Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms (ERA 223)

• ClinicalTrials.gov Identifier: NCT02043678
• Recruitment Status: Completed
• First Posted: January 23, 2014
• Results First Posted: March 5, 2019
• Last Update Posted: February 26, 2024
• Sponsor: Bayer
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Prostatic Neoplasms
• Interventions: Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Matching placebo (normal saline); Drug: Abiraterone; Drug: Prednisone/Prednisolone
• Enrollment: 806

Participant Flow

Recruitment Details	Study was conducted at multiple centers in 19 countries between 30 March 2014 (first participant first visit) and 31 October 2019 (data cut-off date).
Pre-assignment Details	Overall, 1144 participants were screened. Of them, 338 participants did not complete screening, 806 participants were randomized to treatment and 786 participants received study treatment.

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Period Title: Overall Study
Started	401	405
Treated	390	396
Completed [1]	0	0
Not Completed	401	405
Reason Not Completed
Never treated	11	9
AE with clinical progressive disease(PD)	18	18
AE without clinical PD	51	34
Lost to Follow-up	1	1
Other	19	16
Clinical PD	108	138
Radiological PD	91	80
Protocol-driven decision point	56	56
Withdrawal by Subject	12	15
Ongoing with treatment	34	38
[1] Completed treatment

Baseline Characteristics

Arm/Group Title		Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred	Total
Arm/Group Description		Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).	Total of all reporting groups
Overall Number of Baseline Participants		401	405	806
Baseline Analysis Population Description		Intent-to-treat analysis set (ITT) included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	401 participants	405 participants	806 participants
		70.9 (8.5)	71.4 (8.4)	71.1 (8.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	401 100.0%	405 100.0%	806 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Hispanic or Latino	17 4.2%	23 5.7%	40 5.0%
	Not Hispanic or Latino	361 90.0%	355 87.7%	716 88.8%
	Unknown or Not Reported	23 5.7%	27 6.7%	50 6.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	American Indian or Alaska Native	1 0.2%	1 0.2%	2 0.2%
	Asian	79 19.7%	78 19.3%	157 19.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	10 2.5%	16 4.0%	26 3.2%
	White	285 71.1%	284 70.1%	569 70.6%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	26 6.5%	26 6.4%	52 6.5%
Weight [1]; Mean (Standard Deviation); Unit of measure: Kilograms (kg)
	Number Analyzed	396 participants	400 participants	796 participants
		82.19 (16.75)	82.40 (16.01)	82.30 (16.37)
		[1] Measure Analysis Population Description: ITT analysis set with evaluable number of participants
Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Missing	19 4.7%	24 5.9%	43 5.3%
	Stage I	27 6.7%	18 4.4%	45 5.6%
	Stage IIA	22 5.5%	20 4.9%	42 5.2%
	Stage IIB	34 8.5%	49 12.1%	83 10.3%
	Stage III	102 25.4%	88 21.7%	190 23.6%
	Stage IV	197 49.1%	206 50.9%	403 50.0%
		[1] Measure Description: TNM staging system stands for Tumour, Node, Metastasis. Stage I: cancer is in half of one side of the prostate or less. Stage II: cancer is in more than half of one side of the prostate, completely contained within the prostate gland. Stage III: cancer has broken through the capsule of the prostate gland, and may have spread into tubes that carry semen. Stage IV: cancer has spread into nearby body organs, such as the back passage or bladder; or has spread to nearby lymph nodes; or has spread to other parts of the body outside the pelvis, such as the lungs or liver.
Cancer pain assessment by Brief Pain Inventory-Short Form (BPI-SF) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Missing	25 6.2%	33 8.1%	58 7.2%
	Asymptomatic (Worst pain score = 0)	195 48.6%	198 48.9%	393 48.8%
	Mildly Symptomatic (Worst pain score 1 - 3)	181 45.1%	174 43.0%	355 44.0%
		[1] Measure Description: The BPI-SF is a short, self-administered questionnaire with 11 items designed to evaluate the intensity of, and the impairment caused by pain. Four items measure pain intensity (pain now, average pain, worst pain, and least pain) using 0 ("no pain") to 10 ("pain as bad as you can imagine") numeric rating scales, and 7 items measure the level of interference with function caused by pain (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life) using 0 (no interference) to 10 (complete interference) rating scales.
Gleason score at diagnosis [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Missing	15 3.7%	18 4.4%	33 4.1%
	Less than (<) 8	140 34.9%	154 38.0%	294 36.5%
	Greater than or equal to (>=) 8	246 61.3%	233 57.5%	479 59.4%
		[1] Measure Description: The Gleason score is an indication of prognosis based on prostate pathology. The total score ranges from 2 to 10 (ie: "1+1" to "5+5") with a higher score reflecting less-differentiated tumors with worse prognosis. The total score is a sum of two numbers which are based on the microscopic appearance of cells. The first number is the score based on the dominant, cell morphology (scored 1-5) and the second number is based on the highest grade of the non-dominant cell pattern (scored 1-5).
Prostate-specific antigen [1]; Mean (Standard Deviation); Unit of measure: Micrograms per liter (ug/L)
	Number Analyzed	396 participants	401 participants	797 participants
		92.39 (191.62)	92.33 (328.00)	92.36 (268.85)
		[1] Measure Analysis Population Description: ITT set with evaluable number of participants.
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Missing	2 0.5%	3 0.7%	5 0.6%
	0	262 65.3%	281 69.4%	543 67.4%
	1	137 34.2%	121 29.9%	258 32.0%
		[1] Measure Description: Eastern cooperative oncology group (ECOG) performance status: 0= Fully active, able to carry on all pre-disease performance without restriction; 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3= Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4= Completely disabled, cannot carry on any self-care, totally confined to bed or chair.
Extent of Disease; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	401 participants	405 participants	806 participants
	Normal or abnormal because of benign bone disease	2 0.5%	0 0.0%	2 0.2%
	< 6 metastases	134 33.4%	141 34.8%	275 34.1%
	6-20 metastases	175 43.6%	181 44.7%	356 44.2%
	>20 lesions but not a superscan	71 17.7%	70 17.3%	141 17.5%
	Superscan	19 4.7%	13 3.2%	32 4.0%

Outcome Measures

1. Primary Outcome

Title	Symptomatic Skeletal Event Free Survival (SSE-FS)
Description	SSE-FS was defined as time (months) from randomization to the earliest of onset date of skeletal symptoms treated with external beam radiotherapy (EBRT), onset date of pathological bone fracture, onset date of spinal cord compression, procedure date of tumor-related orthopedic surgery, or death from any cause. Subjects who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Subjects alive at the survival cut-off date are censored at the last date known to be alive. Subjects with multiple events are only counted for the category in which the first event occurred. If multiple SSE (component events) occur on the same date for 1 subject, the subject is only counted into 1 category in the order of: spinal cord compression > bone fracture > orthopedic surgery > EBRT.
Time Frame	From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) analysis set (included all randomized participants)

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	401	405
Median (95% Confidence Interval); Unit of Measure: Months
	22.3; (20.4 to 24.8)	26.0; (21.8 to 28.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2636
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.122
	Confidence Interval	(2-Sided) 95%; 0.917 to 1.374
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Subjects alive at the survival cut-off date were censored at the last date known to be alive.
Time Frame	From randomization until death from any cause, up to 67 months

Outcome Measure Data

Analysis Population Description

ITT analysis set (included all randomized participants)

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	401	405
Median (95% Confidence Interval); Unit of Measure: Months
	30.1; (27.5 to 33.2)	34.8; (31.5 to 37.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1194
	Comments	[Not Specified]
	Method	Cox Proportional Hazards model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.151
	Confidence Interval	(2-Sided) 95%; 0.964 to 1.374
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Radiological Progression Free Survival (rPFS)
Description	rPFS was defined as the time (months) from the date of randomization to the date of confirmed radiological progression or death (if death occurred before progression) based on independent assessment.
Time Frame	From randomization until the date of confirmed radiological progression or death, up to 47 months

Outcome Measure Data

Analysis Population Description

ITT analysis set (included all randomized participants)

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	401	405
Median (95% Confidence Interval); Unit of Measure: Months
	11.2; (9.1 to 11.8)	12.4; (10.8 to 14.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1283
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.152
	Confidence Interval	(2-Sided) 95%; 0.960 to 1.383
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Time to Pain Progression
Description	Time to pain progression was defined as the interval from randomization to the first date a subject experienced pain progression, assessed by BPI-SF (see Baseline Characteristics) and defined as: an increase of 2 or more points in the average worst pain score (WPS) from baseline observed at 2 consecutive evaluations >= 4 weeks apart or initiation of short- or long-acting opioid use for pain for subjects with WPS 0 at baseline; an increase of 2 or more points in the average WPS from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart and an average WPS of ≥ 4 OR initiation of short- or long-acting opioid use for pain for subjects with WPS 1 to 3 at baseline. Subjects without pain progression at the end of study are censored at the last date known to have not progressed: the last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Subjects with no on-study assessment or no baseline assessment are censored at the date of randomization.
Time Frame	From randomization until the date of pain progression based on pain score, up to 47 months

Outcome Measure Data

Analysis Population Description

ITT analysis set (included all randomized participants)

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	401	405
Median (95% Confidence Interval); Unit of Measure: Months
	14.4; (11.1 to 20.1)	18.7; (15.4 to 23.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1669
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.145
	Confidence Interval	(2-Sided) 95%; 0.945 to 1.389
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Time to Cytotoxic Chemotherapy
Description	Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Participants who have not started cytotoxic chemotherapy during the study were censored at the last assessment date.
Time Frame	From randomization until the date of first cytotoxic chemotherapy, up to 47 months

Outcome Measure Data

Analysis Population Description

ITT analysis set (included all randomized participants)

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	401	405
Median (95% Confidence Interval); Unit of Measure: Months
	29.5; (26.5 to 35.7)	28.5 [1]; (23.7 to NA)

[1]

Upper limit cannot be estimated due to censored data.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7871
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.033
	Confidence Interval	(2-Sided) 95%; 0.816 to 1.308
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Time to Opiate Use for Cancer Pain
Description	Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.
Time Frame	From randomization until the date of opiate use, up to 47 months

Outcome Measure Data

Analysis Population Description

ITT analysis set excluding participants who had opiate use at baseline

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	398	392
Median (95% Confidence Interval); Unit of Measure: Months
	19.0; (14.4 to 23.2)	22.6; (18.0 to 25.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 Dichloride + Abi/Pred, Placebo + Abi/Pred
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2467
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.126
	Confidence Interval	(2-Sided) 95%; 0.921 to 1.378
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Drug-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
Time Frame	From start of study treatment until the end of the treatment period, up to 65 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
Any TEAE	382 97.4%	387 98.2%
Any drug-related TEAE	265 67.6%	271 68.8%
Radium-223/Placebo-related TEAE	92 23.5%	92 23.4%
Any serious TEAE	175 44.6%	172 43.7%
Any drug-related serious TEAE	32 8.2%	29 7.4%
Radium-223/Placebo-related serious TEAE	11 2.8%	7 1.8%

8. Secondary Outcome

Title	Number of Subjects With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity
Description	An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Radium-223/placebo-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to radium-223 or placebo decided by the investigators.
Time Frame	From start of study treatment until the end of the treatment period, up to 65 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
TEAE - Grade 1	44 11.2%	53 13.5%
TEAE - Grade 2	28 7.1%	24 6.1%
TEAE - Grade 3	19 4.8%	13 3.3%
TEAE - Grade 4	1 0.3%	2 0.5%
Serious TEAE - Grade 2	3 0.8%	0 0.0%
Serious TEAE - Grade 3	8 2.0%	5 1.3%
Serious TEAE - Grade 4	0 0.0%	2 0.5%

9. Secondary Outcome

Title	Number of Participants With Any Treatment-emergent Additional Primary Malignancies
Description	Treatment-emergent additional primary malignancies were adverse events identified as additional primary malignancies that occurred after start of study treatment until the end of the treatment period.
Time Frame	From start of study treatment until 4 weeks after last study treatment, up to 65 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
	26 6.6%	25 6.3%

10. Secondary Outcome

Title	Number of Participants With Treatment-emergent Bone Fractures
Description	Treatment-emergent fractures were adverse events identified as fractures that occurred after start of study treatment until the end of the treatment period. All bone fractures and bone-associated events (e.g., osteoporosis) were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator's causality assessment.
Time Frame	From start of study treatment until 4 weeks after last study treatment, up to 65 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
	107 27.3%	49 12.4%

11. Secondary Outcome

Title	Number of Participants With Post-treatment Adverse Events
Description	An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
Time Frame	After the treatment period, up to 46 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
Any events	138 35.2%	133 33.8%
Any drug-related events	18 4.6%	9 2.3%
Any chemotherapy-related events	31 7.9%	34 8.6%
Any additional primary malignancies	6 1.5%	7 1.8%

12. Secondary Outcome

Title	Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity
Description	An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
Time Frame	After the treatment period, up to 46 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
Grade 1	3 0.8%	3 0.8%
Grade 2	9 2.3%	3 0.8%
Grade 3	5 1.3%	3 0.8%
Grade 4	1 0.3%	0 0.0%

13. Secondary Outcome

Title	Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders
Description	Post-treatment blood and lymphatic system disorders were adverse events identified as blood and lymphatic system disorders that occurred after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study.
Time Frame	After the treatment period, up to 46 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
Anaemia	5 1.3%	4 1.0%
Bone marrow failure	1 0.3%	0 0.0%
Febrile neutropenia	5 1.3%	8 2.0%
Leukopenia	1 0.3%	0 0.0%
Neutropenia	8 2.0%	3 0.8%
Pancytopenia	0 0.0%	1 0.3%
Thrombocytopenia	2 0.5%	2 0.5%

14. Secondary Outcome

Title	Number of Participants With Post-treatment Bone Fractures
Description	Post-treatment fractures were adverse events identified as fractures that occured after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study. All bone fractures and bone-associated events (e.g., osteoporosis), were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator's causality assessment.
Time Frame	After the treatment period, up to 46 months

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): included all randomized subjects who received at least one dose of any study drug

Arm/Group Title	Radium-223 Dichloride + Abi/Pred	Placebo + Abi/Pred
Arm/Group Description:	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).	Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
Overall Number of Participants Analyzed	392	394
Measure Type: Count of Participants; Unit of Measure: Participants
Lumbar vertebral fracture	0 0.0%	1 0.3%
Rib fracture	0 0.0%	1 0.3%
Spinal compression fracture	0 0.0%	1 0.3%
Thoracic vertebral fracture	0 0.0%	1 0.3%
Traumatic fracture	6 1.5%	2 0.5%
Osteoporotic fracture	6 1.5%	0 0.0%
Pathological fracture	12 3.1%	13 3.3%

Adverse Events

Time Frame	From start of study treatment to cut-off date 31-OCT-2019, which is about 67 months.
Adverse Event Reporting Description	Adverse events (AEs) included any event arising or worsening from the start of the study treatment. All occurrences of additional malignancies, chemotherapy-related events, bone fractures and bone associated events were reported as AE regardless of the investigator's causality assessment.
Arm/Group Title	Radium-223 Dichloride + Abi/Pred		Placebo + Abi/Pred
Arm/Group Description	Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).		Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).
All-Cause Mortality
	Radium-223 Dichloride + Abi/Pred		Placebo + Abi/Pred
	Affected / at Risk (%)		Affected / at Risk (%)
Total	254/392 (64.80%)		242/394 (61.42%)
Serious Adverse Events
	Radium-223 Dichloride + Abi/Pred		Placebo + Abi/Pred
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	190/392 (48.47%)		185/394 (46.95%)
Blood and lymphatic system disorders
Anaemia * 1	9/392 (2.30%)	19	4/394 (1.02%)	5
Disseminated intravascular coagulation * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Febrile neutropenia * 1	3/392 (0.77%)	3	6/394 (1.52%)	6
Leukopenia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Lymphopenia * 1	1/392 (0.26%)	6	0/394 (0.00%)	0
Neutropenia * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Pancytopenia * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Thrombocytopenia * 1	3/392 (0.77%)	9	0/394 (0.00%)	0
Bone marrow failure * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Cardiac disorders
Acute myocardial infarction * 1	5/392 (1.28%)	6	4/394 (1.02%)	4
Aortic valve incompetence * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Aortic valve stenosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Arrhythmia * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Atrial fibrillation * 1	4/392 (1.02%)	5	8/394 (2.03%)	8
Atrial flutter * 1	1/392 (0.26%)	2	1/394 (0.25%)	1
Atrioventricular block complete * 1	2/392 (0.51%)	3	0/394 (0.00%)	0
Cardiac arrest * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Cardiac failure * 1	1/392 (0.26%)	2	3/394 (0.76%)	6
Cardiac failure congestive * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Cardio-respiratory arrest * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Coronary artery stenosis * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Coronary ostial stenosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Myocardial infarction * 1	3/392 (0.77%)	4	1/394 (0.25%)	1
Sinus bradycardia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Ventricular fibrillation * 1	1/392 (0.26%)	2	1/394 (0.25%)	2
Ventricular tachycardia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Acute coronary syndrome * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Cardiac disorder * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Congenital, familial and genetic disorders
Inborn error of metabolism * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Ear and labyrinth disorders
Vertigo * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Endocrine disorders
Primary adrenal insufficiency * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Eye disorders
Cataract * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Retinal artery occlusion * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Gastrointestinal disorders
Abdominal pain * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Abdominal pain lower * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Constipation * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Diarrhoea * 1	3/392 (0.77%)	3	5/394 (1.27%)	5
Diverticulum intestinal haemorrhagic * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Duodenal ulcer * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Dysphagia * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Enterocolitis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Gastric haemorrhage * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Gastric ulcer * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Gastrointestinal disorder * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Gastrointestinal haemorrhage * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Ileus * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Incarcerated inguinal hernia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Inguinal hernia * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Large intestine perforation * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Nausea * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Oesophageal achalasia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Oesophageal ulcer * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Rectal haemorrhage * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Small intestinal obstruction * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Small intestinal perforation * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Vomiting * 1	3/392 (0.77%)	3	2/394 (0.51%)	2
Lower gastrointestinal haemorrhage * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Large intestine polyp * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Anal prolapse * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
General disorders
Asthenia * 1	1/392 (0.26%)	2	4/394 (1.02%)	6
Death * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Fatigue * 1	2/392 (0.51%)	2	2/394 (0.51%)	2
Influenza like illness * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Malaise * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Oedema peripheral * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Pain * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Pyrexia * 1	5/392 (1.28%)	5	4/394 (1.02%)	4
Sudden death * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Peripheral swelling * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
General physical health deterioration * 1	10/392 (2.55%)	14	13/394 (3.30%)	19
Physical deconditioning * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Non-cardiac chest pain * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Multiple organ dysfunction syndrome * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Hepatobiliary disorders
Cholecystitis * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Cholecystitis acute * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Hepatic function abnormal * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Bile duct obstruction * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Hepatobiliary disease * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Infections and infestations
Acute sinusitis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Appendicitis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Bacteraemia * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Bronchitis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Cellulitis * 1	3/392 (0.77%)	3	2/394 (0.51%)	2
Clostridium difficile colitis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Diverticulitis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Encephalitis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Erysipelas * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Gastroenteritis * 1	3/392 (0.77%)	3	2/394 (0.51%)	2
Gastroenteritis clostridial * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Gastrointestinal infection * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Infection * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Influenza * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Lower respiratory tract infection * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Lyme disease * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Osteomyelitis * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Pneumonia * 1	12/392 (3.06%)	15	16/394 (4.06%)	20
Pulmonary tuberculosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Sepsis * 1	2/392 (0.51%)	4	4/394 (1.02%)	7
Septic shock * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Sinusitis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Skin infection * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Upper respiratory tract infection * 1	0/392 (0.00%)	0	5/394 (1.27%)	6
Urinary tract infection * 1	18/392 (4.59%)	21	10/394 (2.54%)	12
Viral upper respiratory tract infection * 1	0/392 (0.00%)	0	2/394 (0.51%)	3
Wound infection * 1	1/392 (0.26%)	3	0/394 (0.00%)	0
Urosepsis * 1	1/392 (0.26%)	1	6/394 (1.52%)	12
Tooth infection * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Acute endocarditis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Neutropenic sepsis * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Groin infection * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Pulmonary sepsis * 1	2/392 (0.51%)	4	1/394 (0.25%)	1
Arthritis bacterial * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Clostridium difficile infection * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Staphylococcal infection * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Pneumonia bacterial * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Arthritis infective * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Respiratory tract infection * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Encephalitis fungal * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Gastroenteritis norovirus * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Large intestine infection * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Injury, poisoning and procedural complications
Alcohol poisoning * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Fall * 1	0/392 (0.00%)	0	3/394 (0.76%)	3
Femoral neck fracture * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Femur fracture * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Humerus fracture * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Joint dislocation * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Pneumothorax traumatic * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Radius fracture * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Soft tissue injury * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Spinal compression fracture * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Subdural haematoma * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Ulna fracture * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Traumatic fracture * 1	13/392 (3.32%)	19	5/394 (1.27%)	5
Lumbar vertebral fracture * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Brain contusion * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Pseudophakic bullous keratopathy * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Investigations
Alanine aminotransferase increased * 1	2/392 (0.51%)	6	1/394 (0.25%)	1
Aspartate aminotransferase increased * 1	2/392 (0.51%)	5	1/394 (0.25%)	1
Blood bilirubin increased * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Blood lactate dehydrogenase increased * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Platelet count decreased * 1	1/392 (0.26%)	1	1/394 (0.25%)	3
Weight decreased * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Influenza A virus test positive * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Metabolism and nutrition disorders
Dehydration * 1	4/392 (1.02%)	4	1/394 (0.25%)	1
Diabetes mellitus * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Hypercalcaemia * 1	0/392 (0.00%)	0	1/394 (0.25%)	3
Hyperglycaemia * 1	1/392 (0.26%)	1	2/394 (0.51%)	3
Hypokalaemia * 1	2/392 (0.51%)	3	1/394 (0.25%)	3
Hyponatraemia * 1	1/392 (0.26%)	2	2/394 (0.51%)	11
Iron deficiency * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Decreased appetite * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Hypophagia * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Musculoskeletal and connective tissue disorders
Arthralgia * 1	3/392 (0.77%)	3	2/394 (0.51%)	2
Back pain * 1	8/392 (2.04%)	10	11/394 (2.79%)	12
Bone pain * 1	7/392 (1.79%)	8	5/394 (1.27%)	8
Bursitis * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Lumbar spinal stenosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Muscular weakness * 1	3/392 (0.77%)	4	2/394 (0.51%)	3
Musculoskeletal pain * 1	1/392 (0.26%)	1	1/394 (0.25%)	2
Neck pain * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Osteoarthritis * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Osteonecrosis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Osteoporosis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Osteoporotic fracture * 1	9/392 (2.30%)	14	1/394 (0.25%)	3
Pain in extremity * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Pathological fracture * 1	8/392 (2.04%)	13	4/394 (1.02%)	4
Rhabdomyolysis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Spinal osteoarthritis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Mobility decreased * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Intervertebral disc protrusion * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Osteonecrosis of jaw * 1	3/392 (0.77%)	3	1/394 (0.25%)	1
Spinal pain * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Adenocarcinoma of colon * 1	1/392 (0.26%)	3	1/394 (0.25%)	1
Anaplastic thyroid cancer * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
B-cell lymphoma * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Basal cell carcinoma * 1	3/392 (0.77%)	8	6/394 (1.52%)	12
Bladder cancer * 1	1/392 (0.26%)	1	2/394 (0.51%)	3
Bladder cancer recurrent * 1	1/392 (0.26%)	1	2/394 (0.51%)	6
Bladder transitional cell carcinoma * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Bowen's disease * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Bronchial carcinoma * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Cholangiocarcinoma * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Chronic lymphocytic leukaemia * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Colon cancer * 1	3/392 (0.77%)	3	1/394 (0.25%)	1
Gastric cancer * 1	1/392 (0.26%)	1	1/394 (0.25%)	3
Kaposi's sarcoma * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Lung adenocarcinoma * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Malignant melanoma * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Meningioma * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Nasal sinus cancer * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Pancreatic carcinoma * 1	1/392 (0.26%)	1	1/394 (0.25%)	2
Small cell lung cancer * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Squamous cell carcinoma of skin * 1	7/392 (1.79%)	8	7/394 (1.78%)	23
Tumour pain * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Intestinal adenocarcinoma * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Colorectal cancer metastatic * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Carcinoid tumour of the small bowel * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Thyroid cancer metastatic * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Lung neoplasm malignant * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Non-small cell lung cancer metastatic * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Brain neoplasm * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Colorectal cancer * 1	2/392 (0.51%)	3	0/394 (0.00%)	0
Hepatocellular carcinoma * 1	1/392 (0.26%)	2	0/394 (0.00%)	0
Nervous system disorders
Alexia * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Carotid artery stenosis * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Cauda equina syndrome * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Cerebrovascular accident * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Dizziness * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Haemorrhage intracranial * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Monoplegia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Neuralgia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Paraparesis * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Peripheral sensory neuropathy * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Presyncope * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Radiculopathy * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Sciatica * 1	2/392 (0.51%)	3	0/394 (0.00%)	0
Seizure * 1	1/392 (0.26%)	1	2/394 (0.51%)	2
Spinal cord compression * 1	7/392 (1.79%)	7	9/394 (2.28%)	9
Subarachnoid haemorrhage * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Syncope * 1	2/392 (0.51%)	2	2/394 (0.51%)	2
Transient global amnesia * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Transient ischaemic attack * 1	2/392 (0.51%)	2	2/394 (0.51%)	2
Spinal epidural haematoma * 1	0/392 (0.00%)	0	1/394 (0.25%)	2
Cognitive disorder * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Vascular dementia * 1	1/392 (0.26%)	3	0/394 (0.00%)	0
Ischaemic stroke * 1	2/392 (0.51%)	2	0/394 (0.00%)	0
Parkinson's disease * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Facial neuralgia * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Psychiatric disorders
Confusional state * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Delirium * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Depression * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Renal and urinary disorders
Dysuria * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Haematuria * 1	5/392 (1.28%)	6	4/394 (1.02%)	5
Hydronephrosis * 1	0/392 (0.00%)	0	4/394 (1.02%)	4
Nephrolithiasis * 1	2/392 (0.51%)	3	0/394 (0.00%)	0
Renal colic * 1	0/392 (0.00%)	0	2/394 (0.51%)	3
Urinary bladder haemorrhage * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Urinary incontinence * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Urinary retention * 1	4/392 (1.02%)	5	3/394 (0.76%)	3
Urinary tract obstruction * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Chronic kidney disease * 1	1/392 (0.26%)	3	0/394 (0.00%)	0
Urethral stenosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Acute kidney injury * 1	2/392 (0.51%)	2	2/394 (0.51%)	7
Ureterolithiasis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Reproductive system and breast disorders
Gynaecomastia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Pelvic pain * 1	0/392 (0.00%)	0	2/394 (0.51%)	3
Prostatism * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease * 1	2/392 (0.51%)	2	1/394 (0.25%)	2
Dyspnoea * 1	1/392 (0.26%)	1	4/394 (1.02%)	5
Interstitial lung disease * 1	1/392 (0.26%)	3	0/394 (0.00%)	0
Pleural effusion * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Pneumonia aspiration * 1	0/392 (0.00%)	0	2/394 (0.51%)	3
Pneumonitis * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
Pulmonary embolism * 1	6/392 (1.53%)	7	2/394 (0.51%)	2
Respiratory failure * 1	2/392 (0.51%)	3	1/394 (0.25%)	1
Lower respiratory tract inflammation * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Organising pneumonia * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Skin and subcutaneous tissue disorders
Skin ulcer * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Vascular disorders
Aortic dissection * 1	1/392 (0.26%)	1	2/394 (0.51%)	3
Aortic stenosis * 1	0/392 (0.00%)	0	1/394 (0.25%)	1
Circulatory collapse * 1	1/392 (0.26%)	1	0/394 (0.00%)	0
Hypertension * 1	1/392 (0.26%)	1	2/394 (0.51%)	3
Hypotension * 1	2/392 (0.51%)	2	1/394 (0.25%)	1
Lymphoedema * 1	0/392 (0.00%)	0	2/394 (0.51%)	2
Peripheral ischaemia * 1	2/392 (0.51%)	5	0/394 (0.00%)	0
Deep vein thrombosis * 1	1/392 (0.26%)	1	1/394 (0.25%)	1
1 Term from vocabulary, MedDRA (22.1); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Radium-223 Dichloride + Abi/Pred		Placebo + Abi/Pred
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	369/392 (94.13%)		376/394 (95.43%)
Blood and lymphatic system disorders
Anaemia * 1	65/392 (16.58%)	134	61/394 (15.48%)	113
Gastrointestinal disorders
Abdominal pain * 1	23/392 (5.87%)	24	15/394 (3.81%)	17
Constipation * 1	69/392 (17.60%)	81	79/394 (20.05%)	97
Diarrhoea * 1	69/392 (17.60%)	107	71/394 (18.02%)	102
Dyspepsia * 1	20/392 (5.10%)	23	15/394 (3.81%)	16
Nausea * 1	76/392 (19.39%)	91	67/394 (17.01%)	74
Vomiting * 1	40/392 (10.20%)	48	40/394 (10.15%)	45
General disorders
Asthenia * 1	37/392 (9.44%)	48	43/394 (10.91%)	60
Fatigue * 1	103/392 (26.28%)	142	95/394 (24.11%)	136
Influenza like illness * 1	12/392 (3.06%)	16	20/394 (5.08%)	24
Oedema peripheral * 1	57/392 (14.54%)	78	64/394 (16.24%)	77
Pyrexia * 1	28/392 (7.14%)	33	34/394 (8.63%)	49
Infections and infestations
Influenza * 1	22/392 (5.61%)	23	13/394 (3.30%)	21
Nasopharyngitis * 1	31/392 (7.91%)	40	38/394 (9.64%)	53
Upper respiratory tract infection * 1	28/392 (7.14%)	39	33/394 (8.38%)	43
Urinary tract infection * 1	39/392 (9.95%)	54	31/394 (7.87%)	38
Injury, poisoning and procedural complications
Fall * 1	60/392 (15.31%)	87	50/394 (12.69%)	70
Traumatic fracture * 1	42/392 (10.71%)	72	23/394 (5.84%)	48
Contusion * 1	28/392 (7.14%)	38	31/394 (7.87%)	37
Investigations
Alanine aminotransferase increased * 1	69/392 (17.60%)	180	61/394 (15.48%)	149
Aspartate aminotransferase increased * 1	61/392 (15.56%)	127	55/394 (13.96%)	104
Weight decreased * 1	20/392 (5.10%)	32	24/394 (6.09%)	34
Metabolism and nutrition disorders
Hyperglycaemia * 1	12/392 (3.06%)	18	23/394 (5.84%)	50
Hypokalaemia * 1	43/392 (10.97%)	76	43/394 (10.91%)	75
Decreased appetite * 1	65/392 (16.58%)	82	52/394 (13.20%)	54
Musculoskeletal and connective tissue disorders
Arthralgia * 1	91/392 (23.21%)	133	88/394 (22.34%)	155
Back pain * 1	151/392 (38.52%)	250	138/394 (35.03%)	209
Bone pain * 1	69/392 (17.60%)	96	76/394 (19.29%)	100
Muscle spasms * 1	27/392 (6.89%)	32	30/394 (7.61%)	34
Muscular weakness * 1	25/392 (6.38%)	39	36/394 (9.14%)	50
Musculoskeletal pain * 1	46/392 (11.73%)	55	47/394 (11.93%)	58
Myalgia * 1	25/392 (6.38%)	29	23/394 (5.84%)	26
Neck pain * 1	17/392 (4.34%)	18	24/394 (6.09%)	30
Osteoporosis * 1	27/392 (6.89%)	28	1/394 (0.25%)	1
Osteoporotic fracture * 1	26/392 (6.63%)	75	1/394 (0.25%)	1
Pain in extremity * 1	52/392 (13.27%)	73	58/394 (14.72%)	80
Pathological fracture * 1	48/392 (12.24%)	68	26/394 (6.60%)	40
Musculoskeletal chest pain * 1	28/392 (7.14%)	41	31/394 (7.87%)	39
Spinal pain * 1	30/392 (7.65%)	35	27/394 (6.85%)	34
Nervous system disorders
Dizziness * 1	45/392 (11.48%)	54	35/394 (8.88%)	41
Headache * 1	30/392 (7.65%)	45	31/394 (7.87%)	39
Psychiatric disorders
Insomnia * 1	32/392 (8.16%)	35	25/394 (6.35%)	26
Renal and urinary disorders
Haematuria * 1	31/392 (7.91%)	44	21/394 (5.33%)	28
Reproductive system and breast disorders
Pelvic pain * 1	12/392 (3.06%)	16	21/394 (5.33%)	31
Respiratory, thoracic and mediastinal disorders
Cough * 1	36/392 (9.18%)	42	41/394 (10.41%)	50
Dyspnoea * 1	20/392 (5.10%)	28	31/394 (7.87%)	35
Vascular disorders
Hypertension * 1	61/392 (15.56%)	164	80/394 (20.30%)	213
Hot flush * 1	23/392 (5.87%)	25	51/394 (12.94%)	53
1 Term from vocabulary, MedDRA (22.1); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: Bayer
• Phone: 1-888-8422937
• EMail: clinical-trials-contact@bayer.com

Publications of Results:

Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nole F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X. Epub 2019 Feb 6. Erratum In: Lancet Oncol. 2019 Oct;20(10):e559.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shore N, Higano CS, George DJ, Sternberg CN, Saad F, Tombal B, Miller K, Kalinovsky J, Jiao X, Tangirala K, Sartor O. Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2020 Dec;23(4):680-688. doi: 10.1038/s41391-020-0236-0. Epub 2020 May 13.

Matsubara N, Kimura G, Uemura H, Uemura H, Nakamura M, Nagamori S, Mizokami A, Kikukawa H, Hosono M, Kinuya S, Krissel H, Siegel J, Kakehi Y. A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study. Int J Clin Oncol. 2020 Apr;25(4):720-731. doi: 10.1007/s10147-019-01589-6. Epub 2019 Dec 10.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02043678
• Other Study ID Numbers: 15396; 2013-003438-33 ( EudraCT Number )
• First Submitted: January 21, 2014
• First Posted: January 23, 2014
• Results First Submitted: February 12, 2019
• Results First Posted: March 5, 2019
• Last Update Posted: February 26, 2024