Study on Prolonging Bone Metastasis-Free Survival in Men With Hormone Refractory Prostate Cancer

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00286091
• Collaborator: (none)
• Enrollment: 1,435
• Arms: 2
• Actual Duration (Months): 98.5

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in men with hormone refractory (androgen independent) prostate cancer who have no bone metastasis at baseline.

Condition or Disease	Intervention/Treatment	Phase
Hormone Refractory Prostate Cancer	Biological: Denosumab; Biological: Placebo	Phase 3

Detailed Description

Participants were randomized to receive denosumab 120 mg or placebo every 4 weeks (Q4W) until approximately 660 participants developed bone metastasis or died and the primary efficacy and safety analyses were completed.

All participants undergoing scheduled assessments were offered open-label denosumab 120 mg subcutaneous (SC) until they either developed a bone metastasis, obtained access to commercially available product in this setting, or for up to 3 years, whichever came first. For participants who ended participation before the open-label extension (OLE) phase or withdrew from investigational product during the OLE phase, their survival data was to be collected every 6 months for up to 3 years after their last dose of investigational product.

Participants in the Czech Republic and United Kingdom were enrolled under a separate protocol for the OLE phase per Health Authority request, and are reported separately (Study 20080585; NCT01824342).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1435 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab on Prolonging Bone Metastasis-Free Survival in Men With Hormone Refractory Prostate Cancer
• Actual Study Start Date: Jan 24, 2006
• Actual Primary Completion Date: Jul 30, 2010
• Actual Study Completion Date: Apr 9, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo subcutaneous injections every 4 weeks during the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injection every 4 weeks during the open-label extension phase.	Biological: Placebo; Same volume subcutaneous injection
Experimental: Denosumb Participants received 120 mg denosumab administered by subcutaneous injection every 4 weeks during the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injection every 4 weeks during the open-label extension phase.	Biological: Denosumab; Administered by subcutaneous injection; Other Names: XGEVA®

Outcome Measures

Primary Outcome Measures

1. Bone Metastasis-free Survival [From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.]

   The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method.

Secondary Outcome Measures

1. Time to First Bone Metastasis [From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.]

   Time from randomization to the date of first occurrence of bone metastasis (either symptomatic or asymptomatic), excluding death. Participants who did not develop bone metastasis were censored at their last on-study bone assessment date or the primary analysis data cut-off date, whichever was first. Median time to first bone metastasis was estimated using the Kaplan-Meier method.

2. Overall Survival [From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.]

   Time from randomization to the date of death. Participants who were still alive or lost to follow-up by the primary analysis data cut-off date were censored at their last contact date (on-study or during survival follow-up) or the primary analysis data cut-off date, whichever was first.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• men with histologically confirmed prostate cancer

• bilateral orchiectomy at least 6 months before randomization or continuous androgen-deprivation therapy (ADT) with a gonadotropin releasing hormone (GnRH) agonist or antagonist for at least 6 months before randomization

• total testosterone level less than 50 ng/dL,

• hormone refractory (androgen independent) prostate cancer demonstrated during continuous ADT/post-orchiectomy defined as: 3 consecutive prostate-specific antigen (PSA) values with PSA1 < PSA2 < PSA3, each PSA value must be separated by at least 2 weeks, PSA2 and PSA3 greater than or equal to 1.0 ng/mL,

• high risk for development of bone metastasis defined as PSA value greater than or equal to 8.0 ng/mL, obtained no more than 3 months before randomization OR PSA doubling time less than or equal to 10.0 months

Exclusion Criteria:

• prior or current evidence of radiographically detectable bone metastasis

• known prior or current evidence of any metastatic involvement of distant organs (lymph node metastases in any region is acceptable)

• prior or current intravenous bisphosphonate administration

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00286091
• Other Study ID Numbers: 20050147
• First Posted: Feb 3, 2006
• Last Update Posted: Oct 17, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Amgen: Hormone refractory prostate cancer; androgen independent; ADT; bone metastasis
• Additional relevant MeSH terms: Prostatic Neoplasms; Neoplasm Metastasis; Denosumab

Study Results

Participant Flow

Recruitment Details	Eligible subjects were men ≥ 18 years old with histologically-confirmed, castrate-resistant prostate cancer who were chemically or surgically castrated. The first patient was enrolled into the study on 03 February 2006 and the last patient was enrolled on 23 July 2008.
Pre-assignment Detail	Participants were randomized to denosumab or placebo in the double-blind treatment phase. All participants undergoing scheduled assessments were offered open-label denosumab for up to 3 years in the open-label extension phase. Three enrolled patients were excluded from all datasets per ethics committee's instructions due to eligibility violations.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.
Period Title: Double-blind Treatment Phase
STARTED	716	716
Received Treatment	709	716
On Study at Primary Data Analysis Cutoff	164	174
COMPLETED	132	123
NOT COMPLETED	584	593
Period Title: Double-blind Treatment Phase
STARTED	110	104
Received Treatment	109	101
COMPLETED	33	33
NOT COMPLETED	77	71

Baseline Characteristics

Arm/Group Title	Placebo	Denosumab	Total
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Total of all reporting groups
Overall Participants	716	716	1432
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.2 (8.3)	73.2 (8.8)	73.2 (8.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	716 100%	716 100%	1432 100%
Race/Ethnicity, Customized (participants) [Number]
White or Caucasian	604 84.4%	606 84.6%	1210 84.5%
Black or African American	35 4.9%	41 5.7%	76 5.3%
Hispanic or Latino	37 5.2%	32 4.5%	69 4.8%
Asian	18 2.5%	17 2.4%	35 2.4%
Japanese	2 0.3%	0 0%	2 0.1%
American Indian or Alaska Native	2 0.3%	0 0%	2 0.1%
Native Hawaiian or Other Pacific Islander	1 0.1%	0 0%	1 0.1%
Other	17 2.4%	18 2.5%	35 2.4%
Unknown	0 0%	2 0.3%	2 0.1%
Eastern Cooperative Oncology Group (ECOG)Pperformance Status (participants) [Number]
Grade 0	514 71.8%	505 70.5%	1019 71.2%
Grade 1	199 27.8%	210 29.3%	409 28.6%
Grade 2	3 0.4%	1 0.1%	4 0.3%
Grade 3	0 0%	0 0%	0 0%
Grade 4	0 0%	0 0%	0 0%
Prostate-Specific Antigen (PSA) Doubling Time (participants) [Number]
≤ 10 months	580 81%	574 80.2%	1154 80.6%
> 10 months	136 19%	142 19.8%	278 19.4%
Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL (participants) [Number]
Yes	471 65.8%	473 66.1%	944 65.9%
No	245 34.2%	243 33.9%	488 34.1%
Prior Chemotherapy Regimens (participants) [Number]
Yes	54 7.5%	63 8.8%	117 8.2%
No	662 92.5%	653 91.2%	1315 91.8%

Outcome Measures

1. Primary Outcome

Title	Bone Metastasis-free Survival
Description	The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method.
Time Frame	From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized participants)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.
Measure Participants	716	716
Median (95% Confidence Interval) [days]	768.0	897.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	Primary and secondary endpoint analyses were conducted hierarchically. To preserve an overall type I error rate of 0.05, a 0.0488 2-sided test of bone metastasis-free survival was performed. If superiority of denosumab over placebo was established, time to first bone metastasis was tested with a 2-sided significance level of 0.050. If superiority of denosumab over placebo was also established, overall survival time was tested at a 2-sided significance level of 0.050.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0284
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.73 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

2. Secondary Outcome

Title	Time to First Bone Metastasis
Description	Time from randomization to the date of first occurrence of bone metastasis (either symptomatic or asymptomatic), excluding death. Participants who did not develop bone metastasis were censored at their last on-study bone assessment date or the primary analysis data cut-off date, whichever was first. Median time to first bone metastasis was estimated using the Kaplan-Meier method.
Time Frame	From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.
Measure Participants	716	716
Median (95% Confidence Interval) [days]	897.0	1010.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0317
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

3. Secondary Outcome

Title	Overall Survival
Description	Time from randomization to the date of death. Participants who were still alive or lost to follow-up by the primary analysis data cut-off date were censored at their last contact date (on-study or during survival follow-up) or the primary analysis data cut-off date, whichever was first.
Time Frame	From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.	Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.
Measure Participants	716	716
Median (95% Confidence Interval) [days]	1365.0	1335.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9125
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

Adverse Events

Time Frame	Median investigational product exposure was 18.4 and 19.3 months in the placebo and denosumab groups respectively during the double blind phase and 23.7 and 24.9 months during the open-label treatment phase.
Adverse Event Reporting Description	Four participants who were randomized to placebo received ≥ 1 dose of denosumab; therefore, these participants were included within the denosumab group for the safety analyses. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	DB: Placebo		DB: Denosumab 120 mg Q4W		OLE: Placebo/ Denosumab 120 mg Q4W		OLE: Denosumab/ Denosumab 120 mg Q4W
Arm/Group Description	Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind (DB) treatment phase.		Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase.		Participants who received placebo in the double-blind treatment phase received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension (OLE) phase.		Participants who received denosumab in the double-blind treatment phase received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.
All Cause Mortality
	DB: Placebo		DB: Denosumab 120 mg Q4W		OLE: Placebo/ Denosumab 120 mg Q4W		OLE: Denosumab/ Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	DB: Placebo		DB: Denosumab 120 mg Q4W		OLE: Placebo/ Denosumab 120 mg Q4W		OLE: Denosumab/ Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	332/705 (47.1%)		341/720 (47.4%)		39/109 (35.8%)		36/101 (35.6%)
Blood and lymphatic system disorders
Anaemia	12/705 (1.7%)		25/720 (3.5%)		2/109 (1.8%)		3/101 (3%)
Anaemia of malignant disease	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Bone marrow failure	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Coagulopathy	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Febrile neutropenia	1/705 (0.1%)		4/720 (0.6%)		0/109 (0%)		1/101 (1%)
Haemorrhagic anaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Iron deficiency anaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lymphadenopathy	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Neutropenia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Retroperitoneal lymphadenopathy	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Spontaneous haematoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Thrombocytopenia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Cardiac disorders
Acute coronary syndrome	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Acute myocardial infarction	2/705 (0.3%)		4/720 (0.6%)		0/109 (0%)		0/101 (0%)
Angina pectoris	3/705 (0.4%)		5/720 (0.7%)		0/109 (0%)		0/101 (0%)
Angina unstable	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Arrhythmia	4/705 (0.6%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Atrial fibrillation	12/705 (1.7%)		6/720 (0.8%)		0/109 (0%)		1/101 (1%)
Atrial flutter	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Atrial tachycardia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Bradycardia	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Cardiac arrest	3/705 (0.4%)		2/720 (0.3%)		1/109 (0.9%)		1/101 (1%)
Cardiac failure	3/705 (0.4%)		3/720 (0.4%)		1/109 (0.9%)		0/101 (0%)
Cardiac failure congestive	7/705 (1%)		6/720 (0.8%)		1/109 (0.9%)		0/101 (0%)
Cardiac tamponade	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cardiac valve disease	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cardio-respiratory arrest	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cardiogenic shock	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cardiomyopathy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cardiopulmonary failure	0/705 (0%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Cardiovascular insufficiency	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cor pulmonale	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Coronary artery disease	3/705 (0.4%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Coronary artery stenosis	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Coronary artery thrombosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Ischaemic cardiomyopathy	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Left ventricular dysfunction	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Myocardial infarction	10/705 (1.4%)		12/720 (1.7%)		4/109 (3.7%)		1/101 (1%)
Myocardial ischaemia	0/705 (0%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Pericardial effusion	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Right ventricular failure	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Sick sinus syndrome	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Sinus bradycardia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Tachycardia	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Trifascicular block	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Ventricular hypertrophy	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Ventricular tachycardia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Congenital, familial and genetic disorders
Phimosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Syringomyelia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Ear and labyrinth disorders
Vertigo	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Eye disorders
Cataract	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Eyelid ptosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Glaucoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Optic ischaemic neuropathy	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Gastrointestinal disorders
Abdominal pain	6/705 (0.9%)		3/720 (0.4%)		1/109 (0.9%)		1/101 (1%)
Abdominal pain lower	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Acute abdomen	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Anal fistula	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Anal haemorrhage	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Ascites	3/705 (0.4%)		2/720 (0.3%)		1/109 (0.9%)		0/101 (0%)
Colitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Colitis ulcerative	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Constipation	2/705 (0.3%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Diarrhoea	1/705 (0.1%)		4/720 (0.6%)		0/109 (0%)		0/101 (0%)
Diverticulitis intestinal haemorrhagic	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Diverticulum intestinal	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Diverticulum intestinal haemorrhagic	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Duodenal ulcer	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Dyspepsia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Enterovesical fistula	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Faecaloma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gastric ulcer	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gastritis	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		1/101 (1%)
Gastrointestinal angiodysplasia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gastrointestinal disorder	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gastrointestinal haemorrhage	2/705 (0.3%)		5/720 (0.7%)		0/109 (0%)		1/101 (1%)
Gastrooesophageal reflux disease	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Haematemesis	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Haematochezia	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Haemorrhoidal haemorrhage	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Haemorrhoids	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Ileus	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Ileus paralytic	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Inguinal hernia	3/705 (0.4%)		4/720 (0.6%)		0/109 (0%)		0/101 (0%)
Inguinal hernia, obstructive	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Intestinal haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Intestinal mass	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Intestinal obstruction	4/705 (0.6%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Intra-abdominal haemorrhage	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Large intestinal stenosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Large intestine perforation	1/705 (0.1%)		2/720 (0.3%)		1/109 (0.9%)		0/101 (0%)
Large intestine polyp	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Lower gastrointestinal haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Melaena	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Nausea	3/705 (0.4%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
Oesophageal rupture	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Oesophageal stenosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Oesophagitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Oral mucosa erosion	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pancreatitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Peptic ulcer perforation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Periodontal disease	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Rectal haemorrhage	4/705 (0.6%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Rectal stenosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Small intestinal haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Small intestinal obstruction	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Subileus	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Tongue haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Toothache	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Upper gastrointestinal haemorrhage	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Varices oesophageal	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Vomiting	3/705 (0.4%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
General disorders
Asthenia	10/705 (1.4%)		9/720 (1.3%)		0/109 (0%)		0/101 (0%)
Chest pain	3/705 (0.4%)		4/720 (0.6%)		0/109 (0%)		0/101 (0%)
Chills	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Death	4/705 (0.6%)		4/720 (0.6%)		1/109 (0.9%)		1/101 (1%)
Device battery issue	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Device malfunction	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Device occlusion	1/705 (0.1%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Disease progression	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Fatigue	0/705 (0%)		3/720 (0.4%)		1/109 (0.9%)		0/101 (0%)
General physical health deterioration	3/705 (0.4%)		5/720 (0.7%)		0/109 (0%)		1/101 (1%)
Generalised oedema	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hernia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Impaired healing	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Local swelling	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Malaise	0/705 (0%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Multi-organ failure	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Non-cardiac chest pain	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		1/101 (1%)
Oedema peripheral	1/705 (0.1%)		2/720 (0.3%)		1/109 (0.9%)		0/101 (0%)
Pain	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pyrexia	5/705 (0.7%)		10/720 (1.4%)		0/109 (0%)		1/101 (1%)
Sudden cardiac death	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Sudden death	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Hepatobiliary disorders
Acute hepatic failure	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bile duct stone	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cholangitis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cholecystitis	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Cholecystitis acute	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cholelithiasis	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cholestasis	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hepatic failure	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Hepatitis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Hyperbilirubinaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Jaundice	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Immune system disorders
Anaphylactic reaction	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Infections and infestations
Abscess	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Abscess jaw	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Abscess of salivary gland	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Acute sinusitis	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Anal infection	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Appendicitis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Arthritis bacterial	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Arthritis infective	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bacteraemia	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Bronchitis	4/705 (0.6%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Bronchopneumonia	0/705 (0%)		3/720 (0.4%)		1/109 (0.9%)		0/101 (0%)
Cardiac infection	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cellulitis	4/705 (0.6%)		6/720 (0.8%)		1/109 (0.9%)		2/101 (2%)
Chest wall abscess	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Chronic sinusitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Clostridium bacteraemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Clostridium colitis	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Cystitis	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Dental fistula	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Device related infection	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Device related sepsis	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Diverticulitis	1/705 (0.1%)		2/720 (0.3%)		1/109 (0.9%)		2/101 (2%)
Empyema	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Endocarditis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Enterococcal infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Epiglottitis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gangrene	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gastroenteritis	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Gastrointestinal infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gingival abscess	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Herpes zoster	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Human ehrlichiosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Infected skin ulcer	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Liver abscess	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lobar pneumonia	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Localised infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Lower respiratory tract infection	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lung infection	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Neutropenic infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Oral candidiasis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Orchitis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Osteomyelitis	0/705 (0%)		4/720 (0.6%)		1/109 (0.9%)		0/101 (0%)
Osteomyelitis acute	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Osteomyelitis chronic	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Penile infection	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Perineal abscess	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Perineal infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pneumonia	16/705 (2.3%)		13/720 (1.8%)		2/109 (1.8%)		1/101 (1%)
Pneumonia pneumococcal	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pseudomonal sepsis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pulmonary tuberculosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pyelonephritis	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Rectal abscess	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Scrotal abscess	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Sepsis	8/705 (1.1%)		6/720 (0.8%)		0/109 (0%)		1/101 (1%)
Septic shock	1/705 (0.1%)		1/720 (0.1%)		2/109 (1.8%)		0/101 (0%)
Sialoadenitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Tooth infection	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Upper respiratory tract infection	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Urinary tract infection	15/705 (2.1%)		15/720 (2.1%)		2/109 (1.8%)		3/101 (3%)
Urinary tract infection bacterial	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Urosepsis	4/705 (0.6%)		3/720 (0.4%)		0/109 (0%)		2/101 (2%)
Viral infection	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Wound infection	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Injury, poisoning and procedural complications
Accidental overdose	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Back injury	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cervical vertebral fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cystitis radiation	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Facial bones fracture	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Fall	1/705 (0.1%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Femoral neck fracture	1/705 (0.1%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Femur fracture	8/705 (1.1%)		1/720 (0.1%)		1/109 (0.9%)		1/101 (1%)
Fibula fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Foreign body	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gastroenteritis radiation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gastrointestinal stoma complication	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Head injury	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Hip fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Humerus fracture	2/705 (0.3%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Incisional hernia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Injury	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Laceration	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Lumbar vertebral fracture	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Post procedural haematuria	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Post procedural haemorrhage	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Radius fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Retinal injury	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Rib fracture	0/705 (0%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
Road traffic accident	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Spinal compression fracture	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Sternal fracture	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Subdural haematoma	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Tendon rupture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Tibia fracture	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Toxicity to various agents	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Traumatic intracranial haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Wrist fracture	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Investigations
Aspiration bronchial	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Blood creatinine increased	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Blood potassium decreased	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Blood pressure increased	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Blood urine present	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Haemoglobin decreased	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Heart rate increased	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Laboratory test abnormal	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Ultrasound liver abnormal	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Weight decreased	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metabolism and nutrition disorders
Cachexia	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Decreased appetite	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Dehydration	9/705 (1.3%)		7/720 (1%)		0/109 (0%)		3/101 (3%)
Diabetes mellitus	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Diabetes mellitus inadequate control	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Electrolyte imbalance	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gout	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Hyperkalaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hypocalcaemia	1/705 (0.1%)		1/720 (0.1%)		2/109 (1.8%)		0/101 (0%)
Hypoglycaemia	1/705 (0.1%)		3/720 (0.4%)		0/109 (0%)		1/101 (1%)
Hypokalaemia	0/705 (0%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
Hypovolaemia	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Iron deficiency	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Malnutrition	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Type 2 diabetes mellitus	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Arthritis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Back pain	7/705 (1%)		9/720 (1.3%)		0/109 (0%)		0/101 (0%)
Bone pain	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Dupuytren's contracture	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Exostosis of jaw	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Flank pain	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Fracture nonunion	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Hypercreatinaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Intervertebral disc degeneration	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Intervertebral disc disorder	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Jaw disorder	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Joint effusion	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lumbar spinal stenosis	1/705 (0.1%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Muscular weakness	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Musculoskeletal chest pain	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Musculoskeletal pain	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Myalgia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Neck pain	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Osteitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Osteoarthritis	4/705 (0.6%)		7/720 (1%)		0/109 (0%)		1/101 (1%)
Osteonecrosis of jaw	0/705 (0%)		12/720 (1.7%)		1/109 (0.9%)		5/101 (5%)
Pain in extremity	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Rhabdomyolysis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Rheumatoid arthritis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Rotator cuff syndrome	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Spinal osteoarthritis	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Weight bearing difficulty	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Basal cell carcinoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Bladder cancer	2/705 (0.3%)		7/720 (1%)		0/109 (0%)		0/101 (0%)
Bladder cancer recurrent	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Choroid melanoma	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Colon cancer	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Colon cancer metastatic	1/705 (0.1%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Colorectal cancer	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gastric cancer	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gastrointestinal stromal tumour	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Gastrointestinal tract adenoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Large intestine benign neoplasm	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Laryngeal cancer	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lip squamous cell carcinoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Lipoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lung neoplasm malignant	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Malignant melanoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Mantle cell lymphoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Meningioma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastases to abdominal cavity	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastases to bladder	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastases to bone	5/705 (0.7%)		10/720 (1.4%)		0/109 (0%)		0/101 (0%)
Metastases to central nervous system	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Metastases to larynx	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Metastases to liver	4/705 (0.6%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Metastases to lung	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastases to lymph nodes	6/705 (0.9%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Metastases to peritoneum	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Metastases to skin	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Metastases to small intestine	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Metastases to soft tissue	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastases to spine	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Metastasis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastatic malignant melanoma	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Metastatic pain	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Metastatic squamous cell carcinoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Myeloproliferative disorder	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Neoplasm prostate	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Non-Hodgkin's lymphoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Non-small cell lung cancer	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Oesophageal adenocarcinoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Oesophageal carcinoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pancreatic carcinoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pancreatic neoplasm	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Papillary thyroid cancer	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Papilloma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Plasma cell myeloma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Prostate cancer	21/705 (3%)		15/720 (2.1%)		1/109 (0.9%)		1/101 (1%)
Prostate cancer metastatic	6/705 (0.9%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Prostate cancer recurrent	0/705 (0%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
Rectal adenocarcinoma	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Rectal cancer	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Rectosigmoid cancer	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Renal cancer	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Renal cell carcinoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Small cell lung cancer	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Small intestine carcinoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Squamous cell carcinoma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Tumour haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Nervous system disorders
Aphasia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Ataxia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Carotid artery stenosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Carotid artery thrombosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cerebellar infarction	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cerebral infarction	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Cerebral ischaemia	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cerebrovascular accident	10/705 (1.4%)		8/720 (1.1%)		2/109 (1.8%)		2/101 (2%)
Cerebrovascular disorder	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Coma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Complex partial seizures	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Convulsion	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Dementia	0/705 (0%)		1/720 (0.1%)		1/109 (0.9%)		1/101 (1%)
Dizziness	0/705 (0%)		4/720 (0.6%)		0/109 (0%)		0/101 (0%)
Encephalopathy	1/705 (0.1%)		0/720 (0%)		1/109 (0.9%)		1/101 (1%)
Epilepsy	3/705 (0.4%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Gait apraxia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Grand mal convulsion	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hemiparesis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Hypertonia	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Ischaemic stroke	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Lethargy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Loss of consciousness	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Neuropathy peripheral	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Paraparesis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Parkinson's disease	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Petit mal epilepsy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Presyncope	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Somnolence	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Spinal cord compression	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Syncope	4/705 (0.6%)		8/720 (1.1%)		1/109 (0.9%)		0/101 (0%)
Transient ischaemic attack	1/705 (0.1%)		2/720 (0.3%)		1/109 (0.9%)		1/101 (1%)
Vertebral artery occlusion	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Psychiatric disorders
Abnormal behaviour	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Completed suicide	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Confusional state	4/705 (0.6%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Delirium	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Depression	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Disorientation	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Mental status changes	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Renal and urinary disorders
Anuria	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Azotaemia	0/705 (0%)		5/720 (0.7%)		0/109 (0%)		0/101 (0%)
Bladder dilatation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bladder neck obstruction	1/705 (0.1%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Bladder neck sclerosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bladder obstruction	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bladder outlet obstruction	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bladder perforation	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Calculus bladder	3/705 (0.4%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Calculus ureteric	0/705 (0%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Calculus urinary	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cystitis haemorrhagic	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cystitis noninfective	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Dysuria	3/705 (0.4%)		7/720 (1%)		0/109 (0%)		0/101 (0%)
Haematinuria	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Haematuria	25/705 (3.5%)		37/720 (5.1%)		2/109 (1.8%)		5/101 (5%)
Haemorrhage urinary tract	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hydronephrosis	11/705 (1.6%)		15/720 (2.1%)		0/109 (0%)		1/101 (1%)
Hydroureter	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Incontinence	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Micturition disorder	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Micturition urgency	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Nephrolithiasis	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Nocturia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Obstructive uropathy	2/705 (0.3%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Oliguria	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pollakiuria	1/705 (0.1%)		6/720 (0.8%)		0/109 (0%)		0/101 (0%)
Polyuria	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Renal failure	9/705 (1.3%)		16/720 (2.2%)		1/109 (0.9%)		2/101 (2%)
Renal failure acute	16/705 (2.3%)		12/720 (1.7%)		4/109 (3.7%)		2/101 (2%)
Renal failure chronic	3/705 (0.4%)		2/720 (0.3%)		1/109 (0.9%)		0/101 (0%)
Ureteric dilatation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Ureteric obstruction	4/705 (0.6%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Ureteric stenosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Urethral obstruction	3/705 (0.4%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Urethral pain	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Urethral stenosis	4/705 (0.6%)		3/720 (0.4%)		1/109 (0.9%)		0/101 (0%)
Urinary bladder haemorrhage	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Urinary hesitation	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Urinary incontinence	1/705 (0.1%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Urinary retention	33/705 (4.7%)		56/720 (7.8%)		6/109 (5.5%)		5/101 (5%)
Urinary tract disorder	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Urinary tract obstruction	12/705 (1.7%)		5/720 (0.7%)		1/109 (0.9%)		1/101 (1%)
Urinary tract pain	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Urine abnormality	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Urogenital haemorrhage	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	3/705 (0.4%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Pelvic pain	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Perineal pain	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Prostatic haemorrhage	3/705 (0.4%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Prostatic obstruction	2/705 (0.3%)		0/720 (0%)		4/109 (3.7%)		0/101 (0%)
Prostatic perforation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Prostatism	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Prostatomegaly	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Scrotal oedema	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Testicular atrophy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Testicular pain	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Acute respiratory distress syndrome	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Acute respiratory failure	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Aspiration	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Asthma	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Atelectasis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Bronchomalacia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Chronic obstructive pulmonary disease	3/705 (0.4%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cough	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Dyspnoea	7/705 (1%)		10/720 (1.4%)		0/109 (0%)		3/101 (3%)
Emphysema	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Epistaxis	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		1/101 (1%)
Haemoptysis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lung disorder	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pleural effusion	5/705 (0.7%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Pleuritic pain	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pneumonia aspiration	0/705 (0%)		0/720 (0%)		0/109 (0%)		1/101 (1%)
Pneumonitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pneumothorax	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Pulmonary arterial hypertension	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pulmonary embolism	8/705 (1.1%)		9/720 (1.3%)		1/109 (0.9%)		3/101 (3%)
Pulmonary fibrosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Pulmonary oedema	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Respiratory distress	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Respiratory failure	3/705 (0.4%)		3/720 (0.4%)		2/109 (1.8%)		0/101 (0%)
Sinus disorder	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Sleep apnoea syndrome	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Dermatitis contact	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Skin ulcer	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Social circumstances
Physical disability	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Surgical and medical procedures
Bladder catheterisation	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cancer surgery	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cardioversion	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Cataract operation	2/705 (0.3%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Colostomy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Cystostomy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Debridement	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Finger amputation	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Heart valve operation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Hip arthroplasty	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Inguinal hernia repair	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Knee arthroplasty	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Orchidectomy	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Skin graft	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Stent placement	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Transurethral prostatectomy	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Vascular disorders
Aortic aneurysm	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Aortic dilatation	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Arterial thrombosis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Deep vein thrombosis	6/705 (0.9%)		8/720 (1.1%)		0/109 (0%)		1/101 (1%)
Embolism	0/705 (0%)		0/720 (0%)		1/109 (0.9%)		0/101 (0%)
Haematoma	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Haemorrhage	0/705 (0%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Hypertension	3/705 (0.4%)		3/720 (0.4%)		0/109 (0%)		3/101 (3%)
Hypertensive crisis	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Hypotension	4/705 (0.6%)		5/720 (0.7%)		0/109 (0%)		1/101 (1%)
Intermittent claudication	1/705 (0.1%)		3/720 (0.4%)		0/109 (0%)		0/101 (0%)
Ischaemia	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Lymphoedema	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Orthostatic hypotension	1/705 (0.1%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Pelvic venous thrombosis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Peripheral arterial occlusive disease	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Peripheral ischaemia	1/705 (0.1%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Phlebitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Shock	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Superior vena cava syndrome	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Thrombophlebitis	0/705 (0%)		2/720 (0.3%)		0/109 (0%)		0/101 (0%)
Thrombosis	3/705 (0.4%)		1/720 (0.1%)		1/109 (0.9%)		0/101 (0%)
Vascular occlusion	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Vasculitis	0/705 (0%)		1/720 (0.1%)		0/109 (0%)		0/101 (0%)
Venous thrombosis	2/705 (0.3%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Venous thrombosis limb	1/705 (0.1%)		0/720 (0%)		0/109 (0%)		0/101 (0%)
Other (Not Including Serious) Adverse Events
	DB: Placebo		DB: Denosumab 120 mg Q4W		OLE: Placebo/ Denosumab 120 mg Q4W		OLE: Denosumab/ Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	585/705 (83%)		599/720 (83.2%)		80/109 (73.4%)		74/101 (73.3%)
Blood and lymphatic system disorders
Anaemia	74/705 (10.5%)		80/720 (11.1%)		12/109 (11%)		10/101 (9.9%)
Gastrointestinal disorders
Abdominal pain	47/705 (6.7%)		59/720 (8.2%)		3/109 (2.8%)		7/101 (6.9%)
Constipation	124/705 (17.6%)		128/720 (17.8%)		13/109 (11.9%)		15/101 (14.9%)
Dental caries	10/705 (1.4%)		16/720 (2.2%)		3/109 (2.8%)		6/101 (5.9%)
Diarrhoea	102/705 (14.5%)		110/720 (15.3%)		8/109 (7.3%)		10/101 (9.9%)
Nausea	95/705 (13.5%)		98/720 (13.6%)		4/109 (3.7%)		14/101 (13.9%)
Toothache	16/705 (2.3%)		32/720 (4.4%)		1/109 (0.9%)		6/101 (5.9%)
Vomiting	55/705 (7.8%)		59/720 (8.2%)		3/109 (2.8%)		10/101 (9.9%)
General disorders
Asthenia	91/705 (12.9%)		92/720 (12.8%)		8/109 (7.3%)		11/101 (10.9%)
Fatigue	82/705 (11.6%)		98/720 (13.6%)		5/109 (4.6%)		8/101 (7.9%)
Oedema peripheral	88/705 (12.5%)		94/720 (13.1%)		5/109 (4.6%)		11/101 (10.9%)
Infections and infestations
Bronchitis	32/705 (4.5%)		40/720 (5.6%)		3/109 (2.8%)		3/101 (3%)
Influenza	38/705 (5.4%)		49/720 (6.8%)		7/109 (6.4%)		6/101 (5.9%)
Nasopharyngitis	72/705 (10.2%)		68/720 (9.4%)		7/109 (6.4%)		4/101 (4%)
Upper respiratory tract infection	23/705 (3.3%)		46/720 (6.4%)		8/109 (7.3%)		8/101 (7.9%)
Urinary tract infection	96/705 (13.6%)		108/720 (15%)		15/109 (13.8%)		14/101 (13.9%)
Injury, poisoning and procedural complications
Fall	42/705 (6%)		36/720 (5%)		3/109 (2.8%)		3/101 (3%)
Investigations
Weight decreased	42/705 (6%)		39/720 (5.4%)		4/109 (3.7%)		6/101 (5.9%)
Metabolism and nutrition disorders
Decreased appetite	61/705 (8.7%)		63/720 (8.8%)		7/109 (6.4%)		5/101 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	116/705 (16.5%)		123/720 (17.1%)		11/109 (10.1%)		9/101 (8.9%)
Back pain	159/705 (22.6%)		166/720 (23.1%)		24/109 (22%)		8/101 (7.9%)
Muscle spasms	28/705 (4%)		46/720 (6.4%)		6/109 (5.5%)		1/101 (1%)
Musculoskeletal pain	59/705 (8.4%)		58/720 (8.1%)		8/109 (7.3%)		5/101 (5%)
Osteoarthritis	24/705 (3.4%)		24/720 (3.3%)		6/109 (5.5%)		1/101 (1%)
Osteonecrosis of jaw	0/705 (0%)		17/720 (2.4%)		1/109 (0.9%)		12/101 (11.9%)
Pain in extremity	88/705 (12.5%)		101/720 (14%)		12/109 (11%)		10/101 (9.9%)
Pain in jaw	7/705 (1%)		25/720 (3.5%)		2/109 (1.8%)		6/101 (5.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone	58/705 (8.2%)		56/720 (7.8%)		0/109 (0%)		1/101 (1%)
Nervous system disorders
Dizziness	56/705 (7.9%)		63/720 (8.8%)		7/109 (6.4%)		6/101 (5.9%)
Headache	54/705 (7.7%)		67/720 (9.3%)		3/109 (2.8%)		5/101 (5%)
Psychiatric disorders
Insomnia	44/705 (6.2%)		46/720 (6.4%)		4/109 (3.7%)		2/101 (2%)
Renal and urinary disorders
Dysuria	66/705 (9.4%)		73/720 (10.1%)		5/109 (4.6%)		7/101 (6.9%)
Haematuria	90/705 (12.8%)		87/720 (12.1%)		17/109 (15.6%)		11/101 (10.9%)
Nocturia	26/705 (3.7%)		39/720 (5.4%)		3/109 (2.8%)		3/101 (3%)
Pollakiuria	50/705 (7.1%)		61/720 (8.5%)		1/109 (0.9%)		2/101 (2%)
Urinary incontinence	30/705 (4.3%)		30/720 (4.2%)		8/109 (7.3%)		4/101 (4%)
Urinary retention	63/705 (8.9%)		73/720 (10.1%)		6/109 (5.5%)		7/101 (6.9%)
Respiratory, thoracic and mediastinal disorders
Cough	60/705 (8.5%)		55/720 (7.6%)		6/109 (5.5%)		4/101 (4%)
Dyspnoea	57/705 (8.1%)		61/720 (8.5%)		4/109 (3.7%)		4/101 (4%)
Skin and subcutaneous tissue disorders
Rash	32/705 (4.5%)		37/720 (5.1%)		2/109 (1.8%)		3/101 (3%)
Vascular disorders
Hot flush	32/705 (4.5%)		41/720 (5.7%)		1/109 (0.9%)		1/101 (1%)
Hypertension	49/705 (7%)		59/720 (8.2%)		5/109 (4.6%)		6/101 (5.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.