Participants |
| Race/Ethnicity, Customized Not reported | 6 Participants | 6 Participants | 5 Participants | 17 Participants |
| Race/Ethnicity, Customized White | 104 Participants | 102 Participants | 108 Participants | 314 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 130 Participants | 130 Participants | 131 Participants | 391 Participants |
| Time from first bone metastases progression to most recent progression | 7.9 months | 8.9 months | 13.4 months | 9.5 months |
| Time from initial bone metastases diagnosis to randomization | 30.8 months | 29.9 months | 37.5 months | 31.7 months |
| Time from initial prostate cancer diagnosis to randomization | 58.9 months | 72.9 months | 67.1 months | 66.8 months |
| Time from most recent bone metastases progression to randomization | 2.3 months | 2.8 months | 1.9 months | 2.4 months |
| Time from most recent prostate cancer progression to randomization | 1.4 months | 1.4 months | 1.3 months | 1.3 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 98 / 125 | 100 / 124 | 102 / 121 |
| other Total, other adverse events | 109 / 125 | 111 / 124 | 111 / 121 |
| serious Total, serious adverse events | 25 / 125 | 36 / 124 | 37 / 121 |
Outcome results
Primary
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.
Time frame: 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)
Population: Week 24 (W24): All ITT participants in Arm A (standard dose) and Arm C (extended dosing) treated with radium-223 dichloride and eligible for further treatment at W24 (i.e., 7th injection). All participants who received 6 doses from Arm A and participants who received \>=6 doses from Arm C were included .
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose | 41 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose | 40 Participants |
Primary
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.
Time frame: 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)
Population: Intent-to-treat (ITT): All randomized participants. Data from Arm C are truncated at 7th dose date when pooling with Arm A, therefore Pooled Arm A+C included 261 participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose | 85 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose | 118 Participants |
Primary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized | 80 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized | 85 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized | 92 Participants |
Primary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose | 13.2 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose | 10.8 months |
p-value: 0.313480% CI: [0.939, 1.69]Log Rank
Primary
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.
Time frame: 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)
Population: Intent-to-treat (ITT): All randomized participants. Data from Arm C are truncated at 7th dose date when pooling with Arm A, therefore Pooled Arm A+C included 261 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose | 12.9 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose | 12.3 months |
p-value: 0.704780% CI: [0.878, 1.272]Log Rank
Primary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized | 13.1 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized | 12.9 months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized | 9.6 months |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose | 43 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose | 38 Participants |
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose | 89 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose | 106 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With an Overall Survival - Three Dose Groups As Randomized | 83 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With an Overall Survival - Three Dose Groups As Randomized | 89 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With an Overall Survival - Three Dose Groups As Randomized | 93 Participants |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose | 10 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose | 15 Participants |
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose | 31 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose | 68 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized | 32 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized | 31 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized | 46 Participants |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose | 43 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose | 43 Participants |
Secondary
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.
Time frame: 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)
Population: Baseline is randomization date
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose | 49 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose | 47 Participants |
Secondary
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).
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose | 77 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose | 141 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized | 77 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized | 77 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized | 90 Participants |
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose | 63 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose | 115 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized | 66 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized | 63 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized | 67 Participants |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | 19 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | 25 Participants |
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 42 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 62 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 37 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 42 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 48 Participants |
Secondary
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).
Time frame: 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)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 118 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Grade 1 | 23 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Grade 2 | 52 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Grade 3 | 38 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Grade 4 | 4 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Grade 5 | 1 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Serious | 25 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Treatment-Emergent Adverse Events | Any drug-related TEAE | 73 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 2 | 40 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Serious | 36 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 3 | 46 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 4 | 11 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 5 | 2 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 119 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 1 | 20 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Treatment-Emergent Adverse Events | Any drug-related TEAE | 73 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 2 | 34 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 1 | 18 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 116 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 3 | 49 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Serious | 37 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 5 | 4 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Grade 4 | 11 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Treatment-Emergent Adverse Events | Any drug-related TEAE | 57 Participants |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Overall Survival Event - Three Dose Groups as Randomized | 15.8 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Overall Survival Event - Three Dose Groups as Randomized | 16.0 months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Overall Survival Event - Three Dose Groups as Randomized | 14.4 months |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Overall Survival - Extended Dose vs. Standard Dose | 16.5 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Overall Survival - Extended Dose vs. Standard Dose | 15.2 months |
p-value: 0.995880% CI: [0.744, 1.341]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Overall Survival - High Dose vs. Standard Dose | 16.0 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Overall Survival - High Dose vs. Standard Dose | 14.9 months |
p-value: 0.620580% CI: [0.892, 1.297]Log Rank
Secondary
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.
Time frame: 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)
Population: Baseline is randomization date
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Radiological Progression Free Survival - Extended Dose vs. Standard Dose | 8.9 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Radiological Progression Free Survival - Extended Dose vs. Standard Dose | 9.0 months |
p-value: 0.789680% CI: [0.804, 1.396]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Radiological Progression Free Survival - High Dose vs. Standard Dose | 7.5 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Radiological Progression Free Survival - High Dose vs. Standard Dose | 6.0 months |
p-value: 0.828480% CI: [0.805, 1.167]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Radiological Progression Free Survival - Three Dose Groups as Randomized | 6.3 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Radiological Progression Free Survival - Three Dose Groups as Randomized | 7.5 months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Radiological Progression Free Survival - Three Dose Groups as Randomized | 6.1 months |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | Week 12 | 31.8 percentage |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | Overall (confirmed) | 40.9 percentage |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | Week 12 | 30.0 percentage |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose | Overall (confirmed) | 55.0 percentage |
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Week 12 | 16.7 percentage |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Overall (confirmed) | 27.1 percentage |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Week 12 | 16.0 percentage |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Overall (confirmed) | 26.0 percentage |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Week 12 | 18.6 percentage |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Timepoint Pain Improvement Rate - Three Dose Groups as Randomized | Overall (confirmed) | 37.2 percentage |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | NA months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose | 19.5 months |
p-value: 0.15580% CI: [1.041, 2.306]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 24.1 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose | 26.3 months |
p-value: 0.746180% CI: [0.823, 1.385]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized | NA months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 24.1 months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized | 18.8 months |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Pain Progression - Extended Dose vs. Standard Dose | NA months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Pain Progression - Extended Dose vs. Standard Dose | NA months |
p-value: 0.721480% CI: [0.505, 1.475]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Pain Progression - High Dose vs. Standard Dose | NA months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Pain Progression - High Dose vs. Standard Dose | NA months |
p-value: 0.621480% CI: [0.678, 1.188]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Pain Progression - Three Dose Groups as Randomized | NA months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Pain Progression - Three Dose Groups as Randomized | NA months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Time to Pain Progression - Three Dose Groups as Randomized | 10.1 months |
Secondary
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.
Time frame: 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)
Population: Week 24 (W24)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Radiological Progression - Extended Dose vs. Standard Dose | 8.9 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Radiological Progression - Extended Dose vs. Standard Dose | 9.0 months |
p-value: 0.575480% CI: [0.85, 1.514]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Radiological Progression - High Dose vs. Standard Dose | 8.7 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Radiological Progression - High Dose vs. Standard Dose | 6.2 months |
p-value: 0.927480% CI: [0.803, 1.21]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Time to Radiological Progression - Three Dose Groups as Randomized | 6.2 months |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Time to Radiological Progression - Three Dose Groups as Randomized | 8.7 months |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Time to Radiological Progression - Three Dose Groups as Randomized | 6.6 months |
Other Pre-specified
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Weak Opioid | 5 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Missing | 2 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Weak Opioid | 1 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Strong Opioid | 24 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | Strong Opioid - No Change | 22 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | No analgesic or Non-opioid - No Change | 46 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to No analgesic or Non-opioid | 18 Participants |
| Radium-223 88 kBq/kg, 6 Doses (Arm B) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Missing | 5 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | Strong Opioid - No Change | 27 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Weak Opioid | 0 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to No analgesic or Non-opioid | 9 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Missing | 0 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Strong Opioid | 26 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Weak Opioid | 8 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | No analgesic or Non-opioid - No Change | 41 Participants |
| Pooled Radium-223 55 kBq/kg (Arms A and C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Missing | 5 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | Strong Opioid - No Change | 26 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Weak Opioid | 12 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Weak Opioid | 2 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Missing | 5 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to Missing | 4 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | No analgesic or Non-opioid - No Change | 30 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From No analgesic or Non-opioid to Strong Opioid | 25 Participants |
| Radium-223 55 kBq/kg, 12 Doses (Arm C) | Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline | From Strong Opioid to No analgesic or Non-opioid | 13 Participants |