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Clinical Trial Results:
A phase III randomized, double-blind, placebo-controlled trial of radium-223 dichloride in combination with abiraterone acetate and prednisone/prednisolone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with bone predominant metastatic castration-resistant prostate cancer (CRPC)

Summary
EudraCT number	2013-003438-33
Trial protocol	IT ES FI SE DE BE GB NL NO PL FR
Global end of trial date

Results information
Results version number	v1
This version publication date	28 Feb 2019
First version publication date	28 Feb 2019
Other versions	v2

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BAY88-8223/15396

ISRCTN number

-

US NCT number

NCT02043678

WHO universal trial number (UTN)

-

Sponsor organisation name

Bayer AG

Sponsor organisation address

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

Public contact

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

Scientific contact

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

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

No

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

No

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

No

Analysis stage

Interim

Date of interim/final analysis

15 Feb 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Feb 2018

Global end of trial reached?

No

Main objective of the trial

The primary objective of this study was to compare, in subjects with asymptomatic or mildly symptomatic chemotherapy-naïve bone-predominant metastatic CRPC, the clinical benefit of radium-223 dichloride versus placebo in combination with abiraterone and prednisone/prednisolone.

Protection of trial subjects

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

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

30 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

7 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 55

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 51

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

Spain: 72

Country: Number of subjects enrolled

Finland: 14

Country: Number of subjects enrolled

France: 29

Country: Number of subjects enrolled

United Kingdom: 64

Country: Number of subjects enrolled

Italy: 52

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Norway: 8

Country: Number of subjects enrolled

Sweden: 13

Country: Number of subjects enrolled

United States: 90

Country: Number of subjects enrolled

Israel: 59

Country: Number of subjects enrolled

Japan: 114

Country: Number of subjects enrolled

Singapore: 40

Country: Number of subjects enrolled

Brazil: 51

Country: Number of subjects enrolled

Poland: 28

Country: Number of subjects enrolled

Russian Federation: 29

Worldwide total number of subjects

806

EEA total number of subjects

317

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

167

From 65 to 84 years

601

85 years and over

38

Subject disposition

Top of page

Recruitment details

Study was conducted at multiple centers in 19 countries between 30 March 2014 (first subject first visit) and 15 February 2018 (data cut-off date).

Screening details

Overall, 1144 subjects were screened. Of them, 338 subjects did not complete screening, 806 subjects were randomized to treatment and 786 subjects received study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Radium-223 dichloride + Abi/Pred

Arm description

Subjects received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Arm type

Experimental

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received abiraterone acetate tablets 1000 milligrams (mg) every day until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Investigational medicinal product name

Prednisone/prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 5 mg prednisone/prednisolone twice daily until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Investigational medicinal product name

Radium-223 dichloride

Investigational medicinal product code

BAY88-8223

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects received 6 IV administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) at intervals of 4 weeks.

Placebo + Abi/Pred

Arm description

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).

Arm type

Placebo

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received abiraterone acetate tablets 1000 milligrams (mg) every day until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Investigational medicinal product name

Prednisone/prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 5 mg prednisone/prednisolone twice daily until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

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

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks.

Number of subjects in period 1	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Started	401	405
Treated	390	396
Completed	0	0
Not completed	401	405
Consent withdrawn by subject	10	13
Ongoing with treatment	87	104
AE without clinical PD	41	31
Unspecified	15	8
AE with clinical progressive disease (PD)	17	15
Clinical PD	88	112
Radiological PD	78	67
Never treated	11	9
Lost to follow-up	1	1
Protocol-driven decision point	53	45

Baseline characteristics

Top of page

Reporting group title

Radium-223 dichloride + Abi/Pred

Reporting group description

Subjects received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Reporting group title

Placebo + Abi/Pred

Reporting group description

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).

Reporting group values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred	Total
Number of subjects	401	405	806
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	70.9 ± 8.5	71.4 ± 8.4	-
Sex: Female, Male
Units: Subjects
Female	0	0	0
Male	401	405	806
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	1	2
Asian	79	78	157
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	10	16	26
White	285	284	569
More than one race	0	0	0
Unknown or Not Reported	26	26	52
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	17	23	40
Not Hispanic or Latino	361	355	716
Unknown or Not Reported	23	27	50
Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification)
TNM staging system stands for Tumour, Node, Metastasis. Stage I: cancer is in half of one side of the prostate or less. Stage II: cancer is in more than half of one side of the prostate, completely contained within the prostate gland. Stage III: cancer has broken through the capsule of the prostate gland, and may have spread into tubes that carry semen. Stage IV: cancer has spread into nearby body organs, such as the back passage or bladder; or has spread to nearby lymph nodes; or has spread to other parts of the body outside the pelvis, such as the lungs or liver.
Units: Subjects
Missing	19	24	43
Stage I	27	18	45
Stage IIA	22	20	42
Stage IIB	34	49	83
Stage III	102	88	190
Stage IV	197	206	403
Cancer pain assessment by Brief Pain Inventory-Short Form (BPI-SF)
The BPI-SF is a short, self-administered questionnaire with 11 items designed to evaluate the intensity of, and the impairment caused by pain. Four items measure pain intensity (pain now, average pain, worst pain, and least pain) using 0 (“no pain”) to 10 (“pain as bad as you can imagine”) numeric rating scales, and 7 items measure the level of interference with function caused by pain (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life) using 0 (no interference) to 10 (complete interference) rating scales.
Units: Subjects
Missing	25	33	58
Asymptomatic (Worst pain score = 0)	195	198	393
Mildly Symptomatic (Worst pain score 1 - 3)	181	174	355
Gleason score at diagnosis
The Gleason score is an indication of prognosis based on prostate pathology. The total score ranges from 2 to 10 (ie: "1+1" to "5+5") with a higher score reflecting less-differentiated tumors with worse prognosis. The total score is a sum of two numbers which are based on the microscopic appearance of cells. The first number is the score based on the dominant, cell morphology (scored 1-5) and the second number is based on the highest grade of the non-dominant cell pattern (scored 1-5).
Units: Subjects
Missing	15	18	33
Less than (<) 8	140	154	294
Greater than or equal to (>=) 8	246	233	479
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern cooperative oncology group (ECOG) performance status: 0= Fully active, able to carry on all pre-disease performance without restriction; 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3= Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4= Completely disabled, cannot carry on any self-care, totally confined to bed or chair.
Units: Subjects
Missing	2	3	5
ECOG=0	262	281	543
ECOG=1	137	121	258
Extent of Disease
Units: Subjects
Normal or abnormal because of benign bone disease	2	0	2
< 6 metastases	134	141	275
6-20 metastases	175	181	356
>20 lesions but not a superscan	71	70	141
Superscan	19	13	32
Weight
Units: Kilograms (kg)
arithmetic mean (standard deviation)	82.19 ± 16.75	82.40 ± 16.01	-
Prostate-specific antigen
Units: Micrograms per liter (ug/L)
arithmetic mean (standard deviation)	92.39 ± 191.62	92.33 ± 328.00	-

End points

Top of page

Reporting group title

Radium-223 dichloride + Abi/Pred

Reporting group description

Subjects received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Reporting group title

Placebo + Abi/Pred

Reporting group description

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).

Subject analysis set title

Intent-to-treat analysis set (ITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Included all randomized subjects.

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

Included all randomized subjects who received at least one dose of any study drug.

Primary: Symptomatic Skeletal Event Free Survival (SSE-FS)

Top of page

End point title

Symptomatic Skeletal Event Free Survival (SSE-FS)

End point description

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

End point type

Primary

End point timeframe

From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	401 ^[1]	405 ^[2]
Units: Months
median (confidence interval 95%)	22.3 (20.4 to 24.8)	26.0 (21.8 to 28.3)

Notes
[1] - ITT
[2] - ITT

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2636

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

1.122

Confidence interval

level

95%

sides

2-sided

lower limit

0.917

upper limit

1.374

Secondary: Overall Survival (OS)

Top of page

End point title

Overall Survival (OS)

End point description

OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Subjects alive at the survival cut-off date were censored at the last date known to be alive. In the below table, "99999" indicates that upper limit cannot be estimated due to censored data.

End point type

Secondary

End point timeframe

From randomization until death from any cause, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	401 ^[3]	405 ^[4]
Units: Months
median (confidence interval 95%)	30.7 (25.8 to 99999)	33.3 (30.2 to 41.1)

Notes
[3] - ITT
[4] - ITT

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.128

Method

Cox Proportional Hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.195

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.505

Secondary: Radiological Progression Free Survival (rPFS)

Top of page

End point title

Radiological Progression Free Survival (rPFS)

End point description

rPFS was defined as the time (months) from the date of randomization to the date of confirmed radiological progression or death (if death occurred before progression) based on independent assessment.

End point type

Secondary

End point timeframe

From randomization until the date of confirmed radiological progression or death, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	401 ^[5]	405 ^[6]
Units: Months
median (confidence interval 95%)	11.2 (9.1 to 11.8)	12.4 (10.8 to 14.5)

Notes
[5] - ITT
[6] - ITT

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1283

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

1.152

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

1.383

Secondary: Time to Pain Progression

Top of page

End point title

Time to Pain Progression

End point description

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

End point type

Secondary

End point timeframe

From randomization until the date of pain progression based on pain score, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	401 ^[7]	405 ^[8]
Units: Months
median (confidence interval 95%)	14.4 (11.1 to 20.1)	18.7 (15.4 to 23.1)

Notes
[7] - ITT
[8] - ITT

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1669

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

1.145

Confidence interval

level

95%

sides

2-sided

lower limit

0.945

upper limit

1.389

Secondary: Time to Cytotoxic Chemotherapy

Top of page

End point title

Time to Cytotoxic Chemotherapy

End point description

Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Subjects who have not started cytotoxic chemotherapy during the study were censored at the last assessment date. In the below table, "99999" indicates that upper limit cannot be estimated due to censored data.

End point type

Secondary

End point timeframe

From randomization until the date of first cytotoxic chemotherapy, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	401 ^[9]	405 ^[10]
Units: Months
median (confidence interval 95%)	29.5 (26.5 to 35.7)	28.5 (23.7 to 99999)

Notes
[9] - ITT
[10] - ITT

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7871

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

1.033

Confidence interval

level

95%

sides

2-sided

lower limit

0.816

upper limit

1.308

Secondary: Time to Opiate Use for Cancer Pain

Top of page

End point title

Time to Opiate Use for Cancer Pain

End point description

Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.

End point type

Secondary

End point timeframe

From randomization until the date of opiate use, up to 47 months

End point values	Radium-223 dichloride + Abi/Pred	Placebo + Abi/Pred
Number of subjects analysed	398 ^[11]	392 ^[12]
Units: Months
median (confidence interval 95%)	19.0 (14.4 to 23.2)	22.6 (18.0 to 25.7)

Notes
[11] - ITT set excluding subjects who had opiate use at baseline
[12] - ITT set excluding subjects who had opiate use at baseline

Radium-223 dichloride+Abi/Pred vs Placebo+Abi/Pred

Comparison groups

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

Number of subjects included in analysis

790

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2467

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

1.126

Confidence interval

level

95%

sides

2-sided

lower limit

0.921

upper limit

1.378

Adverse events

Top of page

Timeframe for reporting adverse events

From start of study treatment until the end of the treatment period, up to 47 months

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Placebo + Abi/Pred

Reporting group description

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met).

Reporting group title

Radium-223 dichloride + Abi/Pred

Reporting group description

Subjects received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Serious adverse events	Placebo + Abi/Pred	Radium-223 dichloride + Abi/Pred
Total subjects affected by serious adverse events
subjects affected / exposed	155 / 394 (39.34%)	160 / 392 (40.82%)
number of deaths (all causes)	140	151
number of deaths resulting from adverse events	20	26
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	5 / 394 (1.27%)	3 / 392 (0.77%)
occurrences causally related to treatment / all	0 / 9	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer recurrent
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Cholangiocarcinoma
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Kaposi's sarcoma
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal sinus cancer
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	7 / 394 (1.78%)	6 / 392 (1.53%)
occurrences causally related to treatment / all	0 / 20	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid cancer metastatic
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Brain neoplasm
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic dissection
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Circulatory collapse
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 394 (0.51%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 394 (0.76%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 394 (0.51%)	5 / 392 (1.28%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	2 / 2	0 / 0
Peripheral swelling
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	8 / 394 (2.03%)	9 / 392 (2.30%)
occurrences causally related to treatment / all	0 / 11	0 / 12
deaths causally related to treatment / all	7 / 7	6 / 6
Non-cardiac chest pain
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	2 / 2
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatism
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 394 (1.02%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Pneumonia aspiration
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonitis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 394 (0.51%)	5 / 392 (1.28%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Lower respiratory tract inflammation
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax traumatic
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	3 / 394 (0.76%)	11 / 392 (2.81%)
occurrences causally related to treatment / all	1 / 3	1 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	4 / 394 (1.02%)	4 / 392 (1.02%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	2 / 2
Aortic valve incompetence
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Atrial fibrillation
subjects affected / exposed	7 / 394 (1.78%)	4 / 392 (1.02%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	1 / 1
Cardiac failure
subjects affected / exposed	3 / 394 (0.76%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Coronary artery stenosis
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary ostial stenosis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	2 / 2
Sinus bradycardia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Ventricular tachycardia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cauda equina syndrome
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Monoplegia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	8 / 394 (2.03%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Transient global amnesia
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 394 (0.51%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal epidural haematoma
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Parkinson's disease
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial neuralgia
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nerve root compression
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 394 (0.51%)	7 / 392 (1.79%)
occurrences causally related to treatment / all	0 / 2	4 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal artery occlusion
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	5 / 394 (1.27%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	2 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal achalasia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 394 (0.25%)	3 / 392 (0.77%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disease
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	3 / 394 (0.76%)	5 / 392 (1.28%)
occurrences causally related to treatment / all	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	4 / 394 (1.02%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 394 (0.51%)	4 / 392 (1.02%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Primary adrenal insufficiency
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 394 (0.51%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	10 / 394 (2.54%)	8 / 392 (2.04%)
occurrences causally related to treatment / all	0 / 11	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	5 / 394 (1.27%)	4 / 392 (1.02%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 394 (0.25%)	3 / 392 (0.77%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	2 / 394 (0.51%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	1 / 394 (0.25%)	8 / 392 (2.04%)
occurrences causally related to treatment / all	0 / 3	5 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	3 / 394 (0.76%)	6 / 392 (1.53%)
occurrences causally related to treatment / all	0 / 3	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Intervertebral disc protrusion
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 394 (0.51%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 394 (0.51%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 394 (0.00%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lyme disease
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	10 / 394 (2.54%)	8 / 392 (2.04%)
occurrences causally related to treatment / all	1 / 14	0 / 9
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 394 (0.76%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	2 / 2	2 / 2
Septic shock
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	4 / 394 (1.02%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	9 / 394 (2.28%)	14 / 392 (3.57%)
occurrences causally related to treatment / all	0 / 9	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Urosepsis
subjects affected / exposed	7 / 394 (1.78%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 13	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Tooth infection
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	1 / 1
Arthritis bacterial
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Arthritis infective
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 394 (0.25%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis fungal
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Gastroenteritis norovirus
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 394 (0.00%)	4 / 392 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 394 (0.51%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 394 (0.25%)	2 / 392 (0.51%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 394 (0.51%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 394 (0.00%)	1 / 392 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 394 (0.25%)	0 / 392 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo + Abi/Pred	Radium-223 dichloride + Abi/Pred
Total subjects affected by non serious adverse events
subjects affected / exposed	366 / 394 (92.89%)	360 / 392 (91.84%)
Vascular disorders
Hypertension
subjects affected / exposed	78 / 394 (19.80%)	58 / 392 (14.80%)
occurrences all number	191	155
Hot flush
subjects affected / exposed	49 / 394 (12.44%)	23 / 392 (5.87%)
occurrences all number	51	25
General disorders and administration site conditions
Asthenia
subjects affected / exposed	40 / 394 (10.15%)	34 / 392 (8.67%)
occurrences all number	54	44
Oedema peripheral
subjects affected / exposed	60 / 394 (15.23%)	51 / 392 (13.01%)
occurrences all number	69	64
Fatigue
subjects affected / exposed	79 / 394 (20.05%)	89 / 392 (22.70%)
occurrences all number	109	119
Pyrexia
subjects affected / exposed	27 / 394 (6.85%)	24 / 392 (6.12%)
occurrences all number	38	29
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	35 / 394 (8.88%)	33 / 392 (8.42%)
occurrences all number	41	37
Dyspnoea
subjects affected / exposed	26 / 394 (6.60%)	17 / 392 (4.34%)
occurrences all number	27	21
Psychiatric disorders
Insomnia
subjects affected / exposed	22 / 394 (5.58%)	25 / 392 (6.38%)
occurrences all number	23	28
Investigations
Alanine aminotransferase increased
subjects affected / exposed	59 / 394 (14.97%)	68 / 392 (17.35%)
occurrences all number	145	176
Aspartate aminotransferase increased
subjects affected / exposed	53 / 394 (13.45%)	60 / 392 (15.31%)
occurrences all number	102	124
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	38 / 394 (9.64%)	55 / 392 (14.03%)
occurrences all number	49	76
Traumatic fracture
subjects affected / exposed	14 / 394 (3.55%)	37 / 392 (9.44%)
occurrences all number	31	63
Contusion
subjects affected / exposed	26 / 394 (6.60%)	24 / 392 (6.12%)
occurrences all number	32	30
Nervous system disorders
Dizziness
subjects affected / exposed	30 / 394 (7.61%)	38 / 392 (9.69%)
occurrences all number	35	44
Headache
subjects affected / exposed	27 / 394 (6.85%)	28 / 392 (7.14%)
occurrences all number	35	42
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	45 / 394 (11.42%)	54 / 392 (13.78%)
occurrences all number	80	112
Gastrointestinal disorders
Constipation
subjects affected / exposed	72 / 394 (18.27%)	56 / 392 (14.29%)
occurrences all number	86	64
Abdominal pain
subjects affected / exposed	12 / 394 (3.05%)	22 / 392 (5.61%)
occurrences all number	14	23
Diarrhoea
subjects affected / exposed	57 / 394 (14.47%)	64 / 392 (16.33%)
occurrences all number	82	101
Dyspepsia
subjects affected / exposed	15 / 394 (3.81%)	20 / 392 (5.10%)
occurrences all number	15	22
Nausea
subjects affected / exposed	59 / 394 (14.97%)	66 / 392 (16.84%)
occurrences all number	64	80
Vomiting
subjects affected / exposed	31 / 394 (7.87%)	37 / 392 (9.44%)
occurrences all number	34	45
Renal and urinary disorders
Haematuria
subjects affected / exposed	15 / 394 (3.81%)	25 / 392 (6.38%)
occurrences all number	20	36
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	75 / 394 (19.04%)	79 / 392 (20.15%)
occurrences all number	128	111
Bone pain
subjects affected / exposed	52 / 394 (13.20%)	47 / 392 (11.99%)
occurrences all number	68	65
Back pain
subjects affected / exposed	119 / 394 (30.20%)	133 / 392 (33.93%)
occurrences all number	170	219
Muscle spasms
subjects affected / exposed	28 / 394 (7.11%)	25 / 392 (6.38%)
occurrences all number	31	30
Muscular weakness
subjects affected / exposed	28 / 394 (7.11%)	24 / 392 (6.12%)
occurrences all number	36	38
Musculoskeletal pain
subjects affected / exposed	43 / 394 (10.91%)	40 / 392 (10.20%)
occurrences all number	53	47
Myalgia
subjects affected / exposed	21 / 394 (5.33%)	22 / 392 (5.61%)
occurrences all number	24	27
Neck pain
subjects affected / exposed	21 / 394 (5.33%)	16 / 392 (4.08%)
occurrences all number	24	17
Osteoporosis
subjects affected / exposed	1 / 394 (0.25%)	23 / 392 (5.87%)
occurrences all number	1	23
Osteoporotic fracture
subjects affected / exposed	1 / 394 (0.25%)	23 / 392 (5.87%)
occurrences all number	1	58
Pain in extremity
subjects affected / exposed	50 / 394 (12.69%)	45 / 392 (11.48%)
occurrences all number	67	61
Musculoskeletal chest pain
subjects affected / exposed	25 / 394 (6.35%)	26 / 392 (6.63%)
occurrences all number	29	35
Pathological fracture
subjects affected / exposed	14 / 394 (3.55%)	33 / 392 (8.42%)
occurrences all number	24	47
Spinal pain
subjects affected / exposed	21 / 394 (5.33%)	21 / 392 (5.36%)
occurrences all number	24	24
Infections and infestations
Influenza
subjects affected / exposed	12 / 394 (3.05%)	20 / 392 (5.10%)
occurrences all number	18	21
Upper respiratory tract infection
subjects affected / exposed	29 / 394 (7.36%)	23 / 392 (5.87%)
occurrences all number	36	30
Nasopharyngitis
subjects affected / exposed	34 / 394 (8.63%)	30 / 392 (7.65%)
occurrences all number	48	37
Urinary tract infection
subjects affected / exposed	26 / 394 (6.60%)	36 / 392 (9.18%)
occurrences all number	30	49
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	39 / 394 (9.90%)	39 / 392 (9.95%)
occurrences all number	65	62
Decreased appetite
subjects affected / exposed	38 / 394 (9.64%)	53 / 392 (13.52%)
occurrences all number	39	66

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Were there any global substantial amendments to the protocol? Yes

25 Aug 2014

Amendment 1 (integrated protocol Version 2.0) specified the following key modifications: 1. Modified the inclusion criterion to clarify the permitted age range. 2. Modified the inclusion criterion to expand the permitted estimated GFR. 3. Clarified study treatment is either radium-223 dichloride (Arm A) or placebo (Arm B). 4. Clarified the maximum radium-223 dichloride treatment duration. 7. Clarified that abiraterone is not considered study medication after an on-study SSE. 8. Clarified he process for maintaining the blind. 9. Corrected the hemoglobin level that must be met for dosing. 10. Added collection of SSEs during the screening period. 11. Clarified that survival status would be collected throughout the study. 12. Clarified that collection of cancer-related treatments includes androgen synthesis inhibitors/androgen receptor antagonists and excludes analgesics. 13. Added the modified RECIST v1.1 criteria.

11 Jun 2015

Amendment 2 (integrated protocol Version 3.0) specified the following key modifications: 1. Updated dosing and dose calibration of radium-223 dichloride to reflect revised NIST standardization for radium-223. 2. Removed cytological confirmation of adenocarcinoma of the prostate from inclusion criteria; histological confirmation only. 3. Clarified that the treatment period ended when a subject received abiraterone/prednisone as the standard of care (non-IMP) after an SSE. 4. Added an exclusion for immunotherapy (e.g., sipuleucel-T) within 4 weeks before the first dose of radium-223 dichloride. 5. Clarified duration of prohibited concomitant therapy was from screening onwards. 6. Clarified potassium requirement for ECG collection.

12 Sep 2016

Amendment 4 (integrated protocol Version 4.0) specified the following key modifications: 1. Clarified continuation of medical castration. 2. Clarified documentation of radiological progression. 3. Clarified study drug handling if administration was postponed more than 3 days. 4. Clarified treatment unblinding procedures. 5. Removed bisphosphonate timing requirements.

02 Apr 2018

Amendment 6 (integrated protocol Version 5.0) specified the following modifications: 1. Requested that bone fractures and bone-associated events (e.g., osteoporosis) were to be reported as (S)AEs, including during long-term follow-up, regardless of the investigator’s causality assessment. 2. Added an independent radiological review of fractures. 3. Added that radium-223 dichloride should not be given in combination with abiraterone plus prednisone/prednisolone during follow-up.

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.

Occurrence of "±” in relation with standard deviation is auto generated. Decimal places were automatically truncated if last decimals is equals to zero.

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