Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Men With Hormone-refractory Prostate Cancer

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00321620
• Collaborator: (none)
• Enrollment: 1,904
• Arms: 2
• Actual Duration (Months): 70.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid (Zometa®) in the treatment of bone metastases in men with hormone-refractory prostate cancer

Condition or Disease	Intervention/Treatment	Phase
Bone Metastases	Drug: zoledronic acid; Biological: denosumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1904 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid (Zometa®) in the Treatment of Bone Metastases in Men With Hormone-Refractory Prostate Cancer
• Actual Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Feb 24, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: zoledronic acid	Drug: zoledronic acid; Q4W 4 mg zoledronic acid IV over minimum 15 minutes and 120 mg denosumab placebo SC; Other Names: Zometa
Experimental: denosumab	Biological: denosumab; Q4W 120 mg denosumab SC and 4 mg zoledronic acid placebo IV over a minimum of 15 minutes

Outcome Measures

Primary Outcome Measures

1. Time to the First On-Study SRE (Non-inferiority) [Up to 40.5 months]

   Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported.

Secondary Outcome Measures

1. Time to the First On-Study SRE (Superiority) [Up to 40.5 months]

   Time to the first on-study skeletal-related event (SRE), analyzed for superiority of denosumab. Kaplan-Meier estimates of the median and its dispersion are reported.

2. Time to the First-And-Subsequent On-Study SRE [Up to 40.5 months]

   Time to the first-and-subsequent on-study skeletal-related event (SRE), analyzed for superiority of denosumab using multiple event analysis, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men >/= 18 years of age with histologically confirmed prostate cancer

• Radiographic evidence of at least one bone metastasis

• Failure of at least one hormonal therapy as evidenced by a rising PSA

• Serum testosterone level of <50 ng/dL

• ECOG PS 0, 1, or 2

• Adequate organ function

Exclusion Criteria:

• Current or prior IV bisphosphonate administration

• Current or prior oral bisphosphonates for bone mets

• Life expectancy of less than 6 months

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:

• Notice regarding posted summaries of trial results
• AmgenTrials clinical trials website

Publications

• Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140-6736(10)62344-6. Epub 2011 Feb 25.
• Fizazi K, Massard C, Smith M, Rader M, Brown J, Milecki P, Shore N, Oudard S, Karsh L, Carducci M, Damião R, Wang H, Ying W, Goessl C. Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer. Eur Urol. 2015 Jul;68(1):42-50. doi: 10.1016/j.eururo.2014.10.001. Epub 2014 Oct 29.
• Smith MR, Coleman RE, Klotz L, Pittman K, Milecki P, Ng S, Chi KN, Balakumaran A, Wei R, Wang H, Braun A, Fizazi K. Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events. Ann Oncol. 2015 Feb;26(2):368-74. doi: 10.1093/annonc/mdu519. Epub 2014 Nov 25. Erratum in: Ann Oncol. 2015 Jun;26(6):1274.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00321620
• Other Study ID Numbers: 20050103
• First Posted: May 4, 2006
• Last Update Posted: Aug 29, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Amgen: Bone metastases; Hormone-refractory prostate cancer; Skeletal; Fractures; Compressions; Bisphosphonates
• Additional relevant MeSH terms: Prostatic Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Zoledronic Acid; Denosumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 12 May 2006 through 18 December 2008.
Pre-assignment Detail	1904 participants were enrolled, however 3 were excluded from all analyses as Institutional Review Board review activities and oversight were not ensured.

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Period Title: Overall Study
STARTED	951	950
Received Investigational Product	946	942
COMPLETED	208	228
NOT COMPLETED	743	722

Baseline Characteristics

Arm/Group Title	Zoledronic Acid	Denosumab	Total
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks	Total of all reporting groups
Overall Participants	951	950	1901
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	71.0 (8.4)	70.5 (8.7)	70.8 (8.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	951 100%	950 100%	1901 100%
Race/Ethnicity, Customized (Number) [Number]
White or Caucasian	810 85.2%	829 87.3%	1639 86.2%
Black or African American	35 3.7%	38 4%	73 3.8%
Hispanic or Latino	57 6%	45 4.7%	102 5.4%
Asian	26 2.7%	22 2.3%	48 2.5%
Native Hawaiian or Other Pacific Islander	1 0.1%	1 0.1%	2 0.1%
Other	22 2.3%	15 1.6%	37 1.9%
Prostate-Specific Antigen (PSA) Stratification Factor (Number) [Number]
PSA level < 10 ng/mL	145 15.2%	145 15.3%	290 15.3%
PSA level ≥ 10 ng/mL	806 84.8%	805 84.7%	1611 84.7%
Previous Skeletal-Related Event (SRE) Stratification Factor (Number) [Number]
Yes	231 24.3%	232 24.4%	463 24.4%
No	720 75.7%	718 75.6%	1438 75.6%
Current Prostate Cancer Chemotherapy Stratification Factor (Number) [Number]
Yes	132 13.9%	132 13.9%	264 13.9%
No	819 86.1%	818 86.1%	1637 86.1%

Outcome Measures

1. Primary Outcome

Title	Time to the First On-Study SRE (Non-inferiority)
Description	Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported.
Time Frame	Up to 40.5 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	951	950
Median (95% Confidence Interval) [Days]	521.0	629.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A synthesis method was used for the non-inferiority test for the hypothesis that denosumab preserves as least 50% of the effect of zoledronic acid vs. placebo.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	() 95%; 0.71 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prostate-specific antigen level, and current chemotherapy)

2. Secondary Outcome

Title	Time to the First On-Study SRE (Superiority)
Description	Time to the first on-study skeletal-related event (SRE), analyzed for superiority of denosumab. Kaplan-Meier estimates of the median and its dispersion are reported.
Time Frame	Up to 40.5 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	951	950
Median (95% Confidence Interval) [Days]	521.0	629.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Regression, Cox
	Comments	P-value was adjusted for multiplicity according to a hierarchical testing strategy and Hochberg procedure.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	() 95%; 0.71 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prostate-specific antigen level, and current chemotherapy).

3. Secondary Outcome

Title	Time to the First-And-Subsequent On-Study SRE
Description	Time to the first-and-subsequent on-study skeletal-related event (SRE), analyzed for superiority of denosumab using multiple event analysis, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events.
Time Frame	Up to 40.5 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	951	950
Number [Events]	584	494

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Anderson-Gill model
	Comments	P-value was adjusted for multiplicity according to a hierarchical testing strategy and Hochberg procedure.
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.82
	Confidence Interval	() 95%; 0.71 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prostate-specific antigen level, and current chemotherapy).

Adverse Events

Time Frame	up to 3 years 5 months
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events. One subject who was randomized to zoledronic acid and received denosumab as the 1st investigational product was analyzed on the denosumab arm for safety analyses.
Arm/Group Title	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
Arm/Group Description
All Cause Mortality
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	568/945 (60.1%)		594/943 (63%)
Blood and lymphatic system disorders
Anaemia	82/945 (8.7%)		108/943 (11.5%)
Anaemia of malignant disease	1/945 (0.1%)		0/943 (0%)
Coagulopathy	1/945 (0.1%)		0/943 (0%)
Disseminated intravascular coagulation	2/945 (0.2%)		3/943 (0.3%)
Febrile bone marrow aplasia	1/945 (0.1%)		0/943 (0%)
Febrile neutropenia	8/945 (0.8%)		8/943 (0.8%)
Haemorrhagic anaemia	0/945 (0%)		1/943 (0.1%)
Heparin-induced thrombocytopenia	0/945 (0%)		1/943 (0.1%)
Hypercoagulation	0/945 (0%)		1/943 (0.1%)
Leukopenia	1/945 (0.1%)		3/943 (0.3%)
Lymphadenopathy	0/945 (0%)		3/943 (0.3%)
Neutropenia	4/945 (0.4%)		10/943 (1.1%)
Normochromic normocytic anaemia	0/945 (0%)		1/943 (0.1%)
Pancytopenia	3/945 (0.3%)		1/943 (0.1%)
Splenic infarction	1/945 (0.1%)		0/943 (0%)
Thrombocytopenia	5/945 (0.5%)		10/943 (1.1%)
Cardiac disorders
Acute coronary syndrome	2/945 (0.2%)		1/943 (0.1%)
Acute myocardial infarction	7/945 (0.7%)		5/943 (0.5%)
Angina pectoris	5/945 (0.5%)		1/943 (0.1%)
Angina unstable	1/945 (0.1%)		2/943 (0.2%)
Arrhythmia	2/945 (0.2%)		6/943 (0.6%)
Arteriosclerosis coronary artery	1/945 (0.1%)		0/943 (0%)
Atrial fibrillation	8/945 (0.8%)		10/943 (1.1%)
Atrial flutter	3/945 (0.3%)		0/943 (0%)
Atrial tachycardia	0/945 (0%)		1/943 (0.1%)
Atrioventricular block complete	0/945 (0%)		1/943 (0.1%)
Bundle branch block right	0/945 (0%)		1/943 (0.1%)
Cardiac arrest	4/945 (0.4%)		5/943 (0.5%)
Cardiac asthma	0/945 (0%)		1/943 (0.1%)
Cardiac failure	23/945 (2.4%)		21/943 (2.2%)
Cardiac failure acute	1/945 (0.1%)		2/943 (0.2%)
Cardiac failure congestive	7/945 (0.7%)		8/943 (0.8%)
Cardio-respiratory arrest	12/945 (1.3%)		7/943 (0.7%)
Cardiogenic shock	0/945 (0%)		2/943 (0.2%)
Cardiomegaly	1/945 (0.1%)		0/943 (0%)
Cardiopulmonary failure	6/945 (0.6%)		2/943 (0.2%)
Cardiovascular insufficiency	3/945 (0.3%)		1/943 (0.1%)
Coronary artery disease	0/945 (0%)		2/943 (0.2%)
Coronary artery stenosis	1/945 (0.1%)		0/943 (0%)
Ischaemic cardiomyopathy	1/945 (0.1%)		0/943 (0%)
Left ventricular failure	2/945 (0.2%)		2/943 (0.2%)
Myocardial infarction	13/945 (1.4%)		9/943 (1%)
Myocardial ischaemia	6/945 (0.6%)		5/943 (0.5%)
Sick sinus syndrome	1/945 (0.1%)		0/943 (0%)
Supraventricular tachycardia	1/945 (0.1%)		2/943 (0.2%)
Tachyarrhythmia	1/945 (0.1%)		0/943 (0%)
Tachycardia	1/945 (0.1%)		3/943 (0.3%)
Ventricular fibrillation	1/945 (0.1%)		0/943 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/945 (0.1%)		0/943 (0%)
Hypoacusis	0/945 (0%)		1/943 (0.1%)
Vertigo	0/945 (0%)		2/943 (0.2%)
Endocrine disorders
Adrenal insufficiency	1/945 (0.1%)		0/943 (0%)
Eye disorders
Blindness unilateral	0/945 (0%)		1/943 (0.1%)
Cataract	1/945 (0.1%)		0/943 (0%)
Diplopia	0/945 (0%)		3/943 (0.3%)
Retinal artery thrombosis	0/945 (0%)		1/943 (0.1%)
Vision blurred	0/945 (0%)		1/943 (0.1%)
Visual impairment	2/945 (0.2%)		0/943 (0%)
Gastrointestinal disorders
Abdominal pain	12/945 (1.3%)		8/943 (0.8%)
Abdominal pain lower	0/945 (0%)		1/943 (0.1%)
Abdominal pain upper	3/945 (0.3%)		3/943 (0.3%)
Anal fissure	0/945 (0%)		2/943 (0.2%)
Anal haemorrhage	0/945 (0%)		1/943 (0.1%)
Ascites	1/945 (0.1%)		2/943 (0.2%)
Colitis	1/945 (0.1%)		1/943 (0.1%)
Colitis ulcerative	1/945 (0.1%)		0/943 (0%)
Colonic obstruction	1/945 (0.1%)		1/943 (0.1%)
Constipation	9/945 (1%)		5/943 (0.5%)
Diarrhoea	13/945 (1.4%)		12/943 (1.3%)
Dysphagia	1/945 (0.1%)		2/943 (0.2%)
Enterovesical fistula	0/945 (0%)		1/943 (0.1%)
Faecal incontinence	2/945 (0.2%)		1/943 (0.1%)
Faecaloma	1/945 (0.1%)		0/943 (0%)
Faeces discoloured	1/945 (0.1%)		0/943 (0%)
Gastric ulcer	0/945 (0%)		1/943 (0.1%)
Gastric ulcer haemorrhage	0/945 (0%)		2/943 (0.2%)
Gastric ulcer perforation	1/945 (0.1%)		0/943 (0%)
Gastritis erosive	0/945 (0%)		1/943 (0.1%)
Gastrointestinal disorder	2/945 (0.2%)		0/943 (0%)
Gastrointestinal haemorrhage	4/945 (0.4%)		3/943 (0.3%)
Gastrointestinal obstruction	0/945 (0%)		2/943 (0.2%)
Gingival bleeding	0/945 (0%)		2/943 (0.2%)
Haematemesis	3/945 (0.3%)		2/943 (0.2%)
Haematochezia	1/945 (0.1%)		1/943 (0.1%)
Ileus	0/945 (0%)		3/943 (0.3%)
Ileus paralytic	0/945 (0%)		1/943 (0.1%)
Inguinal hernia	2/945 (0.2%)		0/943 (0%)
Intestinal obstruction	4/945 (0.4%)		4/943 (0.4%)
Intestinal perforation	0/945 (0%)		1/943 (0.1%)
Lower gastrointestinal haemorrhage	1/945 (0.1%)		2/943 (0.2%)
Melaena	0/945 (0%)		1/943 (0.1%)
Nausea	14/945 (1.5%)		8/943 (0.8%)
Obstruction gastric	0/945 (0%)		1/943 (0.1%)
Odynophagia	1/945 (0.1%)		0/943 (0%)
Oesophageal ulcer	0/945 (0%)		1/943 (0.1%)
Oesophagitis	0/945 (0%)		1/943 (0.1%)
Pancreatitis	1/945 (0.1%)		0/943 (0%)
Pancreatitis acute	0/945 (0%)		1/943 (0.1%)
Peritonitis	0/945 (0%)		2/943 (0.2%)
Proctalgia	1/945 (0.1%)		0/943 (0%)
Rectal haemorrhage	3/945 (0.3%)		3/943 (0.3%)
Rectal stenosis	1/945 (0.1%)		0/943 (0%)
Rectourethral fistula	0/945 (0%)		1/943 (0.1%)
Reflux gastritis	0/945 (0%)		1/943 (0.1%)
Retroperitoneal haematoma	0/945 (0%)		1/943 (0.1%)
Retroperitoneal haemorrhage	1/945 (0.1%)		0/943 (0%)
Small intestinal obstruction	0/945 (0%)		3/943 (0.3%)
Stomatitis	1/945 (0.1%)		0/943 (0%)
Subileus	0/945 (0%)		1/943 (0.1%)
Upper gastrointestinal haemorrhage	3/945 (0.3%)		6/943 (0.6%)
Vomiting	22/945 (2.3%)		24/943 (2.5%)
General disorders
Abasia	1/945 (0.1%)		0/943 (0%)
Asthenia	29/945 (3.1%)		37/943 (3.9%)
Catheter related complication	3/945 (0.3%)		2/943 (0.2%)
Catheter site pain	1/945 (0.1%)		1/943 (0.1%)
Chest discomfort	1/945 (0.1%)		1/943 (0.1%)
Chest pain	13/945 (1.4%)		9/943 (1%)
Chills	1/945 (0.1%)		0/943 (0%)
Death	10/945 (1.1%)		11/943 (1.2%)
Discomfort	1/945 (0.1%)		0/943 (0%)
Disease progression	2/945 (0.2%)		0/943 (0%)
Drug intolerance	1/945 (0.1%)		0/943 (0%)
Fatigue	10/945 (1.1%)		20/943 (2.1%)
Gait disturbance	0/945 (0%)		1/943 (0.1%)
General physical health deterioration	28/945 (3%)		29/943 (3.1%)
Generalised oedema	1/945 (0.1%)		2/943 (0.2%)
Hernia	0/945 (0%)		1/943 (0.1%)
Impaired healing	0/945 (0%)		1/943 (0.1%)
Inflammation	0/945 (0%)		1/943 (0.1%)
Localised oedema	2/945 (0.2%)		0/943 (0%)
Malaise	3/945 (0.3%)		3/943 (0.3%)
Mucosal inflammation	2/945 (0.2%)		0/943 (0%)
Multi-organ failure	18/945 (1.9%)		18/943 (1.9%)
Oedema	3/945 (0.3%)		1/943 (0.1%)
Oedema peripheral	8/945 (0.8%)		13/943 (1.4%)
Pain	12/945 (1.3%)		16/943 (1.7%)
Performance status decreased	2/945 (0.2%)		9/943 (1%)
Pyrexia	18/945 (1.9%)		19/943 (2%)
Sudden death	2/945 (0.2%)		3/943 (0.3%)
Suprapubic pain	1/945 (0.1%)		0/943 (0%)
Terminal state	0/945 (0%)		1/943 (0.1%)
Hepatobiliary disorders
Bile duct obstruction	0/945 (0%)		1/943 (0.1%)
Bile duct stone	0/945 (0%)		1/943 (0.1%)
Biliary tract disorder	1/945 (0.1%)		0/943 (0%)
Cholecystitis	1/945 (0.1%)		1/943 (0.1%)
Cholecystitis acute	1/945 (0.1%)		1/943 (0.1%)
Cholelithiasis	3/945 (0.3%)		0/943 (0%)
Cholelithiasis obstructive	1/945 (0.1%)		0/943 (0%)
Hepatic failure	6/945 (0.6%)		10/943 (1.1%)
Hepatitis	1/945 (0.1%)		0/943 (0%)
Hepatomegaly	0/945 (0%)		1/943 (0.1%)
Hepatorenal syndrome	0/945 (0%)		1/943 (0.1%)
Hyperbilirubinaemia	1/945 (0.1%)		0/943 (0%)
Jaundice	1/945 (0.1%)		1/943 (0.1%)
Jaundice cholestatic	0/945 (0%)		1/943 (0.1%)
Infections and infestations
Abscess intestinal	0/945 (0%)		1/943 (0.1%)
Alveolar osteitis	0/945 (0%)		1/943 (0.1%)
Anal abscess	1/945 (0.1%)		0/943 (0%)
Appendicitis	1/945 (0.1%)		1/943 (0.1%)
Bacteraemia	1/945 (0.1%)		1/943 (0.1%)
Bronchitis	1/945 (0.1%)		6/943 (0.6%)
Bronchopneumonia	1/945 (0.1%)		3/943 (0.3%)
Candidiasis	0/945 (0%)		1/943 (0.1%)
Catheter related infection	1/945 (0.1%)		1/943 (0.1%)
Cellulitis	4/945 (0.4%)		6/943 (0.6%)
Central line infection	1/945 (0.1%)		0/943 (0%)
Cholecystitis infective	1/945 (0.1%)		0/943 (0%)
Clostridial infection	1/945 (0.1%)		0/943 (0%)
Clostridium difficile colitis	1/945 (0.1%)		1/943 (0.1%)
Cystitis	1/945 (0.1%)		0/943 (0%)
Dermo-hypodermitis	0/945 (0%)		1/943 (0.1%)
Device related infection	0/945 (0%)		1/943 (0.1%)
Diverticulitis	2/945 (0.2%)		1/943 (0.1%)
Endotoxaemia	0/945 (0%)		1/943 (0.1%)
Enterococcal sepsis	0/945 (0%)		1/943 (0.1%)
Erysipelas	1/945 (0.1%)		2/943 (0.2%)
Fungal oesophagitis	0/945 (0%)		1/943 (0.1%)
Gangrene	0/945 (0%)		2/943 (0.2%)
Gastroenteritis	3/945 (0.3%)		1/943 (0.1%)
Gastroenteritis viral	0/945 (0%)		1/943 (0.1%)
Gastrointestinal infection	1/945 (0.1%)		1/943 (0.1%)
Herpes zoster	2/945 (0.2%)		1/943 (0.1%)
Infection	3/945 (0.3%)		1/943 (0.1%)
Infective exacerbation of chronic obstructive airways disease	0/945 (0%)		1/943 (0.1%)
Influenza	1/945 (0.1%)		0/943 (0%)
Kidney infection	1/945 (0.1%)		0/943 (0%)
Lobar pneumonia	1/945 (0.1%)		3/943 (0.3%)
Lower respiratory tract infection	0/945 (0%)		1/943 (0.1%)
Ludwig angina	0/945 (0%)		1/943 (0.1%)
Lung infection	3/945 (0.3%)		2/943 (0.2%)
Meningitis bacterial	1/945 (0.1%)		0/943 (0%)
Necrotising fasciitis	2/945 (0.2%)		0/943 (0%)
Neutropenic sepsis	0/945 (0%)		3/943 (0.3%)
Oesophageal candidiasis	0/945 (0%)		1/943 (0.1%)
Oral candidiasis	1/945 (0.1%)		0/943 (0%)
Orchitis	1/945 (0.1%)		0/943 (0%)
Osteomyelitis	1/945 (0.1%)		0/943 (0%)
Otitis media	0/945 (0%)		1/943 (0.1%)
Penile abscess	1/945 (0.1%)		0/943 (0%)
Peridiverticulitis	0/945 (0%)		1/943 (0.1%)
Perirectal abscess	1/945 (0.1%)		1/943 (0.1%)
Pneumonia	24/945 (2.5%)		40/943 (4.2%)
Pneumonia bacterial	1/945 (0.1%)		0/943 (0%)
Pneumonia klebsiella	1/945 (0.1%)		0/943 (0%)
Post procedural sepsis	0/945 (0%)		1/943 (0.1%)
Postoperative wound infection	0/945 (0%)		1/943 (0.1%)
Pulmonary sepsis	1/945 (0.1%)		0/943 (0%)
Pyelonephritis	2/945 (0.2%)		4/943 (0.4%)
Pyelonephritis acute	1/945 (0.1%)		2/943 (0.2%)
Pyelonephritis chronic	1/945 (0.1%)		1/943 (0.1%)
Renal abscess	1/945 (0.1%)		1/943 (0.1%)
Scrotal abscess	0/945 (0%)		1/943 (0.1%)
Sepsis	11/945 (1.2%)		12/943 (1.3%)
Septic shock	4/945 (0.4%)		5/943 (0.5%)
Skin infection	2/945 (0.2%)		0/943 (0%)
Staphylococcal infection	2/945 (0.2%)		0/943 (0%)
Staphylococcal sepsis	0/945 (0%)		3/943 (0.3%)
Subcutaneous abscess	0/945 (0%)		1/943 (0.1%)
Tongue abscess	0/945 (0%)		1/943 (0.1%)
Urinary tract infection	30/945 (3.2%)		28/943 (3%)
Urosepsis	4/945 (0.4%)		5/943 (0.5%)
Wound infection	0/945 (0%)		1/943 (0.1%)
Injury, poisoning and procedural complications
Cardiac pacemaker malfunction	0/945 (0%)		1/943 (0.1%)
Concussion	0/945 (0%)		1/943 (0.1%)
Contusion	1/945 (0.1%)		0/943 (0%)
Cystitis radiation	1/945 (0.1%)		0/943 (0%)
Device failure	1/945 (0.1%)		0/943 (0%)
Device malfunction	1/945 (0.1%)		0/943 (0%)
Drug toxicity	1/945 (0.1%)		2/943 (0.2%)
Extradural haematoma	0/945 (0%)		1/943 (0.1%)
Fall	3/945 (0.3%)		4/943 (0.4%)
Femur fracture	3/945 (0.3%)		4/943 (0.4%)
Fracture	1/945 (0.1%)		1/943 (0.1%)
Gastroenteritis radiation	0/945 (0%)		1/943 (0.1%)
Head injury	1/945 (0.1%)		3/943 (0.3%)
Ilium fracture	0/945 (0%)		1/943 (0.1%)
Joint dislocation	1/945 (0.1%)		1/943 (0.1%)
Kidney rupture	0/945 (0%)		1/943 (0.1%)
Lumbar vertebral fracture	4/945 (0.4%)		0/943 (0%)
Medical device discomfort	0/945 (0%)		1/943 (0.1%)
Mouth injury	1/945 (0.1%)		0/943 (0%)
Overdose	2/945 (0.2%)		0/943 (0%)
Poisoning	1/945 (0.1%)		0/943 (0%)
Post procedural haemorrhage	0/945 (0%)		1/943 (0.1%)
Procedural pain	1/945 (0.1%)		0/943 (0%)
Renal haematoma	0/945 (0%)		1/943 (0.1%)
Rib fracture	2/945 (0.2%)		1/943 (0.1%)
Skin laceration	1/945 (0.1%)		0/943 (0%)
Stent occlusion	0/945 (0%)		1/943 (0.1%)
Sternal fracture	0/945 (0%)		1/943 (0.1%)
Subdural haematoma	2/945 (0.2%)		7/943 (0.7%)
Subdural haemorrhage	1/945 (0.1%)		1/943 (0.1%)
Tendon rupture	1/945 (0.1%)		0/943 (0%)
Thoracic vertebral fracture	1/945 (0.1%)		3/943 (0.3%)
Tibia fracture	0/945 (0%)		1/943 (0.1%)
Traumatic lung injury	1/945 (0.1%)		0/943 (0%)
Wound dehiscence	0/945 (0%)		1/943 (0.1%)
Investigations
Aspiration bronchial	1/945 (0.1%)		1/943 (0.1%)
Blood alkaline phosphatase increased	0/945 (0%)		1/943 (0.1%)
Blood bilirubin increased	1/945 (0.1%)		1/943 (0.1%)
Blood creatinine	0/945 (0%)		1/943 (0.1%)
Blood creatinine increased	0/945 (0%)		5/943 (0.5%)
Blood pressure systolic abnormal	0/945 (0%)		1/943 (0.1%)
Blood urine present	0/945 (0%)		1/943 (0.1%)
General physical condition abnormal	1/945 (0.1%)		0/943 (0%)
Glomerular filtration rate	1/945 (0.1%)		0/943 (0%)
Haemoglobin decreased	6/945 (0.6%)		2/943 (0.2%)
Hepatic enzyme increased	0/945 (0%)		1/943 (0.1%)
International normalised ratio decreased	0/945 (0%)		1/943 (0.1%)
Liver function test abnormal	0/945 (0%)		1/943 (0.1%)
Occult blood positive	0/945 (0%)		1/943 (0.1%)
Platelet count decreased	2/945 (0.2%)		0/943 (0%)
Prostatic specific antigen increased	1/945 (0.1%)		4/943 (0.4%)
Prothrombin time prolonged	0/945 (0%)		1/943 (0.1%)
Urine output decreased	0/945 (0%)		1/943 (0.1%)
Weight decreased	1/945 (0.1%)		1/943 (0.1%)
Metabolism and nutrition disorders
Cachexia	12/945 (1.3%)		14/943 (1.5%)
Decreased appetite	13/945 (1.4%)		13/943 (1.4%)
Dehydration	19/945 (2%)		36/943 (3.8%)
Diabetes mellitus	2/945 (0.2%)		2/943 (0.2%)
Electrolyte imbalance	1/945 (0.1%)		0/943 (0%)
Failure to thrive	2/945 (0.2%)		2/943 (0.2%)
Feeding disorder	1/945 (0.1%)		0/943 (0%)
Fluid overload	1/945 (0.1%)		0/943 (0%)
Gout	0/945 (0%)		1/943 (0.1%)
Hypercreatininaemia	0/945 (0%)		1/943 (0.1%)
Hyperglycaemia	1/945 (0.1%)		1/943 (0.1%)
Hyperkalaemia	5/945 (0.5%)		6/943 (0.6%)
Hypermetabolism	0/945 (0%)		1/943 (0.1%)
Hypernatraemia	1/945 (0.1%)		0/943 (0%)
Hyperosmolar state	1/945 (0.1%)		0/943 (0%)
Hypoalbuminaemia	1/945 (0.1%)		0/943 (0%)
Hypocalcaemia	7/945 (0.7%)		24/943 (2.5%)
Hypoglycaemia	3/945 (0.3%)		4/943 (0.4%)
Hypokalaemia	5/945 (0.5%)		4/943 (0.4%)
Hypomagnesaemia	1/945 (0.1%)		1/943 (0.1%)
Hyponatraemia	4/945 (0.4%)		4/943 (0.4%)
Hypophosphataemia	0/945 (0%)		6/943 (0.6%)
Metabolic acidosis	1/945 (0.1%)		3/943 (0.3%)
Metabolic disorder	0/945 (0%)		1/943 (0.1%)
Polydipsia	1/945 (0.1%)		0/943 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/945 (1%)		11/943 (1.2%)
Back pain	36/945 (3.8%)		29/943 (3.1%)
Bone pain	34/945 (3.6%)		24/943 (2.5%)
Cervical spinal stenosis	1/945 (0.1%)		0/943 (0%)
Flank pain	1/945 (0.1%)		3/943 (0.3%)
Groin pain	2/945 (0.2%)		1/943 (0.1%)
Intervertebral disc disorder	0/945 (0%)		1/943 (0.1%)
Intervertebral disc protrusion	1/945 (0.1%)		0/943 (0%)
Joint effusion	1/945 (0.1%)		0/943 (0%)
Joint range of motion decreased	0/945 (0%)		1/943 (0.1%)
Joint swelling	0/945 (0%)		1/943 (0.1%)
Lumbar spinal stenosis	1/945 (0.1%)		0/943 (0%)
Mobility decreased	1/945 (0.1%)		0/943 (0%)
Muscle haemorrhage	1/945 (0.1%)		1/943 (0.1%)
Muscular weakness	4/945 (0.4%)		9/943 (1%)
Musculoskeletal chest pain	2/945 (0.2%)		3/943 (0.3%)
Musculoskeletal pain	7/945 (0.7%)		1/943 (0.1%)
Myalgia	0/945 (0%)		1/943 (0.1%)
Myopathy	2/945 (0.2%)		0/943 (0%)
Neck mass	1/945 (0.1%)		0/943 (0%)
Neck pain	1/945 (0.1%)		1/943 (0.1%)
Osteitis	1/945 (0.1%)		0/943 (0%)
Osteoarthritis	2/945 (0.2%)		1/943 (0.1%)
Osteochondrosis	1/945 (0.1%)		0/943 (0%)
Osteonecrosis	4/945 (0.4%)		14/943 (1.5%)
Osteoporosis	1/945 (0.1%)		0/943 (0%)
Pain in extremity	20/945 (2.1%)		10/943 (1.1%)
Pathological fracture	1/945 (0.1%)		1/943 (0.1%)
Rhabdomyolysis	1/945 (0.1%)		0/943 (0%)
Sarcopenia	0/945 (0%)		1/943 (0.1%)
Spinal column stenosis	1/945 (0.1%)		1/943 (0.1%)
Spinal disorder	0/945 (0%)		1/943 (0.1%)
Spondylolisthesis	1/945 (0.1%)		0/943 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile duct cancer	1/945 (0.1%)		0/943 (0%)
Bladder cancer	2/945 (0.2%)		2/943 (0.2%)
Bladder transitional cell carcinoma	0/945 (0%)		1/943 (0.1%)
Cancer pain	0/945 (0%)		1/943 (0.1%)
Colon cancer	1/945 (0.1%)		0/943 (0%)
Gastric cancer	1/945 (0.1%)		1/943 (0.1%)
Lung adenocarcinoma	0/945 (0%)		1/943 (0.1%)
Lung carcinoma cell type unspecified recurrent	0/945 (0%)		1/943 (0.1%)
Malignant neoplasm progression	3/945 (0.3%)		2/943 (0.2%)
Meningioma benign	1/945 (0.1%)		1/943 (0.1%)
Metastases to bladder	0/945 (0%)		2/943 (0.2%)
Metastases to bone	9/945 (1%)		10/943 (1.1%)
Metastases to bone marrow	0/945 (0%)		2/943 (0.2%)
Metastases to central nervous system	6/945 (0.6%)		14/943 (1.5%)
Metastases to liver	5/945 (0.5%)		13/943 (1.4%)
Metastases to lung	4/945 (0.4%)		4/943 (0.4%)
Metastases to lymph nodes	1/945 (0.1%)		0/943 (0%)
Metastases to meninges	5/945 (0.5%)		3/943 (0.3%)
Metastases to rectum	0/945 (0%)		1/943 (0.1%)
Metastasis	1/945 (0.1%)		3/943 (0.3%)
Metastatic neoplasm	1/945 (0.1%)		3/943 (0.3%)
Metastatic pain	3/945 (0.3%)		5/943 (0.5%)
Nasal sinus cancer	0/945 (0%)		1/943 (0.1%)
Neoplasm progression	1/945 (0.1%)		2/943 (0.2%)
Neoplasm prostate	1/945 (0.1%)		2/943 (0.2%)
Pancreatic carcinoma	1/945 (0.1%)		0/943 (0%)
Pancreatic carcinoma metastatic	1/945 (0.1%)		0/943 (0%)
Paraneoplastic syndrome	0/945 (0%)		1/943 (0.1%)
Pituitary tumour benign	0/945 (0%)		1/943 (0.1%)
Prostate cancer	56/945 (5.9%)		34/943 (3.6%)
Prostate cancer metastatic	17/945 (1.8%)		8/943 (0.8%)
Rectal cancer	1/945 (0.1%)		1/943 (0.1%)
Renal cell carcinoma	0/945 (0%)		1/943 (0.1%)
Transitional cell carcinoma	0/945 (0%)		1/943 (0.1%)
Waldenstrom's macroglobulinaemia	0/945 (0%)		1/943 (0.1%)
Nervous system disorders
Balance disorder	0/945 (0%)		1/943 (0.1%)
Brown-Sequard syndrome	1/945 (0.1%)		0/943 (0%)
Cauda equina syndrome	1/945 (0.1%)		0/943 (0%)
Cerebral artery embolism	1/945 (0.1%)		0/943 (0%)
Cerebral haematoma	0/945 (0%)		1/943 (0.1%)
Cerebral haemorrhage	5/945 (0.5%)		4/943 (0.4%)
Cerebral infarction	0/945 (0%)		2/943 (0.2%)
Cerebral ischaemia	4/945 (0.4%)		5/943 (0.5%)
Cerebrovascular accident	5/945 (0.5%)		15/943 (1.6%)
Cerebrovascular disorder	2/945 (0.2%)		2/943 (0.2%)
Cervical cord compression	1/945 (0.1%)		1/943 (0.1%)
Cognitive disorder	1/945 (0.1%)		1/943 (0.1%)
Convulsion	2/945 (0.2%)		2/943 (0.2%)
Depressed level of consciousness	2/945 (0.2%)		0/943 (0%)
Diabetic hyperglycaemic coma	0/945 (0%)		1/943 (0.1%)
Diplegia	1/945 (0.1%)		0/943 (0%)
Dizziness	3/945 (0.3%)		3/943 (0.3%)
Dysaesthesia	1/945 (0.1%)		0/943 (0%)
Dysarthria	0/945 (0%)		1/943 (0.1%)
Embolic stroke	0/945 (0%)		1/943 (0.1%)
Encephalitis	0/945 (0%)		1/943 (0.1%)
Epidural lipomatosis	1/945 (0.1%)		0/943 (0%)
Facial palsy	1/945 (0.1%)		3/943 (0.3%)
Facial paresis	1/945 (0.1%)		0/943 (0%)
Grand mal convulsion	1/945 (0.1%)		0/943 (0%)
Haemorrhage intracranial	1/945 (0.1%)		2/943 (0.2%)
Haemorrhagic stroke	2/945 (0.2%)		1/943 (0.1%)
Headache	4/945 (0.4%)		1/943 (0.1%)
Hemiparesis	1/945 (0.1%)		2/943 (0.2%)
Hemiplegia	0/945 (0%)		1/943 (0.1%)
Hepatic encephalopathy	1/945 (0.1%)		1/943 (0.1%)
Hypertonia	1/945 (0.1%)		0/943 (0%)
Hypoaesthesia	2/945 (0.2%)		1/943 (0.1%)
Hypotonia	0/945 (0%)		1/943 (0.1%)
Intracranial pressure increased	0/945 (0%)		1/943 (0.1%)
Ischaemic stroke	1/945 (0.1%)		1/943 (0.1%)
Lethargy	1/945 (0.1%)		1/943 (0.1%)
Loss of consciousness	2/945 (0.2%)		3/943 (0.3%)
Mental impairment	0/945 (0%)		1/943 (0.1%)
Monoparesis	2/945 (0.2%)		2/943 (0.2%)
Myoclonus	1/945 (0.1%)		0/943 (0%)
Nerve root compression	0/945 (0%)		1/943 (0.1%)
Neuralgia	1/945 (0.1%)		2/943 (0.2%)
Neurological decompensation	0/945 (0%)		1/943 (0.1%)
Paraesthesia	4/945 (0.4%)		1/943 (0.1%)
Paralysis	1/945 (0.1%)		0/943 (0%)
Paraparesis	2/945 (0.2%)		1/943 (0.1%)
Paraplegia	5/945 (0.5%)		4/943 (0.4%)
Peripheral motor neuropathy	1/945 (0.1%)		1/943 (0.1%)
Peripheral sensorimotor neuropathy	1/945 (0.1%)		0/943 (0%)
Polyneuropathy	1/945 (0.1%)		0/943 (0%)
Presyncope	0/945 (0%)		1/943 (0.1%)
Radicular syndrome	0/945 (0%)		1/943 (0.1%)
Sciatica	1/945 (0.1%)		0/943 (0%)
Somnolence	1/945 (0.1%)		1/943 (0.1%)
Spinal cord compression	33/945 (3.5%)		24/943 (2.5%)
Spinal cord ischaemia	0/945 (0%)		1/943 (0.1%)
Subarachnoid haemorrhage	1/945 (0.1%)		1/943 (0.1%)
Syncope	6/945 (0.6%)		10/943 (1.1%)
Transient ischaemic attack	4/945 (0.4%)		3/943 (0.3%)
Trigeminal neuralgia	0/945 (0%)		1/943 (0.1%)
Psychiatric disorders
Abnormal behaviour	1/945 (0.1%)		0/943 (0%)
Agitation	1/945 (0.1%)		0/943 (0%)
Anxiety	1/945 (0.1%)		2/943 (0.2%)
Confusional state	10/945 (1.1%)		12/943 (1.3%)
Delirium	0/945 (0%)		1/943 (0.1%)
Depression	2/945 (0.2%)		2/943 (0.2%)
Disorientation	2/945 (0.2%)		1/943 (0.1%)
Emotional distress	1/945 (0.1%)		0/943 (0%)
Hypochondriasis	0/945 (0%)		1/943 (0.1%)
Mental status changes	2/945 (0.2%)		1/943 (0.1%)
Sopor	0/945 (0%)		1/943 (0.1%)
Renal and urinary disorders
Anuria	0/945 (0%)		1/943 (0.1%)
Azotaemia	4/945 (0.4%)		1/943 (0.1%)
Bladder obstruction	0/945 (0%)		1/943 (0.1%)
Bladder perforation	0/945 (0%)		1/943 (0.1%)
Calculus bladder	1/945 (0.1%)		1/943 (0.1%)
Calculus ureteric	1/945 (0.1%)		0/943 (0%)
Calculus urinary	0/945 (0%)		1/943 (0.1%)
Dysuria	2/945 (0.2%)		2/943 (0.2%)
Faecaluria	0/945 (0%)		1/943 (0.1%)
Haematuria	37/945 (3.9%)		23/943 (2.4%)
Haemorrhage urinary tract	1/945 (0.1%)		3/943 (0.3%)
Hydronephrosis	12/945 (1.3%)		19/943 (2%)
Neurogenic bladder	1/945 (0.1%)		0/943 (0%)
Obstructive uropathy	4/945 (0.4%)		2/943 (0.2%)
Oliguria	0/945 (0%)		1/943 (0.1%)
Pollakiuria	0/945 (0%)		2/943 (0.2%)
Polyuria	1/945 (0.1%)		0/943 (0%)
Renal colic	1/945 (0.1%)		0/943 (0%)
Renal cyst	0/945 (0%)		1/943 (0.1%)
Renal disorder	1/945 (0.1%)		1/943 (0.1%)
Renal failure	28/945 (3%)		26/943 (2.8%)
Renal failure acute	16/945 (1.7%)		18/943 (1.9%)
Renal failure chronic	2/945 (0.2%)		2/943 (0.2%)
Renal impairment	5/945 (0.5%)		2/943 (0.2%)
Renal pain	1/945 (0.1%)		0/943 (0%)
Ureteric obstruction	2/945 (0.2%)		2/943 (0.2%)
Urethral haemorrhage	0/945 (0%)		1/943 (0.1%)
Urethral obstruction	0/945 (0%)		1/943 (0.1%)
Urethral stenosis	1/945 (0.1%)		1/943 (0.1%)
Urinary bladder haemorrhage	2/945 (0.2%)		1/943 (0.1%)
Urinary incontinence	1/945 (0.1%)		2/943 (0.2%)
Urinary retention	35/945 (3.7%)		32/943 (3.4%)
Urinary tract disorder	0/945 (0%)		3/943 (0.3%)
Urinary tract obstruction	6/945 (0.6%)		5/943 (0.5%)
Urine odour abnormal	1/945 (0.1%)		0/943 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/945 (0%)		1/943 (0.1%)
Genital pain	1/945 (0.1%)		0/943 (0%)
Oedema genital	4/945 (0.4%)		0/943 (0%)
Pelvic pain	1/945 (0.1%)		1/943 (0.1%)
Penile pain	1/945 (0.1%)		0/943 (0%)
Perineal pain	1/945 (0.1%)		0/943 (0%)
Prostatic cyst	1/945 (0.1%)		0/943 (0%)
Prostatic disorder	0/945 (0%)		1/943 (0.1%)
Prostatic haemorrhage	1/945 (0.1%)		0/943 (0%)
Prostatic obstruction	1/945 (0.1%)		1/943 (0.1%)
Prostatitis	1/945 (0.1%)		2/943 (0.2%)
Prostatomegaly	2/945 (0.2%)		0/943 (0%)
Scrotal oedema	0/945 (0%)		1/943 (0.1%)
Scrotal pain	0/945 (0%)		1/943 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	3/945 (0.3%)		2/943 (0.2%)
Acute respiratory distress syndrome	1/945 (0.1%)		2/943 (0.2%)
Acute respiratory failure	4/945 (0.4%)		1/943 (0.1%)
Asthma	0/945 (0%)		1/943 (0.1%)
Bronchopneumopathy	1/945 (0.1%)		0/943 (0%)
Chronic obstructive pulmonary disease	1/945 (0.1%)		2/943 (0.2%)
Chronic respiratory failure	1/945 (0.1%)		1/943 (0.1%)
Cough	1/945 (0.1%)		2/943 (0.2%)
Dyspnoea	28/945 (3%)		36/943 (3.8%)
Dyspnoea exertional	1/945 (0.1%)		0/943 (0%)
Emphysema	2/945 (0.2%)		1/943 (0.1%)
Epistaxis	2/945 (0.2%)		4/943 (0.4%)
Haemoptysis	0/945 (0%)		1/943 (0.1%)
Haemothorax	0/945 (0%)		1/943 (0.1%)
Hydrothorax	2/945 (0.2%)		0/943 (0%)
Hypoxia	1/945 (0.1%)		2/943 (0.2%)
Interstitial lung disease	1/945 (0.1%)		0/943 (0%)
Lung disorder	2/945 (0.2%)		1/943 (0.1%)
Lung infiltration	0/945 (0%)		1/943 (0.1%)
Orthopnoea	1/945 (0.1%)		0/943 (0%)
Pleural effusion	9/945 (1%)		12/943 (1.3%)
Pleural haemorrhage	1/945 (0.1%)		0/943 (0%)
Pleurisy	1/945 (0.1%)		1/943 (0.1%)
Pneumonitis	1/945 (0.1%)		2/943 (0.2%)
Pneumothorax	1/945 (0.1%)		0/943 (0%)
Pulmonary embolism	16/945 (1.7%)		20/943 (2.1%)
Pulmonary hypertension	0/945 (0%)		1/943 (0.1%)
Pulmonary oedema	5/945 (0.5%)		3/943 (0.3%)
Pulmonary thrombosis	1/945 (0.1%)		1/943 (0.1%)
Respiratory acidosis	0/945 (0%)		1/943 (0.1%)
Respiratory disorder	2/945 (0.2%)		0/943 (0%)
Respiratory distress	0/945 (0%)		1/943 (0.1%)
Respiratory failure	14/945 (1.5%)		24/943 (2.5%)
Respiratory tract congestion	1/945 (0.1%)		0/943 (0%)
Tachypnoea	1/945 (0.1%)		0/943 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/945 (0%)		1/943 (0.1%)
Decubitus ulcer	2/945 (0.2%)		0/943 (0%)
Erythema	1/945 (0.1%)		0/943 (0%)
Hypoaesthesia facial	1/945 (0.1%)		0/943 (0%)
Periorbital oedema	0/945 (0%)		1/943 (0.1%)
Purpura	0/945 (0%)		1/943 (0.1%)
Skin toxicity	0/945 (0%)		1/943 (0.1%)
Skin ulcer	0/945 (0%)		1/943 (0.1%)
Stasis dermatitis	0/945 (0%)		1/943 (0.1%)
Social circumstances
Walking disability	1/945 (0.1%)		0/943 (0%)
Surgical and medical procedures
Catheter placement	0/945 (0%)		1/943 (0.1%)
Ostectomy	0/945 (0%)		1/943 (0.1%)
Spinal operation	1/945 (0.1%)		0/943 (0%)
Transurethral prostatectomy	3/945 (0.3%)		2/943 (0.2%)
Ureteral stent insertion	0/945 (0%)		1/943 (0.1%)
Vascular disorders
Accelerated hypertension	0/945 (0%)		1/943 (0.1%)
Aortic dissection	1/945 (0.1%)		0/943 (0%)
Circulatory collapse	1/945 (0.1%)		1/943 (0.1%)
Deep vein thrombosis	8/945 (0.8%)		8/943 (0.8%)
Embolism	0/945 (0%)		1/943 (0.1%)
Extremity necrosis	0/945 (0%)		1/943 (0.1%)
Extrinsic vascular compression	0/945 (0%)		1/943 (0.1%)
Haematoma	1/945 (0.1%)		0/943 (0%)
Haemorrhage	1/945 (0.1%)		0/943 (0%)
Hypertension	3/945 (0.3%)		5/943 (0.5%)
Hypertensive crisis	1/945 (0.1%)		1/943 (0.1%)
Hypotension	8/945 (0.8%)		8/943 (0.8%)
Hypovolaemic shock	0/945 (0%)		1/943 (0.1%)
Orthostatic hypotension	0/945 (0%)		1/943 (0.1%)
Pelvic venous thrombosis	2/945 (0.2%)		0/943 (0%)
Phlebitis	2/945 (0.2%)		2/943 (0.2%)
Shock	1/945 (0.1%)		1/943 (0.1%)
Thrombophlebitis	1/945 (0.1%)		0/943 (0%)
Thrombosis	3/945 (0.3%)		0/943 (0%)
Venous thrombosis	2/945 (0.2%)		2/943 (0.2%)
Venous thrombosis limb	2/945 (0.2%)		1/943 (0.1%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	853/945 (90.3%)		844/943 (89.5%)
Blood and lymphatic system disorders
Anaemia	313/945 (33.1%)		300/943 (31.8%)
Gastrointestinal disorders
Abdominal pain	57/945 (6%)		67/943 (7.1%)
Constipation	247/945 (26.1%)		233/943 (24.7%)
Diarrhoea	143/945 (15.1%)		174/943 (18.5%)
Nausea	242/945 (25.6%)		271/943 (28.7%)
Vomiting	138/945 (14.6%)		155/943 (16.4%)
General disorders
Asthenia	226/945 (23.9%)		219/943 (23.2%)
Chest pain	62/945 (6.6%)		67/943 (7.1%)
Fatigue	217/945 (23%)		247/943 (26.2%)
Oedema peripheral	171/945 (18.1%)		187/943 (19.8%)
Pain	85/945 (9%)		78/943 (8.3%)
Pyrexia	121/945 (12.8%)		87/943 (9.2%)
Infections and infestations
Urinary tract infection	105/945 (11.1%)		88/943 (9.3%)
Investigations
Blood creatinine increased	50/945 (5.3%)		41/943 (4.3%)
Weight decreased	131/945 (13.9%)		150/943 (15.9%)
Metabolism and nutrition disorders
Decreased appetite	263/945 (27.8%)		264/943 (28%)
Hypocalcaemia	45/945 (4.8%)		105/943 (11.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	197/945 (20.8%)		188/943 (19.9%)
Back pain	271/945 (28.7%)		290/943 (30.8%)
Bone pain	230/945 (24.3%)		221/943 (23.4%)
Muscle spasms	27/945 (2.9%)		51/943 (5.4%)
Muscular weakness	58/945 (6.1%)		52/943 (5.5%)
Musculoskeletal chest pain	54/945 (5.7%)		47/943 (5%)
Musculoskeletal pain	133/945 (14.1%)		111/943 (11.8%)
Myalgia	57/945 (6%)		36/943 (3.8%)
Pain in extremity	184/945 (19.5%)		192/943 (20.4%)
Nervous system disorders
Dizziness	63/945 (6.7%)		54/943 (5.7%)
Headache	71/945 (7.5%)		61/943 (6.5%)
Paraesthesia	69/945 (7.3%)		53/943 (5.6%)
Psychiatric disorders
Anxiety	52/945 (5.5%)		45/943 (4.8%)
Depression	39/945 (4.1%)		50/943 (5.3%)
Insomnia	94/945 (9.9%)		89/943 (9.4%)
Renal and urinary disorders
Dysuria	52/945 (5.5%)		62/943 (6.6%)
Haematuria	76/945 (8%)		76/943 (8.1%)
Urinary retention	47/945 (5%)		62/943 (6.6%)
Respiratory, thoracic and mediastinal disorders
Cough	82/945 (8.7%)		91/943 (9.7%)
Dyspnoea	95/945 (10.1%)		117/943 (12.4%)
Skin and subcutaneous tissue disorders
Alopecia	62/945 (6.6%)		58/943 (6.2%)

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 aftercompletion. 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.