Trial Outcomes & Findings for Standard Dose Versus High Dose and Versus Extended Standard Dose Radium-223 Dichloride in Castration-resistant Prostate Cancer Metastatic to the Bone (NCT NCT02023697)

NCT ID: NCT02023697

Last Updated: 2019-07-12

Results Overview

Symptomatic skeletal event (SSE) free survival is based on the following events: the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); the occurrence of spinal cord compression; a tumor related orthopedic surgical intervention, and death. In this evaluation - comparison 1, SSE-FS following randomization is defined in ITT participants as the time from randomization to an SSE or death, whichever occurs first.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

391 participants

Primary outcome timeframe

From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)

Results posted on

2019-07-12

Participant Flow

Of the 391 participants assigned to treatment in the intention to treatment (ITT) analysis set, 370 participants (94.6%) received at least one dose of radium-223 dichloride, and a total of 21 participants (5.4%) never received treatment

Participant milestones

Participant milestones
Measure	Radium-223 Dichloride 55 kBq/kg, 6 Doses (Arm A) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses ("standard dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 88 kBq/kg, 6 Doses (Arm B) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 88 kBq/kg IV every 28 days for up to 6 doses ("high dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.
Treatment Period STARTED	130	130	131
Treatment Period Received Treatment	125	124	121
Treatment Period COMPLETED	84	67	29
Treatment Period NOT COMPLETED	46	63	102
Active Follow-up Period STARTED	120	120	116
Active Follow-up Period COMPLETED	28	21	17
Active Follow-up Period NOT COMPLETED	92	99	99
Long-term Follow-up Period STARTED	28	21	17
Long-term Follow-up Period COMPLETED	0	0	0
Long-term Follow-up Period NOT COMPLETED	28	21	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Radium-223 Dichloride 55 kBq/kg, 6 Doses (Arm A) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses ("standard dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 88 kBq/kg, 6 Doses (Arm B) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 88 kBq/kg IV every 28 days for up to 6 doses ("high dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.
Treatment Period Radiological progression	13	17	26
Treatment Period Never Treated	5	6	10
Treatment Period Adverse Event	13	25	23
Treatment Period Logistical difficulties	1	1	1
Treatment Period Clinical progression	10	8	28
Treatment Period Withdrawal by Subject	4	5	13
Treatment Period Safety outcome reached	0	1	0
Treatment Period Physician Decision	0	0	1
Active Follow-up Period Withdrawal by Subject	5	13	7
Active Follow-up Period Lost to Follow-up	1	1	1
Active Follow-up Period Deterioration of general condition	1	1	1
Active Follow-up Period Other unspecified	2	0	1
Active Follow-up Period Clinical progression	0	2	1
Active Follow-up Period Radiological progression	0	0	1
Active Follow-up Period Death	83	82	87
Long-term Follow-up Period Death	9	6	4
Long-term Follow-up Period Withdrawal by Subject	6	3	0
Long-term Follow-up Period Lost to Follow-up	1	0	1
Long-term Follow-up Period Entered the long-term follow-up study	6	9	6
Long-term Follow-up Period Technical problems	0	0	1
Long-term Follow-up Period Other unspecified	6	3	5

Baseline Characteristics

The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Radium-223 Dichloride 55 kBq/kg, 6 Doses (Arm A) n=130 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses ("standard dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 88 kBq/kg IV every 28 days for up to 6 doses ("high dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose"). Participants who discontinued study treatment and who did not have an SSE entered an active follow-up period with clinic visits. Participants from the treatment period or the active follow-up period with clinic visits who could no longer travel entered an active follow-up period without clinic visits. All study participants eligible for further follow-up were either in this study or in a separate long term follow-up study for up to 7 years.	Total n=391 Participants Total of all reporting groups
Age, Continuous	70.6 years STANDARD_DEVIATION 8.6 • n=130 Participants	70.9 years STANDARD_DEVIATION 8.3 • n=130 Participants	70.0 years STANDARD_DEVIATION 8.1 • n=131 Participants	70.5 years STANDARD_DEVIATION 8.3 • n=391 Participants
Sex: Female, Male Female	0 Participants n=130 Participants	0 Participants n=130 Participants	0 Participants n=131 Participants	0 Participants n=391 Participants
Sex: Female, Male Male	130 Participants n=130 Participants	130 Participants n=130 Participants	131 Participants n=131 Participants	391 Participants n=391 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=130 Participants	3 Participants n=130 Participants	6 Participants n=131 Participants	10 Participants n=391 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	125 Participants n=130 Participants	124 Participants n=130 Participants	120 Participants n=131 Participants	369 Participants n=391 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=130 Participants	3 Participants n=130 Participants	5 Participants n=131 Participants	12 Participants n=391 Participants
Race/Ethnicity, Customized White	104 Participants n=130 Participants	102 Participants n=130 Participants	108 Participants n=131 Participants	314 Participants n=391 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=130 Participants	5 Participants n=130 Participants	5 Participants n=131 Participants	13 Participants n=391 Participants
Race/Ethnicity, Customized Asian	17 Participants n=130 Participants	17 Participants n=130 Participants	13 Participants n=131 Participants	47 Participants n=391 Participants
Race/Ethnicity, Customized Not reported	6 Participants n=130 Participants	6 Participants n=130 Participants	5 Participants n=131 Participants	17 Participants n=391 Participants
ECOG PS 0	48 Participants n=130 Participants	59 Participants n=130 Participants	49 Participants n=131 Participants	156 Participants n=391 Participants
ECOG PS 1	78 Participants n=130 Participants	67 Participants n=130 Participants	77 Participants n=131 Participants	222 Participants n=391 Participants
ECOG PS 2	4 Participants n=130 Participants	4 Participants n=130 Participants	5 Participants n=131 Participants	13 Participants n=391 Participants
Average Worst Pain Score (WPS)	3.6 scores on a scale STANDARD_DEVIATION 2.6 • n=128 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	3.3 scores on a scale STANDARD_DEVIATION 2.5 • n=125 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	3.4 scores on a scale STANDARD_DEVIATION 2.6 • n=122 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	3.4 scores on a scale STANDARD_DEVIATION 2.5 • n=375 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.
Extent of disease Normal or abnormal because of benign bone disease	0 Participants n=130 Participants	1 Participants n=130 Participants	0 Participants n=131 Participants	1 Participants n=391 Participants
Extent of disease <6 metastases	19 Participants n=130 Participants	22 Participants n=130 Participants	19 Participants n=131 Participants	60 Participants n=391 Participants
Extent of disease 6-20 metastases	52 Participants n=130 Participants	53 Participants n=130 Participants	52 Participants n=131 Participants	157 Participants n=391 Participants
Extent of disease >20 lesions but not a superscan	47 Participants n=130 Participants	48 Participants n=130 Participants	54 Participants n=131 Participants	149 Participants n=391 Participants
Extent of disease Superscan	12 Participants n=130 Participants	6 Participants n=130 Participants	6 Participants n=131 Participants	24 Participants n=391 Participants
Time from initial prostate cancer diagnosis to randomization	58.9 months n=130 Participants	72.9 months n=130 Participants	67.1 months n=131 Participants	66.8 months n=391 Participants
Time from initial bone metastases diagnosis to randomization	30.8 months n=130 Participants	29.9 months n=130 Participants	37.5 months n=131 Participants	31.7 months n=391 Participants
Time from most recent prostate cancer progression to randomization	1.4 months n=129 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	1.4 months n=130 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	1.3 months n=131 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	1.3 months n=390 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.
Time from most recent bone metastases progression to randomization	2.3 months n=118 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	2.8 months n=119 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	1.9 months n=121 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	2.4 months n=358 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.
Body Mass Index	28.4 kg/m^2 STANDARD_DEVIATION 5.2 • n=126 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	28.0 kg/m^2 STANDARD_DEVIATION 5.2 • n=127 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	29.1 kg/m^2 STANDARD_DEVIATION 5.4 • n=124 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	28.5 kg/m^2 STANDARD_DEVIATION 5.3 • n=377 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.
Time from first bone metastases progression to most recent progression	7.9 months n=118 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	8.9 months n=119 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	13.4 months n=120 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.	9.5 months n=357 Participants • The last assessment collected prior to randomization was used as baseline value. If no assessment was done prior to randomization, then the assessment collected after randomization but prior to first dose was used as baseline. Number of analyzed reflect the participants with data available at baseline.

PRIMARY outcome

Timeframe: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)

Population: Intent-to-treat (ITT): All randomized participants. Data from Arm C are truncated at 7th dose date when pooling with Arm A, therefore Pooled Arm A+C included 261 participants.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose	—	85 Participants	118 Participants

PRIMARY outcome

Population: Intent-to-treat (ITT): All randomized participants. Data from Arm C are truncated at 7th dose date when pooling with Arm A, therefore Pooled Arm A+C included 261 participants.

In this evaluation - comparison 1, SSE-FS following randomization is defined in ITT participants as the time from randomization to an SSE or death, whichever occurs first.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose	—	12.9 months Interval 10.9 to 14.8	12.3 months Interval 10.3 to 13.5

PRIMARY outcome

Population: Week 24 (W24): All ITT participants in Arm A (standard dose) and Arm C (extended dosing) treated with radium-223 dichloride and eligible for further treatment at W24 (i.e., 7th injection). All participants who received 6 doses from Arm A and participants who received \>=6 doses from Arm C were included .

Symptomatic skeletal event (SSE) free survival is based on the following events: the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); the occurrence of spinal cord compression; a tumor related orthopedic surgical intervention, and death. In this evaluation - Comparison 2, SSE-FS from 6th dose is defined in W24 participants as the time from Week 24 baseline (the 6th dose date) to an SSE or death, whichever occurs first.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose	—	41 Participants	40 Participants

PRIMARY outcome

Population: Week 24 (W24)

In this evaluation - Comparison 2, SSE-FS from 6th dose is defined in W24 participants as the time from Week 24 baseline (the 6th dose date) to an SSE or death, whichever occurs first.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose	—	13.2 months Interval 9.2 to 18.1	10.8 months Interval 8.1 to 13.8

PRIMARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized	92 Participants	80 Participants	85 Participants

PRIMARY outcome

Population: ITT

Symptomatic skeletal event (SSE) is defined as follows: The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms; The occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral); The occurrence of spinal cord compression; A tumor related orthopedic surgical intervention.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized	9.6 months Interval 9.0 to 10.9	13.1 months Interval 11.0 to 14.6	12.9 months Interval 10.9 to 14.8

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Overall survival was defined as the time in days from the applicable start date to the date of death due to any cause. Participants who were still alive or who were lost to survival follow-up as of database cut-off date were to be censored at the last known alive date on or prior to database cut-off date.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose	—	89 Participants	106 Participants

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Overall Survival - High Dose vs. Standard Dose	—	16.0 months Interval 14.7 to 17.2	14.9 months Interval 13.7 to 16.7

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose	—	43 Participants	38 Participants

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Overall Survival - Extended Dose vs. Standard Dose	—	16.5 months Interval 14.0 to 19.9	15.2 months Interval 14.0 to 19.0

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With an Overall Survival - Three Dose Groups As Randomized	93 Participants	83 Participants	89 Participants

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Overall Survival Event - Three Dose Groups as Randomized	14.4 months Interval 12.1 to 16.5	15.8 months Interval 14.3 to 18.1	16.0 months Interval 14.7 to 17.2

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose	—	42 Participants	62 Participants

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose	—	24.1 months Interval 18.0 to There were no sufficient events observed in this study to calculate the upper limit.	26.3 months Interval 26.3 to There were no sufficient events observed in this study to calculate the upper limit.

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose	—	19 Participants	25 Participants

SECONDARY outcome

Population: Week 24 (W24)

Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose	—	NA months Interval 21.2 to There were no sufficient events observed in this study to calculate the median or its upper limit of 80% CI.	19.5 months Interval 12.3 to 23.4

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized	48 Participants	37 Participants	42 Participants

SECONDARY outcome

Population: ITT

Time to first SSE is defined as the time in days from the applicable start date to the first SSE on or following the start date.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized	18.8 months Interval 15.1 to 25.6	NA months Interval 26.3 to There were no sufficient events observed in this study to calculate the median or its upper limit of 80% CI.	24.1 months Interval 18.0 to There were no sufficient events observed in this study to calculate the upper limit of 80% CI.

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Radiological progression of soft tissue disease is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Magnetic resonance imaging (MRI) or computed tomography (CT) scans. Radiological progression of osseous disease is determined according to adapted PCWG2 criteria based on whole body technetium-99 bone scans. Radiological bone progression is determined if at least one of the following criteria is met: The first bone scan with ≥2 new lesions compared to baseline is observed \<12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); or The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from randomization and the new lesions are verified on the next bone scan ≥6 weeks later (a total of ≥2 new lesions compared to baseline).

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose	—	77 Participants	141 Participants

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Radiological progression free survival is defined as the time in days from the applicable start date to the date of subsequent radiological disease progression or death from any cause (if death occurs before such progression). Participants not experiencing death or radiological disease progression as of database cut-off were censored at the last radiological disease progression assessment.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Radiological Progression Free Survival - High Dose vs. Standard Dose	—	7.5 months Interval 5.9 to 8.6	6.0 months Interval 5.2 to 6.2

SECONDARY outcome

Population: Baseline is randomization date

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose	—	49 Participants	47 Participants

SECONDARY outcome

Population: Baseline is randomization date

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Radiological Progression Free Survival - Extended Dose vs. Standard Dose	—	8.9 months Interval 6.3 to 11.8	9.0 months Interval 7.5 to 9.6

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized	90 Participants	77 Participants	77 Participants

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Radiological Progression Free Survival - Three Dose Groups as Randomized	6.1 months Interval 5.2 to 6.6	6.3 months Interval 5.1 to 7.2	7.5 months Interval 5.9 to 8.6

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose	—	63 Participants	115 Participants

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Time to radiological progression is defined as the time in days from the applicable start date to the date of subsequent radiological progression. Participants without radiological progression as of database cut-off date, whether or not surviving, were censored at the last radiological progression assessment.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=261 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Radiological Progression - High Dose vs. Standard Dose	—	8.7 months Interval 6.2 to 9.7	6.2 months Interval 6.0 to 6.6

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose	—	43 Participants	43 Participants

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=84 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=69 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Radiological Progression - Extended Dose vs. Standard Dose	—	8.9 months Interval 6.3 to 14.6	9.0 months Interval 7.2 to 10.2

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized	67 Participants	66 Participants	63 Participants

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Radiological Progression - Three Dose Groups as Randomized	6.6 months Interval 6.0 to 8.7	6.2 months Interval 5.9 to 7.1	8.7 months Interval 6.2 to 9.7

SECONDARY outcome

Population: ITT

Timepoint pain improvement rate is defined as the proportion of participants with a 30% and 2-point decrease in Worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart among participants with a WPS score ≥ 4 at baseline.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Timepoint Pain Improvement Rate - Three Dose Groups as Randomized Week 12	18.6 percentage Interval 11.1 to 28.5	16.7 percentage Interval 10.1 to 25.7	16.0 percentage Interval 9.5 to 24.7
Timepoint Pain Improvement Rate - Three Dose Groups as Randomized Overall (confirmed)	37.2 percentage Interval 27.3 to 48.1	27.1 percentage Interval 18.7 to 37.0	26.0 percentage Interval 17.9 to 35.6

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=22 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=20 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose Week 12	—	31.8 percentage Interval 18.7 to 47.7	30.0 percentage Interval 16.6 to 46.7
Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose Overall (confirmed)	—	40.9 percentage Interval 26.4 to 56.8	55.0 percentage Interval 38.5 to 70.7

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Participants were divided in 3 groups according to baseline pain evaluation: asymptomatic subjects (WPS 0 to \< 1 at baseline); mildly symptomatic subjects (WPS 1-3 at baseline); and symptomatic subjects with WPS \> 3 and ≤ 7 at baseline). Pain progression was defined as the occurrence of a pain increase of 2 or more points in the average (i.e., average of 7-day assessments) "worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart. Participants with insufficient applicable baseline assessments or without adequate post-baseline assessments were to be censored at the applicable baseline date.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=113 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=218 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose	—	31 Participants	68 Participants

SECONDARY outcome

Population: ITT. Data from Arm C are truncated at 7th dose date when pooling with Arm A.

The time to pain progression is defined for each applicable baseline for applicable participants as the time (in days) from the respective baseline until occurrence of the first post-baseline pain progression event.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=113 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=218 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Pain Progression - High Dose vs. Standard Dose	—	NA months Interval 9.4 to There were no sufficient pain progression events observed in this study to calculate the median or its upper limit of 80% CI.	NA months Interval 8.6 to There were no sufficient pain progression events observed in this study to calculate the median or its upper limit of 80% CI.

SECONDARY outcome

Population: Week 24 (W24)

Pain progression is defined for each baseline in participants evaluable for pain progression at the applicable baseline, i.e., participants with a WPS of ≤ 7 at the respective baseline assessment.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=78 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=65 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose	—	10 Participants	15 Participants

SECONDARY outcome

Population: Week 24 (W24)

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=78 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=65 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Pain Progression - Extended Dose vs. Standard Dose	—	NA months There were no sufficient pain progression events observed in this study to calculate the median or its 80% CI.	NA months There were no sufficient pain progression events observed in this study to calculate the median or its 80% CI.

SECONDARY outcome

Population: ITT

Pain progression is defined for each baseline in participants evaluable for pain progression at the applicable baseline, i.e., participants with a WPS of ≤ 7 at the respective baseline assessment.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=108 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=110 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=113 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized	46 Participants	32 Participants	31 Participants

SECONDARY outcome

Population: ITT

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=108 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=110 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=113 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Time to Pain Progression - Three Dose Groups as Randomized	10.1 months Interval 8.8 to 11.8	NA months Interval 8.9 to There were no sufficient pain progression events observed in this study to calculate the median or its upper limit of 80% CI.	NA months Interval 9.4 to There were no sufficient pain progression events observed in this study to calculate the median or its upper limit of 80% CI.

SECONDARY outcome

Population: Safety Analysis Set

Treatment-emergent adverse events are events starting or worsening from the initiation of treatment until 30 days after the last administration of radium-223 dichloride. The intensity of an AE is classified according to the grades specified by the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE).

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=125 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=124 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=121 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With Treatment-Emergent Adverse Events Any TEAE	116 Participants	118 Participants	119 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 1	18 Participants	23 Participants	20 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 2	34 Participants	52 Participants	40 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 3	49 Participants	38 Participants	46 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 4	11 Participants	4 Participants	11 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 5	4 Participants	1 Participants	2 Participants
Number of Participants With Treatment-Emergent Adverse Events Serious	37 Participants	25 Participants	36 Participants
Number of Participants With Treatment-Emergent Adverse Events Any drug-related TEAE	57 Participants	73 Participants	73 Participants

OTHER_PRE_SPECIFIED outcome

Analgesic use in this study were captured via two methods: Analgesic concomitant medication case report form, where the physician records the analgesic medication prescribed to manage pain; 24 hour analgesic consumption case report form, in which all analgesic medication taken in the last 24 hours.

Outcome measures

Outcome measures
Measure	Radium-223 Dichloride 55 kBq/kg, 12 Doses (Arm C) n=131 Participants Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").	Radium-223 88 kBq/kg, 6 Doses (Arm B) n=130 Participants Participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Pooled Radium-223 55 kBq/kg (Arms A and C) n=130 Participants Pooled Arms A and C, participants who were randomized in a 1:1:1 fashion received radium-223 dichloride 55 kBq/kg IV every 28 days for up to 6 and 12 doses, respectively.
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline Strong Opioid - No Change	26 Participants	22 Participants	27 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From Strong Opioid to Weak Opioid	2 Participants	1 Participants	0 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From Strong Opioid to No analgesic or Non-opioid	13 Participants	18 Participants	9 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From Strong Opioid to Missing	4 Participants	2 Participants	0 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From No analgesic or Non-opioid to Strong Opioid	25 Participants	24 Participants	26 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From No analgesic or Non-opioid to Weak Opioid	12 Participants	5 Participants	8 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline No analgesic or Non-opioid - No Change	30 Participants	46 Participants	41 Participants
Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline From No analgesic or Non-opioid to Missing	5 Participants	5 Participants	5 Participants

Adverse Events

Radium-223 55 kBq/kg Arm A (6 Doses)

Serious events: 25 serious events

Other events: 109 other events

Deaths: 98 deaths

Radium-223 88 kBq/kg Arm B (6 Doses)

Serious events: 36 serious events

Other events: 111 other events

Deaths: 100 deaths

Radium-223 55 kBq/kg Arm C (12 Doses)

Serious events: 37 serious events

Other events: 111 other events

Deaths: 102 deaths

Serious adverse events

Other adverse events

Additional Information

Therapeutic Area Head

Bayer AG

Phone: (+) 1-888-8422937

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Radium-223 55 kBq/kg Arm A (6 Doses) n=125 participants at risk Participants who were randomized in a 1:1:1 fashion received Xofigo (Radium-223 dichloride, BAY88-8223) 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses ("standard dose").	Radium-223 88 kBq/kg Arm B (6 Doses) n=124 participants at risk Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 88 kBq/kg IV every 28 days for up to 6 doses ("high dose").	Radium-223 55 kBq/kg Arm C (12 Doses) n=121 participants at risk Participants who were randomized in a 1:1:1 fashion received Radium-223 dichloride (Xofigo, BAY88-8223) 55 kBq/kg IV every 28 days for up to 12 doses ("extended dose").
Blood and lymphatic system disorders Anaemia	23.2% 29/125 • Number of events 64 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	26.6% 33/124 • Number of events 69 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	24.8% 30/121 • Number of events 79 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Blood and lymphatic system disorders Neutropenia	1.6% 2/125 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	8.1% 10/124 • Number of events 21 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.1% 5/121 • Number of events 16 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Blood and lymphatic system disorders Thrombocytopenia	5.6% 7/125 • Number of events 14 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	8.1% 10/124 • Number of events 26 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	8.3% 10/121 • Number of events 33 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Gastrointestinal disorders Abdominal pain	4.0% 5/125 • Number of events 5 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	2.4% 3/124 • Number of events 3 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	8.3% 10/121 • Number of events 12 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Gastrointestinal disorders Constipation	16.8% 21/125 • Number of events 27 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	8.1% 10/124 • Number of events 11 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	14.9% 18/121 • Number of events 20 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Gastrointestinal disorders Diarrhoea	20.8% 26/125 • Number of events 34 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	22.6% 28/124 • Number of events 39 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	21.5% 26/121 • Number of events 32 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Gastrointestinal disorders Nausea	24.8% 31/125 • Number of events 38 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	23.4% 29/124 • Number of events 33 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	23.1% 28/121 • Number of events 39 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Gastrointestinal disorders Vomiting	9.6% 12/125 • Number of events 16 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	12.1% 15/124 • Number of events 19 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	14.0% 17/121 • Number of events 22 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
General disorders Asthenia	9.6% 12/125 • Number of events 15 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	7.3% 9/124 • Number of events 11 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	14.0% 17/121 • Number of events 25 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
General disorders Fatigue	31.2% 39/125 • Number of events 58 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	29.8% 37/124 • Number of events 46 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	28.9% 35/121 • Number of events 49 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
General disorders Oedema peripheral	7.2% 9/125 • Number of events 10 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.8% 6/124 • Number of events 6 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
General disorders Pyrexia	3.2% 4/125 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	7.3% 9/124 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.1% 5/121 • Number of events 5 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Infections and infestations Urinary tract infection	1.6% 2/125 • Number of events 2 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.6% 7/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	1.7% 2/121 • Number of events 3 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Injury, poisoning and procedural complications Fall	2.4% 3/125 • Number of events 5 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	7.3% 9/124 • Number of events 14 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.3% 4/121 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Investigations Neutrophil count decreased	3.2% 4/125 • Number of events 6 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	7.3% 9/124 • Number of events 22 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	2.5% 3/121 • Number of events 11 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Investigations Weight decreased	9.6% 12/125 • Number of events 17 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.8% 6/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	15.7% 19/121 • Number of events 24 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Metabolism and nutrition disorders Decreased appetite	24.8% 31/125 • Number of events 39 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	19.4% 24/124 • Number of events 25 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	21.5% 26/121 • Number of events 31 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Arthralgia	16.0% 20/125 • Number of events 26 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	13.7% 17/124 • Number of events 22 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	15.7% 19/121 • Number of events 24 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Back pain	16.0% 20/125 • Number of events 25 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	14.5% 18/124 • Number of events 19 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	19.8% 24/121 • Number of events 29 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Bone pain	18.4% 23/125 • Number of events 26 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	15.3% 19/124 • Number of events 21 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	22.3% 27/121 • Number of events 32 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Muscular weakness	4.8% 6/125 • Number of events 8 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	6.5% 8/124 • Number of events 8 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	1.7% 2/121 • Number of events 2 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.2% 9/125 • Number of events 11 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.6% 7/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	9.1% 11/121 • Number of events 12 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Myalgia	5.6% 7/125 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.2% 4/124 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.3% 4/121 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Pain in extremity	10.4% 13/125 • Number of events 15 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	7.3% 9/124 • Number of events 10 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	9.9% 12/121 • Number of events 13 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Pathological fracture	1.6% 2/125 • Number of events 2 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.2% 4/124 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	8.8% 11/125 • Number of events 15 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.0% 5/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	6.6% 8/121 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Musculoskeletal and connective tissue disorders Spinal pain	3.2% 4/125 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	0.81% 1/124 • Number of events 1 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 12 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Nervous system disorders Dizziness	2.4% 3/125 • Number of events 3 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	2.4% 3/124 • Number of events 3 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	6.6% 8/121 • Number of events 10 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Nervous system disorders Headache	5.6% 7/125 • Number of events 8 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.8% 6/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.0% 6/121 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Psychiatric disorders Depression	3.2% 4/125 • Number of events 5 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	0.81% 1/124 • Number of events 1 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Psychiatric disorders Insomnia	7.2% 9/125 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.8% 6/124 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.1% 5/121 • Number of events 6 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Respiratory, thoracic and mediastinal disorders Cough	2.4% 3/125 • Number of events 5 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.2% 4/124 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.4% 8/125 • Number of events 8 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	3.2% 4/124 • Number of events 4 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.
Vascular disorders Hypertension	4.8% 6/125 • Number of events 7 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	4.0% 5/124 • Number of events 9 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.	5.8% 7/121 • Number of events 17 • From starting of study medication over a period of approximately 3 years since first participant was enrolled.