Clinical Trial Results:
A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2007-006195-11
Trial protocol	SE FR GB BE SK ES CZ NL IT DE
Global end of trial date	13 Feb 2014

Results information
Results version number	v2(current)
This version publication date	24 Jul 2016
First version publication date	30 Jul 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set NA

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

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Trial information

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Sponsor protocol code

BAY88-8223/15245

ISRCTN number

US NCT number

NCT00699751

WHO universal trial number (UTN)

Other trial identifiers

Other: BC1-06

Sponsor organisation name

Bayer AG

Sponsor organisation address

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

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

13 Feb 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Feb 2014

Was the trial ended prematurely?

Main objective of the trial

To compare, in subjects with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care (BSoC) plus radium-223 dichloride versus BSoC plus placebo, with the primary efficacy endpoint being overall survival.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. 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. The formal interim analysis (IA) was performed using the data cut-off date of 14 October 2010 when a total of 316 deaths had been observed; this resulted in the Independent data monitoring committee's (IDMC) recommendation to unblind the study, to stop further placebo treatment, and to offer radium-223 dichloride to placebo subjects who were still participating in the study (who had not withdrawn from the study) and who fulfilled the eligibility criteria as defined in amendment 6 to the Protocol BC1-06, as the primary efficacy analysis of overall survival had crossed the prespecified boundary for efficacy.

Background therapy

BSoC was regarded as the routine standard of care at each center, for example local external beam radiation therapy (EBRT), corticosteroids, antiandrogens, estrogens (example: stilboestrol), estramustine or ketoconazole.

Evidence for comparator

Actual start date of recruitment

12 Jun 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 138

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Australia: 30

Country: Number of subjects enrolled

Brazil: 39

Country: Number of subjects enrolled

Canada: 20

Country: Number of subjects enrolled

Czech Republic: 52

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 56

Country: Number of subjects enrolled

Hong Kong: 21

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Poland: 61

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

Slovakia: 22

Country: Number of subjects enrolled

Spain: 46

Country: Number of subjects enrolled

Sweden: 90

Country: Number of subjects enrolled

United Kingdom: 258

Country: Number of subjects enrolled

United States: 23

Worldwide total number of subjects

921

EEA total number of subjects

775

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

231

From 65 to 84 years

673

85 years and over

Subject disposition

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Recruitment details

Subjects with progressive symptomatic HRPC, with at least 2 skeletal metastases on bone scan and no known visceral metastases, could participate in the study.

Screening details

Subjects were to be randomized in a 2:1, a total of 921 subjects were enrolled in the study and were randomized to receive either Alpharadin [Radium-223 dichloride (Xofigo, BAY88-8223)] or placebo study treatment, which resulted in 614 subjects enrolled in the Alpharadin group and 307 enrolled in the placebo group.

Period 1 title

Baseline period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Radium-223 dichloride (Xofigo, BAY88-8223)

Arm description

Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Placebo

Arm description

Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Number of subjects in period 1	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Started	614	307
Completed	614	307

Period 2 title

Overall study

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Radium-223 Dichloride (Xofigo, BAY88-8223)

Arm description

Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Placebo

Arm description

Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Placebo Randomized, Then Switched to Radium-223 Dichloride

Arm description

Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals from randomization to data cut-off date of 15 July 2011; subjects received radium-223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals from 15 July 2011 to the end of study.

Arm type

Experimental

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Xofigo

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Isotonic saline for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Number of subjects in period 2	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo	Placebo Randomized, Then Switched to Radium-223 Dichloride
Started	614	307	26
Completed all 6 Injections	389	145	17
Entered 3-Year Follow-up Period	407	168	15 ^[1]
Completed 3-Year Follow-up Period	49 ^[2]	12 ^[3]	0 ^[4]
Completed	389	145	17
Not completed	225	162	9
Adverse Event	97	63	4
Investigator Request	27	27	1
Death	28	29	-
Unspecified	30	20	-
Subject Request	43	23	-
Treatment Completion Page not expected	-	-	4

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Of subjects who completed treatment of all 6 injections, only a few subjects entered the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Of subjects who started treatment, only a few subjects entered and completed the 3-year follow-up period voluntarily. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm.

Baseline characteristics

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Reporting group title

Radium-223 dichloride (Xofigo, BAY88-8223)

Reporting group description

Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Reporting group title

Placebo

Reporting group description

Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.

Reporting group values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo	Total
Number of subjects	614	307	307
Age categorical
Units: Subjects
Age continuous
Units: Years
arithmetic mean (standard deviation)	70.2 ( 8.1 )	70.8 ( 7.87 )	-
Gender categorical
Units: Subjects
Male	614	307	921
Total Alkaline Phosphatase (ALP)
The total amount of ALP in the blood was determined at baseline.
Units: Subjects
< 220 Units/Liter (U/L)	348	169	517
>= 220 U/L	266	138	404
Current use of bisphosphonates
Subjects may have been on bisphosphonate therapy during the study.
Units: Subjects
Yes	250	124	374
No	364	183	547
Any prior use of docetaxel
Units: Subjects
Yes	352	174	526
No	262	133	395

End points

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Reporting group title

Radium-223 dichloride (Xofigo, BAY88-8223)

Reporting group description

Radium-223 50 kiloBecquerel (kBq)/kilogram (kg) body weight for 6 IV administrations separated by 4 weeks intervals plus BSoC.

Reporting group title

Placebo

Reporting group description

Isotonic saline for 6 intravenous (IV) administrations separated by 4 weeks intervals plus BSoC.

Reporting group title

Radium-223 Dichloride (Xofigo, BAY88-8223)

Reporting group description

Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.

Reporting group title

Placebo

Reporting group description

Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.

Reporting group title

Placebo Randomized, Then Switched to Radium-223 Dichloride

Reporting group description

Subject analysis set title

Intent-to-treat (ITT) population

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT population (N=921) was defined as all randomized subjects.

Primary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the time from date of randomization to the date of death.

End point type

Primary

End point timeframe

From randomization to death due to any cause until the data cut-off date (15JUL2011) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[1]	307 ^[2]
Units: Months
median (confidence interval 95%)	14.9 (13.9 to 16.1)	11.3 (10.1 to 12.8)

Notes
[1] - ITT population.
[2] - ITT population.

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of overall survival, and also for the secondary endpoints, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.00005 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.691

Confidence interval

level

95%

sides

2-sided

lower limit

0.578

upper limit

0.827

Notes
[3] - Comparison with placebo
[4] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Total Alkaline Phosphatase (ALP) Progression

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End point title

Time to Total Alkaline Phosphatase (ALP) Progression

End point description

The time from the first study drug administration to when ALP progression was observed, defined as: 1) In subjects with no ALP decline from baseline; a greater than or equal to 25 percent (%) increase from baseline value and an increase in absolute value of greater than or equal to 2 nanogram (ng)/milliliter (mL), at least 12 weeks from baseline; 2) In subjects with initial ALP decline from baseline; the time from start of treatment to first ALP increase that was greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later. '99999" indicates 95% confidence interval upper limit was not estimable due to insufficient number of subjects with events.

End point type

Secondary

End point timeframe

From randomization to first ALP progression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[5]	307 ^[6]
Units: Months
median (confidence interval 95%)	7.4 (7.1 to 99999)	3.8 (3.6 to 4.2)

Notes
[5] - The ITT population was all randomized subjects.
[6] - The ITT population was all randomized subjects.

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of time to total ALP progression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

< 0.00001 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.169

Confidence interval

level

95%

sides

2-sided

lower limit

0.131

upper limit

0.22

Notes
[7] - Comparison with placebo
[8] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Percentage of Subjects With Total ALP Response at Week 12

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End point title

Percentage of Subjects With Total ALP Response at Week 12

End point description

ALP levels were measured in subjects' blood at Week 12 and compared to baseline values. A confirmed total ALP response (either >=30% or 50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.

End point type

Secondary

End point timeframe

At Baseline and Week 12 based of 10 Oct 2014 cutoff date

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	497 ^[9]	211 ^[10]
Units: Percentage of subjects
number (not applicable)
>=30% reduction of ALP in blood level	59.4	6.2
>=50% reduction of ALP in blood level	32.6	1.4
Confirmed Total ALP Response (>=30%)	47.1	3.3
Confirmed Total ALP Response (>=50%)	27.4	0.9

Notes
[9] - Subjects in the ITT population and had no missing values for this endpoint.
[10] - Subjects in the ITT population and had no missing values for this endpoint.

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of >=30% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

< 0.001 ^[12]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[11] - Comparison with placebo
[12] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. >=30% reduction in blood level.

Statistical Analysis 2

Statistical analysis description

The null hypothesis for the comparison of >=50% reduction in blood level, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

< 0.001 ^[14]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[13] - Comparison with placebo
[14] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. >=50% reduction in blood level.

Statistical Analysis 3

Statistical analysis description

The null hypothesis for the comparison of Confirmed Total ALP Response (>=30%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

< 0.001 ^[16]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[15] - Comparison with placebo
[16] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Confirmed Total ALP Response (>=30%).

Statistical Analysis 4

Statistical analysis description

The null hypothesis for the comparison of Confirmed Total ALP Response (>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

< 0.001 ^[18]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[17] - Comparison with placebo
[18] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Confirmed Total ALP Response (>=50%).

Secondary: Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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End point title

Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

End point description

ALP levels were measured in subjects' blood at EOT (Week 24) and compared to baseline values. A confirmed total ALP response (>=50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.

End point type

Secondary

End point timeframe

At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase) based on 10 Oct 2014 cutoff date

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	589 ^[19]	288 ^[20]
Units: Percentage of subjects
number (not applicable)
>=30% reduction of ALP in blood level	59.9	4.5
>=50% reduction of ALP in blood level	34.6	1.7
Confirmed Total ALP Response (>=50%)	13.9	1

Notes
[19] - Subjects in the ITT population and had no missing values for this endpoint
[20] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

< 0.001 ^[22]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[21] - Comparison with placebo
[22] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

< 0.001 ^[24]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[23] - Comparison with placebo
[24] - Confirmed Total ALP Response (>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.001 ^[26]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[25] - Comparison with placebo
[26] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Percentage of Subjects With Total ALP Normalization at Week 12

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End point title

Percentage of Subjects With Total ALP Normalization at Week 12

End point description

The return of total ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in subjects who had ALP above the upper limit of normal (ULN) at baseline.

End point type

Secondary

End point timeframe

At Baseline and Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	321 ^[27]	140 ^[28]
Units: Percentage of subjects
number (not applicable)	34	1.4

Notes
[27] - Subjects in the ITT population and had no missing values for this endpoint.
[28] - Subjects in the ITT population and had no missing values for this endpoint.

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Total ALP normalization, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

461

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

< 0.001 ^[30]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[29] - comparison with placebo
[30] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Total ALP normalization.

Secondary: Percentage Change From Baseline in Total ALP at Week 12

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End point title

Percentage Change From Baseline in Total ALP at Week 12

End point description

ALP level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (ALP level at week 12 minus ALP level at baseline)/(ALP level at baseline)*100.

End point type

Secondary

End point timeframe

At Baseline and Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	497 ^[31]	211 ^[32]
Units: Percentage change
least squares mean (standard error)	-32.2 ( 1.8 )	37.2 ( 2.77 )

Notes
[31] - Subjects in the ITT population and had no missing values for this endpoint
[32] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Percentage change from baseline, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

< 0.001 ^[34]

Method

ANCOVA

Confidence interval

Notes
[33] - comparison with placebo
[34] - Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel. Percentage change from Baseline.

Secondary: Maximum Percentage Decrease From Baseline in Total ALP up to Week 12

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End point title

Maximum Percentage Decrease From Baseline in Total ALP up to Week 12

End point description

ALP level was measured in subject's blood up to week 12 and the maximum percent decrease from the baseline up to Week 12 value was calculated as the minimum value of [(ALP level up to week 12 minus ALP level at baseline)/(ALP level at baseline)*100] by subject, and set to zero if no decrease from baseline.

End point type

Secondary

End point timeframe

From baseline to Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	582 ^[35]	284 ^[36]
Units: Percentage change
least squares mean (standard error)	-38.9 ( 0.76 )	-5.9 ( 1.09 )

Notes
[35] - Subjects in the ITT population and had no missing values for this endpoint
[36] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Maximum Percentage decrease from baseline to week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

< 0.001 ^[38]

Method

ANCOVA

Confidence interval

Notes
[37] - Comparison with placebo
[38] - Maximum percentage decrease from baseline to week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

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End point title

Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

End point description

ALP level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (ALP level at EOT minus ALP level at baseline)/(ALP level at baseline)*100.

End point type

Secondary

End point timeframe

At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase) based on 10 Oct 2014 cutoff date

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	589 ^[39]	288 ^[40]
Units: Percent change
least squares mean (standard error)	-29.9 ( 3.13 )	62.1 ( 4.48 )

Notes
[39] - Subjects in the ITT population and had no missing values for this endpoint.
[40] - Subjects in the ITT population and had no missing values for this endpoint.

Statistical Analysis 1

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

< 0.001 ^[42]

Method

ANCOVA

Confidence interval

Notes
[41] - Comparison with placebo.
[42] - Percentage change from baseline. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment

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End point title

Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment

End point description

ALP level was measured in subject's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 week treatment value was calculated as the minimum value of [(ALP level up to week 24 minus ALP level at baseline)/(ALP level at baseline)*100] by subject, and set to zero if no decrease from baseline.

End point type

Secondary

End point timeframe

From baseline During the 24 Week Treatment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	589 ^[43]	288 ^[44]
Units: Percentage change
least squares mean (standard error)	-44.4 ( 0.8 )	-7.5 ( 1.14 )

Notes
[43] - Subjects in the ITT population and had no missing values for this endpoint
[44] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Maximum Percentage decrease from baseline during the 24 week treatment, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

< 0.001 ^[46]

Method

ANCOVA

Confidence interval

Notes
[45] - Comparison with placebo
[46] - Maximum Percentage decrease from baseline. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Time to Prostate Specific Antigen (PSA) Progression

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End point title

Time to Prostate Specific Antigen (PSA) Progression

End point description

The time from the first study drug administration to when PSA progression was observed, defined as: 1) In subjects with no PSA decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial PSA decline from baseline; the time from start of treatment to first PSA increase that was greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later.

End point type

Secondary

End point timeframe

From randomization to first PSA progression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[47]	307 ^[48]
Units: Months
median (confidence interval 95%)	3.6 (3.5 to 3.8)	3.4 (3.3 to 3.5)

Notes
[47] - The ITT population was all randomized subjects
[48] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to PSA progression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

< 0.00001 ^[50]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.643

Confidence interval

level

95%

sides

2-sided

lower limit

0.539

upper limit

0.768

Notes
[49] - Comparison with placebo
[50] - Time to PSA progression. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Percentage of Subjects With PSA Response at Week 12

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End point title

Percentage of Subjects With PSA Response at Week 12

End point description

PSA levels were measured in subjects' blood at Week 12 and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.

End point type

Secondary

End point timeframe

At Baseline and Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	493 ^[51]	210 ^[52]
Units: Percentage of subjects
number (not applicable)
>=30% reduction of PSA in blood level	16.4	6.2
>=50% reduction of PSA in blood level	7.7	4.3
Confirmed PSA Response (>=50%)	5.7	1.9

Notes
[51] - Subjects in the ITT population and had no missing values for this endpoint
[52] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Radium-223 dichloride (Xofigo, BAY88-8223)

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

< 0.001 ^[54]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[53] - Comparison with placebo
[54] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

= 0.106 ^[56]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[55] - Comparison with placebo
[56] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical analysis description

The null hypothesis for the comparison of Confirmed PSA Response(>=50%), was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

= 0.032 ^[58]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[57] - Comparison with placebo
[58] - Confirmed PSA Response(>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Top of page

End point title

Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

End point description

PSA levels were measured in subjects' blood at EOT (Week 24) and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.

End point type

Secondary

End point timeframe

At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	590 ^[59]	286 ^[60]
Units: Percentage of subjects
number (not applicable)
>=30% reduction in blood level	14.2	4.5
>=50% reduction in blood level	9	3.1
Confirmed PSA Response (>=50%)	6.1	1.7

Notes
[59] - Subjects in the ITT population and had no missing values for this endpoint
[60] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

< 0.001 ^[62]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[61] - Comparison with placebo
[62] - >=30% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

= 0.002 ^[64]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[63] - Comparison with placebo
[64] - >=50% reduction in blood level. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

= 0.005 ^[66]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[65] - Comparison with placebo
[66] - Confirmed PSA Response(>=50%). Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Percentage Change From Baseline in PSA at Week 12

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End point title

Percentage Change From Baseline in PSA at Week 12

End point description

PSA level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (PSA level at week 12 minus PSA level at baseline)/(PSA level at baseline)*100.

End point type

Secondary

End point timeframe

At Baseline and Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	493 ^[67]	210 ^[68]
Units: Percent change
least squares mean (standard error)	83.3 ( 152.48 )	543.8 ( 233.69 )

Notes
[67] - Subjects in the ITT population and had no missing values for this endpoint
[68] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Percentage change from baseline in PSA at Week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[69]

P-value

= 0.16 ^[70]

Method

ANCOVA

Confidence interval

Notes
[69] - Comparison with placebo
[70] - Percentage change from baseline in PSA at Week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Maximum Percentage Decrease From Baseline in PSA up to Week 12

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End point title

Maximum Percentage Decrease From Baseline in PSA up to Week 12

End point description

PSA level was measured in subject's blood up to Week 12 and the maximum percent decrease from the baseline up to week 12 value was calculated as the minimum value of [(PSA level up to week 12 minus PSA level at baseline)/(PSA level at baseline)*100] by subject, and set to zero if no decrease from baseline.

End point type

Secondary

End point timeframe

From baseline up to Week 12

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	581 ^[71]	283 ^[72]
Units: Percentage change
least squares mean (standard error)	-13 ( 0.9 )	-7.8 ( 1.28 )

Notes
[71] - Subjects in the ITT population and had no missing values for this endpoint
[72] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline up to Week 12, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.004 ^[74]

Method

ANCOVA

Confidence interval

Notes
[73] - Comparison with placebo
[74] - Maximum Percentage Decrease from Baseline up to Week 12. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Top of page

End point title

Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

End point description

PSA level was measured in subject’s blood at EOT (Week 24) and the percent change from the baseline value was calculated (PSA level at EOT minus PSA level at baseline)/(PSA level at baseline)*100.

End point type

Secondary

End point timeframe

At Baseline and End of Treatment (Week 24 or at the time the subject dies or discontinues treatment phase)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	590 ^[75]	286 ^[76]
Units: Percentage change
least squares mean (standard error)	144.3 ( 15.38 )	191.1 ( 22.1 )

Notes
[75] - Subjects in the ITT population and had no missing values for this endpoint
[76] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Percentage change from baseline in PSA at EOT, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

other ^[77]

P-value

= 0.009 ^[78]

Method

ANCOVA

Confidence interval

Notes
[77] - Comparison with placebo
[78] - Percentage change from baseline in PSA at EOT. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period

Top of page

End point title

Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period

End point description

PSA level was measured in subject's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 Week treatment value was calculated as the minimum value of [(PSA level up to week 24 minus PSA level at baseline)/(PSA level at baseline)*100] by subject, and set to zero if no decrease from baseline.

End point type

Secondary

End point timeframe

From baseline to End of Treatment (Week 24; 4 weeks post last injection)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	590 ^[79]	286 ^[80]
Units: Percentage change
least squares mean (standard error)	-16.4 ( 1.01 )	-9.3 ( 1.45 )

Notes
[79] - Subjects in the ITT population and had no missing values for this endpoint
[80] - Subjects in the ITT population and had no missing values for this endpoint

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

other ^[81]

P-value

< 0.001 ^[82]

Method

ANCOVA

Confidence interval

Notes
[81] - Comparison with placebo
[82] - Maximum Percentage Decrease from Baseline in PSA response During the 24 Week Treatment Period. Adjusting for the binary stratification factors, total ALP, current use of Bisphosphonates and prior use of Docetaxel.

Secondary: Time to First Skeletal Related Event (SRE)

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End point title

Time to First Skeletal Related Event (SRE)

End point description

A skeletal related event was the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention. For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

End point type

Secondary

End point timeframe

From randomization to first SRE until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[83]	307 ^[84]
Units: Months
median (confidence interval 95%)	16.4 (14.3 to 18.3)	8.1 (6.7 to 11.9)

Notes
[83] - The ITT population was all randomized subjects
[84] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of time to first SRE, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[85]

P-value

= 0.00012 ^[86]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.657

Confidence interval

level

95%

sides

2-sided

lower limit

0.529

upper limit

0.814

Notes
[85] - Comparison with placebo
[86] - Time to first Skeletal Related Event (SRE). Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms

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End point title

Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms

End point description

The start date of therapy was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

End point type

Secondary

End point timeframe

From randomization to first EBRT until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[87]	307 ^[88]
Units: Months
median (confidence interval 95%)	18 (15.9 to 20.6)	10.7 (7.6 to 18.5)

Notes
[87] - The ITT population was all randomized subjects
[88] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of time to EBRT, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[89]

P-value

= 0.00008 ^[90]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.639

Confidence interval

level

95%

sides

2-sided

lower limit

0.511

upper limit

0.8

Notes
[89] - Comparison with placebo
[90] - Time to External Beam Radiotherapy. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms

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End point title

Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms

End point description

The start date of the radioisotopes was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.

End point type

Secondary

End point timeframe

From randomization to first use of radioisotopes until the data cut-off date (10 Oct 2014)approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[91]	307 ^[92]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[91] - The ITT population was all randomized subjects.
[92] - The ITT population was all randomized subjects.

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Receiving Radio-isotope, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[93]

P-value

= 0.00191 ^[94]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.344

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.695

Notes
[93] - Comparison with placebo
[94] - Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral

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End point title

Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral

End point description

The start date of the event was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.

End point type

Secondary

End point timeframe

From randomization to occurrence of first new symptomatic pathological bone fractures until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[95]	307 ^[96]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[95] - The ITT population was all randomized subjects
[96] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Pathological Bone Fracture, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[97]

P-value

= 0.53277 ^[98]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.847

Confidence interval

level

95%

sides

2-sided

lower limit

0.504

upper limit

1.426

Notes
[97] - Comparison with placebo.
[98] - Time to Pathological Bone Fracture. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention

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End point title

Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention

End point description

The start date of the intervention was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.

End point type

Secondary

End point timeframe

From randomization to occurrence of first tumor related orthopedic surgical intervention until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[99]	307 ^[100]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[99] - The ITT population was all randomized subjects
[100] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Surgical Intervention, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[101]

P-value

= 0.89567 ^[102]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.949

Confidence interval

level

95%

sides

2-sided

lower limit

0.435

upper limit

2.07

Notes
[101] - Comparison with placebo
[102] - Time to Surgical Intervention. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Spinal Cord Compression

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End point title

Time to Occurrence of First Spinal Cord Compression

End point description

The start date of the compression was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. '99999' indicates that values were not reported since median survival time was not reached.

End point type

Secondary

End point timeframe

From randomization to first spinal cord compression until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[103]	307 ^[104]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[103] - The ITT population was all randomized subjects
[104] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Spinal Cord Compression, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[105]

P-value

= 0.14486 ^[106]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.404

upper limit

1.145

Notes
[105] - Comparison with placebo
[106] - Time to Spinal Cord Compression. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Start of any Other Anti-cancer Treatment

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End point title

Time to Occurrence of First Start of any Other Anti-cancer Treatment

End point description

The start date of the treatment was used as the time of the event. If an event had not occurred at the time of the analysis or the subject had been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.

End point type

Secondary

End point timeframe

From randomization to first start of any other anti-cancer treatment until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[107]	307 ^[108]
Units: Months
median (confidence interval 95%)	15.4 (12.6 to 17)	12.7 (11 to 14.7)

Notes
[107] - The ITT population was all randomized subjects
[108] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Other Cancer Treatment, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[109]

P-value

= 0.00932 ^[110]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.727

Confidence interval

level

95%

sides

2-sided

lower limit

0.571

upper limit

0.925

Notes
[109] - comparison with placebo
[110] - Time to Other Cancer Treatment. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Secondary: Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline

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End point title

Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline

End point description

ECOG scores were: 0 = fully active; 1 = restricted in physically strenuous activity; 2 = ambulatory and capable of all self-care but unable to work; 3 = capable of only limited self-care; 4 = completely disabled; 5 = death. The visit at which a 2-point or more deterioration in PS was observed was the time of the event. ECOG was assessed at every visit. If a marked deterioration in PS had not occurred at the time of the analysis or the subject was lost to follow-up, the time-to-event variables were censored at the last assessment date.

End point type

Secondary

End point timeframe

From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until the data cut-off date (10 Oct 2014) approximately 3 years after start of enrollment

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[111]	307 ^[112]
Units: Months
median (confidence interval 95%)	23.4 (20.4 to 26.5)	18.4 (13.1 to 24.5)

Notes
[111] - The ITT population was all randomized subjects
[112] - The ITT population was all randomized subjects

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the comparison of Time to Marked Deterioration of ECOG PS, was that there was no difference between Alpharadin and placebo for that endpoint; the alternative hypothesis was that a difference exists. The hazard ratio (Alpharadin:Placebo) was from a Cox proportional hazards model stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Comparison groups

Radium-223 dichloride (Xofigo, BAY88-8223) v Placebo

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

other ^[113]

P-value

= 0.00187 ^[114]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.546

upper limit

0.873

Notes
[113] - Comparison with placebo
[114] - Time to Marked Deterioration of ECOG PS. Stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel.

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0

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End point title

Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0

End point description

ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.

End point type

Other pre-specified

End point timeframe

Week 0

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	600 ^[115]	305 ^[116]
Units: Subjects
number (not applicable)
ECOG Grade 0	136	72
ECOG Grade 1	376	191
ECOG Grade 2	82	40
ECOG Grade 3	6	1
ECOG Grade 4	0	0
ECOG Grade 5	0	0
Missing	0	1

Notes
[115] - Subjects in the ITT population and with ECOG analyzed
[116] - Subjects in the ITT population and with ECOG analyzed

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8

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End point title

Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8

End point description

ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.

End point type

Other pre-specified

End point timeframe

Week 8

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	569 ^[117]	267 ^[118]
Units: Subjects
number (not applicable)
ECOG Grade 0	133	49
ECOG Grade 1	315	142
ECOG Grade 2	103	53
ECOG Grade 3	13	15
ECOG Grade 4	0	3
ECOG Grade 5	1	1
Missing	4	4

Notes
[117] - Subjects in the ITT population and with ECOG analyzed
[118] - Subjects in the ITT population and with ECOG analyzed

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16

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End point title

Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16

End point description

ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.

End point type

Other pre-specified

End point timeframe

Week 16

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	471 ^[119]	196 ^[120]
Units: Subjects
number (not applicable)
ECOG Grade 0	101	29
ECOG Grade 1	257	113
ECOG Grade 2	85	42
ECOG Grade 3	19	11
ECOG Grade 4	4	0
ECOG Grade 5	0	0
Missing	5	1

Notes
[119] - Subjects in the ITT population and with ECOG analyzed
[120] - Subjects in the ITT population and with ECOG analyzed

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24

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End point title

Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24

End point description

ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.

End point type

Other pre-specified

End point timeframe

Week 24

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	363 ^[121]	138 ^[122]
Units: Subjects
number (not applicable)
ECOG Grade 0	74	22
ECOG Grade 1	181	66
ECOG Grade 2	85	36
ECOG Grade 3	17	10
ECOG Grade 4	5	4
ECOG Grade 5	0	0
Missing	1	0

Notes
[121] - Subjects in the ITT population and with ECOG analyzed
[122] - Subjects`in the ITT population and with ECOG analyzed

No statistical analyses for this end point

Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)

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End point title

Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)

End point description

The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Prostate Cancer Trial Outcome Index (TOI): Physical Well-being (PWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 104 (best).

End point type

Other pre-specified

End point timeframe

Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[123]	307 ^[124]
Units: Scores on a scale
median (full range (min-max))
Week 0 (Baseline)	65 (17 to 104)	64 (23 to 96)
Week 16	65 (11 to 98)	61.31 (19 to 96.5)
Week 24	61 (17 to 102)	60 (17 to 97)
Follow-up Visit 2 (Week 42)	61 (10 to 95)	60.5 (16.7 to 97)

Notes
[123] - The ITT population was all randomized subjects
[124] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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End point title

Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point description

The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Possible scores were 0 to 104; the higher the score, the better the quality of life. The changes from baseline (range -104 to 104) in the domain FACT-P TOI were summarized using descriptive statistics at Week 16, Week 24, and Follow-up Visit 2.

End point type

Other pre-specified

End point timeframe

Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[125]	307 ^[126]
Units: Scores on a scale
median (full range (min-max))
At Week 16	-1.55 (-49.3 to 38)	-4.15 (-43 to 46)
At Week 24	-4 (-60.4 to 40)	-5.67 (-39 to 41)
At Follow-up Visit 2 (Week 42)	-5 (-89 to 44.5)	-5.5 (-47.4 to 25)

Notes
[125] - The ITT population was all randomized subjects
[126] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16

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End point title

Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16

End point description

The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 – Not at all; 4 – Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Week 16.

End point type

Other pre-specified

End point timeframe

At Week 16

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[127]	307 ^[128]
Units: Scores on a scale
median (full range (min-max))
physical well being	20 (3 to 28)	19.83 (1 to 28)
social/family well being	22 (0 to 28)	21.5 (0 to 28)
emotional well being	18 (0 to 24)	16.8 (2 to 24)
functional well being	16 (0 to 28)	15 (0 to 28)
the prostate cancer subscale	29 (1 to 46.9)	27.6 (9 to 42.5)

Notes
[127] - The ITT population was all randomized subjects
[128] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24

Top of page

End point title

Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24

End point description

End point type

Other pre-specified

End point timeframe

At Week 24

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[129]	307 ^[130]
Units: Scores on a scale
median (full range (min-max))
physical well being	19 (3 to 28)	18.67 (3 to 28)
social/family well being	21 (0 to 28)	21 (9 to 28)
emotional well being	17 (4 to 24)	16 (1.2 to 24)
functional well being	15 (0 to 28)	14 (0 to 28)
the prostate cancer subscale	28 (3.6 to 46)	27.64 (5 to 43)

Notes
[129] - The ITT population was all randomized subjects
[130] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)

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End point title

Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)

End point description

End point type

Other pre-specified

End point timeframe

At Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[131]	307 ^[132]
Units: Scores on a scale
median (full range (min-max))
physical well being	19 (0 to 28)	18 (1 to 28)
social/family well being	22 (0 to 28)	22 (9 to 33.8)
emotional well being	17 (0 to 24)	16 (3 to 24)
functional well being	14 (1 to 28)	14 (4 to 28)
the prostate cancer subscale	28 (3 to 42)	29 (6.5 to 43)

Notes
[131] - The ITT population was all randomized subjects
[132] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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End point title

Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point description

The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score of the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) was calculated at Week 16, Week 24, and Follow-up Visit 2.FACT-P Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 156 (best).

End point type

Other pre-specified

End point timeframe

At Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[133]	307 ^[134]
Units: Scores on a scale
median (full range (min-max))
At Week 16	100.68 (30 to 147)	99.9 (33.7 to 144)
At Week 24	98 (41.8 to 152)	97.5 (47 to 149)
At Follow-up Visit 2 (Week 42)	97.83 (41 to 145)	97.38 (40.9 to 147.8)

Notes
[133] - The ITT population was all randomized subjects
[134] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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End point title

Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point description

The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. Total possible score was 156; a higher score indicates a better quality of life. The changes from baseline in the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -156 to 156.

End point type

Other pre-specified

End point timeframe

Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[135]	307 ^[136]
Units: Scores on a scale
median (full range (min-max))
At Week 16	-2 (-58 to 58)	-5.67 (-58 to 47)
At Week 24	-5 (-67.2 to 63.5)	-9.4 (-42.8 to 48.8)
At Follow-up Visit 2 (Week 42)	-6.17 (-97 to 63.5)	-7 (-54.7 to 23.7)

Notes
[135] - The ITT population was all randomized subjects
[136] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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End point title

Absolute Scores for Functional Assessment of Cancer Therapy – General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point description

The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. The FACT-G absolute total score (physical, social/family, emotional, and functional well-being) was calculated at Week 16, Week 24, and Follow-up Visit 2. FACT-G Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB). Score ranges from 0 (worst) to 108 (best).

End point type

Other pre-specified

End point timeframe

At Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[137]	307 ^[138]
Units: Scores on a scale
median (full range (min-max))
At Week 16	73 (17 to 106)	72 (27.7 to 108)
At Week 24	71 (28 to 107)	69 (37 to 106)
At Follow-up Visit 2 (Week 42)	70 (22 to 107)	70.25 (32.2 to 104.8)

Notes
[137] - The ITT population was all randomized subjects
[138] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

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End point title

Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point description

The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. Total possible score was 108; a higher score indicates a better quality of life. The changes from baseline in the FACT-G total score (physical, social/family, emotional, and functional well-being) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -108 to 108.

End point type

Other pre-specified

End point timeframe

Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	614 ^[139]	307 ^[140]
Units: Scores on a scale
median (full range (min-max))
At Week 16	-1 (-38.3 to 40)	-4 (-53 to 32.8)
At Week 24	-4.08 (-49 to 49.5)	-7 (-35.8 to 41.8)
At Follow-up Visit 2 (Week 42)	-3.67 (-58 to 40.5)	-6 (-33.8 to 18.7)

Notes
[139] - The ITT population was all randomized subjects
[140] - The ITT population was all randomized subjects

No statistical analyses for this end point

Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16

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End point title

Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16

End point description

The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at Week 16, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).

End point type

Other pre-specified

End point timeframe

Week 16

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	477 ^[141]	205 ^[142]
Units: Subjects
number (not applicable)
mobility - Grade 1	191	64
mobility - Grade 2	278	129
mobility - Grade 3	7	10
mobility - Missing	1	2
self-care - Grade 1	346	140
self-care - Grade 2	123	54
self-care - Grade 3	7	10
self-care - Missing	1	1
usual activities - Grade 1	199	67
usual activities - Grade 2	233	105
usual activities - Grade 3	44	32
usual activities - Missing	1	1
pain/discomfort - Grade 1	79	23
pain/discomfort - Grade 2	351	159
pain/discomfort - Grade 3	46	22
pain/discomfort - Missing	1	1
anxiety/depression - Grade 1	285	104
anxiety/depression - Grade 2	171	95
anxiety/depression - Grade 3	15	4
anxiety/depression - Missing	6	2

Notes
[141] - The ITT population was all randomized subjects with with EQ-5D analyzed.
[142] - The ITT population was all randomized subjects with with EQ5D analysed.

No statistical analyses for this end point

Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24

Top of page

End point title

Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24

End point description

The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at Week 24, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).

End point type

Other pre-specified

End point timeframe

Week 24

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	368 ^[143]	140 ^[144]
Units: Subjects
number (not applicable)
mobility - Grade 1	129	39
mobility - Grade 2	225	93
mobility - Grade 3	11	5
mobility - Missing	3	3
self-care - Grade 1	256	89
self-care - Grade 2	102	46
self-care - Grade 3	6	3
self-care - Missing	4	2
usual activities - Grade 1	140	38
usual activities - Grade 2	187	79
usual activities - Grade 3	37	20
usual activities - Missing	4	3
pain/discomfort - Grade 1	56	21
pain/discomfort - Grade 2	270	95
pain/discomfort - Grade 3	39	21
pain/discomfort - Missing	3	3
anxiety/depression - Grade 1	195	64
anxiety/depression - Grade 2	159	71
anxiety/depression - Grade 3	10	2
anxiety/depression - Missing	4	3

Notes
[143] - The ITT population was all randomized subjects with with EQ-5D analyzed.
[144] - The ITT population was all randomized subjects with with EQ5D analysed.

No statistical analyses for this end point

Other pre-specified: Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)

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End point title

Number of Subjects in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)

End point description

The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of subjects with EQ-5D at follow-up visit 8, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’).

End point type

Other pre-specified

End point timeframe

Follow-up Visit 8 (Week 139)

End point values	Radium-223 dichloride (Xofigo, BAY88-8223)	Placebo
Number of subjects analysed	41 ^[145]	13 ^[146]
Units: Subjects
number (not applicable)
mobility - Grade 1	9	2
mobility - Grade 2	30	10
mobility - Grade 3	1	1
mobility - Missing	1	0
self-care - Grade 1	26	7
self-care - Grade 2	12	3
self-care - Grade 3	2	3
self-care - Missing	1	0
usual activities - Grade 1	13	2
usual activities - Grade 2	19	7
usual activities - Grade 3	8	4
usual activities - Missing	1	0
pain/discomfort - Grade 1	5	1
pain/discomfort - Grade 2	32	11
pain/discomfort - Grade 3	3	1
pain/discomfort - Missing	1	0
anxiety/depression - Grade 1	24	6
anxiety/depression - Grade 2	15	7
anxiety/depression - Grade 3	1	0
anxiety/depression - Missing	1	0

Notes
[145] - The ITT population was all randomized subjects with with EQ-5D analyzed.
[146] - The ITT population was all randomized subjects with with EQ-5D analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event data were collected from first dose of study drug to the final data as of 10OCT2014

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

11.0

Reporting group title

Radium-223 Dichloride (Xofigo, BAY88-8223)

Reporting group description

Subjects received BSoC plus radium-223 50 kBq/kg body weight for 6 IV administrations separated by 4 weeks intervals.

Reporting group title

Placebo Randomized, Then Switched to Radium-223 Dichloride

Reporting group description

Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals from first dose of study drug to data cut-off date of 15 July 2011; Subjects received radium-223 50 kBq/kg body weight for 6 intravenous administrations separated by 4 weeks intervals from 15 July 2011 to the end of study.

Reporting group title

Placebo

Reporting group description

Subjects received BSoC plus isotonic saline for 6 IV administrations separated by 4 weeks intervals.

Serious adverse events	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo Randomized, Then Switched to Radium-223 Dichloride	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	286 / 600 (47.67%)	17 / 24 (70.83%)	185 / 301 (61.46%)
number of deaths (all causes)	520	18	251
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of bladder
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Metastases to liver
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Metastases to lymph nodes
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	65 / 600 (10.83%)	2 / 24 (8.33%)	38 / 301 (12.62%)
occurrences causally related to treatment / all	0 / 67	0 / 2	0 / 42
deaths causally related to treatment / all	0 / 53	0 / 2	0 / 35
Metastases to meninges
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Bone marrow tumour cell infiltration
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Lymphangiosis carcinomatosa
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Benign urinary tract neoplasm
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	5 / 600 (0.83%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 4	0 / 0	0 / 1
Gait disturbance
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	6 / 600 (1.00%)	0 / 24 (0.00%)	9 / 301 (2.99%)
occurrences causally related to treatment / all	4 / 7	0 / 0	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	6 / 600 (1.00%)	0 / 24 (0.00%)	6 / 301 (1.99%)
occurrences causally related to treatment / all	6 / 9	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	15 / 600 (2.50%)	1 / 24 (4.17%)	8 / 301 (2.66%)
occurrences causally related to treatment / all	3 / 15	0 / 1	1 / 8
deaths causally related to treatment / all	0 / 6	0 / 1	0 / 2
Sudden death
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Drug intolerance
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatic haemorrhage
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Scrotal oedema
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	6 / 600 (1.00%)	0 / 24 (0.00%)	5 / 301 (1.66%)
occurrences causally related to treatment / all	2 / 6	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 3
Epistaxis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	3 / 8	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pleuritic pain
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	7 / 600 (1.17%)	0 / 24 (0.00%)	6 / 301 (1.99%)
occurrences causally related to treatment / all	1 / 7	0 / 0	0 / 6
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 3
Pneumonia aspiration
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pulmonary oedema
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	6 / 600 (1.00%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Aggression
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intentional self-injury
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic specific antigen increased
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis radiation
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 600 (0.17%)	1 / 24 (4.17%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intentional overdose
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Therapeutic agent toxicity
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stent occlusion
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Medical device complication
subjects affected / exposed	1 / 600 (0.17%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	4 / 301 (1.33%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	4 / 301 (1.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Atrioventricular block complete
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Coronary artery disease
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 2
Left ventricular dysfunction
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Supraventricular tachycardia
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	1 / 2
Acute coronary syndrome
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Aphasia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hydrocephalus
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial palsy
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraplegia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 600 (0.33%)	1 / 24 (4.17%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Spinal cord compression
subjects affected / exposed	21 / 600 (3.50%)	1 / 24 (4.17%)	16 / 301 (5.32%)
occurrences causally related to treatment / all	0 / 21	0 / 1	0 / 16
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radicular syndrome
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nerve root compression
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paresis cranial nerve
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	50 / 600 (8.33%)	1 / 24 (4.17%)	25 / 301 (8.31%)
occurrences causally related to treatment / all	49 / 70	1 / 1	15 / 35
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Aplastic anaemia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	5 / 600 (0.83%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	5 / 6	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	14 / 600 (2.33%)	1 / 24 (4.17%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	11 / 14	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	8 / 600 (1.33%)	0 / 24 (0.00%)	4 / 301 (1.33%)
occurrences causally related to treatment / all	2 / 8	0 / 0	0 / 4
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	4 / 301 (1.33%)
occurrences causally related to treatment / all	2 / 4	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecal incontinence
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	9 / 600 (1.50%)	0 / 24 (0.00%)	5 / 301 (1.66%)
occurrences causally related to treatment / all	3 / 10	0 / 0	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 600 (0.17%)	1 / 24 (4.17%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	11 / 600 (1.83%)	0 / 24 (0.00%)	7 / 301 (2.33%)
occurrences causally related to treatment / all	6 / 20	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erosive duodenitis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	11 / 600 (1.83%)	0 / 24 (0.00%)	7 / 301 (2.33%)
occurrences causally related to treatment / all	1 / 13	0 / 0	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	8 / 600 (1.33%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 10	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	4 / 600 (0.67%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Micturition urgency
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	7 / 600 (1.17%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
Urinary incontinence
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal pain
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage urinary tract
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	10 / 600 (1.67%)	0 / 24 (0.00%)	9 / 301 (2.99%)
occurrences causally related to treatment / all	1 / 10	0 / 0	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	61 / 600 (10.17%)	1 / 24 (4.17%)	50 / 301 (16.61%)
occurrences causally related to treatment / all	6 / 76	0 / 1	6 / 56
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	5 / 600 (0.83%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 600 (0.17%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	14 / 600 (2.33%)	1 / 24 (4.17%)	11 / 301 (3.65%)
occurrences causally related to treatment / all	1 / 14	1 / 1	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Catheter related infection
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	10 / 600 (1.67%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	1 / 12	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Listeriosis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Lower respiratory tract infection
subjects affected / exposed	8 / 600 (1.33%)	0 / 24 (0.00%)	2 / 301 (0.66%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	17 / 600 (2.83%)	1 / 24 (4.17%)	7 / 301 (2.33%)
occurrences causally related to treatment / all	1 / 18	0 / 1	1 / 8
deaths causally related to treatment / all	1 / 5	0 / 0	0 / 0
Pneumonia primary atypical
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	7 / 600 (1.17%)	0 / 24 (0.00%)	4 / 301 (1.33%)
occurrences causally related to treatment / all	1 / 7	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Upper respiratory tract infection
subjects affected / exposed	1 / 600 (0.17%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	5 / 600 (0.83%)	0 / 24 (0.00%)	6 / 301 (1.99%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Urosepsis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 600 (0.00%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	5 / 600 (0.83%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Dehydration
subjects affected / exposed	12 / 600 (2.00%)	0 / 24 (0.00%)	3 / 301 (1.00%)
occurrences causally related to treatment / all	10 / 20	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 600 (0.33%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	3 / 600 (0.50%)	0 / 24 (0.00%)	1 / 301 (0.33%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 600 (0.17%)	0 / 24 (0.00%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 600 (0.00%)	1 / 24 (4.17%)	0 / 301 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Radium-223 Dichloride (Xofigo, BAY88-8223)	Placebo Randomized, Then Switched to Radium-223 Dichloride	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	524 / 600 (87.33%)	23 / 24 (95.83%)	254 / 301 (84.39%)
Investigations
Weight decreased
subjects affected / exposed	74 / 600 (12.33%)	2 / 24 (8.33%)	44 / 301 (14.62%)
occurrences all number	74	2	45
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	12 / 600 (2.00%)	3 / 24 (12.50%)	4 / 301 (1.33%)
occurrences all number	13	3	4
Nervous system disorders
Dizziness
subjects affected / exposed	45 / 600 (7.50%)	2 / 24 (8.33%)	26 / 301 (8.64%)
occurrences all number	53	2	30
Headache
subjects affected / exposed	25 / 600 (4.17%)	2 / 24 (8.33%)	9 / 301 (2.99%)
occurrences all number	29	2	9
Paraesthesia
subjects affected / exposed	16 / 600 (2.67%)	2 / 24 (8.33%)	4 / 301 (1.33%)
occurrences all number	16	2	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	161 / 600 (26.83%)	8 / 24 (33.33%)	81 / 301 (26.91%)
occurrences all number	247	10	104
Thrombocytopenia
subjects affected / exposed	59 / 600 (9.83%)	2 / 24 (8.33%)	15 / 301 (4.98%)
occurrences all number	71	2	16
Neutropenia
subjects affected / exposed	28 / 600 (4.67%)	2 / 24 (8.33%)	3 / 301 (1.00%)
occurrences all number	37	3	4
General disorders and administration site conditions
Fatigue
subjects affected / exposed	157 / 600 (26.17%)	9 / 24 (37.50%)	73 / 301 (24.25%)
occurrences all number	192	10	86
Asthenia
subjects affected / exposed	35 / 600 (5.83%)	2 / 24 (8.33%)	17 / 301 (5.65%)
occurrences all number	43	2	19
Oedema peripheral
subjects affected / exposed	76 / 600 (12.67%)	2 / 24 (8.33%)	29 / 301 (9.63%)
occurrences all number	82	2	34
Pyrexia
subjects affected / exposed	38 / 600 (6.33%)	0 / 24 (0.00%)	15 / 301 (4.98%)
occurrences all number	58	0	24
Gastrointestinal disorders
Constipation
subjects affected / exposed	105 / 600 (17.50%)	2 / 24 (8.33%)	60 / 301 (19.93%)
occurrences all number	111	2	68
Abdominal pain
subjects affected / exposed	21 / 600 (3.50%)	2 / 24 (8.33%)	13 / 301 (4.32%)
occurrences all number	21	2	15
Diarrhoea
subjects affected / exposed	153 / 600 (25.50%)	7 / 24 (29.17%)	43 / 301 (14.29%)
occurrences all number	242	12	60
Nausea
subjects affected / exposed	210 / 600 (35.00%)	11 / 24 (45.83%)	98 / 301 (32.56%)
occurrences all number	294	12	126
Vomiting
subjects affected / exposed	108 / 600 (18.00%)	3 / 24 (12.50%)	34 / 301 (11.30%)
occurrences all number	151	3	45
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	47 / 600 (7.83%)	0 / 24 (0.00%)	21 / 301 (6.98%)
occurrences all number	54	0	22
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	14 / 600 (2.33%)	2 / 24 (8.33%)	5 / 301 (1.66%)
occurrences all number	15	2	6
Urinary retention
subjects affected / exposed	20 / 600 (3.33%)	3 / 24 (12.50%)	12 / 301 (3.99%)
occurrences all number	20	3	13
Psychiatric disorders
Insomnia
subjects affected / exposed	31 / 600 (5.17%)	0 / 24 (0.00%)	17 / 301 (5.65%)
occurrences all number	33	0	17
Musculoskeletal and connective tissue disorders
Joint swelling
subjects affected / exposed	2 / 600 (0.33%)	2 / 24 (8.33%)	3 / 301 (1.00%)
occurrences all number	2	2	3
Bone pain
subjects affected / exposed	287 / 600 (47.83%)	11 / 24 (45.83%)	174 / 301 (57.81%)
occurrences all number	476	19	321
Muscular weakness
subjects affected / exposed	8 / 600 (1.33%)	2 / 24 (8.33%)	15 / 301 (4.98%)
occurrences all number	8	2	18
Infections and infestations
Nasopharyngitis
subjects affected / exposed	13 / 600 (2.17%)	4 / 24 (16.67%)	8 / 301 (2.66%)
occurrences all number	13	4	11
Urinary tract infection
subjects affected / exposed	47 / 600 (7.83%)	5 / 24 (20.83%)	22 / 301 (7.31%)
occurrences all number	55	8	23
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	104 / 600 (17.33%)	4 / 24 (16.67%)	53 / 301 (17.61%)
occurrences all number	115	5	57
Hypokalaemia
subjects affected / exposed	14 / 600 (2.33%)	2 / 24 (8.33%)	6 / 301 (1.99%)
occurrences all number	16	2	7
Hyponatraemia
subjects affected / exposed	2 / 600 (0.33%)	3 / 24 (12.50%)	2 / 301 (0.66%)
occurrences all number	2	3	2
Decreased appetite
subjects affected / exposed	36 / 600 (6.00%)	1 / 24 (4.17%)	13 / 301 (4.32%)
occurrences all number	39	1	13

More information

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Were there any global substantial amendments to the protocol? Yes

23 May 2008

The main rationale for this amendment was to make sure that the most important baseline parameters which might have an impact on the primary and secondary efficacy endpoints were well balanced between the two study groups. Changes were: 1. Removed stratification factors for ECOG and any prior cytotoxic therapy 2. Added stratification factors for current use of bisphosphonates (yes or no) and prior use of docetaxel (yes or no).

09 Jul 2008

The main rationale for this amendment was to ensure that the study meets its stated objectives and yields robust conclusions, with adequate monitoring of data to detect emerging risk/benefit trends. The key changes were: 1. Changed the sample size requirements for the study, from 450 subjects to 750 subjects randomized to account for the introduction of prior docetaxel use (yes/no) as a stratification factor during randomization 2. Planned for an unblinded IA of overall survival, to be reviewed by the IDMC 3. Changed PSA outcome and reporting to adhere to the Prostate Cancer Clinical Trials Working Group 2, published March, 2008.

10 Jul 2009

The main rationale for this amendment was to add clarifications to various sections in the protocol. The key changes were: 1. Recommended that the screening hematology values were measured at a maximum of 1 week prior to randomization, and that the first injection was to be done as soon as possible after randomization 2. Clarified that while screening hemoglobin (Hb) was required to be 10 gram per deciliter (g/dL), the Hb level should not have been lower than 8 g/dL within 24 hours before any injection. If, prior to first injection, the subject had a Hb level of <8 g/dL, the subject should not have received study drug and would directly go into the follow-up phase 3. Clarified that it was accepted that after documented PSA progression, the PSA could decline pre-randomization, provided that the screening value was at least 5 ng/mL 4. Clarified that for traumatic fractures in weight-bearing bones during treatment phase, the study drug administration was to be delayed 2-4 weeks from the occurrence of the fracture 5. Changed the collection of date of death: To collect date of death for all subjects until the last subject had been followed for 3 years 6. Changedthe interval between injection of bisphosphonates and injection of study drug: Injection of bisphosphonates was to be done at least 2 hours before or after study drug administration 7. Changed the analysis of the primary efficacy endpoint from Cox proportional hazards regression to a stratified log-rank test 8. Changed the timing of sample size re-estimation, from approximately 350 subjects to 500-600 subjects enrolled 9. Changed the definition of the Safety population from all randomized subjects to all randomized subjects who had received at least 1 study drug treatment 10. Added sub-group analyses for safety and secondary efficacy variables in order to examine relationships between exposure and response.

23 Jun 2010

The main rationale for this amendment was to increase the sample size of the study due to an increase in the statistical power from 80% to 90%. The rationale for the increase in power was to 1. Reduce the risk of false negative results 2. Get a better estimate of the primary efficacy endpoint 3. Get a better estimate of the secondary endpoints and subgroup analyses 4. Increase the body of safety data. The same assumptions as in the original sample size calculation have been used for the calculation. Changes: 1. Increased statistical power from 80% to 90% and increased the sample size from 750 to 900 with an increase in the accrual period from 24 to 30 months 2. Changed time of IA to be after approximately 320 events were observed 3. Made various minor clarifications and administrative changes.

20 Jan 2011

The main rationale for this amendment was to control for overall false positive rate (type I error rate) for the analysis of the secondary endpoints by using a gatekeeping procedure. Five secondary endpoints have been identified as main secondary endpoints and have been ordered hierarchically according to their clinical importance. Changes were: 1. Defined 5 main secondary endpoints: including creating a composite endpoint for the time to occurrence of first SRE based on disease events already being collected and adding total ALP normalization, 2. Provided IDMC members with the opportunity to request analysis results for the main secondary endpoints provided that the IA met the efficacy criterion for overall survival; additionally, if the study was stopped based on the recommendation of the IDMC, then all remaining planned analyses were to be performed according to what was described in the final analysis in the protocol and the statistical analysis plan.

24 Jun 2011

The main rationale for this amendment was to offer placebo subjects who are still participating in the study (that is, have not withdrawn from the study) and who fulfil the eligibility criteria as defined in this protocol addendum, a full course of Alpharadin treatment (50 kBq/kg body weight administered 6 times, at intervals of 4 weeks). 1. Changes to study design and reference therapy (placebo) due to IDMC approval to unblind the study, allowing access to Alpharadin for subjects who previously received placebo 2. Added clarification regarding analysis populations to account for placebo subjects receiving Alpharadin after unblinding 3. Clarified definition of disease events.

Were there any global interruptions to the trial? No

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

'99999' in the reported data indicates that the data were not calculated. Decimal places were automatically truncated if last decimal equals zero.

http://www.ncbi.nlm.nih.gov/pubmed/23863050
http://www.ncbi.nlm.nih.gov/pubmed/25439694

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Clinical trials

Clinical Trial Results: A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival

Primary: Overall Survival

Secondary: Time to Total Alkaline Phosphatase (ALP) Progression

Secondary: Time to Total Alkaline Phosphatase (ALP) Progression

Secondary: Percentage of Subjects With Total ALP Response at Week 12

Secondary: Percentage of Subjects With Total ALP Response at Week 12

Secondary: Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage of Subjects With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage of Subjects With Total ALP Normalization at Week 12

Secondary: Percentage of Subjects With Total ALP Normalization at Week 12

Secondary: Percentage Change From Baseline in Total ALP at Week 12

Secondary: Percentage Change From Baseline in Total ALP at Week 12

Secondary: Maximum Percentage Decrease From Baseline in Total ALP up to Week 12

Secondary: Maximum Percentage Decrease From Baseline in Total ALP up to Week 12

Secondary: Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment

Secondary: Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment

Secondary: Time to Prostate Specific Antigen (PSA) Progression

Secondary: Time to Prostate Specific Antigen (PSA) Progression

Secondary: Percentage of Subjects With PSA Response at Week 12

Secondary: Percentage of Subjects With PSA Response at Week 12

Secondary: Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage of Subjects With PSA Response at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage Change From Baseline in PSA at Week 12

Secondary: Percentage Change From Baseline in PSA at Week 12

Secondary: Maximum Percentage Decrease From Baseline in PSA up to Week 12

Secondary: Maximum Percentage Decrease From Baseline in PSA up to Week 12

Secondary: Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Subject Dies or Discontinues Treatment Phase)

Secondary: Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period

Secondary: Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period

Secondary: Time to First Skeletal Related Event (SRE)

Secondary: Time to First Skeletal Related Event (SRE)

Secondary: Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms

Secondary: Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms

Secondary: Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms

Secondary: Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms

Secondary: Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral

Secondary: Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral

Secondary: Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention

Secondary: Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention

Secondary: Time to Occurrence of First Spinal Cord Compression

Secondary: Time to Occurrence of First Spinal Cord Compression

Secondary: Time to Occurrence of First Start of any Other Anti-cancer Treatment

Secondary: Time to Occurrence of First Start of any Other Anti-cancer Treatment

Secondary: Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline

Secondary: Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24

Other pre-specified: Number of Subjects With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24

Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)

Other pre-specified: Absolute Scores for Functional Assessment of Cancer Therapy – Prostate (FACT-P) Trial Outcome Index (TOI)

Other pre-specified: Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Other pre-specified: Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)

Other pre-specified: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)

Other pre-specified: Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Other pre-specified: Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Other pre-specified: Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Other pre-specified: Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)

Clinical Trial Results:
A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases