Re-treatment Safety of Radium-223 Dichloride in Castration-resistant Prostate Cancer With Bone Metastases

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01934790
• Collaborator: (none)
• Enrollment: 45
• Locations: 16
• Arm: 1
• Actual Duration (Months): 39.7
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Eligible subjects must have completed 6 doses of treatment of radium-223 dichloride and experienced no radium-223 dichloride-related SAEs (serious adverse events) or CTCAE (Common Terminology Criteria for Adverse Events) Grade 3 or 4 adverse event during or after the initial course of radium-223 dichloride that led to the discontinuation of treatment. 40 Subjects will be enrolled and will receive up to 6 doses of radium-223 dichloride 50 kBq/kg IV every 4 weeks.

The subject will be evaluated for AEs (adverse events) and laboratory tests at each visit every 4 weeks, prior to receiving radium-223 dichloride.

After the end of treatment visit the subjects will enter the active follow up period. Related AEs and SAEs and Lab tests will be evaluated at each visit every 4 weeks for the first 12 weeks, then every 12 weeks for up to 2 years after the last dose of radium-223 dichloride.

After the 2 years of active follow-up, subjects will enter the long-term follow-up period and will be followed via telephone follow-up at 6-month intervals for late toxicities and survival up to 7 years after the last dose of radium-223 dichloride or until death.

Joint safety reviews will regularly take place to oversee safety of the subjects conducted at regular intervals.

An interim analysis of the safety data will be conducted during the study.

Condition or Disease	Intervention/Treatment	Phase
Prostatic Neoplasms	Drug: Radium-223 dichloride (Xofigo, BAY88-8223)	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Re-treatment Safety Study of Radium-223 Dichloride in Subjects With Castration-resistant Prostate Cancer With Bone Metastases Who Received an Initial Course of Six Doses of Radium-223 Dichloride 50 kBq/kg Every Four Weeks
• Actual Study Start Date: Dec 22, 2013
• Actual Primary Completion Date: Jun 4, 2015
• Actual Study Completion Date: Apr 12, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radium-223 dichloride (Xofigo, BAY88-8223) Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (AEs) [Up to 2.5 years]

   An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.

2. Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) [Up to 2.5 years]

   TESAE occurred after the start of radium-223 dichloride treatment until 30 days after the last dose and results in death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly / birth defect; is another medically important serious event as judged by the investigator; or is an occurrence of leukemia, myelodysplastic syndrome, aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary malignancy, such as acute myeloid leukemia.

3. Number of Participants With Radium-223 Dichloride-related AEs in the Active Follow-up Period [Up to 2 years after last treatment]

   An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study.

4. Number of Participants With Radium-223 Dichloride-related SAEs in the Active Follow-up Period [Up to 2 years after last treatment]

   Treatment-related SAE is any SAE that, according to the investigator's causality assessment, is possibly or probably related to treatment with radium-223 dichloride.

5. Number of Participants With High/Low Abnormalities in Hematology Variables at Any Visit After Treatment Start [Up to 2.5 years]

6. Number of Participants With High/Low Abnormalities in Biochemistry Variables at Any Visit After Treatment Start [Up to 2.5 years]

7. Number of Participants Who Discontinued Radium-223 Dichloride Treatment Due to Treatment Emergent AEs or Death [Up to 2.5 years]

   An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.

Other Outcome Measures

1. Radiological Progression Free Survival (rPFS) [Up to 2 years after last treatment]

   Radiological progression-free survival (rPFS) was defined as the time from the treatment start date to the date of radiological disease progression or death from any cause (if death occurred before such progression), as documented by the investigator. Participants not experiencing death or radiological disease progression at the database cutoff for primary completion were censored at the last radiological disease progression assessment.

2. Time to Radiological Bone Progression [Up to 2 years after last treatment]

   Time to radiological bone progression was defined as the time (days) from the treatment start date to the date of radiological bone progression (according to the adapted PCWG2 [Prostate Cancer Clinical Trials Working Group 2] criteria), as documented by the investigator. Participants not experiencing radiological bone progression at the database cutoff for primary completion were censored at the last radiological bone progression assessment.

3. Percentage of Participants With Total Alkaline Phosphatase (ALP) Response [Up to 2.5 years]

   Total alkaline phosphatase (ALP) response was defined as ≥ 30% reduction of the blood total ALP level compared with the baseline values. Total ALP response rate was defined as the number of participants with total ALP response divided by the total number of participants evaluable for total ALP response.

4. Time to Total ALP Progression [Up to 2 years after last treatment]

   Total ALP progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value to at least 1.5 x ULN (upper limit of normal). The time to total ALP progression was defined as the time (days) from the treatment start date to the date of first total ALP progression. Participants not experiencing ALP progression at the database cutoff date, whether or not surviving, were censored at the last ALP laboratory assessment.

5. Percent Change in Total ALP [Baseline and Week 12, Week 24]

6. Percentage of Participants With Prostate Specific Antigen (PSA) Response [Up to 2.5 years]

   Prostate specific antigen (PSA) response was defined as a ≥ 30% reduction of blood PSA level compared with the baseline value, confirmed by a second subsequent PSA value with a ≥ 30% reduction from baseline approximately 4 or more weeks later. Prostate specific antigen response rate was defined as the number of participants with PSA response divided by the total number of participants evaluable for PSA response.

7. Time to PSA Progression [Up to 2 years after last treatment]

   Prostate specific antigen progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value, and an increase in absolute value of ≥ 2 ng/mL above nadir. The time to PSA progression was defined as the time (days) from the treatment start date to the date of first PSA progression. Participants without PSA progression as of the database cutoff for primary completion, whether or not surviving, were censored at the last PSA laboratory assessment.

8. Overall Survival [Up to 2 years after last treatment]

   Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.

9. Percentage of Participants With Pain Improvement [Up to 2.5 years]

   Pain improvement was defined in evaluable participants (participants with worst pain score [WPS] of 4 at baseline) as a 30% and 2-point decrease in WPS over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management. Pain improvement rate was the number of participants with pain improvement, divided by the total number of evaluable participants WPS was the mean of the WPS in the last 24 hours from the preceding 7 days.

10. Time to Pain Progression [Up to 2.5 years]

    Pain progression was defined in participants evaluable for pain progression at baseline, i.e., participants with a WPS of ≤ 7 at the baseline assessment. Pain assessment occurred daily for 1 week, beginning 1 week prior to each visit and including the day of the visit. An evaluable pain assessment interval required completion of a minimum of 4 out of 7 daily questions. Pain progression was defined as the occurrence of either a pain increase or an increase in pain management with respect to baseline, whichever occurred first.

11. Time to First Symptomatic Skeletal Event (SSE) [Up to 2 years after last treatment]

    Time to first symptomatic skeletal event (SSE) is the time (days) from the treatment start date to the first SSE on or following the start date. Participants not experiencing an SSE at the database cutoff date for primary completion, whether or not surviving, were censored at the last assessment for SSEs.

12. SSE-free Survival [Up to 2 years after last treatment]

    The SSE-FS is the time (days) from the treatment start date to the first SSE on or following the start date or death, whichever occurred first. Participants not experiencing death or an SSE at the database cutoff date for primary completion were censored at the last assessment for SSEs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate at any given point in time during disease history

• CRPC (castration-resistant prostate cancer) with clinical or radiologically confirmed bone progression

• Treatment with 6 injections of radium-223 dichloride 50 kBq/kg and no evidence of progression to bone (according to Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) during the first course of treatment

• Signed written informed consent prior to participating in any study related procedures. Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria:

• History of a radium-223 dichloride-related serious adverse event (SAE) or CTCAE Grade 3 or 4 adverse event (AE) during or after the initial course of radium-223 dichloride treatment that led to the discontinuation of treatment

• Less than 30 days from the last dose administered in the initial course of radium-223 dichloride treatment

• Visceral metastases 1 cm or greater in largest diameter and / or requiring local or systemic therapeutic intervention, as assessed by abdominal and pelvic magnetic resonance imaging (MRI) / computed tomography (CT) scan and / or chest X-ray within 30 days of the start of treatment

• Lymphadenopathy with lymph nodes exceeding 6 cm in short-axis diameter and / or requiring local or systemic therapeutic intervention. Enlarged lymph nodes of any size if the lymphadenopathy is thought to be a contributor to concurrent hydronephrosis.

• Current central nervous system (CNS) metastases

• Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone)

• Treatment with chemotherapy after the initial course of radium-223 dichloride treatment

• Prior hemibody external radiotherapy

• Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188

• Any other serious illness or medical conditions

• Crohn's disease or ulcerative colitis

• History of documented bone marrow dysplasia

• Unmanageable fecal incontinence

• Imminent or established spinal cord compression based on clinical findings and / or MRI that has not yet been treated

• Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		New Orleans	Louisiana	United States	70112
2		Omaha	Nebraska	United States	68130
3		Syracuse	New York	United States	13210
4		Kuopio		Finland	70210
5		Haifa		Israel	3109601
6		Jerusalem		Israel	9112001
7		Kfar Saba		Israel	4428164
8		Petah Tikva		Israel	4941492
9		Forlì-Cesena	Emilia-Romagna	Italy	47014
10		Milano	Lombardia	Italy	20133
11		Bergen		Norway	5021
12		Lørenskog		Norway	1478
13		Córdoba	Andalucía	Spain	14004
14		Barcelona		Spain	08025
15		Málaga		Spain	29010
16		Umeå		Sweden	901 85

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01934790
• Other Study ID Numbers: 16506; 2013-003046-17
• First Posted: Sep 4, 2013
• Last Update Posted: Mar 26, 2018
• Last Verified: Mar 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Prostatic Neoplasms; Radium Ra 223 dichloride

Study Results

Participant Flow

Recruitment Details	Overall, 59 participants were screened in 7 countries worldwide, from 22-Dec-2013 (first patient first visit) to 12-Apr-2017 (last patient last visit).
Pre-assignment Detail	The study was conducted at 16 study centers that screened 59 participants. Of them, 14 were screening failures and the remaining 45 participants were assigned to treatment.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Period Title: Treatment
STARTED	45
Participants Received Study Treatment	44
COMPLETED	29
NOT COMPLETED	16
Period Title: Treatment
STARTED	34
COMPLETED	10
NOT COMPLETED	24
Period Title: Treatment
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Overall Participants	44
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	71
Age, Customized (Count of Participants)
< 65 years	13 29.5%
>=65 years	31 70.5%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	44 100%
Baseline Eastern Cooperative Oncology Group (ECOG) Performance status (PS) score (Number) [Number]
0	14 31.8%
1	27 61.4%
2	3 6.8%
Number of bone lesions (Number) [Number]
1-5	18 40.9%
6-20	15 34.1%
> 20, not a superscan	6 13.6%
Superscan	5 11.4%
Prostate specific antigen (PSA) - mean value (microgram per liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [microgram per liter]	211.59 (452.84)
Total alkaline phosphatase (ALP) - mean value (Unit per liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Unit per liter]	122.60 (118.49)
Time from initial diagnosis of bone metastasis (Months) [Median (Full Range) ]
Median (Full Range) [Months]	43.12
Time from initial diagnosis (Months) [Median (Full Range) ]
Median (Full Range) [Months]	80.34
Time since initial treatment with radium-223 dichloride (Months) [Median (Full Range) ]
Median (Full Range) [Months]	6.05
Prostate specific antigen (PSA) - median value (microgram per liter) [Median (Full Range) ]
Median (Full Range) [microgram per liter]	67.66
Total alkaline phosphatase (ALP) - median value (Unit per liter) [Median (Full Range) ]
Median (Full Range) [Unit per liter]	85

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (AEs)
Description	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Number [Participants]	41 93.2%

2. Primary Outcome

Title	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
Description	TESAE occurred after the start of radium-223 dichloride treatment until 30 days after the last dose and results in death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly / birth defect; is another medically important serious event as judged by the investigator; or is an occurrence of leukemia, myelodysplastic syndrome, aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary malignancy, such as acute myeloid leukemia.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Number [Participants]	13 29.5%

3. Primary Outcome

Title	Number of Participants With Radium-223 Dichloride-related AEs in the Active Follow-up Period
Description	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	1 2.3%

4. Primary Outcome

Title	Number of Participants With Radium-223 Dichloride-related SAEs in the Active Follow-up Period
Description	Treatment-related SAE is any SAE that, according to the investigator's causality assessment, is possibly or probably related to treatment with radium-223 dichloride.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	0 0%

5. Primary Outcome

Title	Number of Participants With High/Low Abnormalities in Hematology Variables at Any Visit After Treatment Start
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Eosinophils (GIGA/L) - High	1 2.3%
Ery. Mean Corpuscular HGB Conc. (g/dL) - High	1 2.3%
Ery. Mean Corpuscular Hemoglobin (pg) - High	16 36.4%
Ery. Mean Corpuscular Volume (fL) - High	22 50%
Leukocytes (GIGA/L) - High	5 11.4%
Monocytes (GIGA/L) - High	7 15.9%
Neutrophils (GIGA/L) - High	9 20.5%
Platelets (GIGA/L) - High	1 2.3%
Basophils (GIGA/L) - Low	2 4.5%
Eosinophils (GIGA/L) - Low	7 15.9%
Ery. Mean Corpuscular HGB Conc. (g/dL) - Low	17 38.6%
Ery. Mean Corpuscular Hemoglobin (pg) - Low	4 9.1%
Ery. Mean Corpuscular Volume (fL)	3 6.8%
Erythrocytes (T/L) - Low	43 97.7%
Hematocrit (%) - Low	43 97.7%
Hemoglobin (g/dL) - Low	43 97.7%
Leukocytes (GIGA/L) - Low	21 47.7%
Lymphocytes (GIGA/L) - Low	36 81.8%
Monocytes (GIGA/L) - Low	2 4.5%
Neutrophils (GIGA/L) - Low	10 22.7%
Platelets (GIGA/L) - Low	11 25%

6. Primary Outcome

Title	Number of Participants With High/Low Abnormalities in Biochemistry Variables at Any Visit After Treatment Start
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Alanine Aminotransferase (U/L) - High	2 4.5%
Alkaline Phosphatase (U/L) - High	14 31.8%
Aspartate Aminotransferase (U/L) - High	6 13.6%
Bilirubin (mg/dL) - High	1 2.3%
Creatinine (mg/dL) - High	7 15.9%
Sodium (mmol/L) - High	6 13.6%
Alanine Aminotransferase (U/L) - Low	4 9.1%
Albumin (g/dL) - Low	10 22.7%
Aspartate Aminotransferase (U/L) - Low	1 2.3%
Bilirubin (mg/dL) - Low	4 9.1%
Creatinine (mg/dL) - Low	7 15.9%
Sodium (mmol/L) - Low	14 31.8%

7. Primary Outcome

Title	Number of Participants Who Discontinued Radium-223 Dichloride Treatment Due to Treatment Emergent AEs or Death
Description	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Number [Participants]	2 4.5%

8. Other Pre-specified Outcome

Title	Radiological Progression Free Survival (rPFS)
Description	Radiological progression-free survival (rPFS) was defined as the time from the treatment start date to the date of radiological disease progression or death from any cause (if death occurred before such progression), as documented by the investigator. Participants not experiencing death or radiological disease progression at the database cutoff for primary completion were censored at the last radiological disease progression assessment.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	9.9

9. Other Pre-specified Outcome

Title	Time to Radiological Bone Progression
Description	Time to radiological bone progression was defined as the time (days) from the treatment start date to the date of radiological bone progression (according to the adapted PCWG2 [Prostate Cancer Clinical Trials Working Group 2] criteria), as documented by the investigator. Participants not experiencing radiological bone progression at the database cutoff for primary completion were censored at the last radiological bone progression assessment.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	NA

10. Other Pre-specified Outcome

Title	Percentage of Participants With Total Alkaline Phosphatase (ALP) Response
Description	Total alkaline phosphatase (ALP) response was defined as ≥ 30% reduction of the blood total ALP level compared with the baseline values. Total ALP response rate was defined as the number of participants with total ALP response divided by the total number of participants evaluable for total ALP response.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
12 Week	39.4 89.5%
24 Week	30.6 69.5%
Anytime	43.2 98.2%

11. Other Pre-specified Outcome

Title	Time to Total ALP Progression
Description	Total ALP progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value to at least 1.5 x ULN (upper limit of normal). The time to total ALP progression was defined as the time (days) from the treatment start date to the date of first total ALP progression. Participants not experiencing ALP progression at the database cutoff date, whether or not surviving, were censored at the last ALP laboratory assessment.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	NA

12. Other Pre-specified Outcome

Title	Percent Change in Total ALP
Time Frame	Baseline and Week 12, Week 24

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Week 12	-17.1 (32.74)
Week 24	-15.0 (35.10)

13. Other Pre-specified Outcome

Title	Percentage of Participants With Prostate Specific Antigen (PSA) Response
Description	Prostate specific antigen (PSA) response was defined as a ≥ 30% reduction of blood PSA level compared with the baseline value, confirmed by a second subsequent PSA value with a ≥ 30% reduction from baseline approximately 4 or more weeks later. Prostate specific antigen response rate was defined as the number of participants with PSA response divided by the total number of participants evaluable for PSA response.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
12 Week	6.3 14.3%
24 Week	0 0%
Anytime	9.1 20.7%

14. Other Pre-specified Outcome

Title	Time to PSA Progression
Description	Prostate specific antigen progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value, and an increase in absolute value of ≥ 2 ng/mL above nadir. The time to PSA progression was defined as the time (days) from the treatment start date to the date of first PSA progression. Participants without PSA progression as of the database cutoff for primary completion, whether or not surviving, were censored at the last PSA laboratory assessment.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	2.2

15. Other Pre-specified Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	24.4

16. Other Pre-specified Outcome

Title	Percentage of Participants With Pain Improvement
Description	Pain improvement was defined in evaluable participants (participants with worst pain score [WPS] of 4 at baseline) as a 30% and 2-point decrease in WPS over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management. Pain improvement rate was the number of participants with pain improvement, divided by the total number of evaluable participants WPS was the mean of the WPS in the last 24 hours from the preceding 7 days.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
12 Week	0 0%
24 Week	0 0%
Anytime	8.3 18.9%

17. Other Pre-specified Outcome

Title	Time to Pain Progression
Description	Pain progression was defined in participants evaluable for pain progression at baseline, i.e., participants with a WPS of ≤ 7 at the baseline assessment. Pain assessment occurred daily for 1 week, beginning 1 week prior to each visit and including the day of the visit. An evaluable pain assessment interval required completion of a minimum of 4 out of 7 daily questions. Pain progression was defined as the occurrence of either a pain increase or an increase in pain management with respect to baseline, whichever occurred first.
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	NA

18. Other Pre-specified Outcome

Title	Time to First Symptomatic Skeletal Event (SSE)
Description	Time to first symptomatic skeletal event (SSE) is the time (days) from the treatment start date to the first SSE on or following the start date. Participants not experiencing an SSE at the database cutoff date for primary completion, whether or not surviving, were censored at the last assessment for SSEs.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	16.7

19. Other Pre-specified Outcome

Title	SSE-free Survival
Description	The SSE-FS is the time (days) from the treatment start date to the first SSE on or following the start date or death, whichever occurred first. Participants not experiencing death or an SSE at the database cutoff date for primary completion were censored at the last assessment for SSEs.
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
Median (95% Confidence Interval) [Months]	12.8

20. Post-Hoc Outcome

Title	Number of Participants With New SSE Related AEs During the Follow-up Period
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	0 0%

21. Post-Hoc Outcome

Title	Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	1 2.3%

22. Post-Hoc Outcome

Title	Number of Deaths During Study Treatment or Follow-up Period
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): all participants who received at least one dose of study drug.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	44
During Treatment Period	1 2.3%
During Active follow-up Period	23 52.3%
During Long-term follow-up Period	4 9.1%

23. Post-Hoc Outcome

Title	Number of Participants With Significant Meaningful Changes for Clinical Laboratory NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Toxicity Grades During the Follow-up Period
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	0 0%

24. Post-Hoc Outcome

Title	Number of Participants With Body Weight Changes During the Follow-up Period
Description	Participants were counted once during active follow-up for both increases (using the maximum body weight) and decreases (using the minimum body weight).
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Increases < 5%	23 52.3%
Increases 5-10%	4 9.1%
Increases > 10%	0 0%
Decreases < 5%	13 29.5%
Decreases 5-10%	9 20.5%
Decreases > 10%	5 11.4%

25. Post-Hoc Outcome

Title	Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score Worsened to >=3 During the Follow-up Period
Time Frame	Up to 2 years after last treatment

Outcome Measure Data

Analysis Population Description

Active Follow-up Analysis Set: participants who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.

Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
Measure Participants	34
Number [Participants]	4 9.1%

Adverse Events

Time Frame	From start of study treatment until 30 days after last dose of study medication up to 2.5 years
Arm/Group Title	Radium-223 Dichloride (Xofigo, BAY88-8223)
Arm/Group Description	Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections
All Cause Mortality
	Radium-223 Dichloride (Xofigo, BAY88-8223)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Radium-223 Dichloride (Xofigo, BAY88-8223)
	Affected / at Risk (%)	# Events
Total	13/44 (29.5%)
Cardiac disorders
Acute myocardial infarction	1/44 (2.3%)	1
Myocardial infarction	1/44 (2.3%)	1
Supraventricular tachycardia	1/44 (2.3%)	1
Eye disorders
Glaucoma	1/44 (2.3%)	1
Uveitis	1/44 (2.3%)	1
Gastrointestinal disorders
Haemorrhoidal haemorrhage	1/44 (2.3%)	1
General disorders
General physical health deterioration	2/44 (4.5%)	2
Injury, poisoning and procedural complications
Stomatitis radiation	1/44 (2.3%)	1
Metabolism and nutrition disorders
Dehydration	2/44 (4.5%)	2
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw	1/44 (2.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/44 (2.3%)	1
Nervous system disorders
Dementia Alzheimer's type	1/44 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/44 (2.3%)	1
Pleural effusion	1/44 (2.3%)	1
Vascular disorders
Peripheral ischaemia	1/44 (2.3%)	2
Other (Not Including Serious) Adverse Events
	Radium-223 Dichloride (Xofigo, BAY88-8223)
	Affected / at Risk (%)	# Events
Total	35/44 (79.5%)
Blood and lymphatic system disorders
Anaemia	6/44 (13.6%)	6
Gastrointestinal disorders
Abdominal pain	3/44 (6.8%)	3
Constipation	3/44 (6.8%)	3
Diarrhoea	9/44 (20.5%)	11
Nausea	11/44 (25%)	13
Vomiting	5/44 (11.4%)	8
General disorders
Asthenia	4/44 (9.1%)	4
Fatigue	12/44 (27.3%)	12
Oedema peripheral	4/44 (9.1%)	5
Injury, poisoning and procedural complications
Fall	5/44 (11.4%)	8
Investigations
White blood cell count decreased	3/44 (6.8%)	3
Metabolism and nutrition disorders
Decreased appetite	8/44 (18.2%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	6/44 (13.6%)	7
Back pain	5/44 (11.4%)	5
Bone pain	3/44 (6.8%)	3
Musculoskeletal pain	3/44 (6.8%)	3
Myalgia	3/44 (6.8%)	3
Spinal pain	3/44 (6.8%)	3
Nervous system disorders
Headache	4/44 (9.1%)	4
Vascular disorders
Hypertension	6/44 (13.6%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The agreed point of publication is 12-18 months after database lock at the earliest. Bayer will have 30-45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior of publication if multi-center data.