Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma.

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00330759
• Collaborator: (none)
• Enrollment: 1,779
• Arms: 2
• Actual Duration (Months): 64

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 (lytic bone lesions from multiple myeloma) in subjects with advanced cancer and multiple myeloma (excluding breast and prostate cancer)

Condition or Disease	Intervention/Treatment	Phase
Bone Metastases	Biological: Denosumab; Drug: Zoledronic Acid	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1779 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• 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 Subjects With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma.
• Actual Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: zoledronic acid denosumab placebo with active zoledronic acid	Drug: Zoledronic Acid; 4 milligrams intravenous Zoledronic Acid over minimum 15 minutes every 4 weeks; Other Names: Zometa
Experimental: denosumab active denosumab with zoledronic acid placebo	Biological: Denosumab; 120 milligrams by subcutaneous injection every 4 weeks

Outcome Measures

Primary Outcome Measures

1. Time to the First On-Study Skeletal-Related Event (Non-Inferiority) [up to 33 months]

   Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.

Secondary Outcome Measures

1. Time to First On-Study Skeletal-Related Event (Superiority) [up to 33 months]

   Time to first on-study skeletal-related event (SRE) using a test for superiority. Median was estimated using the Kaplan-Meier method.

2. Time to the First-and-Subsequent On-Study Skeletal-Related Event [up to 33 months]

   Time to the first-and-subsequent on-study skeletal-related event (SRE) using multiple event analysis. To be considered a subsequent SRE, 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: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults with histologically/cystologically confirmed advanced cancers including solid tumors, multiple myeloma, and lymphoma

• Radiographic evidence of at least one bone metastasis (or lytic bone lesion from multiple myeloma); ECOG performance status 0, 1, or 2

• Adequate organ function

Exclusion Criteria:

• Diagnosis of breast or prostate cancer

• Current or prior intravenous bisphosphonate administration

• Current or prior oral bisphosphonates for bone metastases, life expectancy of less than 6 months

• Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw

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
• Notice regarding posted summaries of trial results

Publications

• Henry D, Vadhan-Raj S, Hirsh V, von Moos R, Hungria V, Costa L, Woll PJ, Scagliotti G, Smith G, Feng A, Jun S, Dansey R, Yeh H. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer. 2014 Mar;22(3):679-87. doi: 10.1007/s00520-013-2022-1. Epub 2013 Oct 26.
• Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/JCO.2010.31.3304. Epub 2011 Feb 22.
• Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, Solal-Celigny P, Rodriguez G, Krzakowski M, Mehta ND, Lipton L, García-Sáenz JA, Pereira JR, Prabhash K, Ciuleanu TE, Kanarev V, Wang H, Balakumaran A, Jacobs I. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012 Dec;7(12):1823-1829. doi: 10.1097/JTO.0b013e31826aec2b.
• Vadhan-Raj S, von Moos R, Fallowfield LJ, Patrick DL, Goldwasser F, Cleeland CS, Henry DH, Novello S, Hungria V, Qian Y, Feng A, Yeh H, Chung K. Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol. 2012 Dec;23(12):3045-3051. doi: 10.1093/annonc/mds175. Epub 2012 Jul 31.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00330759
• Other Study ID Numbers: 20050244
• First Posted: May 29, 2006
• Last Update Posted: Aug 31, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Amgen: Bone metastases; lytic bone lesions; advanced cancer; multiple myeloma; lymphoma; solid tumors; skeletal related events; skeletal fractures; spinal cord compressions, radiation to bone; surgery to bone, bisphosphonates; denosumab
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasm Metastasis; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Zoledronic Acid; Denosumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 21 June 2006 through 16 May 2008
Pre-assignment Detail	A total of 1779 participants were enrolled in the study. Three participants from one site were excluded from all analyses because Institutional Review Board (IRB) 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 by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Period Title: Overall Study
STARTED	890	886
Received Investigational Product	878	878
COMPLETED	178	180
NOT COMPLETED	712	706

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 by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks	Total of all reporting groups
Overall Participants	890	886	1776
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.6 (10.7)	59.3 (11.4)	59.9 (11.1)
Sex: Female, Male (Count of Participants)
Female	338 38%	298 33.6%	636 35.8%
Male	552 62%	588 66.4%	1140 64.2%
Race/Ethnicity, Customized (Number) [Number]
White or Caucasian	770 86.5%	770 86.9%	1540 86.7%
Black or African American	29 3.3%	20 2.3%	49 2.8%
Hispanic or Latino	36 4%	49 5.5%	85 4.8%
Asian	44 4.9%	36 4.1%	80 4.5%
Japanese	1 0.1%	3 0.3%	4 0.2%
American Indian or Alaska Native	2 0.2%	0 0%	2 0.1%
Other	8 0.9%	8 0.9%	16 0.9%
Tumor Type Stratification Factor (Number) [Number]
Multiple myeloma	93 10.4%	86 9.7%	179 10.1%
Other	452 50.8%	457 51.6%	909 51.2%
Non-small cell lung cancer	345 38.8%	343 38.7%	688 38.7%
Previous Skeletal-Related Event Stratification Factor (Number) [Number]
Yes	446 50.1%	440 49.7%	886 49.9%
No	444 49.9%	446 50.3%	890 50.1%
Systematic Anti-Cancer Therapy Stratification Factor (Number) [Number]
Yes	747 83.9%	746 84.2%	1493 84.1%
No	143 16.1%	140 15.8%	283 15.9%

Outcome Measures

1. Primary Outcome

Title	Time to the First On-Study Skeletal-Related Event (Non-Inferiority)
Description	Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.
Time Frame	up to 33 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 by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	890	886
Median (95% Confidence Interval) [Days]	496.0	625.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A synthesis approach was used for a non-inferiority test of the hypothesis that denosumab preserves at least 50% of the effect of zoledronic acid vs. placebo.
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Regression, Cox
	Comments	Stratified by tumor type, previous skeletal-related event, and systematic anti-cancer therapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	() 95%; 0.71 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First On-Study Skeletal-Related Event (Superiority)
Description	Time to first on-study skeletal-related event (SRE) using a test for superiority. Median was estimated using the Kaplan-Meier method.
Time Frame	up to 33 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 by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	890	886
Median (95% Confidence Interval) [Days]	496.0	625.0

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	0.060
	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	0.84
	Confidence Interval	() 95%; 0.71 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by tumor type, previous skeletal-related event, and systematic anti-cancer therapy

3. Secondary Outcome

Title	Time to the First-and-Subsequent On-Study Skeletal-Related Event
Description	Time to the first-and-subsequent on-study skeletal-related event (SRE) using multiple event analysis. To be considered a subsequent SRE, 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 33 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 by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	890	886
Number [Events]	436	392

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	0.145
	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	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	() 95%; 0.77 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by tumor type, previous skeletal-related event, and systematic anti-cancer therapy

Adverse Events

Time Frame	up to 2 years 9 months
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
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	581/878 (66.2%)		552/878 (62.9%)
Blood and lymphatic system disorders
Agranulocytosis	0/878 (0%)		1/878 (0.1%)
Anaemia	49/878 (5.6%)		25/878 (2.8%)
Anaemia of chronic disease	0/878 (0%)		1/878 (0.1%)
Aplastic anaemia	0/878 (0%)		1/878 (0.1%)
Bone marrow failure	1/878 (0.1%)		1/878 (0.1%)
Coagulopathy	2/878 (0.2%)		2/878 (0.2%)
Disseminated intravascular coagulation	2/878 (0.2%)		0/878 (0%)
Erythropenia	1/878 (0.1%)		0/878 (0%)
Febrile bone marrow aplasia	0/878 (0%)		1/878 (0.1%)
Febrile neutropenia	31/878 (3.5%)		21/878 (2.4%)
Granulocytopenia	0/878 (0%)		1/878 (0.1%)
Hyperviscosity syndrome	0/878 (0%)		1/878 (0.1%)
Leukocytosis	3/878 (0.3%)		0/878 (0%)
Leukopenia	6/878 (0.7%)		3/878 (0.3%)
Neutropenia	11/878 (1.3%)		14/878 (1.6%)
Pancytopenia	11/878 (1.3%)		7/878 (0.8%)
Retroperitoneal lymphadenopathy	1/878 (0.1%)		0/878 (0%)
Thrombocytopenia	23/878 (2.6%)		17/878 (1.9%)
Cardiac disorders
Acute coronary syndrome	0/878 (0%)		1/878 (0.1%)
Acute myocardial infarction	3/878 (0.3%)		3/878 (0.3%)
Angina pectoris	0/878 (0%)		3/878 (0.3%)
Angina unstable	0/878 (0%)		1/878 (0.1%)
Arrhythmia	0/878 (0%)		4/878 (0.5%)
Arrhythmia supraventricular	1/878 (0.1%)		0/878 (0%)
Atrial fibrillation	7/878 (0.8%)		7/878 (0.8%)
Atrial flutter	1/878 (0.1%)		1/878 (0.1%)
Bradycardia	2/878 (0.2%)		0/878 (0%)
Cardiac arrest	3/878 (0.3%)		12/878 (1.4%)
Cardiac disorder	1/878 (0.1%)		0/878 (0%)
Cardiac failure	5/878 (0.6%)		10/878 (1.1%)
Cardiac failure acute	1/878 (0.1%)		2/878 (0.2%)
Cardiac failure congestive	3/878 (0.3%)		4/878 (0.5%)
Cardiac tamponade	1/878 (0.1%)		0/878 (0%)
Cardio-respiratory arrest	3/878 (0.3%)		4/878 (0.5%)
Cardio-respiratory distress	0/878 (0%)		1/878 (0.1%)
Cardiogenic shock	1/878 (0.1%)		1/878 (0.1%)
Cardiomyopathy	0/878 (0%)		1/878 (0.1%)
Cardiopulmonary failure	9/878 (1%)		8/878 (0.9%)
Congestive cardiomyopathy	0/878 (0%)		1/878 (0.1%)
Extrasystoles	1/878 (0.1%)		0/878 (0%)
Intracardiac thrombus	0/878 (0%)		1/878 (0.1%)
Left ventricular failure	0/878 (0%)		1/878 (0.1%)
Myocardial infarction	4/878 (0.5%)		3/878 (0.3%)
Myocardial ischaemia	2/878 (0.2%)		1/878 (0.1%)
Palpitations	1/878 (0.1%)		0/878 (0%)
Paroxysmal arrhythmia	0/878 (0%)		1/878 (0.1%)
Pericardial effusion	5/878 (0.6%)		6/878 (0.7%)
Pericarditis	1/878 (0.1%)		1/878 (0.1%)
Sinus tachycardia	0/878 (0%)		1/878 (0.1%)
Supraventricular tachycardia	3/878 (0.3%)		0/878 (0%)
Tachycardia	2/878 (0.2%)		3/878 (0.3%)
Ventricular fibrillation	1/878 (0.1%)		0/878 (0%)
Ventricular tachycardia	1/878 (0.1%)		1/878 (0.1%)
Ear and labyrinth disorders
Vertigo	2/878 (0.2%)		1/878 (0.1%)
Endocrine disorders
Goitre	1/878 (0.1%)		0/878 (0%)
Hypopituitarism	0/878 (0%)		1/878 (0.1%)
Hypothyroidism	0/878 (0%)		1/878 (0.1%)
Eye disorders
Diplopia	1/878 (0.1%)		1/878 (0.1%)
Retinal vein occlusion	0/878 (0%)		1/878 (0.1%)
Vision blurred	1/878 (0.1%)		0/878 (0%)
Visual acuity reduced	0/878 (0%)		1/878 (0.1%)
Visual impairment	1/878 (0.1%)		1/878 (0.1%)
Gastrointestinal disorders
Abdominal pain	17/878 (1.9%)		18/878 (2.1%)
Abdominal pain lower	0/878 (0%)		1/878 (0.1%)
Abdominal pain upper	2/878 (0.2%)		5/878 (0.6%)
Aphagia	0/878 (0%)		1/878 (0.1%)
Ascites	6/878 (0.7%)		4/878 (0.5%)
Caecitis	1/878 (0.1%)		0/878 (0%)
Colitis	0/878 (0%)		1/878 (0.1%)
Colonic obstruction	0/878 (0%)		1/878 (0.1%)
Colonic polyp	1/878 (0.1%)		0/878 (0%)
Constipation	9/878 (1%)		4/878 (0.5%)
Diarrhoea	13/878 (1.5%)		14/878 (1.6%)
Diarrhoea haemorrhagic	1/878 (0.1%)		0/878 (0%)
Diverticulum	1/878 (0.1%)		0/878 (0%)
Duodenal ulcer	2/878 (0.2%)		0/878 (0%)
Duodenal ulcer perforation	0/878 (0%)		1/878 (0.1%)
Dysphagia	5/878 (0.6%)		7/878 (0.8%)
Enteritis	1/878 (0.1%)		0/878 (0%)
Enterocolitis haemorrhagic	1/878 (0.1%)		0/878 (0%)
Enterovesical fistula	0/878 (0%)		1/878 (0.1%)
Faecal incontinence	2/878 (0.2%)		0/878 (0%)
Faecaloma	2/878 (0.2%)		0/878 (0%)
Gastric haemorrhage	1/878 (0.1%)		0/878 (0%)
Gastritis	0/878 (0%)		2/878 (0.2%)
Gastrointestinal disorder	0/878 (0%)		1/878 (0.1%)
Gastrointestinal haemorrhage	8/878 (0.9%)		3/878 (0.3%)
Gastrointestinal hypomotility	2/878 (0.2%)		0/878 (0%)
Haematemesis	2/878 (0.2%)		4/878 (0.5%)
Haematochezia	1/878 (0.1%)		0/878 (0%)
Haemorrhoidal haemorrhage	0/878 (0%)		1/878 (0.1%)
Haemorrhoids	1/878 (0.1%)		0/878 (0%)
Ileus	4/878 (0.5%)		4/878 (0.5%)
Inguinal hernia	1/878 (0.1%)		0/878 (0%)
Intestinal ischaemia	0/878 (0%)		1/878 (0.1%)
Intestinal obstruction	4/878 (0.5%)		8/878 (0.9%)
Intestinal perforation	2/878 (0.2%)		2/878 (0.2%)
Intra-abdominal haemorrhage	1/878 (0.1%)		0/878 (0%)
Large intestine perforation	0/878 (0%)		2/878 (0.2%)
Mechanical ileus	0/878 (0%)		1/878 (0.1%)
Melaena	1/878 (0.1%)		1/878 (0.1%)
Nausea	16/878 (1.8%)		14/878 (1.6%)
Neutropenic colitis	1/878 (0.1%)		0/878 (0%)
Obstruction gastric	0/878 (0%)		2/878 (0.2%)
Odynophagia	1/878 (0.1%)		0/878 (0%)
Oesophageal stenosis	1/878 (0.1%)		1/878 (0.1%)
Oesophagitis	2/878 (0.2%)		0/878 (0%)
Pancreatitis acute	1/878 (0.1%)		0/878 (0%)
Peritoneal haemorrhage	0/878 (0%)		1/878 (0.1%)
Peritonitis	2/878 (0.2%)		1/878 (0.1%)
Pneumoperitoneum	0/878 (0%)		1/878 (0.1%)
Rectal haemorrhage	0/878 (0%)		2/878 (0.2%)
Retching	0/878 (0%)		1/878 (0.1%)
Sigmoiditis	0/878 (0%)		1/878 (0.1%)
Small intestinal obstruction	2/878 (0.2%)		2/878 (0.2%)
Stomatitis	1/878 (0.1%)		1/878 (0.1%)
Subileus	0/878 (0%)		2/878 (0.2%)
Upper gastrointestinal haemorrhage	2/878 (0.2%)		1/878 (0.1%)
Vomiting	24/878 (2.7%)		21/878 (2.4%)
General disorders
Adverse event	1/878 (0.1%)		0/878 (0%)
Asthenia	16/878 (1.8%)		21/878 (2.4%)
Catheter related complication	1/878 (0.1%)		0/878 (0%)
Chest discomfort	2/878 (0.2%)		1/878 (0.1%)
Chest pain	10/878 (1.1%)		14/878 (1.6%)
Chills	1/878 (0.1%)		0/878 (0%)
Death	8/878 (0.9%)		6/878 (0.7%)
Disease progression	13/878 (1.5%)		8/878 (0.9%)
Euthanasia	0/878 (0%)		1/878 (0.1%)
Fatigue	6/878 (0.7%)		11/878 (1.3%)
Feeling abnormal	0/878 (0%)		1/878 (0.1%)
Gait disturbance	0/878 (0%)		1/878 (0.1%)
General physical health deterioration	38/878 (4.3%)		26/878 (3%)
Generalised oedema	0/878 (0%)		1/878 (0.1%)
Hernia	1/878 (0.1%)		0/878 (0%)
Hyperpyrexia	0/878 (0%)		1/878 (0.1%)
Inflammation of wound	0/878 (0%)		1/878 (0.1%)
Local swelling	0/878 (0%)		2/878 (0.2%)
Malaise	1/878 (0.1%)		1/878 (0.1%)
Mucosal inflammation	2/878 (0.2%)		2/878 (0.2%)
Multi-organ failure	8/878 (0.9%)		10/878 (1.1%)
Oedema	2/878 (0.2%)		0/878 (0%)
Oedema peripheral	7/878 (0.8%)		5/878 (0.6%)
Organ failure	2/878 (0.2%)		1/878 (0.1%)
Pain	6/878 (0.7%)		12/878 (1.4%)
Performance status decreased	8/878 (0.9%)		3/878 (0.3%)
Pyrexia	21/878 (2.4%)		26/878 (3%)
Sudden death	0/878 (0%)		1/878 (0.1%)
Suprapubic pain	1/878 (0.1%)		0/878 (0%)
Systemic inflammatory response syndrome	0/878 (0%)		1/878 (0.1%)
Hepatobiliary disorders
Bile duct obstruction	2/878 (0.2%)		0/878 (0%)
Bile duct stone	1/878 (0.1%)		0/878 (0%)
Cholecystitis	1/878 (0.1%)		1/878 (0.1%)
Cholestasis	1/878 (0.1%)		0/878 (0%)
Hepatic failure	4/878 (0.5%)		2/878 (0.2%)
Hepatic function abnormal	1/878 (0.1%)		1/878 (0.1%)
Hepatorenal failure	1/878 (0.1%)		2/878 (0.2%)
Hepatorenal syndrome	1/878 (0.1%)		0/878 (0%)
Hyperbilirubinaemia	1/878 (0.1%)		2/878 (0.2%)
Jaundice	1/878 (0.1%)		2/878 (0.2%)
Jaundice cholestatic	1/878 (0.1%)		0/878 (0%)
Liver disorder	0/878 (0%)		1/878 (0.1%)
Immune system disorders
Anaphylactic reaction	1/878 (0.1%)		0/878 (0%)
Drug hypersensitivity	0/878 (0%)		3/878 (0.3%)
Hypersensitivity	0/878 (0%)		1/878 (0.1%)
Infections and infestations
Abdominal infection	0/878 (0%)		1/878 (0.1%)
Abdominal wall infection	1/878 (0.1%)		0/878 (0%)
Abscess	0/878 (0%)		1/878 (0.1%)
Abscess limb	0/878 (0%)		1/878 (0.1%)
Arthritis bacterial	1/878 (0.1%)		0/878 (0%)
Aspergillosis	1/878 (0.1%)		0/878 (0%)
Bacteraemia	1/878 (0.1%)		1/878 (0.1%)
Bacterial infection	1/878 (0.1%)		0/878 (0%)
Bacterial sepsis	0/878 (0%)		1/878 (0.1%)
Brain abscess	0/878 (0%)		1/878 (0.1%)
Bronchitis	3/878 (0.3%)		3/878 (0.3%)
Bronchopneumonia	4/878 (0.5%)		2/878 (0.2%)
Catheter related infection	1/878 (0.1%)		0/878 (0%)
Cavernous sinus thrombosis	1/878 (0.1%)		0/878 (0%)
Cellulitis	5/878 (0.6%)		5/878 (0.6%)
Clostridial infection	0/878 (0%)		1/878 (0.1%)
Cystitis	1/878 (0.1%)		0/878 (0%)
Diverticulitis	2/878 (0.2%)		1/878 (0.1%)
Empyema	0/878 (0%)		1/878 (0.1%)
Febrile infection	1/878 (0.1%)		0/878 (0%)
Fungal skin infection	1/878 (0.1%)		0/878 (0%)
Gangrene	1/878 (0.1%)		0/878 (0%)
Gastritis fungal	0/878 (0%)		1/878 (0.1%)
Gastroenteritis	5/878 (0.6%)		5/878 (0.6%)
Gastrointestinal infection	0/878 (0%)		1/878 (0.1%)
Herpes zoster	1/878 (0.1%)		1/878 (0.1%)
Infected skin ulcer	0/878 (0%)		1/878 (0.1%)
Infection	2/878 (0.2%)		2/878 (0.2%)
Influenza	1/878 (0.1%)		0/878 (0%)
Kidney infection	1/878 (0.1%)		0/878 (0%)
Lobar pneumonia	5/878 (0.6%)		5/878 (0.6%)
Localised infection	1/878 (0.1%)		2/878 (0.2%)
Lower respiratory tract infection	4/878 (0.5%)		0/878 (0%)
Lung abscess	2/878 (0.2%)		2/878 (0.2%)
Lung infection	1/878 (0.1%)		6/878 (0.7%)
Mastoiditis	0/878 (0%)		2/878 (0.2%)
Nasopharyngitis	1/878 (0.1%)		0/878 (0%)
Neutropenic infection	1/878 (0.1%)		0/878 (0%)
Neutropenic sepsis	0/878 (0%)		2/878 (0.2%)
Oesophageal candidiasis	0/878 (0%)		1/878 (0.1%)
Oral candidiasis	0/878 (0%)		1/878 (0.1%)
Orchitis	0/878 (0%)		1/878 (0.1%)
Osteomyelitis	1/878 (0.1%)		1/878 (0.1%)
Osteomyelitis acute	0/878 (0%)		1/878 (0.1%)
Parotitis	0/878 (0%)		1/878 (0.1%)
Perirectal abscess	0/878 (0%)		1/878 (0.1%)
Peritonitis bacterial	1/878 (0.1%)		0/878 (0%)
Pharyngitis	1/878 (0.1%)		1/878 (0.1%)
Pneumocystis jiroveci pneumonia	1/878 (0.1%)		1/878 (0.1%)
Pneumonia	44/878 (5%)		52/878 (5.9%)
Pneumonia haemophilus	1/878 (0.1%)		0/878 (0%)
Pneumonia klebsiella	2/878 (0.2%)		0/878 (0%)
Pneumonia staphylococcal	0/878 (0%)		1/878 (0.1%)
Pseudomembranous colitis	1/878 (0.1%)		0/878 (0%)
Pulmonary mycosis	1/878 (0.1%)		0/878 (0%)
Pulmonary sepsis	0/878 (0%)		1/878 (0.1%)
Purulent discharge	0/878 (0%)		1/878 (0.1%)
Pyelonephritis	1/878 (0.1%)		0/878 (0%)
Pyothorax	0/878 (0%)		1/878 (0.1%)
Rectal abscess	0/878 (0%)		1/878 (0.1%)
Respiratory tract infection	8/878 (0.9%)		4/878 (0.5%)
Salmonellosis	1/878 (0.1%)		0/878 (0%)
Sepsis	11/878 (1.3%)		16/878 (1.8%)
Septic shock	4/878 (0.5%)		6/878 (0.7%)
Sinusitis	1/878 (0.1%)		2/878 (0.2%)
Skin infection	0/878 (0%)		2/878 (0.2%)
Staphylococcal bacteraemia	1/878 (0.1%)		0/878 (0%)
Staphylococcal sepsis	0/878 (0%)		1/878 (0.1%)
Tooth abscess	0/878 (0%)		1/878 (0.1%)
Upper respiratory tract infection	1/878 (0.1%)		0/878 (0%)
Urinary tract infection	9/878 (1%)		9/878 (1%)
Urinary tract infection bacterial	1/878 (0.1%)		0/878 (0%)
Urosepsis	3/878 (0.3%)		2/878 (0.2%)
Viral infection	0/878 (0%)		1/878 (0.1%)
Viral pharyngitis	0/878 (0%)		1/878 (0.1%)
Injury, poisoning and procedural complications
Clavicle fracture	0/878 (0%)		1/878 (0.1%)
Collapse of lung	1/878 (0.1%)		0/878 (0%)
Contusion	1/878 (0.1%)		0/878 (0%)
Device dislocation	0/878 (0%)		1/878 (0.1%)
Drug toxicity	1/878 (0.1%)		1/878 (0.1%)
Femur fracture	7/878 (0.8%)		5/878 (0.6%)
Fractured ischium	1/878 (0.1%)		1/878 (0.1%)
Fractured sacrum	0/878 (0%)		1/878 (0.1%)
Head injury	3/878 (0.3%)		0/878 (0%)
Humerus fracture	0/878 (0%)		1/878 (0.1%)
Ilium fracture	1/878 (0.1%)		0/878 (0%)
Jaw fracture	0/878 (0%)		1/878 (0.1%)
Lumbar vertebral fracture	2/878 (0.2%)		1/878 (0.1%)
Lung injury	0/878 (0%)		1/878 (0.1%)
Post procedural discharge	0/878 (0%)		1/878 (0.1%)
Radiation oesophagitis	1/878 (0.1%)		0/878 (0%)
Radius fracture	1/878 (0.1%)		0/878 (0%)
Rib fracture	0/878 (0%)		1/878 (0.1%)
Skin laceration	0/878 (0%)		1/878 (0.1%)
Splenic rupture	0/878 (0%)		1/878 (0.1%)
Stent-graft endoleak	1/878 (0.1%)		0/878 (0%)
Subdural haematoma	1/878 (0.1%)		0/878 (0%)
Subdural haemorrhage	0/878 (0%)		1/878 (0.1%)
Therapeutic agent toxicity	1/878 (0.1%)		0/878 (0%)
Thoracic vertebral fracture	2/878 (0.2%)		4/878 (0.5%)
Tibia fracture	1/878 (0.1%)		1/878 (0.1%)
Traumatic brain injury	1/878 (0.1%)		0/878 (0%)
Investigations
Alanine aminotransferase increased	0/878 (0%)		1/878 (0.1%)
Aspartate aminotransferase increased	1/878 (0.1%)		1/878 (0.1%)
Blood bilirubin increased	1/878 (0.1%)		0/878 (0%)
Blood calcium decreased	1/878 (0.1%)		0/878 (0%)
Blood creatinine abnormal	1/878 (0.1%)		0/878 (0%)
Blood creatinine increased	3/878 (0.3%)		4/878 (0.5%)
Blood potassium	1/878 (0.1%)		0/878 (0%)
Blood potassium decreased	1/878 (0.1%)		0/878 (0%)
Creatinine renal clearance decreased	0/878 (0%)		1/878 (0.1%)
Haemoglobin decreased	3/878 (0.3%)		0/878 (0%)
Monoclonal immunoglobulin present	1/878 (0.1%)		0/878 (0%)
Platelet count decreased	1/878 (0.1%)		1/878 (0.1%)
Platelet count increased	0/878 (0%)		1/878 (0.1%)
Sputum abnormal	1/878 (0.1%)		0/878 (0%)
Weight decreased	1/878 (0.1%)		1/878 (0.1%)
White blood cell count decreased	1/878 (0.1%)		0/878 (0%)
Metabolism and nutrition disorders
Anorexia	7/878 (0.8%)		6/878 (0.7%)
Cachexia	10/878 (1.1%)		4/878 (0.5%)
Decreased appetite	0/878 (0%)		1/878 (0.1%)
Dehydration	34/878 (3.9%)		35/878 (4%)
Diabetes mellitus	0/878 (0%)		2/878 (0.2%)
Diabetic ketoacidosis	0/878 (0%)		1/878 (0.1%)
Electrolyte imbalance	1/878 (0.1%)		1/878 (0.1%)
Failure to thrive	2/878 (0.2%)		1/878 (0.1%)
Fluid overload	0/878 (0%)		1/878 (0.1%)
Hypercalcaemia	1/878 (0.1%)		3/878 (0.3%)
Hyperglycaemia	1/878 (0.1%)		3/878 (0.3%)
Hyperkalaemia	3/878 (0.3%)		0/878 (0%)
Hypocalcaemia	8/878 (0.9%)		12/878 (1.4%)
Hypoglycaemia	2/878 (0.2%)		0/878 (0%)
Hypokalaemia	5/878 (0.6%)		3/878 (0.3%)
Hypomagnesaemia	3/878 (0.3%)		0/878 (0%)
Hyponatraemia	6/878 (0.7%)		3/878 (0.3%)
Hypophosphataemia	2/878 (0.2%)		0/878 (0%)
Malnutrition	0/878 (0%)		2/878 (0.2%)
Marasmus	1/878 (0.1%)		1/878 (0.1%)
Vitamin D deficiency	0/878 (0%)		1/878 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/878 (1%)		3/878 (0.3%)
Back pain	19/878 (2.2%)		15/878 (1.7%)
Bone pain	15/878 (1.7%)		11/878 (1.3%)
Coccydynia	0/878 (0%)		1/878 (0.1%)
Joint crepitation	1/878 (0.1%)		0/878 (0%)
Mobility decreased	0/878 (0%)		1/878 (0.1%)
Muscle spasms	0/878 (0%)		1/878 (0.1%)
Muscular weakness	5/878 (0.6%)		2/878 (0.2%)
Musculoskeletal chest pain	4/878 (0.5%)		5/878 (0.6%)
Musculoskeletal pain	5/878 (0.6%)		5/878 (0.6%)
Myalgia	0/878 (0%)		1/878 (0.1%)
Neck pain	3/878 (0.3%)		2/878 (0.2%)
Osteitis	1/878 (0.1%)		0/878 (0%)
Osteolysis	1/878 (0.1%)		0/878 (0%)
Osteonecrosis	4/878 (0.5%)		7/878 (0.8%)
Pain in extremity	7/878 (0.8%)		5/878 (0.6%)
Pain in jaw	0/878 (0%)		1/878 (0.1%)
Pathological fracture	1/878 (0.1%)		0/878 (0%)
Polyarthritis	1/878 (0.1%)		0/878 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/878 (0.1%)		0/878 (0%)
Bile duct cancer	0/878 (0%)		1/878 (0.1%)
Cancer pain	2/878 (0.2%)		4/878 (0.5%)
Cervix cancer metastatic	1/878 (0.1%)		1/878 (0.1%)
Colon cancer	0/878 (0%)		1/878 (0.1%)
Colon cancer metastatic	1/878 (0.1%)		2/878 (0.2%)
Hepatic cancer metastatic	0/878 (0%)		2/878 (0.2%)
Lung cancer metastatic	3/878 (0.3%)		6/878 (0.7%)
Malignant ascites	0/878 (0%)		1/878 (0.1%)
Malignant neoplasm progression	100/878 (11.4%)		103/878 (11.7%)
Malignant pleural effusion	2/878 (0.2%)		2/878 (0.2%)
Metastases to abdominal cavity	0/878 (0%)		1/878 (0.1%)
Metastases to bone	8/878 (0.9%)		9/878 (1%)
Metastases to bone marrow	0/878 (0%)		1/878 (0.1%)
Metastases to central nervous system	44/878 (5%)		43/878 (4.9%)
Metastases to gastrointestinal tract	0/878 (0%)		1/878 (0.1%)
Metastases to liver	13/878 (1.5%)		16/878 (1.8%)
Metastases to lung	3/878 (0.3%)		3/878 (0.3%)
Metastases to lymph nodes	3/878 (0.3%)		2/878 (0.2%)
Metastases to meninges	1/878 (0.1%)		1/878 (0.1%)
Metastases to peritoneum	1/878 (0.1%)		1/878 (0.1%)
Metastases to pleura	3/878 (0.3%)		1/878 (0.1%)
Metastases to rectum	1/878 (0.1%)		0/878 (0%)
Metastases to spine	1/878 (0.1%)		0/878 (0%)
Metastasis	3/878 (0.3%)		7/878 (0.8%)
Metastatic bronchial carcinoma	1/878 (0.1%)		0/878 (0%)
Metastatic carcinoma of the bladder	0/878 (0%)		1/878 (0.1%)
Metastatic malignant melanoma	1/878 (0.1%)		0/878 (0%)
Metastatic neoplasm	6/878 (0.7%)		1/878 (0.1%)
Metastatic pain	4/878 (0.5%)		1/878 (0.1%)
Metastatic renal cell carcinoma	2/878 (0.2%)		0/878 (0%)
Multiple myeloma	0/878 (0%)		1/878 (0.1%)
Non-small cell lung cancer metastatic	0/878 (0%)		2/878 (0.2%)
Paraneoplastic syndrome	0/878 (0%)		1/878 (0.1%)
Pericardial effusion malignant	0/878 (0%)		1/878 (0.1%)
Pharyngeal neoplasm benign	0/878 (0%)		1/878 (0.1%)
Rectal cancer	0/878 (0%)		1/878 (0.1%)
Rectal cancer metastatic	0/878 (0%)		1/878 (0.1%)
Sarcoma	1/878 (0.1%)		0/878 (0%)
Small cell lung cancer metastatic	1/878 (0.1%)		1/878 (0.1%)
Tumour associated fever	2/878 (0.2%)		0/878 (0%)
Tumour pain	0/878 (0%)		1/878 (0.1%)
Tumour thrombosis	1/878 (0.1%)		0/878 (0%)
Nervous system disorders
Altered state of consciousness	0/878 (0%)		1/878 (0.1%)
Amnesia	0/878 (0%)		1/878 (0.1%)
Apraxia	1/878 (0.1%)		0/878 (0%)
Ataxia	1/878 (0.1%)		0/878 (0%)
Balance disorder	1/878 (0.1%)		0/878 (0%)
Brain oedema	1/878 (0.1%)		0/878 (0%)
Cauda equina syndrome	0/878 (0%)		1/878 (0.1%)
Cerebral artery embolism	0/878 (0%)		1/878 (0.1%)
Cerebral haemorrhage	1/878 (0.1%)		0/878 (0%)
Cerebral ischaemia	4/878 (0.5%)		2/878 (0.2%)
Cerebrovascular accident	2/878 (0.2%)		5/878 (0.6%)
Cervical cord compression	1/878 (0.1%)		1/878 (0.1%)
Cervical root pain	0/878 (0%)		1/878 (0.1%)
Cognitive disorder	0/878 (0%)		1/878 (0.1%)
Coma	7/878 (0.8%)		5/878 (0.6%)
Coma uraemic	0/878 (0%)		1/878 (0.1%)
Convulsion	5/878 (0.6%)		1/878 (0.1%)
Depressed level of consciousness	1/878 (0.1%)		0/878 (0%)
Diplegia	2/878 (0.2%)		0/878 (0%)
Dizziness	3/878 (0.3%)		4/878 (0.5%)
Dysarthria	1/878 (0.1%)		1/878 (0.1%)
Dyskinesia	1/878 (0.1%)		0/878 (0%)
Encephalopathy	1/878 (0.1%)		0/878 (0%)
Epiduritis	0/878 (0%)		1/878 (0.1%)
Epilepsy	3/878 (0.3%)		2/878 (0.2%)
Facial palsy	1/878 (0.1%)		0/878 (0%)
Facial paresis	0/878 (0%)		1/878 (0.1%)
Haemorrhage intracranial	1/878 (0.1%)		0/878 (0%)
Headache	3/878 (0.3%)		3/878 (0.3%)
Hemiparesis	1/878 (0.1%)		0/878 (0%)
Hemiplegia	0/878 (0%)		1/878 (0.1%)
Hepatic encephalopathy	1/878 (0.1%)		0/878 (0%)
Hydrocephalus	1/878 (0.1%)		0/878 (0%)
Hyperaesthesia	0/878 (0%)		1/878 (0.1%)
Hypoaesthesia	2/878 (0.2%)		1/878 (0.1%)
Intracranial pressure increased	0/878 (0%)		2/878 (0.2%)
Lethargy	3/878 (0.3%)		0/878 (0%)
Loss of consciousness	3/878 (0.3%)		1/878 (0.1%)
Mental impairment	1/878 (0.1%)		0/878 (0%)
Monoparesis	1/878 (0.1%)		0/878 (0%)
Monoplegia	1/878 (0.1%)		1/878 (0.1%)
Motor dysfunction	1/878 (0.1%)		0/878 (0%)
Nerve root compression	1/878 (0.1%)		0/878 (0%)
Neuralgia	1/878 (0.1%)		1/878 (0.1%)
Neuritis	0/878 (0%)		1/878 (0.1%)
Neurological decompensation	1/878 (0.1%)		1/878 (0.1%)
Neurotoxicity	0/878 (0%)		1/878 (0.1%)
Paraesthesia	1/878 (0.1%)		3/878 (0.3%)
Paraparesis	5/878 (0.6%)		5/878 (0.6%)
Paraplegia	3/878 (0.3%)		0/878 (0%)
Parkinson's disease	1/878 (0.1%)		0/878 (0%)
Peripheral motor neuropathy	2/878 (0.2%)		3/878 (0.3%)
Peripheral sensory neuropathy	0/878 (0%)		1/878 (0.1%)
Polyneuropathy	0/878 (0%)		1/878 (0.1%)
Polyneuropathy alcoholic	0/878 (0%)		1/878 (0.1%)
Psychomotor skills impaired	0/878 (0%)		1/878 (0.1%)
Sensory disturbance	0/878 (0%)		1/878 (0.1%)
Sensory loss	0/878 (0%)		1/878 (0.1%)
Somnolence	1/878 (0.1%)		2/878 (0.2%)
Speech disorder	0/878 (0%)		1/878 (0.1%)
Spinal cord compression	26/878 (3%)		27/878 (3.1%)
Syncope	8/878 (0.9%)		3/878 (0.3%)
Transient ischaemic attack	1/878 (0.1%)		0/878 (0%)
Tremor	1/878 (0.1%)		0/878 (0%)
Psychiatric disorders
Anxiety	2/878 (0.2%)		3/878 (0.3%)
Completed suicide	1/878 (0.1%)		0/878 (0%)
Confusional state	9/878 (1%)		4/878 (0.5%)
Emotional distress	0/878 (0%)		1/878 (0.1%)
Insomnia	1/878 (0.1%)		0/878 (0%)
Mental disorder	0/878 (0%)		1/878 (0.1%)
Mental status changes	9/878 (1%)		4/878 (0.5%)
Psychotic disorder due to a general medical condition	0/878 (0%)		1/878 (0.1%)
Renal and urinary disorders
Anuria	2/878 (0.2%)		2/878 (0.2%)
Azotaemia	0/878 (0%)		1/878 (0.1%)
Bladder mass	1/878 (0.1%)		0/878 (0%)
Bladder obstruction	0/878 (0%)		1/878 (0.1%)
Bladder pain	1/878 (0.1%)		0/878 (0%)
Calculus ureteric	2/878 (0.2%)		0/878 (0%)
Chromaturia	1/878 (0.1%)		0/878 (0%)
Dysuria	2/878 (0.2%)		0/878 (0%)
Haematuria	2/878 (0.2%)		8/878 (0.9%)
Hydronephrosis	2/878 (0.2%)		1/878 (0.1%)
Nephroangiosclerosis	1/878 (0.1%)		0/878 (0%)
Oliguria	0/878 (0%)		1/878 (0.1%)
Proteinuria	1/878 (0.1%)		0/878 (0%)
Renal colic	1/878 (0.1%)		0/878 (0%)
Renal failure	13/878 (1.5%)		10/878 (1.1%)
Renal failure acute	15/878 (1.7%)		10/878 (1.1%)
Renal impairment	2/878 (0.2%)		0/878 (0%)
Urethral obstruction	1/878 (0.1%)		0/878 (0%)
Urethral stenosis	0/878 (0%)		1/878 (0.1%)
Urinary bladder haemorrhage	0/878 (0%)		1/878 (0.1%)
Urinary incontinence	2/878 (0.2%)		0/878 (0%)
Urinary retention	9/878 (1%)		3/878 (0.3%)
Urinary tract disorder	1/878 (0.1%)		1/878 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/878 (0.1%)		0/878 (0%)
Dysfunctional uterine bleeding	0/878 (0%)		1/878 (0.1%)
Orchitis noninfective	0/878 (0%)		1/878 (0.1%)
Pelvic pain	2/878 (0.2%)		4/878 (0.5%)
Uterine haemorrhage	1/878 (0.1%)		0/878 (0%)
Vaginal haemorrhage	1/878 (0.1%)		0/878 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/878 (0.1%)		0/878 (0%)
Acute respiratory distress syndrome	1/878 (0.1%)		2/878 (0.2%)
Acute respiratory failure	3/878 (0.3%)		4/878 (0.5%)
Aspiration	1/878 (0.1%)		0/878 (0%)
Asthma	1/878 (0.1%)		0/878 (0%)
Atelectasis	2/878 (0.2%)		1/878 (0.1%)
Bronchial obstruction	1/878 (0.1%)		0/878 (0%)
Bronchitis chronic	0/878 (0%)		1/878 (0.1%)
Bronchospasm	0/878 (0%)		1/878 (0.1%)
Chronic obstructive pulmonary disease	7/878 (0.8%)		6/878 (0.7%)
Cough	8/878 (0.9%)		1/878 (0.1%)
Dysphonia	0/878 (0%)		1/878 (0.1%)
Dyspnoea	54/878 (6.2%)		55/878 (6.3%)
Dyspnoea at rest	0/878 (0%)		1/878 (0.1%)
Emphysema	0/878 (0%)		1/878 (0.1%)
Epistaxis	3/878 (0.3%)		3/878 (0.3%)
Haemoptysis	9/878 (1%)		11/878 (1.3%)
Hydropneumothorax	0/878 (0%)		2/878 (0.2%)
Hydrothorax	1/878 (0.1%)		1/878 (0.1%)
Hypercapnia	0/878 (0%)		1/878 (0.1%)
Hypoxia	4/878 (0.5%)		7/878 (0.8%)
Interstitial lung disease	1/878 (0.1%)		0/878 (0%)
Lung disorder	1/878 (0.1%)		2/878 (0.2%)
Lung infiltration	3/878 (0.3%)		5/878 (0.6%)
Oesophagobronchial fistula	1/878 (0.1%)		0/878 (0%)
Orthopnoea	1/878 (0.1%)		0/878 (0%)
Pharyngeal inflammation	0/878 (0%)		1/878 (0.1%)
Pleural effusion	27/878 (3.1%)		23/878 (2.6%)
Pleurisy	0/878 (0%)		1/878 (0.1%)
Pleuritic pain	1/878 (0.1%)		1/878 (0.1%)
Pneumonitis	1/878 (0.1%)		0/878 (0%)
Pneumothorax	5/878 (0.6%)		1/878 (0.1%)
Productive cough	1/878 (0.1%)		0/878 (0%)
Pulmonary embolism	18/878 (2.1%)		19/878 (2.2%)
Pulmonary haemorrhage	1/878 (0.1%)		2/878 (0.2%)
Pulmonary oedema	4/878 (0.5%)		3/878 (0.3%)
Respiratory arrest	0/878 (0%)		2/878 (0.2%)
Respiratory distress	4/878 (0.5%)		2/878 (0.2%)
Respiratory failure	40/878 (4.6%)		45/878 (5.1%)
Respiratory tract congestion	1/878 (0.1%)		0/878 (0%)
Respiratory tract haemorrhage	1/878 (0.1%)		0/878 (0%)
Tachypnoea	0/878 (0%)		1/878 (0.1%)
Tracheal stenosis	1/878 (0.1%)		0/878 (0%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/878 (0.1%)		0/878 (0%)
Lichenoid keratosis	1/878 (0.1%)		0/878 (0%)
Panniculitis	0/878 (0%)		1/878 (0.1%)
Petechiae	0/878 (0%)		1/878 (0.1%)
Rash	2/878 (0.2%)		1/878 (0.1%)
Skin lesion	0/878 (0%)		1/878 (0.1%)
Stevens-Johnson syndrome	1/878 (0.1%)		0/878 (0%)
Swelling face	0/878 (0%)		1/878 (0.1%)
Social circumstances
Immobile	1/878 (0.1%)		0/878 (0%)
Surgical and medical procedures
Abdominal wall operation	1/878 (0.1%)		0/878 (0%)
Medical device removal	1/878 (0.1%)		0/878 (0%)
Tooth extraction	0/878 (0%)		1/878 (0.1%)
Vascular disorders
Aneurysm	0/878 (0%)		1/878 (0.1%)
Aortic aneurysm	1/878 (0.1%)		0/878 (0%)
Aortic occlusion	1/878 (0.1%)		0/878 (0%)
Arterial thrombosis	1/878 (0.1%)		0/878 (0%)
Arteritis	0/878 (0%)		1/878 (0.1%)
Circulatory collapse	0/878 (0%)		1/878 (0.1%)
Deep vein thrombosis	13/878 (1.5%)		15/878 (1.7%)
Embolism	1/878 (0.1%)		0/878 (0%)
Haematoma	1/878 (0.1%)		1/878 (0.1%)
Haemorrhage	2/878 (0.2%)		2/878 (0.2%)
Hypertension	2/878 (0.2%)		1/878 (0.1%)
Hypertensive crisis	3/878 (0.3%)		0/878 (0%)
Hypotension	6/878 (0.7%)		9/878 (1%)
Hypovolaemic shock	2/878 (0.2%)		1/878 (0.1%)
Jugular vein thrombosis	2/878 (0.2%)		0/878 (0%)
Lymphoedema	0/878 (0%)		1/878 (0.1%)
Orthostatic hypotension	2/878 (0.2%)		0/878 (0%)
Peripheral arterial occlusive disease	0/878 (0%)		1/878 (0.1%)
Peripheral artery aneurysm	0/878 (0%)		1/878 (0.1%)
Peripheral ischaemia	1/878 (0.1%)		1/878 (0.1%)
Phlebitis	1/878 (0.1%)		0/878 (0%)
Shock	0/878 (0%)		1/878 (0.1%)
Subclavian vein thrombosis	1/878 (0.1%)		1/878 (0.1%)
Superior vena caval occlusion	2/878 (0.2%)		2/878 (0.2%)
Thrombosis	3/878 (0.3%)		1/878 (0.1%)
Vena cava thrombosis	2/878 (0.2%)		0/878 (0%)
Venous thrombosis	1/878 (0.1%)		1/878 (0.1%)
Venous thrombosis limb	0/878 (0%)		1/878 (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	767/878 (87.4%)		751/878 (85.5%)
Blood and lymphatic system disorders
Anaemia	264/878 (30.1%)		234/878 (26.7%)
Leukopenia	68/878 (7.7%)		50/878 (5.7%)
Neutropenia	100/878 (11.4%)		90/878 (10.3%)
Thrombocytopenia	86/878 (9.8%)		90/878 (10.3%)
Gastrointestinal disorders
Abdominal pain	86/878 (9.8%)		84/878 (9.6%)
Abdominal pain upper	38/878 (4.3%)		47/878 (5.4%)
Constipation	209/878 (23.8%)		188/878 (21.4%)
Diarrhoea	165/878 (18.8%)		163/878 (18.6%)
Nausea	260/878 (29.6%)		244/878 (27.8%)
Vomiting	167/878 (19%)		174/878 (19.8%)
General disorders
Asthenia	171/878 (19.5%)		156/878 (17.8%)
Chest pain	85/878 (9.7%)		92/878 (10.5%)
Fatigue	216/878 (24.6%)		203/878 (23.1%)
Mucosal inflammation	47/878 (5.4%)		43/878 (4.9%)
Oedema peripheral	135/878 (15.4%)		106/878 (12.1%)
Pain	47/878 (5.4%)		47/878 (5.4%)
Pyrexia	170/878 (19.4%)		125/878 (14.2%)
Infections and infestations
Urinary tract infection	44/878 (5%)		38/878 (4.3%)
Injury, poisoning and procedural complications
Rib fracture	46/878 (5.2%)		39/878 (4.4%)
Thoracic vertebral fracture	44/878 (5%)		35/878 (4%)
Investigations
Weight decreased	105/878 (12%)		99/878 (11.3%)
Metabolism and nutrition disorders
Anorexia	190/878 (21.6%)		163/878 (18.6%)
Dehydration	45/878 (5.1%)		42/878 (4.8%)
Hypocalcaemia	47/878 (5.4%)		88/878 (10%)
Hypokalaemia	63/878 (7.2%)		53/878 (6%)
Musculoskeletal and connective tissue disorders
Arthralgia	137/878 (15.6%)		124/878 (14.1%)
Back pain	183/878 (20.8%)		169/878 (19.2%)
Bone pain	149/878 (17%)		137/878 (15.6%)
Musculoskeletal chest pain	49/878 (5.6%)		53/878 (6%)
Musculoskeletal pain	95/878 (10.8%)		92/878 (10.5%)
Pain in extremity	128/878 (14.6%)		121/878 (13.8%)
Nervous system disorders
Dizziness	72/878 (8.2%)		67/878 (7.6%)
Headache	93/878 (10.6%)		99/878 (11.3%)
Neuropathy peripheral	42/878 (4.8%)		46/878 (5.2%)
Paraesthesia	59/878 (6.7%)		45/878 (5.1%)
Psychiatric disorders
Anxiety	56/878 (6.4%)		73/878 (8.3%)
Depression	56/878 (6.4%)		62/878 (7.1%)
Insomnia	93/878 (10.6%)		89/878 (10.1%)
Respiratory, thoracic and mediastinal disorders
Cough	151/878 (17.2%)		172/878 (19.6%)
Dyspnoea	171/878 (19.5%)		193/878 (22%)
Skin and subcutaneous tissue disorders
Alopecia	62/878 (7.1%)		48/878 (5.5%)
Rash	75/878 (8.5%)		67/878 (7.6%)

Limitations/Caveats

[Not Specified]

More Information

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.