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
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EudraCT number |
2013-003118-42 |
Trial protocol |
DE IT CZ SE FI ES GB |
Global end of trial date |
09 Aug 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Jul 2019
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First version publication date |
17 Jul 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BAY88-8223/16507
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02023697 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Aug 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Aug 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
7 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 17
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Country: Number of subjects enrolled |
Sweden: 14
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
Czech Republic: 4
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Italy: 23
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Country: Number of subjects enrolled |
Canada: 51
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Country: Number of subjects enrolled |
Israel: 70
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Country: Number of subjects enrolled |
China: 6
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Country: Number of subjects enrolled |
United States: 83
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Country: Number of subjects enrolled |
Chile: 4
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Country: Number of subjects enrolled |
Australia: 56
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Country: Number of subjects enrolled |
Korea, Republic of: 39
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Country: Number of subjects enrolled |
France: 6
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Worldwide total number of subjects |
391
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EEA total number of subjects |
82
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
89
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From 65 to 84 years |
292
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85 years and over |
10
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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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
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Period 1 title |
Treatment Period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Period 2
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Period 2 title |
Active follow-up period
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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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”)
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Period 3
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Period 3 title |
Long-term follow-up period
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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Pharmaceutical forms |
Solution for injection
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||||||||||||||||||||||||||||||||||||||||||||||||||||
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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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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”)
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Arm title
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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
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Investigational medicinal product code |
BAY88-8223
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Other name |
Xofigo
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||||||||||||||||||||||||||||||||||||||||||||||||||||
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”)
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Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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”). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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”). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
|
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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”). 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)
|
||
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”). 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. | ||
Reporting group title |
Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)
|
||
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”). 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. | ||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
|
||
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”). 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. | ||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)
|
||
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"). 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. | ||
Reporting group title |
Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)
|
||
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”). 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. | ||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
|
||
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”). 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. | ||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 6 doses (Arm A)
|
||
Reporting group 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. | ||
Reporting group title |
Radium-223 dichloride 88 kBq/kg, 6 doses (Arm B)
|
||
Reporting group 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. | ||
Reporting group title |
Radium-223 dichloride 55 kBq/kg, 12 doses (Arm C)
|
||
Reporting group 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. | ||
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.
|
|
||||||||||
End point title |
Number of Participants with an Event Defining SSE Free Survival - High dose vs. Standard dose [1] [2] | |||||||||
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 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 |
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. |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
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 |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
End point title |
Number of Participants with an Event Defining SSE Free Survival - Three Dose Groups As Randomized [9] | ||||||||||||
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.
|
||||||||||||
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 [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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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 |
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 [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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
Notes [12] - Data from Arm C are truncated at 7th dose date when pooling with Arm A. |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Overall Survival - High dose vs. Standard dose [13] | ||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Notes [14] - Data from Arm C are truncated at 7th dose date when pooling with Arm A. |
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
End point title |
Number of Participants with an Overall survival event - Extended dose vs. Standard dose [15] | |||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
Notes [16] - Week 24 (W24) [17] - Week 24 (W24) |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Overall survival - Extended dose vs. Standard dose [18] | ||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Notes [19] - Week 24 (W24) [20] - Week 24 (W24) |
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
End point title |
Number of Participants with an Overall Survival - Three Dose Groups As Randomized | ||||||||||||
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 |
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)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Overall Survival Event - Three Dose Groups as Randomized | ||||||||||||||||
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 |
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)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants with First Symptomatic Skeletal Event - High dose vs. Standard dose [21] | |||||||||
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 |
Secondary
|
|||||||||
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 [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. |
||||||||||
|
||||||||||
Notes [22] - Data from Arm C are truncated at 7th dose date when pooling with Arm A. |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
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. |
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
End point title |
Number of Participants with First Symptomatic Skeletal Event - Extended dose vs. Standard dose [26] | |||||||||
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 |
Secondary
|
|||||||||
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 [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. |
||||||||||
|
||||||||||
Notes [27] - Week 24 (W24) [28] - Week 24 (W24) |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Notes [30] - "99999" entered below stands for “NA” because of no sufficient events observed for calculation. |
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
End point title |
Number of Participants with First Symptomatic Skeletal Event - Three Dose Groups as Randomized | ||||||||||||
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 |
Secondary
|
||||||||||||
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)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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 |
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 [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 |
|
||||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
End point title |
Number of Participants With a Radiological Progression Event-Free – Extended dose vs. Standard dose [35] | |||||||||
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.
|
|||||||||
End point type |
Secondary
|
|||||||||
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 [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. |
||||||||||
|
||||||||||
Notes [36] - Baseline is randomization date [37] - Baseline is randomization date |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Radiological Progression Free Survival - Extended dose vs. Standard dose [38] | ||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Notes [39] - Baseline is randomization date [40] - Baseline is randomization date |
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
End point title |
Number of Participants with a Radiological Progression Event-Free - Three Dose Groups as Randomized | ||||||||||||
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 Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria based on whole body technetium-99 bone scans.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
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)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Radiological Progression Free Survival - Three Dose Groups as Randomized | ||||||||||||||||
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 |
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)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants With a Radiological Progression Event – High dose vs. Standard dose [41] | |||||||||
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 Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria based on whole body technetium-99 bone scans.
|
|||||||||
End point type |
Secondary
|
|||||||||
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 [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. |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Notes [43] - Data from Arm C are truncated at 7th dose date when pooling with Arm A. |
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
End point title |
Number of Participants With a Radiological Progression Event – Extended dose vs. Standard dose [44] | |||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
Notes [45] - Week 24 (W24) [46] - Week 24 (W24) |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to Radiological Progression - Extended dose vs. Standard dose [47] | ||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
End point title |
Number of Participants with a Radiological Progression event - Three Dose Groups as Randomized | ||||||||||||
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 |
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)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time to Radiological Progression - Three Dose Groups as Randomized | ||||||||||||||||
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 |
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)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
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 |
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)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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 |
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 [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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
Notes [50] - Data from Arm C are truncated at 7th dose date when pooling with Arm A. |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
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. |
|||||||||||||
Statistical analysis title |
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 |
|
||||||||||
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 |
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 [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. |
||||||||||
|
||||||||||
Notes [55] - Week 24 (W24) [56] - Week 24 (W24) |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to Pain Progression - Extended dose vs. Standard dose [57] | ||||||||||||
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 |
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 [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. |
|||||||||||||
|
|||||||||||||
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. |
|||||||||||||
Statistical analysis title |
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 |
|
|||||||||||||
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 |
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)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time to Pain Progression - Three Dose Groups as Randomized | ||||||||||||||||
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 |
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 [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 |
|
|||||||||||||||||||||||||||||||||||||||||||||
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 |
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 [62] - Safety Analysis Set [63] - Safety Analysis Set [64] - Safety Analysis Set |
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
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 |
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)
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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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.
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Radium-223 55 kBq/kg Arm A (6 doses)
|
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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)
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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)
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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”). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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).
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13 Aug 2015 |
Update to procedures for long-term follow-up.
Update to analysis for Comparison 2 from 24 weeks to the 6th dose.
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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.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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.) |