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Clinical Trial Results:
A three arm randomized, open-label Phase II study of radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) versus 80 kBq/kg (88 kBq/kg after implementation of NIST update), and versus 50 kBq/kg (55 kBq/kg after implementation of NIST update) in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to the bone

Summary
EudraCT number	2013-003118-42
Trial protocol	DE IT CZ SE FI ES GB
Global end of trial date	09 Aug 2018

Results information
Results version number	v1(current)
This version publication date	17 Jul 2019
First version publication date	17 Jul 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BAY88-8223/16507

ISRCTN number

US NCT number

NCT02023697

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Aug 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Aug 2018

Was the trial ended prematurely?

Main objective of the trial

Co-primary objectives: - To evaluate efficacy as measured by symptomatic skeletal event-free survival (SSE-FS) of radium-223 dichloride 55 kBq/kg for up to 6 doses compared to radium-223 dichloride 88 kBq/kg for up to 6 doses in subjects with CRPC metastatic to the bone; and  - To evaluate efficacy as measured by SSE-FS of radium223 dichloride 55 kBq/kg for up to 6 additional doses compared to no further radium-223 dichloride treatment in subjects with CRPC metastatic to the bone who previously received radium-223 dichloride 55 kBq/kg for up to 6 doses.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Concomitant best standard of care (BSoC) was permitted according to local clinical practice. Allowed treatments for prostate cancer included anti-androgenic therapies (detailed list in full protocol), surgery, and radiation. Subjects should have remained castrated during the study period (surgically or chemically). Initiation, maintenance or discontinuation of osteoclast inhibitors were left to the discretion of the investigator. Cytotoxic chemotherapy for prostate cancer, other systemic radioisotopes, concomitant hemibody External beam radiotherapy (EBRT), or other investigational drugs were not to be used during the treatment period. If prohibited therapies were considered BSoC during the treatment period, further radium-223 dichloride administrations must have been discontinued, and if possible, prohibited treatment was not to be given within 30 days after the last injection of radium- 223 dichloride.

Evidence for comparator

Actual start date of recruitment

10 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

7 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Sweden: 14

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

Czech Republic: 4

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Canada: 51

Country: Number of subjects enrolled

Israel: 70

Country: Number of subjects enrolled

China: 6

Country: Number of subjects enrolled

United States: 83

Country: Number of subjects enrolled

Chile: 4

Country: Number of subjects enrolled

Australia: 56

Country: Number of subjects enrolled

Korea, Republic of: 39

Country: Number of subjects enrolled

France: 6

Worldwide total number of subjects

391

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

292

85 years and over

Subject disposition

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Recruitment details

Screening details

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

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“standard dose”)

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 88 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“high dose”)

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 12 doses (“extended dose”)

Number of subjects in period 1	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Started	130	130	131
Received Treatment	125	124	121
Completed	84	67	29
Not completed	46	63	102
Clinical progression	10	8	28
Consent withdrawn by subject	4	5	13
Never Treated	5	6	10
Physician decision	-	-	1
Logistical difficulties	1	1	1
Radiological progression	13	17	26
Adverse event, non-fatal	13	25	23
Safety outcome reached	-	1	-

Period 2 title

Active follow-up period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“standard dose”)

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Arm description

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 88 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“high dose”)

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Arm description

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 12 doses (“extended dose”)

Number of subjects in period 2	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Started	120	120	116
Completed	28	21	17
Not completed	92	99	99
Adverse event, serious fatal	83	82	87
Clinical progression	-	2	1
Consent withdrawn by subject	5	13	7
Other unspecified	2	-	1
Radiological progression	-	-	1
Deterioration of general condition	1	1	1
Lost to follow-up	1	1	1

Period 3 title

Long-term follow-up period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Arm description

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”). 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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“standard dose”)

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Arm description

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”). 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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 88 kBq/kg intravenously (IV) every 28 days for up to 6 doses (“high dose”)

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Arm description

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”). 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.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 dichloride (Xofigo, BAY88-8223) was administered 55 kBq/kg intravenously (IV) every 28 days for up to 12 doses (“extended dose”)

Number of subjects in period 3	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Started	28	21	17
Completed	0	0	0
Not completed	28	21	17
Adverse event, serious fatal	9	6	4
Consent withdrawn by subject	6	3	-
Other unspecified	6	3	5
Technical problems	-	-	1
Lost to follow-up	1	-	1
Entered the long-term follow-up study	6	9	6

Baseline characteristics

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Reporting group title

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Reporting group description

Reporting group title

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Reporting group description

Reporting group values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)	Total
Number of subjects	130	130	131	391
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (standard deviation)	70.6 ( 8.6 )	70.9 ( 8.3 )	70.0 ( 8.1 )	-
Gender categorical
Units: Subjects
Female	0	0	0	0
Male	130	130	131	391
Race/Ethnicity
Units: Subjects
White	104	102	108	314
Black or African American	3	5	5	13
Asian	17	17	13	47
Not reported	6	6	5	17
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	3	6	10
Not Hispanic or Latino	125	124	120	369
Unknown or Not Reported	4	3	5	12
ECOG PS
Eastern Cooperative Oncology Group Performance status (ECOG PS): 0-Fully active, able to carry on all pre-diseases performance without restriction, (Karnofsky 90-100); 1- Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature,(Karnofsky 70-80) 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. (Karnofsky 50-60); 3-Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. (Karnofsky 30-40); 4-Completely disabled.
Units: Subjects
ECOG PS=0	48	59	49	156
ECOG PS=1	78	67	77	222
ECOG PS=2	4	4	5	13
Extent of disease
Units: Subjects
Normal or abnormal because of benign bone disease	0	1	0	1
<6 metastases	19	22	19	60
6-20 metastases	52	53	52	157
>20 lesions but not a superscan	47	48	54	149
Superscan	12	6	6	24
Average Worst Pain Score (WPS)
Brief Pain Short Form (BPI-SF) encompasses 4 different items to capture the variability of pain over time (pain at its “worst,” “least,” “average,” and “now”). Only the worst pain score (WPS) in the last 24 hours was assessed (a visual analogic scale ranging 0-10, with 0 meaning “no pain” and 10 meaning “pain as bad as you can imagine”), and the mean score of the 7 days prior to the study visit or telephone contact was calculated and this value was recorded in the participant's reported outcome pain data. Actual number of participants analyzed in Arm A, B, C was 128, 128 and 122, respectively
Units: scores on a scale
arithmetic mean (standard deviation)	3.6 ( 2.6 )	3.3 ( 2.5 )	3.4 ( 2.6 )	-
Time from initial prostate cancer diagnosis to randomization
Units: months
median (full range (min-max))	58.9 (2 to 285)	72.9 (7 to 279)	67.1 (8 to 396)	-
Time from initial bone metastases diagnosis to randomization
Units: months
median (full range (min-max))	30.8 (2 to 231)	29.9 (1 to 170)	37.5 (1 to 397)	-
Time from most recent prostate cancer progression to randomization
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. Actual number of participants analyzed in Arm A was 129.
Units: months
median (full range (min-max))	1.4 (0 to 8)	1.4 (0 to 9)	1.3 (0 to 10)	-
Time from most recent bone metastases progression to randomization
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. Actual number of subjects analyzed in Arm A, B, C was 118, 119, and 121, respectively.
Units: months
median (full range (min-max))	2.3 (0 to 34)	2.8 (0 to 93)	1.9 (0 to 41)	-
Body Mass Index
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. Actual number of participants analyzed in Arm A, B, C was 126, 127, and 124, respectively.
Units: kg/m^2
arithmetic mean (standard deviation)	28.4 ( 5.2 )	28.0 ( 5.2 )	29.1 ( 5.4 )	-
Time from first bone metastases progression to most recent progression
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. Actual number of participants analyzed in Arm A, B, C was 118, 119, and 120, respectively.
Units: months
median (full range (min-max))	7.9 (0 to 72)	8.9 (0 to 71)	13.4 (0 to 120)	-

End points

Top of page

Reporting group title

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Reporting group description

Reporting group title

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Reporting group description

Reporting group title

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Reporting group description

Reporting group title

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)

Reporting group description

Reporting group title

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Reporting group description

Subject analysis set title

Pooled Radium-223 55 kBq/kg (Arms A and C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

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.

Primary: Number of Participants with an Event Defining SSE Free Survival - High dose vs. Standard dose

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End point title

Number of Participants with an Event Defining SSE Free Survival - High dose vs. Standard dose ^[1] ^[2]

End point description

End point type

Primary

End point 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)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis in this end point is descriptive, comparison analysis results are presented in following end point.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261
Units: Count of Participants	85	118

No statistical analyses for this end point

Primary: Symptomatic Skeletal Event-Free Survival - High dose vs. Standard dose

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End point title

Symptomatic Skeletal Event-Free Survival - High dose vs. Standard dose ^[3]

End point description

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.

End point type

Primary

End point timeframe

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261
Units: months
median (confidence interval 80%)	12.9 (10.9 to 14.8)	12.3 (10.3 to 13.5)

Arm B / Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7047

Method

Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.057

Confidence interval

level

80%

sides

2-sided

lower limit

0.878

upper limit

1.272

Primary: Number of Participants with an Event defining SSE Free Survival - Extended dose vs. Standard dose

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End point title

Number of Participants with an Event defining SSE Free Survival - Extended dose vs. Standard dose ^[4] ^[5]

End point description

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. 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 .

End point type

Primary

End point timeframe

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis in this end point is descriptive, comparison analysis results are presented in following end point.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[6]	69 ^[7]
Units: participants	41	40

Notes
[6] - Week 24: participants who received 6 doses from Arm A and who received >=6 doses from Arm C.
[7] - Week 24: participants who received 6 doses from Arm A and who received >=6 doses from Arm C.

No statistical analyses for this end point

Primary: Symptomatic Skeletal Event-Free Survival - Extended dose vs. Standard dose

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End point title

Symptomatic Skeletal Event-Free Survival - Extended dose vs. Standard dose ^[8]

End point description

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.

End point type

Primary

End point timeframe

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84	69
Units: months
median (confidence interval 80%)	13.2 (9.2 to 18.1)	10.8 (8.1 to 13.8)

Arm C /Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A) v Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3134

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.26

Confidence interval

level

80%

sides

2-sided

lower limit

0.939

upper limit

1.69

Primary: Number of Participants with an Event Defining SSE Free Survival - Three Dose Groups As Randomized

Top of page

End point title

Number of Participants with an Event Defining SSE Free Survival - Three Dose Groups As Randomized ^[9]

End point description

End point type

Primary

End point timeframe

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis in this end point is descriptive.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants	80	85	92

No statistical analyses for this end point

Primary: Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized

Top of page

End point title

Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized ^[10]

End point description

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.

End point type

Primary

End point timeframe

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis in this end point is descriptive.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: months
median (confidence interval 80%)	13.1 (11.0 to 14.6)	12.9 (10.9 to 14.8)	9.6 (9.0 to 10.9)

No statistical analyses for this end point

Secondary: Number of Participants with an Overall Survival Event - High dose vs. Standard dose

Top of page

End point title

Number of Participants with an Overall Survival Event - High dose vs. Standard dose ^[11]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261 ^[12]
Units: participants	89	106

Notes
[12] - Data from Arm C are truncated at 7th dose date when pooling with Arm A.

No statistical analyses for this end point

Secondary: Overall Survival - High dose vs. Standard dose

Top of page

End point title

Overall Survival - High dose vs. Standard dose ^[13]

End point description

End point type

Secondary

End point timeframe

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261 ^[14]
Units: months
median (confidence interval 80%)	16.0 (14.7 to 17.2)	14.9 (13.7 to 16.7)

Notes
[14] - Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Arm B/Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6205

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.075

Confidence interval

level

80%

sides

2-sided

lower limit

0.892

upper limit

1.297

Secondary: Number of Participants with an Overall survival event - Extended dose vs. Standard dose

Top of page

End point title

Number of Participants with an Overall survival event - Extended dose vs. Standard dose ^[15]

End point description

End point type

Secondary

End point timeframe

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[16]	69 ^[17]
Units: participants	43	38

Notes
[16] - Week 24 (W24)
[17] - Week 24 (W24)

No statistical analyses for this end point

Secondary: Overall survival - Extended dose vs. Standard dose

Top of page

End point title

Overall survival - Extended dose vs. Standard dose ^[18]

End point description

End point type

Secondary

End point timeframe

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[19]	69 ^[20]
Units: months
median (full range (min-max))	16.5 (14.0 to 19.9)	15.2 (14.0 to 19.0)

Notes
[19] - Week 24 (W24)
[20] - Week 24 (W24)

Arm C/Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A) v Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9958

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.999

Confidence interval

level

80%

sides

2-sided

lower limit

0.744

upper limit

1.341

Secondary: Number of Participants with an Overall Survival - Three Dose Groups As Randomized

Top of page

End point title

Number of Participants with an Overall Survival - Three Dose Groups As Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants	83	89	93

No statistical analyses for this end point

Secondary: Overall Survival Event - Three Dose Groups as Randomized

Top of page

End point title

Overall Survival Event - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: months
median (confidence interval 80%)	15.8 (14.3 to 18.1)	16.0 (14.7 to 17.2)	14.4 (12.1 to 16.5)

No statistical analyses for this end point

Secondary: Number of Participants with First Symptomatic Skeletal Event - High dose vs. Standard dose

Top of page

End point title

Number of Participants with First Symptomatic Skeletal Event - High dose vs. Standard dose ^[21]

End point description

End point type

Secondary

End point timeframe

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261 ^[22]
Units: participants	42	62

Notes
[22] - Data from Arm C are truncated at 7th dose date when pooling with Arm A.

No statistical analyses for this end point

Secondary: Time to First Symptomatic Skeletal Event - High dose vs. Standard dose

Top of page

End point title

Time to First Symptomatic Skeletal Event - High dose vs. Standard dose ^[23]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130 ^[24]	261 ^[25]
Units: months
median (confidence interval 80%)	24.1 (18.0 to 99999)	26.3 (26.3 to 99999)

Notes
[24] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.
[25] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

Arm B/Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7461

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.068

Confidence interval

level

80%

sides

2-sided

lower limit

0.823

upper limit

1.385

Secondary: Number of Participants with First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Top of page

End point title

Number of Participants with First Symptomatic Skeletal Event - Extended dose vs. Standard dose ^[26]

End point description

End point type

Secondary

End point timeframe

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[27]	69 ^[28]
Units: participants	19	25

Notes
[27] - Week 24 (W24)
[28] - Week 24 (W24)

No statistical analyses for this end point

Secondary: Time to First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Top of page

End point title

Time to First Symptomatic Skeletal Event - Extended dose vs. Standard dose ^[29]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[30]	69
Units: months
median (confidence interval 80%)	99999 (21.2 to 99999)	19.5 (12.3 to 23.4)

Notes
[30] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

Arm C/Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A) v Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.155

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.549

Confidence interval

level

80%

sides

2-sided

lower limit

1.041

upper limit

2.306

Secondary: Number of Participants with First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Top of page

End point title

Number of Participants with First Symptomatic Skeletal Event - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants	37	42	48

No statistical analyses for this end point

Secondary: Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Top of page

End point title

Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized

End point description

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.

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130 ^[31]	130 ^[32]	131
Units: months
median (confidence interval 80%)	99999 (26.3 to 99999)	24.1 (18.0 to 99999)	18.8 (15.1 to 25.6)

Notes
[31] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.
[32] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

No statistical analyses for this end point

Secondary: Number of Participants With a Radiological Progression Event-Free – High dose vs. Standard dose

Top of page

End point title

Number of Participants With a Radiological Progression Event-Free – High dose vs. Standard dose ^[33]

End point description

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).

End point type

Secondary

End point timeframe

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261
Units: participants	77	141

No statistical analyses for this end point

Secondary: Radiological Progression Free Survival – High dose vs. Standard dose

Top of page

End point title

Radiological Progression Free Survival – High dose vs. Standard dose ^[34]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261
Units: months
median (confidence interval 80%)	7.5 (5.9 to 8.6)	6.0 (5.2 to 6.2)

Arm B/Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8284

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.969

Confidence interval

level

80%

sides

2-sided

lower limit

0.805

upper limit

1.167

Secondary: Number of Participants With a Radiological Progression Event-Free – Extended dose vs. Standard dose

Top of page

End point title

Number of Participants With a Radiological Progression Event-Free – Extended dose vs. Standard dose ^[35]

End point description

End point type

Secondary

End point timeframe

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[36]	47 ^[37]
Units: participants	49	47

Notes
[36] - Baseline is randomization date
[37] - Baseline is randomization date

No statistical analyses for this end point

Secondary: Radiological Progression Free Survival - Extended dose vs. Standard dose

Top of page

End point title

Radiological Progression Free Survival - Extended dose vs. Standard dose ^[38]

End point description

End point type

Secondary

End point timeframe

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[39]	69 ^[40]
Units: months
median (confidence interval 80%)	8.9 (6.3 to 11.8)	9.0 (7.5 to 9.6)

Notes
[39] - Baseline is randomization date
[40] - Baseline is randomization date

Arm C/Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C) v Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7896

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.059

Confidence interval

level

80%

sides

2-sided

lower limit

0.804

upper limit

1.396

Secondary: Number of Participants with a Radiological Progression Event-Free - Three Dose Groups as Randomized

Top of page

End point title

Number of Participants with a Radiological Progression Event-Free - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants	77	77	90

No statistical analyses for this end point

Secondary: Radiological Progression Free Survival - Three Dose Groups as Randomized

Top of page

End point title

Radiological Progression Free Survival - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: months
median (confidence interval 80%)	6.3 (5.1 to 7.2)	7.5 (5.9 to 8.6)	6.1 (5.2 to 6.6)

No statistical analyses for this end point

Secondary: Number of Participants With a Radiological Progression Event – High dose vs. Standard dose

Top of page

End point title

Number of Participants With a Radiological Progression Event – High dose vs. Standard dose ^[41]

End point description

End point type

Secondary

End point timeframe

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261
Units: participants	63	115

No statistical analyses for this end point

Secondary: Time to Radiological Progression – High dose vs. Standard dose

Top of page

End point title

Time to Radiological Progression – High dose vs. Standard dose ^[42]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	130	261 ^[43]
Units: months
median (confidence interval 80%)	8.7 (6.2 to 9.7)	6.2 (6.0 to 6.6)

Notes
[43] - Data from Arm C are truncated at 7th dose date when pooling with Arm A.

Arm B/Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9274

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.986

Confidence interval

level

80%

sides

2-sided

lower limit

0.803

upper limit

1.21

Secondary: Number of Participants With a Radiological Progression Event – Extended dose vs. Standard dose

Top of page

End point title

Number of Participants With a Radiological Progression Event – Extended dose vs. Standard dose ^[44]

End point description

End point type

Secondary

End point timeframe

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84 ^[45]	69 ^[46]
Units: participants	43	43

Notes
[45] - Week 24 (W24)
[46] - Week 24 (W24)

No statistical analyses for this end point

Secondary: Time to Radiological Progression - Extended dose vs. Standard dose

Top of page

End point title

Time to Radiological Progression - Extended dose vs. Standard dose ^[47]

End point description

End point type

Secondary

End point timeframe

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	84	69
Units: months
median (confidence interval 80%)	8.9 (6.3 to 14.6)	9.0 (7.2 to 10.2)

Arm C/Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C) v Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5754

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.134

Confidence interval

level

80%

sides

2-sided

lower limit

0.85

upper limit

1.514

Secondary: Number of Participants with a Radiological Progression event - Three Dose Groups as Randomized

Top of page

End point title

Number of Participants with a Radiological Progression event - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants	66	63	67

No statistical analyses for this end point

Secondary: Time to Radiological Progression - Three Dose Groups as Randomized

Top of page

End point title

Time to Radiological Progression - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: months
median (confidence interval 80%)	6.2 (5.9 to 7.1)	8.7 (6.2 to 9.7)	6.6 (6.0 to 8.7)

No statistical analyses for this end point

Secondary: Timepoint Pain Improvement Rate - Three Dose Groups as Randomized

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End point title

Timepoint Pain Improvement Rate - Three Dose Groups as Randomized

End point description

Time point 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.

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: percentage
number (confidence interval 80%)
Week 12	16.7 (10.1 to 25.7)	16.0 (9.5 to 24.7)	18.6 (11.1 to 28.5)
Overall (confirmed)	27.1 (18.7 to 37.0)	26.0 (17.9 to 35.6)	37.2 (27.3 to 48.1)

No statistical analyses for this end point

Secondary: Timepoint Pain Improvement Rate - Extended dose vs. Standard dose

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End point title

Timepoint Pain Improvement Rate - Extended dose vs. Standard dose ^[48]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	22	20
Units: percentage
number (confidence interval 80%)
Week 12	31.8 (18.7 to 47.7)	30.0 (16.6 to 46.7)
Overall (confirmed)	40.9 (26.4 to 56.8)	55.0 (38.5 to 70.7)

No statistical analyses for this end point

Secondary: Number of Participants With a Pain Progression Event – High dose vs. Standard dose

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End point title

Number of Participants With a Pain Progression Event – High dose vs. Standard dose ^[49]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	113	218 ^[50]
Units: participants	31	68

Notes
[50] - Data from Arm C are truncated at 7th dose date when pooling with Arm A.

No statistical analyses for this end point

Secondary: Time to Pain Progression – High dose vs. Standard dose

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End point title

Time to Pain Progression – High dose vs. Standard dose ^[51]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm A and C were pooled together as 'standard dose' group based on pre-specified pooling rule.

End point values	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Pooled Radium-223 55 kBq/kg (Arms A and C)
Number of subjects analysed	113 ^[52]	218 ^[53]
Units: months
median (confidence interval 80%)	99999 (9.4 to 99999)	99999 (8.6 to 99999)

Notes
[52] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.
[53] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

Arm B/Arm (A+C)

Comparison groups

Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B) v Pooled Radium-223 55 kBq/kg (Arms A and C)

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6214

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.898

Confidence interval

level

80%

sides

2-sided

lower limit

0.678

upper limit

1.188

Secondary: Number of Participants With a Pain Progression Event – Extended dose vs. Standard dose

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End point title

Number of Participants With a Pain Progression Event – Extended dose vs. Standard dose ^[54]

End point description

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.

End point type

Secondary

End point timeframe

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	78 ^[55]	65 ^[56]
Units: participants	10	15

Notes
[55] - Week 24 (W24)
[56] - Week 24 (W24)

No statistical analyses for this end point

Secondary: Time to Pain Progression - Extended dose vs. Standard dose

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End point title

Time to Pain Progression - Extended dose vs. Standard dose ^[57]

End point description

End point type

Secondary

End point timeframe

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The comparison was performed between "standard dose" (arm A) vs. "extended dose" (Arm C) only, the study was not designed for a comparison between the 3 arms.

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	78 ^[58]	65 ^[59]
Units: months
median (confidence interval 80%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[58] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.
[59] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

Arm C/Arm A

Comparison groups

Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A) v Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7214

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.863

Confidence interval

level

80%

sides

2-sided

lower limit

0.505

upper limit

1.475

Secondary: Number of Participants with a Pain Progression event - Three Dose Groups as Randomized

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End point title

Number of Participants with a Pain Progression event - Three Dose Groups as Randomized

End point description

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.

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	110	113	108
Units: participants	32	31	46

No statistical analyses for this end point

Secondary: Time to Pain Progression - Three Dose Groups as Randomized

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End point title

Time to Pain Progression - Three Dose Groups as Randomized

End point description

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	110 ^[60]	113 ^[61]	108
Units: months
median (confidence interval 80%)	99999 (8.9 to 99999)	99999 (9.4 to 99999)	10.1 (8.8 to 11.8)

Notes
[60] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.
[61] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation.

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent Adverse Events

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End point title

Number of Participants with Treatment-Emergent Adverse Events

End point description

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).

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	124 ^[62]	121 ^[63]	125 ^[64]
Units: participants
Any TEAE	118	119	116
Grade 1	23	20	18
Grade 2	52	40	34
Grade 3	38	46	49
Grade 4	4	11	11
Grade 5	1	2	4
Serious	25	36	37
Any drug-related TEAE	73	73	57

Notes
[62] - Safety Analysis Set
[63] - Safety Analysis Set
[64] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Number of Participants with Change in Analgesic Use from Baseline to Worst Status Post-Baseline

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End point title

Number of Participants with Change in Analgesic Use from Baseline to Worst Status Post-Baseline

End point description

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

End point type

Secondary

End point timeframe

End point values	Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)	Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)	Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
Number of subjects analysed	130	130	131
Units: participants
Strong Opioid - No Change	22	27	26
From Strong Opioid to Weak Opioid	1	0	2
From Strong Opioid to No analgesic or Non-opioid	18	9	13
From Strong Opioid to Missing	2	0	4
From No analgesic or Non-opioid to Strong Opioid	24	26	25
From No analgesic or Non-opioid to Weak Opioid	5	8	12
No analgesic or Non-opioid - No Change	46	41	30
From No analgesic or Non-opioid to Missing	5	5	5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From starting of study medication over a period of approximately 3 years since first participant was enrolled.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

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

Reporting group description

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”).

Reporting group title

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

Reporting group description

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”).

Reporting group title

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

Reporting group description

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”).

Serious adverse events	Radium-223 55 kBq/kg Arm A (6 doses)	Radium-223 88 kBq/kg Arm B (6 doses)	Radium-223 55 kBq/kg Arm C (12 doses)
Total subjects affected by serious adverse events
subjects affected / exposed	25 / 125 (20.00%)	36 / 124 (29.03%)	37 / 121 (30.58%)
number of deaths (all causes)	98	100	102
number of deaths resulting from adverse events	1	2	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Nasal cavity cancer
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 125 (0.80%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 125 (1.60%)	2 / 124 (1.61%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Cystitis radiation
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Traumatic fracture
subjects affected / exposed	1 / 125 (0.80%)	1 / 124 (0.81%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract stoma complication
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Acute coronary syndrome
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IIIrd nerve paralysis
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 125 (0.80%)	6 / 124 (4.84%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Trigeminal nerve disorder
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 125 (2.40%)	6 / 124 (4.84%)	4 / 121 (3.31%)
occurrences causally related to treatment / all	7 / 7	22 / 24	9 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 125 (0.00%)	3 / 124 (2.42%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Leukopenia
subjects affected / exposed	0 / 125 (0.00%)	2 / 124 (1.61%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	13 / 13	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 125 (0.80%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 125 (1.60%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 125 (0.00%)	3 / 124 (2.42%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	24 / 28	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dental caries
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	3 / 121 (2.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 125 (0.00%)	2 / 124 (1.61%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	3 / 125 (2.40%)	1 / 124 (0.81%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coccydynia
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 125 (0.80%)	1 / 124 (0.81%)	3 / 121 (2.48%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 125 (1.60%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Enterocolitis infectious
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Alcohol intolerance
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 125 (0.00%)	1 / 124 (0.81%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 125 (0.80%)	0 / 124 (0.00%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	0 / 125 (0.00%)	0 / 124 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Radium-223 55 kBq/kg Arm A (6 doses)	Radium-223 88 kBq/kg Arm B (6 doses)	Radium-223 55 kBq/kg Arm C (12 doses)
Total subjects affected by non serious adverse events
subjects affected / exposed	109 / 125 (87.20%)	111 / 124 (89.52%)	111 / 121 (91.74%)
Investigations
Neutrophil count decreased
subjects affected / exposed	4 / 125 (3.20%)	9 / 124 (7.26%)	3 / 121 (2.48%)
occurrences all number	6	22	11
Weight decreased
subjects affected / exposed	12 / 125 (9.60%)	6 / 124 (4.84%)	19 / 121 (15.70%)
occurrences all number	17	7	24
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 125 (2.40%)	9 / 124 (7.26%)	4 / 121 (3.31%)
occurrences all number	5	14	4
Vascular disorders
Hypertension
subjects affected / exposed	6 / 125 (4.80%)	5 / 124 (4.03%)	7 / 121 (5.79%)
occurrences all number	7	9	17
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 125 (2.40%)	3 / 124 (2.42%)	8 / 121 (6.61%)
occurrences all number	3	3	10
Headache
subjects affected / exposed	7 / 125 (5.60%)	6 / 124 (4.84%)	6 / 121 (4.96%)
occurrences all number	8	7	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	29 / 125 (23.20%)	33 / 124 (26.61%)	30 / 121 (24.79%)
occurrences all number	64	69	79
Neutropenia
subjects affected / exposed	2 / 125 (1.60%)	10 / 124 (8.06%)	5 / 121 (4.13%)
occurrences all number	7	21	16
Thrombocytopenia
subjects affected / exposed	7 / 125 (5.60%)	10 / 124 (8.06%)	10 / 121 (8.26%)
occurrences all number	14	26	33
General disorders and administration site conditions
Asthenia
subjects affected / exposed	12 / 125 (9.60%)	9 / 124 (7.26%)	17 / 121 (14.05%)
occurrences all number	15	11	25
Fatigue
subjects affected / exposed	39 / 125 (31.20%)	37 / 124 (29.84%)	35 / 121 (28.93%)
occurrences all number	58	46	49
Oedema peripheral
subjects affected / exposed	9 / 125 (7.20%)	6 / 124 (4.84%)	7 / 121 (5.79%)
occurrences all number	10	6	7
Pyrexia
subjects affected / exposed	4 / 125 (3.20%)	9 / 124 (7.26%)	5 / 121 (4.13%)
occurrences all number	4	9	5
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 125 (4.00%)	3 / 124 (2.42%)	10 / 121 (8.26%)
occurrences all number	5	3	12
Constipation
subjects affected / exposed	21 / 125 (16.80%)	10 / 124 (8.06%)	18 / 121 (14.88%)
occurrences all number	27	11	20
Diarrhoea
subjects affected / exposed	26 / 125 (20.80%)	28 / 124 (22.58%)	26 / 121 (21.49%)
occurrences all number	34	39	32
Nausea
subjects affected / exposed	31 / 125 (24.80%)	29 / 124 (23.39%)	28 / 121 (23.14%)
occurrences all number	38	33	39
Vomiting
subjects affected / exposed	12 / 125 (9.60%)	15 / 124 (12.10%)	17 / 121 (14.05%)
occurrences all number	16	19	22
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 125 (2.40%)	4 / 124 (3.23%)	7 / 121 (5.79%)
occurrences all number	5	4	7
Dyspnoea
subjects affected / exposed	8 / 125 (6.40%)	4 / 124 (3.23%)	7 / 121 (5.79%)
occurrences all number	8	4	7
Psychiatric disorders
Depression
subjects affected / exposed	4 / 125 (3.20%)	1 / 124 (0.81%)	7 / 121 (5.79%)
occurrences all number	5	1	7
Insomnia
subjects affected / exposed	9 / 125 (7.20%)	6 / 124 (4.84%)	5 / 121 (4.13%)
occurrences all number	9	7	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	20 / 125 (16.00%)	17 / 124 (13.71%)	19 / 121 (15.70%)
occurrences all number	26	22	24
Back pain
subjects affected / exposed	20 / 125 (16.00%)	18 / 124 (14.52%)	24 / 121 (19.83%)
occurrences all number	25	19	29
Bone pain
subjects affected / exposed	23 / 125 (18.40%)	19 / 124 (15.32%)	27 / 121 (22.31%)
occurrences all number	26	21	32
Muscular weakness
subjects affected / exposed	6 / 125 (4.80%)	8 / 124 (6.45%)	2 / 121 (1.65%)
occurrences all number	8	8	2
Musculoskeletal pain
subjects affected / exposed	9 / 125 (7.20%)	7 / 124 (5.65%)	11 / 121 (9.09%)
occurrences all number	11	7	12
Myalgia
subjects affected / exposed	7 / 125 (5.60%)	4 / 124 (3.23%)	4 / 121 (3.31%)
occurrences all number	9	4	4
Pain in extremity
subjects affected / exposed	13 / 125 (10.40%)	9 / 124 (7.26%)	12 / 121 (9.92%)
occurrences all number	15	10	13
Pathological fracture
subjects affected / exposed	2 / 125 (1.60%)	4 / 124 (3.23%)	7 / 121 (5.79%)
occurrences all number	2	4	9
Musculoskeletal chest pain
subjects affected / exposed	11 / 125 (8.80%)	5 / 124 (4.03%)	8 / 121 (6.61%)
occurrences all number	15	7	9
Spinal pain
subjects affected / exposed	4 / 125 (3.20%)	1 / 124 (0.81%)	7 / 121 (5.79%)
occurrences all number	7	1	12
Infections and infestations
Urinary tract infection
subjects affected / exposed	2 / 125 (1.60%)	7 / 124 (5.65%)	2 / 121 (1.65%)
occurrences all number	2	7	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	31 / 125 (24.80%)	24 / 124 (19.35%)	26 / 121 (21.49%)
occurrences all number	39	25	31

More information

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Were there any global substantial amendments to the protocol? Yes

09 Aug 2013

Addition of an inclusion criteria to only include subjects who are at least 18 years of age. Addition of an inclusion criteria for sexually active males and/or their partners to use effective birth control during the treatment period and for 6 months after last dose of radium-223 dichloride. Revised definition of bone progression based on the adapted PCWG2 criteria for consistency across the radium-223 program following comments from the FDA on another related radium-223 study. This change affected the time points of radiological assessments. Clarification of central review of radiological and quantitated bone scan endpoints. Addition of a study specific dose modification to mandate discontinuation of treatment with radium-223 dichloride in subjects who experience Grade 4 neutropenia lasting > 7 days despite adequate treatment.

19 Nov 2013

Reorganization of the inclusion criterion to specify serum PSA ≥ 2 ng/mL as an inclusion criterion for castration-resistant disease. Update to the radium-223 dichloride dosing and dose calibration to reflect the revised NIST standard. Removal of the dosing restriction with bisphosphonates Addition of an efficacy analysis set (Week 24 analysis set).

13 Aug 2015

Update to procedures for long-term follow-up. Update to analysis for Comparison 2 from 24 weeks to the 6th dose.

16 May 2017

Addition that radium-223 dichloride should not be given with abiraterone plus prednisone/prednisolone. New request that bone fractures and bone associated events (e.g., osteoporosis) need to be reported as (S)AEs, including during long term follow-up, regardless of causality to study treatment. Based on the available data on radium-223 dichloride, initiation of BHAs during the follow-up periods, including bisphosphonates or denosumab, should be considered, taking into consideration applicable guidelines.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Arms in active follow-up period were mutually exclusive, it was marked no due to database constraints (period start number must equal completed number of preceding period.)

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with an Event Defining SSE Free Survival - High dose vs. Standard dose

Primary: Number of Participants with an Event Defining SSE Free Survival - High dose vs. Standard dose

Primary: Symptomatic Skeletal Event-Free Survival - High dose vs. Standard dose

Primary: Symptomatic Skeletal Event-Free Survival - High dose vs. Standard dose

Primary: Number of Participants with an Event defining SSE Free Survival - Extended dose vs. Standard dose

Primary: Number of Participants with an Event defining SSE Free Survival - Extended dose vs. Standard dose

Primary: Symptomatic Skeletal Event-Free Survival - Extended dose vs. Standard dose

Primary: Symptomatic Skeletal Event-Free Survival - Extended dose vs. Standard dose

Primary: Number of Participants with an Event Defining SSE Free Survival - Three Dose Groups As Randomized

Primary: Number of Participants with an Event Defining SSE Free Survival - Three Dose Groups As Randomized

Primary: Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized

Primary: Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized

Secondary: Number of Participants with an Overall Survival Event - High dose vs. Standard dose

Secondary: Number of Participants with an Overall Survival Event - High dose vs. Standard dose

Secondary: Overall Survival - High dose vs. Standard dose

Secondary: Overall Survival - High dose vs. Standard dose

Secondary: Number of Participants with an Overall survival event - Extended dose vs. Standard dose

Secondary: Number of Participants with an Overall survival event - Extended dose vs. Standard dose

Secondary: Overall survival - Extended dose vs. Standard dose

Secondary: Overall survival - Extended dose vs. Standard dose

Secondary: Number of Participants with an Overall Survival - Three Dose Groups As Randomized

Secondary: Number of Participants with an Overall Survival - Three Dose Groups As Randomized

Secondary: Overall Survival Event - Three Dose Groups as Randomized

Secondary: Overall Survival Event - Three Dose Groups as Randomized

Secondary: Number of Participants with First Symptomatic Skeletal Event - High dose vs. Standard dose

Secondary: Number of Participants with First Symptomatic Skeletal Event - High dose vs. Standard dose

Secondary: Time to First Symptomatic Skeletal Event - High dose vs. Standard dose

Secondary: Time to First Symptomatic Skeletal Event - High dose vs. Standard dose

Secondary: Number of Participants with First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Secondary: Number of Participants with First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Secondary: Time to First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Secondary: Time to First Symptomatic Skeletal Event - Extended dose vs. Standard dose

Secondary: Number of Participants with First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Secondary: Number of Participants with First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Secondary: Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Secondary: Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized

Secondary: Number of Participants With a Radiological Progression Event-Free – High dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event-Free – High dose vs. Standard dose

Secondary: Radiological Progression Free Survival – High dose vs. Standard dose

Secondary: Radiological Progression Free Survival – High dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event-Free – Extended dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event-Free – Extended dose vs. Standard dose

Secondary: Radiological Progression Free Survival - Extended dose vs. Standard dose

Secondary: Radiological Progression Free Survival - Extended dose vs. Standard dose

Secondary: Number of Participants with a Radiological Progression Event-Free - Three Dose Groups as Randomized

Secondary: Number of Participants with a Radiological Progression Event-Free - Three Dose Groups as Randomized

Secondary: Radiological Progression Free Survival - Three Dose Groups as Randomized

Secondary: Radiological Progression Free Survival - Three Dose Groups as Randomized

Secondary: Number of Participants With a Radiological Progression Event – High dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event – High dose vs. Standard dose

Secondary: Time to Radiological Progression – High dose vs. Standard dose

Secondary: Time to Radiological Progression – High dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event – Extended dose vs. Standard dose

Secondary: Number of Participants With a Radiological Progression Event – Extended dose vs. Standard dose

Secondary: Time to Radiological Progression - Extended dose vs. Standard dose

Secondary: Time to Radiological Progression - Extended dose vs. Standard dose

Secondary: Number of Participants with a Radiological Progression event - Three Dose Groups as Randomized

Secondary: Number of Participants with a Radiological Progression event - Three Dose Groups as Randomized

Secondary: Time to Radiological Progression - Three Dose Groups as Randomized

Secondary: Time to Radiological Progression - Three Dose Groups as Randomized

Secondary: Timepoint Pain Improvement Rate - Three Dose Groups as Randomized

Secondary: Timepoint Pain Improvement Rate - Three Dose Groups as Randomized

Secondary: Timepoint Pain Improvement Rate - Extended dose vs. Standard dose

Secondary: Timepoint Pain Improvement Rate - Extended dose vs. Standard dose

Secondary: Number of Participants With a Pain Progression Event – High dose vs. Standard dose

Secondary: Number of Participants With a Pain Progression Event – High dose vs. Standard dose

Secondary: Time to Pain Progression – High dose vs. Standard dose

Secondary: Time to Pain Progression – High dose vs. Standard dose

Secondary: Number of Participants With a Pain Progression Event – Extended dose vs. Standard dose

Secondary: Number of Participants With a Pain Progression Event – Extended dose vs. Standard dose

Secondary: Time to Pain Progression - Extended dose vs. Standard dose