A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R)

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ClinicalTrials.gov Identifier: NCT01989754

Recruitment Status : Completed

First Posted : November 21, 2013

Results First Posted : December 11, 2018

Last Update Posted : December 11, 2018

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

The George Institute for Global Health, Australia

Information provided by (Responsible Party):

Janssen Research & Development, LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions	Diabetes Mellitus, Type 2 Albuminuria
Interventions	Drug: Placebo Drug: Canagliflozin, 100 mg Drug: Canagliflozin, 300 mg
Enrollment	5813

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 5,813 participants were randomized. However, 1 participant was randomized twice and only the first randomization was included in the Intent-to-treat (ITT) analysis set. Thus 2,905 and 2,907 participants were randomly assigned to the placebo and canagliflozin groups in the ITT analysis set, respectively.


Arm/Group Title	Placebo (Placebo)	Canagliflozin (Experimental)
Arm/Group Description	Participants received one capsule o...	Participants received canagliflozin...
Arm/Group Description	Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).
Period Title: Overall Study
Started	2905	2907
Treated	2903	2904
Completed	2866 ^[1]	2872 ^[1]
Not Completed	39	35
Reason Not Completed
Withdrawal by Subject	10	14
Lost to Follow-up	28	20
Closed Site	1	1
[1] Participants who died are included in this category.

Baseline Characteristics

Arm/Group Title		Placebo (Placebo)	Canagliflozin (Experimental)	Total
Arm/Group Description		Participants received one capsule o...	Participants received canagliflozin...	Total of all reporting groups
Arm/Group Description		Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).	Total of all reporting groups
Overall Number of Baseline Participants		2905	2907	5812
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	2905 participants	2907 participants	5812 participants
		64 (8.28)	63.9 (8.42)	64 (8.35)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2905 participants	2907 participants	5812 participants
	Female	1111 38.2%	1053 36.2%	2164 37.2%
	Male	1794 61.8%	1854 63.8%	3648 62.8%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2905 participants	2907 participants	5812 participants
	Hispanic or Latino	586 20.2%	604 20.8%	1190 20.5%
	Not Hispanic or Latino	2303 79.3%	2290 78.8%	4593 79.0%
	Unknown or Not Reported	16 0.6%	13 0.4%	29 0.5%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2905 participants	2907 participants	5812 participants
	American Indian or Alaska Native	19 0.7%	14 0.5%	33 0.6%
	Asian	245 8.4%	244 8.4%	489 8.4%
	Native Hawaiian or Other Pacific Islander	09 0.3%	08 0.3%	17 0.3%
	Black or African American	125 4.3%	106 3.6%	231 4.0%
	White	2372 81.7%	2393 82.3%	4765 82.0%
	More than one race	10 0.3%	09 0.3%	19 0.3%
	Unknown or Not Reported	125 4.3%	133 4.6%	258 4.4%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	2905 participants	2907 participants	5812 participants
Asian		245 8.4%	244 8.4%	489 8.4%
Black or African American		125 4.3%	106 3.6%	231 4.0%
Hispanic or Latino		407 14.0%	437 15.0%	844 14.5%
Other		174 6.0%	172 5.9%	346 6.0%
White Non-Hispanic		1954 67.3%	1948 67.0%	3902 67.1%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	2905 participants	2907 participants	5812 participants
ARGENTINA		146 5.0%	159 5.5%	305 5.2%
AUSTRALIA		58 2.0%	51 1.8%	109 1.9%
BELGIUM		86 3.0%	66 2.3%	152 2.6%
BRAZIL		277 9.5%	272 9.4%	549 9.4%
CANADA		136 4.7%	146 5.0%	282 4.9%
CHINA		46 1.6%	46 1.6%	92 1.6%
CZECH REPUBLIC		67 2.3%	72 2.5%	139 2.4%
FRANCE		69 2.4%	55 1.9%	124 2.1%
GERMANY		46 1.6%	55 1.9%	101 1.7%
HUNGARY		82 2.8%	97 3.3%	179 3.1%
ITALY		49 1.7%	49 1.7%	98 1.7%
MALAYSIA		50 1.7%	42 1.4%	92 1.6%
MEXICO		118 4.1%	110 3.8%	228 3.9%
NETHERLANDS		117 4.0%	132 4.5%	249 4.3%
NEW ZEALAND		49 1.7%	56 1.9%	105 1.8%
POLAND		186 6.4%	177 6.1%	363 6.2%
RUSSIAN FEDERATION		213 7.3%	199 6.8%	412 7.1%
SOUTH KOREA		73 2.5%	94 3.2%	167 2.9%
SPAIN		247 8.5%	249 8.6%	496 8.5%
SWEDEN		118 4.1%	103 3.5%	221 3.8%
TAIWAN		44 1.5%	32 1.1%	76 1.3%
UKRAINE		213 7.3%	236 8.1%	449 7.7%
UNITED KINGDOM		78 2.7%	73 2.5%	151 2.6%
UNITED STATES		337 11.6%	336 11.6%	673 11.6%

Outcome Measures

1.Primary Outcome


Title	Progression of Albuminuria
Description	Progression defined as the development of micro-albuminuria (Urine Alb...
Description	Progression defined as the development of micro-albuminuria (Urine Albumin Creatinine Ratio [UACR] 30 to 300 milligram per gram [mg/g]) or macroalbuminuria (Albumin/creatinine ratio [ACR] of greater than [>] 300 mg/g) in a participant with baseline normoalbuminuria (ACR less than [<] 30 mg/g) or the development of macro-albuminuria in a participant with baseline microalbuminuria with an ACR increase greater than or equal to (>=) 30 percent from baseline. Participants with macroalbuminuria at baseline (ACR>300 mg/g) were excluded from the analysis. Event rate was estimated based on the time to the first occurrence of the event.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population included all participants who were randomized. Here 'N' signifies number of participants who were evaluable for this endpoint.


Arm/Group Title	Placebo	Canagliflozin (Experimental)
Arm/Group Description:	Participants received one capsule o...	Participants received canagliflozin...
Arm/Group Description:	Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).
Overall Number of Participants Analyzed	2905	2907
Measure Type: Number Unit of Measure: Events per 1000 patient-year
	153.01	99.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin (Experimental)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Cox proportional hazard method
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95% 0.57 to 0.73
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure
Description	Analyses were using adjudicated events, that is (i.e.) CV death events...
Description	Analyses were using adjudicated events, that is (i.e.) CV death events or hospitalization due to heart failure, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event.
Time Frame	Approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized.


Arm/Group Title	Placebo	Canagliflozin (Experimental)
Arm/Group Description:	Participants received one capsule o...	Participants received canagliflozin...
Arm/Group Description:	Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).
Overall Number of Participants Analyzed	2905	2907
Measure Type: Number Unit of Measure: Events per 1000 patient-years
	21.91	15.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin (Experimental)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	=0.0148
	Comments	[Not Specified]
	Method	Stratified Cox proportional hazard
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95% 0.55 to 0.94
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Cardiovascular (CV) Death
Description	Analyses were using adjudicated events, i.e. CV death events, and adju...
Description	Analyses were using adjudicated events, i.e. CV death events, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event.
Time Frame	Approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized.


Arm/Group Title	Placebo	Canagliflozin (Experimental)
Arm/Group Description:	Participants received one capsule o...	Participants received canagliflozin...
Arm/Group Description:	Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).
Overall Number of Participants Analyzed	2905	2907
Measure Type: Number Unit of Measure: Events per 1000 patient-years
	11.60	10.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin (Experimental)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	=0.4067
	Comments	[Not Specified]
	Method	Stratified Cox proportional hazard
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.61 to 1.22
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Approximately 3 years
Adverse Event Reporting Description	On-treatment analysis set included all randomized participants who were treated and received at least 1 dose of study drug. The number of deaths (all causes) reported here is adjudicated death that occurred within 30 days of the last dose of the study drug.

Arm/Group Title	Placebo (Placebo)	Canagliflozin (Experimental)
Arm/Group Description	Participants received one capsule o...	Participants received canagliflozin...
Arm/Group Description	Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment.	Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated).
All-Cause Mortality
	Placebo (Placebo)	Canagliflozin (Experimental)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	71/2903 (2.45%)	68/2904 (2.34%)
Serious Adverse Events Serious Adverse Events
	Placebo (Placebo)	Canagliflozin (Experimental)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	775/2903 (26.70%)	714/2904 (24.59%)
Blood and lymphatic system disorders
Anaemia ^* 1	6/2903 (0.21%)	10/2904 (0.34%)
Febrile Neutropenia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Iron Deficiency Anaemia ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Polycythaemia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Thrombocytopenia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Cardiac disorders
Acute Coronary Syndrome ^* 1	11/2903 (0.38%)	4/2904 (0.14%)
Acute Left Ventricular Failure ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Acute Myocardial Infarction ^* 1	26/2903 (0.90%)	32/2904 (1.10%)
Adams-Stokes Syndrome ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Angina Pectoris ^* 1	33/2903 (1.14%)	22/2904 (0.76%)
Angina Unstable ^* 1	42/2903 (1.45%)	42/2904 (1.45%)
Aortic Valve Disease ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Aortic Valve Incompetence ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Arrhythmia ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Arteriosclerosis Coronary Artery ^* 1	5/2903 (0.17%)	3/2904 (0.10%)
Atrial Fibrillation ^* 1	18/2903 (0.62%)	14/2904 (0.48%)
Atrial Flutter ^* 1	7/2903 (0.24%)	5/2904 (0.17%)
Atrial Tachycardia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Atrioventricular Block Complete ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Atrioventricular Block Second Degree ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Bradycardia ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Cardiac Arrest ^* 1	9/2903 (0.31%)	5/2904 (0.17%)
Cardiac Disorder ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cardiac Failure ^* 1	41/2903 (1.41%)	19/2904 (0.65%)
Cardiac Failure Acute ^* 1	3/2903 (0.10%)	2/2904 (0.07%)
Cardiac Failure Chronic ^* 1	3/2903 (0.10%)	4/2904 (0.14%)
Cardiac Failure Congestive ^* 1	18/2903 (0.62%)	11/2904 (0.38%)
Cardiac Valve Disease ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Cardio-Respiratory Arrest ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cardiogenic Shock ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Cardiopulmonary Failure ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Conduction Disorder ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Congestive Cardiomyopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Coronary Artery Disease ^* 1	29/2903 (1.00%)	34/2904 (1.17%)
Coronary Artery Insufficiency ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Coronary Artery Occlusion ^* 1	3/2903 (0.10%)	4/2904 (0.14%)
Coronary Artery Stenosis ^* 1	8/2903 (0.28%)	5/2904 (0.17%)
Diabetic Cardiomyopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ischaemic Cardiomyopathy ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Left Ventricular Dysfunction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Left Ventricular Failure ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Mitral Valve Stenosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Myocardial Fibrosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Myocardial Infarction ^* 1	24/2903 (0.83%)	31/2904 (1.07%)
Myocardial Ischaemia ^* 1	9/2903 (0.31%)	7/2904 (0.24%)
Pericardial Effusion ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Pericarditis ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Prinzmetal Angina ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Right Ventricular Failure ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Sinus Bradycardia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Sinus Node Dysfunction ^* 1	4/2903 (0.14%)	0/2904 (0.00%)
Supraventricular Tachycardia ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Tachycardia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tricuspid Valve Incompetence ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ventricular Arrhythmia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ventricular Asystole ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ventricular Extrasystoles ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Ventricular Fibrillation ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Ventricular Tachycardia ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Ear and labyrinth disorders
Haematotympanum ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hypoacusis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Vertigo ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Endocrine disorders
Basedow's Disease ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hyperparathyroidism ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Hyperparathyroidism Primary ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hyperthyroidism ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Eye disorders
Amaurosis Fugax ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cataract ^* 1	3/2903 (0.10%)	10/2904 (0.34%)
Diabetic Retinopathy ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Diplopia ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Eye Haemorrhage ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Eye Pain ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Eyelid Ptosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Glaucoma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Macular Fibrosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Retinal Artery Occlusion ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Retinal Detachment ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Retinopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Gastrointestinal disorders
Abdominal Hernia ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Abdominal Pain ^* 1	5/2903 (0.17%)	2/2904 (0.07%)
Abdominal Pain Lower ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Abdominal Pain Upper ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Anal Fistula ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ascites ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Barrett's Oesophagus ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Bowel Movement Irregularity ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Colitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Colitis Ischaemic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Colitis Microscopic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Colitis Ulcerative ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Colonic Pseudo-Obstruction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Constipation ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Diarrhoea ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Diverticular Perforation ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Diverticulum ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Diverticulum Intestinal ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Duodenal Ulcer ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Duodenal Ulcer Haemorrhage ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Duodenal Ulcer Perforation ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Enterocolitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Food Poisoning ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Gastric Polyps ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Gastroduodenitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Gastrointestinal Haemorrhage ^* 1	3/2903 (0.10%)	3/2904 (0.10%)
Haematemesis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ileus ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Impaired Gastric Emptying ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Inguinal Hernia ^* 1	4/2903 (0.14%)	2/2904 (0.07%)
Intestinal Haemorrhage ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Intestinal Ischaemia ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Intestinal Obstruction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Intestinal Ulcer Perforation ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Large Intestine Perforation ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Lower Gastrointestinal Haemorrhage ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Melaena ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Mesenteric Arterial Occlusion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Mesenteric Vein Thrombosis ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Oesophageal Obstruction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pancreatitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pancreatitis Acute ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Peptic Ulcer ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Pneumoperitoneum ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Rectal Tenesmus ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Salivary Gland Calculus ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Salivary Gland Fistula ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Small Intestinal Obstruction ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Swollen Tongue ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tooth Disorder ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Umbilical Hernia ^* 1	1/2903 (0.03%)	6/2904 (0.21%)
Upper Gastrointestinal Haemorrhage ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Volvulus ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
General disorders
Adverse Drug Reaction ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cardiac Death ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Chest Discomfort ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Chest Pain ^* 1	17/2903 (0.59%)	22/2904 (0.76%)
Complication Associated with Device ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cyst ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Death ^* 1	7/2903 (0.24%)	5/2904 (0.17%)
Drug Intolerance ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Gait Disturbance ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Generalised Oedema ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Impaired Healing ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Malaise ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Non-Cardiac Chest Pain ^* 1	7/2903 (0.24%)	9/2904 (0.31%)
Oedema Peripheral ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Peripheral Swelling ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pyrexia ^* 1	3/2903 (0.10%)	2/2904 (0.07%)
Sudden Cardiac Death ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Sudden Death ^* 1	6/2903 (0.21%)	6/2904 (0.21%)
Vascular Stent Restenosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Vascular Stent Thrombosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hepatobiliary disorders
Bile Duct Stone ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Biliary Colic ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cholangitis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Cholangitis Acute ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Cholecystitis ^* 1	3/2903 (0.10%)	3/2904 (0.10%)
Cholecystitis Acute ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Cholelithiasis ^* 1	7/2903 (0.24%)	5/2904 (0.17%)
Cholelithiasis Obstructive ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Gallbladder Polyp ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Haemobilia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hepatic Cirrhosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hepatic Lesion ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hydrocholecystis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Jaundice Cholestatic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Liver Injury ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Non-Alcoholic Steatohepatitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Immune system disorders
Anaphylactic Reaction ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Drug Hypersensitivity ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Sarcoidosis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Infections and infestations
Abscess ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Abscess Limb ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Abscess Neck ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Appendicitis ^* 1	2/2903 (0.07%)	6/2904 (0.21%)
Arthritis Bacterial ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Bronchitis ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Campylobacter Gastroenteritis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Carbuncle ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Cellulitis ^* 1	11/2903 (0.38%)	9/2904 (0.31%)
Cellulitis Staphylococcal ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cellulitis Streptococcal ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cholecystitis Infective ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Colonic Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Device Related Infection ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Diabetic Foot Infection ^* 1	4/2903 (0.14%)	3/2904 (0.10%)
Diabetic Gangrene ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Diverticulitis ^* 1	3/2903 (0.10%)	3/2904 (0.10%)
Ear Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Empyema ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Endocarditis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Epididymitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Erysipelas ^* 1	5/2903 (0.17%)	0/2904 (0.00%)
Escherichia Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Escherichia Sepsis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Escherichia Urinary Tract Infection ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Eye Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Gangrene ^* 1	2/2903 (0.07%)	5/2904 (0.17%)
Gastroenteritis ^* 1	9/2903 (0.31%)	8/2904 (0.28%)
Gastroenteritis Viral ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Genital Infection Fungal ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hepatitis B ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Herpes Zoster ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hiv Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Infected Dermal Cyst ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Infected Skin Ulcer ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Infection ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Infective Exacerbation of Chronic Obstructive Airways Disease ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Influenza ^* 1	1/2903 (0.03%)	5/2904 (0.17%)
Intervertebral Discitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Laryngitis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Localised Infection ^* 1	6/2903 (0.21%)	5/2904 (0.17%)
Lower Respiratory Tract Infection ^* 1	6/2903 (0.21%)	1/2904 (0.03%)
Lung Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Mastoiditis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Orchitis ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Osteomyelitis ^* 1	5/2903 (0.17%)	6/2904 (0.21%)
Osteomyelitis Chronic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Otitis Media Acute ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Parasitic Gastroenteritis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Paronychia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pelvic Abscess ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Penile Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Perinephric Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Peritonsillar Abscess ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pharyngotonsillitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pneumococcal Sepsis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pneumonia ^* 1	31/2903 (1.07%)	26/2904 (0.90%)
Pneumonia Legionella ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pneumonia Pneumococcal ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Post Procedural Infection ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Post Procedural Sepsis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Postoperative Wound Infection ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pulmonary Sepsis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pulmonary Tuberculosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pyelonephritis ^* 1	2/2903 (0.07%)	5/2904 (0.17%)
Pyelonephritis Acute ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Respiratory Tract Infection ^* 1	13/2903 (0.45%)	5/2904 (0.17%)
Scrotal Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Scrotal Infection ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Sepsis ^* 1	9/2903 (0.31%)	4/2904 (0.14%)
Septic Shock ^* 1	6/2903 (0.21%)	4/2904 (0.14%)
Sinusitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Soft Tissue Infection ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Staphylococcal Infection ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Staphylococcal Sepsis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Stenotrophomonas Infection ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Subcutaneous Abscess ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Tooth Abscess ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Tooth Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tracheobronchitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Upper Respiratory Tract Infection ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Urinary Tract Infection ^* 1	13/2903 (0.45%)	11/2904 (0.38%)
Urinary Tract Infection Enterococcal ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Urosepsis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Wound Infection ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Injury, poisoning and procedural complications
Ankle Fracture ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Arterial Bypass Stenosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Carotid Artery Restenosis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Cataract Operation Complication ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Clavicle Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Concussion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Contusion ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Craniocerebral Injury ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Epiphyseal Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Eye Injury ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Facial Bones Fracture ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Fall ^* 1	4/2903 (0.14%)	5/2904 (0.17%)
Femoral Neck Fracture ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Femur Fracture ^* 1	6/2903 (0.21%)	4/2904 (0.14%)
Fibula Fracture ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Foot Fracture ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Fractured Coccyx ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hand Fracture ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Head Injury ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Hip Fracture ^* 1	5/2903 (0.17%)	3/2904 (0.10%)
Humerus Fracture ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Jaw Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Joint Dislocation ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Laceration ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Ligament Sprain ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Limb Crushing Injury ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Limb Injury ^* 1	2/2903 (0.07%)	5/2904 (0.17%)
Lumbar Vertebral Fracture ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Meniscus Injury ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Patella Fracture ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Pneumocephalus ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Post Laminectomy Syndrome ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Post Procedural Haematoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Post Procedural Haematuria ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Post Procedural Haemorrhage ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Postoperative Hernia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Postoperative Respiratory Failure ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Procedural Headache ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Procedural Pain ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pubis Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Radius Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Rib Fracture ^* 1	4/2903 (0.14%)	4/2904 (0.14%)
Road Traffic Accident ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Spinal Fracture ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Subarachnoid Haemorrhage ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Subdural Haematoma ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Suture Related Complication ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Tendon Injury ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tendon Rupture ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Thermal Burn ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Thoracic Vertebral Fracture ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tibia Fracture ^* 1	1/2903 (0.03%)	4/2904 (0.14%)
Toxicity to Various Agents ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Traumatic Fracture ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Traumatic Ulcer ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ulna Fracture ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Upper Limb Fracture ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Vascular Graft Stenosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Wound ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Wound Dehiscence ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Wound Necrosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Wrist Fracture ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Investigations
Arteriogram Coronary ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Blood Creatinine Increased ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Blood Glucose Increased ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Ejection Fraction Decreased ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Electrocardiogram QT Prolonged ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Electrocardiogram St-T Change ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Electrocardiogram T Wave Inversion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
International Normalised Ratio Increased ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Liver Function Test Increased ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Platelet Count Decreased ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
White Blood Cell Count Decreased ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Metabolism and nutrition disorders
Acidosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cachexia ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Dehydration ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Diabetes Mellitus ^* 1	18/2903 (0.62%)	5/2904 (0.17%)
Diabetes Mellitus Inadequate Control ^* 1	12/2903 (0.41%)	6/2904 (0.21%)
Diabetic Complication ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Diabetic Ketoacidosis ^* 1	2/2903 (0.07%)	5/2904 (0.17%)
Electrolyte Imbalance ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Fluid Overload ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Gout ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Hyperglycaemia ^* 1	11/2903 (0.38%)	5/2904 (0.17%)
Hyperkalaemia ^* 1	5/2903 (0.17%)	2/2904 (0.07%)
Hyperosmolar Hyperglycaemic State ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hypertriglyceridaemia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hypoglycaemia ^* 1	9/2903 (0.31%)	6/2904 (0.21%)
Hypokalaemia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hyponatraemia ^* 1	4/2903 (0.14%)	3/2904 (0.10%)
Hypovolaemia ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Lactic Acidosis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Metabolic Acidosis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Obesity ^* 1	3/2903 (0.10%)	2/2904 (0.07%)
Type 2 Diabetes Mellitus ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	3/2903 (0.10%)	4/2904 (0.14%)
Arthritis ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Arthropathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Back Pain ^* 1	11/2903 (0.38%)	2/2904 (0.07%)
Bursitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Cervical Spinal Stenosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Costochondritis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Dactylitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Dupuytren's Contracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Extremity Contracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Foot Deformity ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Intervertebral Disc Compression ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Intervertebral Disc Disorder ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Intervertebral Disc Protrusion ^* 1	5/2903 (0.17%)	7/2904 (0.24%)
Knee Deformity ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Lumbar Spinal Stenosis ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Muscular Weakness ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Musculoskeletal Chest Pain ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Musculoskeletal Pain ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Osteitis ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Osteoarthritis ^* 1	16/2903 (0.55%)	13/2904 (0.45%)
Osteonecrosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pathological Fracture ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Plantar Fasciitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Polymyalgia Rheumatica ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Rhabdomyolysis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Rotator Cuff Syndrome ^* 1	1/2903 (0.03%)	4/2904 (0.14%)
Sacroiliitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Spinal Column Stenosis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Spinal Osteoarthritis ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Spinal Pain ^* 1	3/2903 (0.10%)	3/2904 (0.10%)
Spondylolisthesis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Synovial Cyst ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tendonitis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tenosynovitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Tenosynovitis Stenosans ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Trigger Finger ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Adenocarcinoma Gastric ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Adenocarcinoma of Colon ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Adenosquamous Cell Lung Cancer ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
B-Cell Lymphoma ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Basal Cell Carcinoma ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Benign Lung Neoplasm ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Benign Neoplasm ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Benign Neoplasm of Thyroid Gland ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Bile Duct Cancer ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Bladder Cancer ^* 1	4/2903 (0.14%)	4/2904 (0.14%)
Bladder Cancer Recurrent ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Bladder Transitional Cell Carcinoma ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Bowen's Disease ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Breast Adenoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Breast Cancer ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Breast Cancer Metastatic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Breast Cancer Stage Ii ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Breast Cancer Stage Iii ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cerebral Hygroma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Cholangiocarcinoma ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Chronic Myeloid Leukaemia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Colon Adenoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Colon Cancer ^* 1	0/2903 (0.00%)	4/2904 (0.14%)
Colon Cancer Metastatic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Colorectal Adenocarcinoma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Colorectal Cancer ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Diffuse Large B-Cell Lymphoma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Gastric Cancer ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Glioblastoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hodgkin's Disease ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Invasive Ductal Breast Carcinoma ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Large Cell Lung Cancer ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Laryngeal Cancer ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Lipoma ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Lung Adenocarcinoma ^* 1	2/2903 (0.07%)	4/2904 (0.14%)
Lung Adenocarcinoma Metastatic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Lung Cancer Metastatic ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Lung Neoplasm Malignant ^* 1	6/2903 (0.21%)	6/2904 (0.21%)
Lymphoma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Malignant Melanoma ^* 1	0/2903 (0.00%)	3/2904 (0.10%)
Malignant Melanoma in Situ ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Malignant Neoplasm of Unknown Primary Site ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Mediastinum Neoplasm ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Meningioma Benign ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Metastases to Central Nervous System ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Metastases to Liver ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Neuroendocrine Carcinoma Metastatic ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Neuroendocrine Tumour ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Non-Hodgkin's Lymphoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Non-Small Cell Lung Cancer ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Oesophageal Squamous Cell Carcinoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ovarian Cancer Metastatic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pancreatic Carcinoma ^* 1	6/2903 (0.21%)	1/2904 (0.03%)
Papillary Cystadenoma Lymphomatosum ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Papillary Thyroid Cancer ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Plasma Cell Myeloma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Prostate Cancer ^* 1	8/2903 (0.28%)	0/2904 (0.00%)
Prostate Cancer Metastatic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Rectal Cancer ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Renal Cancer ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Schwannoma ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Serous Cystadenocarcinoma of Pancreas ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Small Cell Lung Cancer Metastatic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Squamous Cell Carcinoma ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Squamous Cell Carcinoma of Lung ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Squamous Cell Carcinoma of Skin ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Squamous Cell Carcinoma of the Oral Cavity ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Squamous Cell Carcinoma of the Tongue ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tongue Neoplasm Malignant Stage Unspecified ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ureteric Cancer ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Uterine Cancer ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Uterine Leiomyoma ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Nervous system disorders
Basilar Artery Occlusion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Brain Injury ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Brain Stem Infarction ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Brain Stem Stroke ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Carotid Arteriosclerosis ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Carotid Artery Occlusion ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Carotid Artery Stenosis ^* 1	7/2903 (0.24%)	9/2904 (0.31%)
Carpal Tunnel Syndrome ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cerebellar Infarction ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cerebral Haematoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Cerebral Haemorrhage ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Cerebral Infarction ^* 1	5/2903 (0.17%)	4/2904 (0.14%)
Cerebral Ischaemia ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cerebrovascular Accident ^* 1	37/2903 (1.27%)	15/2904 (0.52%)
Cervicobrachial Syndrome ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Cognitive Disorder ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Diabetic Mononeuropathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Diabetic Neuropathy ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Dizziness Postural ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Embolic Stroke ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Epilepsy ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Facial Nerve Disorder ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Generalised Tonic-Clonic Seizure ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Haemorrhagic Stroke ^* 1	4/2903 (0.14%)	2/2904 (0.07%)
Headache ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Hemiparesis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Hydrocephalus ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Hypertensive Encephalopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hypoxic-Ischaemic Encephalopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Intraventricular Haemorrhage ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ischaemic Cerebral Infarction ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Ischaemic Stroke ^* 1	12/2903 (0.41%)	20/2904 (0.69%)
Lacunar Infarction ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Lacunar Stroke ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Lethargy ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Loss of Consciousness ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Lumbar Radiculopathy ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Metabolic Encephalopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Migraine ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Myasthenia Gravis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Myasthenia Gravis Crisis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Nerve Compression ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Neuralgia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Paraesthesia ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Peripheral Nerve Paresis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Presyncope ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Radiculopathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Sciatica ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Seizure ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Sensory Loss ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Spinal Cord Compression ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Syncope ^* 1	8/2903 (0.28%)	10/2904 (0.34%)
Thalamic Infarction ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Toxic Encephalopathy ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Transient Ischaemic Attack ^* 1	10/2903 (0.34%)	8/2904 (0.28%)
Tremor ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Trigeminal Neuralgia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Vascular Encephalopathy ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Vascular Headache ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Vertebral Artery Occlusion ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Vertebrobasilar Insufficiency ^* 1	1/2903 (0.03%)	2/2904 (0.07%)
Vocal Cord Paralysis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Product Issues
Device Breakage ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Device Loosening ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Device Malfunction ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Patient-Device Incompatibility ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Psychiatric disorders
Bipolar Disorder ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Completed Suicide ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Confusional State ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Delirium ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Depression ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Depression Suicidal ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Emotional Disorder ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Major Depression ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Psychotic Disorder ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Suicidal Ideation ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Suicide Attempt ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Renal and urinary disorders
Acute Kidney Injury ^* 1	15/2903 (0.52%)	7/2904 (0.24%)
Bladder Obstruction ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Chronic Kidney Disease ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Diabetic Nephropathy ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Haematuria ^* 1	1/2903 (0.03%)	3/2904 (0.10%)
Hydronephrosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ketonuria ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Nephrolithiasis ^* 1	2/2903 (0.07%)	8/2904 (0.28%)
Nephropathy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Nephropathy Toxic ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Nephrotic Syndrome ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pelvi-Ureteric Obstruction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pollakiuria ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Proteinuria ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Renal Colic ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Renal Failure ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Renal Haematoma ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Renal Impairment ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Renal Injury ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Stress Urinary Incontinence ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Tubulointerstitial Nephritis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Ureterolithiasis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Urethral Stenosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Urinary Incontinence ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Urinary Retention ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Reproductive system and breast disorders
Balanoposthitis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Benign Prostatic Hyperplasia ^* 1	5/2903 (0.17%)	4/2904 (0.14%)
Endometrial Hyperplasia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Endometrial Hypertrophy ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Epididymal Disorder ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Erectile Dysfunction ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Fallopian Tube Cyst ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Metrorrhagia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Peyronie's Disease ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Prostatitis ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Prostatomegaly ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Uterine Polyp ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Uterine Prolapse ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema ^* 1	5/2903 (0.17%)	0/2904 (0.00%)
Acute Respiratory Distress Syndrome ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Acute Respiratory Failure ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Asthma ^* 1	2/2903 (0.07%)	3/2904 (0.10%)
Asthmatic Crisis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Atelectasis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Bronchitis Chronic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Bronchospasm ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Chronic Obstructive Pulmonary Disease ^* 1	11/2903 (0.38%)	2/2904 (0.07%)
Cough ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Dyspnoea ^* 1	8/2903 (0.28%)	8/2904 (0.28%)
Epistaxis ^* 1	0/2903 (0.00%)	3/2904 (0.10%)
Haemoptysis ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Haemothorax ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Hypoventilation ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Mediastinal Effusion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Nasal Obstruction ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Pleural Effusion ^* 1	5/2903 (0.17%)	2/2904 (0.07%)
Pneumonia Aspiration ^* 1	2/2903 (0.07%)	0/2904 (0.00%)
Pneumothorax ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pulmonary Embolism ^* 1	5/2903 (0.17%)	6/2904 (0.21%)
Pulmonary Fibrosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pulmonary Mass ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Pulmonary Oedema ^* 1	6/2903 (0.21%)	0/2904 (0.00%)
Pulmonary Sarcoidosis ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Respiratory Acidosis ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Respiratory Alkalosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Respiratory Failure ^* 1	3/2903 (0.10%)	1/2904 (0.03%)
Sleep Apnoea Syndrome ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Vocal Cord Leukoplakia ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Skin and subcutaneous tissue disorders
Angioedema ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Dermatitis Allergic ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Diabetic Foot ^* 1	9/2903 (0.31%)	10/2904 (0.34%)
Diabetic Ulcer ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Skin Fissures ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Skin Necrosis ^* 1	0/2903 (0.00%)	2/2904 (0.07%)
Skin Ulcer ^* 1	5/2903 (0.17%)	7/2904 (0.24%)
Urticaria ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Social circumstances
Penile Prosthesis User ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Victim of Homicide ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Surgical and medical procedures
Coronary Arterial Stent Insertion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Hospitalisation ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Stent Placement ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Vascular disorders
Aortic Aneurysm ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Aortic Arteriosclerosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Aortic Stenosis ^* 1	4/2903 (0.14%)	5/2904 (0.17%)
Arterial Thrombosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Arteriosclerosis ^* 1	2/2903 (0.07%)	2/2904 (0.07%)
Circulatory Collapse ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Deep Vein Thrombosis ^* 1	2/2903 (0.07%)	1/2904 (0.03%)
Diabetic Vascular Disorder ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Extremity Necrosis ^* 1	5/2903 (0.17%)	3/2904 (0.10%)
Haematoma ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Hypertension ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Hypertensive Crisis ^* 1	6/2903 (0.21%)	1/2904 (0.03%)
Hypotension ^* 1	3/2903 (0.10%)	0/2904 (0.00%)
Hypovolaemic Shock ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Iliac Artery Occlusion ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Intermittent Claudication ^* 1	3/2903 (0.10%)	4/2904 (0.14%)
Orthostatic Hypotension ^* 1	4/2903 (0.14%)	1/2904 (0.03%)
Peripheral Arterial Occlusive Disease ^* 1	9/2903 (0.31%)	9/2904 (0.31%)
Peripheral Artery Occlusion ^* 1	1/2903 (0.03%)	4/2904 (0.14%)
Peripheral Artery Stenosis ^* 1	2/2903 (0.07%)	8/2904 (0.28%)
Peripheral Artery Thrombosis ^* 1	1/2903 (0.03%)	0/2904 (0.00%)
Peripheral Embolism ^* 1	1/2903 (0.03%)	1/2904 (0.03%)
Peripheral Ischaemia ^* 1	5/2903 (0.17%)	7/2904 (0.24%)
Peripheral Vascular Disorder ^* 1	4/2903 (0.14%)	9/2904 (0.31%)
Peripheral Venous Disease ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Poor Peripheral Circulation ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Post Thrombotic Syndrome ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
Vascular Insufficiency ^* 1	0/2903 (0.00%)	1/2904 (0.03%)
1 Term from vocabulary, MedDRA Version 19.1 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo (Placebo)	Canagliflozin (Experimental)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	25/2903 (0.86%)	94/2904 (3.24%)
Reproductive system and breast disorders
Balanoposthitis ^* 1	25/2903 (0.86%)	94/2904 (3.24%)
1 Term from vocabulary, MedDRA Version 19.1 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Director Clinical Development
Organization:	Janssen Research & Development, LLC
Phone:	844-434-4210
EMail:	ClinicalTrialDisclosure@its.jnj.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Young TK, Li JW, Kang A, Heerspink HJL, Hockham C, Arnott C, Neuen BL, Zoungas S, Mahaffey KW, Perkovic V, de Zeeuw D, Fulcher G, Neal B, Jardine M. Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA1c, disease duration and treatment intensity: results from the CANVAS Program. Diabetologia. 2021 Nov;64(11):2402-2414. doi: 10.1007/s00125-021-05524-1. Epub 2021 Aug 26.

Yu J, Li J, Leaver PJ, Arnott C, Huffman MD, Udell JA, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Rosenthal N, Neal B, Figtree GA. Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial. Cardiovasc Res. 2022 Mar 16;118(4):1103-1114. doi: 10.1093/cvr/cvab128.

Yu J, Arnott C, Neuen BL, Heersprink HL, Mahaffey KW, Cannon CP, Khan SS, Baldridge AS, Shah SJ, Huang Y, Li C, Figtree GA, Perkovic V, Jardine MJ, Neal B, Huffman MD. Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program. ESC Heart Fail. 2021 Apr;8(2):1482-1493. doi: 10.1002/ehf2.13236. Epub 2021 Feb 17. Erratum In: ESC Heart Fail. 2021 May 3;:

Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Blais J, Li Q, Jardine MJ, Perkovic V, Wheeler DC. Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. Am J Kidney Dis. 2021 Jan;77(1):23-34.e1. doi: 10.1053/j.ajkd.2020.06.018. Epub 2020 Sep 21.

Oshima M, Neal B, Toyama T, Ohkuma T, Li Q, de Zeeuw D, Heerspink HJL, Mahaffey KW, Fulcher G, Canovatchel W, Matthews DR, Perkovic V. Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program. J Am Soc Nephrol. 2020 Oct;31(10):2446-2456. doi: 10.1681/ASN.2019121312. Epub 2020 Jul 21.

Matthews DR, Wysham C, Davies M, Slee A, Alba M, Lee M, Perkovic V, Mahaffey KW, Neal B. Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program. Diabetes Obes Metab. 2020 Nov;22(11):2199-2203. doi: 10.1111/dom.14143. Epub 2020 Aug 24.

Li J, Woodward M, Perkovic V, Figtree GA, Heerspink HJL, Mahaffey KW, de Zeeuw D, Vercruysse F, Shaw W, Matthews DR, Neal B. Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes. JACC Heart Fail. 2020 Jan;8(1):57-66. doi: 10.1016/j.jchf.2019.08.004. Epub 2019 Oct 29.

Zhou Z, Jardine M, Perkovic V, Matthews DR, Mahaffey KW, de Zeeuw D, Fulcher G, Desai M, Oh R, Simpson R, Watts NB, Neal B. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia. 2019 Oct;62(10):1854-1867. doi: 10.1007/s00125-019-4955-5. Epub 2019 Aug 10.

Figtree GA, Radholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Neal B. Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus. Circulation. 2019 May 28;139(22):2591-2593. doi: 10.1161/CIRCULATIONAHA.119.040057. Epub 2019 Mar 17. No abstract available.

Zhou Z, Lindley RI, Radholm K, Jenkins B, Watson J, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Shaw W, Oh R, Desai M, Matthews DR, Neal B. Canagliflozin and Stroke in Type 2 Diabetes Mellitus. Stroke. 2019 Feb;50(2):396-404. doi: 10.1161/STROKEAHA.118.023009.

Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, Rosenthal N, Jardine MJ, Bakris G, Perkovic V. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function. Circulation. 2018 Oct 9;138(15):1537-1550. doi: 10.1161/CIRCULATIONAHA.118.035901.

Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, Barrett TD, Weidner-Wells M, Deng H, Matthews DR, Neal B. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704. doi: 10.1016/S2213-8587(18)30141-4. Epub 2018 Jun 21.

Wittbrodt ET, Eudicone JM, Bell KF, Enhoffer DM, Latham K, Green JB. Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population. Am J Manag Care. 2018 Apr;24(8 Suppl):S138-S145.

Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program. Circulation. 2018 Jul 31;138(5):458-468. doi: 10.1161/CIRCULATIONAHA.118.034222.

Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018 Jan 23;137(4):323-334. doi: 10.1161/CIRCULATIONAHA.117.032038. Epub 2017 Nov 13.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12.

Layout table for additonal information

Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT01989754
Other Study ID Numbers:	CR102647 2013-003050-25 ( EudraCT Number ) 28431754DIA4003 ( Other Identifier: Janssen Research & Development, LLC )
First Submitted:	October 17, 2013
First Posted:	November 21, 2013
Results First Submitted:	November 19, 2018
Results First Posted:	December 11, 2018
Last Update Posted:	December 11, 2018

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