A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD)

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ClinicalTrials.gov Identifier: NCT03036150

Recruitment Status : Completed

First Posted : January 30, 2017

Results First Posted : July 7, 2021

Last Update Posted : July 7, 2021

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Sponsor:

Information provided by (Responsible Party):

AstraZeneca

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Chronic Kidney Disease
Interventions	Drug: Dapagliflozin Drug: Placebo
Enrollment	4304

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
Period Title: Overall Study
Started	2152	2152
Completed	2142	2147
Not Completed	10	5
Reason Not Completed
Withdrawal by Subject	8	3
Lost to Follow-up	2	2

Baseline Characteristics

Arm/Group Title		Dapagliflozin	Placebo	Total
Arm/Group Description		Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...	Total of all reporting groups
Arm/Group Description		Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use	Total of all reporting groups
Overall Number of Baseline Participants		2152	2152	4304
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	2152 participants	2152 participants	4304 participants
		61.8 (12.1)	61.9 (12.1)	61.8 (12.1)
Age, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	<= 50 years	362 16.8%	370 17.2%	732 17.0%
	> 50 years	1790 83.2%	1782 82.8%	3572 83.0%
Age, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	<= 65 years	1247 57.9%	1239 57.6%	2486 57.8%
	> 65 years	905 42.1%	913 42.4%	1818 42.2%
Age, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	<=65 years	1247 57.9%	1239 57.6%	2486 57.8%
	66-75 years	663 30.8%	667 31.0%	1330 30.9%
	> 75 years	242 11.2%	246 11.4%	488 11.3%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	Female	709 32.9%	716 33.3%	1425 33.1%
	Male	1443 67.1%	1436 66.7%	2879 66.9%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	Hispanic or Latino	522 24.3%	550 25.6%	1072 24.9%
	Not Hispanic or Latino	1630 75.7%	1602 74.4%	3232 75.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	White	1124 52.2%	1166 54.2%	2290 53.2%
	Black or African American	104 4.8%	87 4.0%	191 4.4%
	Asian	749 34.8%	718 33.4%	1467 34.1%
	Native Hawaiian or Other Pacific Islander	1 0.0%	1 0.0%	2 0.0%
	American Indian or Alaska Native	62 2.9%	74 3.4%	136 3.2%
	Other	112 5.2%	106 4.9%	218 5.1%
Most likely etiology of CKD Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	Diabetic Nephropathy	1271 59.1%	1239 57.6%	2510 58.3%
	Ischaemic/Hypertensive Nephropathy	324 15.1%	363 16.9%	687 16.0%
	Chronic Glomerulonephritis	343 15.9%	352 16.4%	695 16.1%
	Other or unknown cause of CKD	214 9.9%	198 9.2%	412 9.6%
eGFR Mean (Standard Deviation) Unit of measure: mL/min/1.73 m2
	Number Analyzed	2152 participants	2152 participants	4304 participants
		43.2 (12.3)	43.0 (12.4)	43.1 (12.4)
Urine albumin creatinine ratio Median (Inter-Quartile Range) Unit of measure: Mg/g
	Number Analyzed	2152 participants	2152 participants	4304 participants
		965 (472 to 1903)	934 (482 to 1869)	949 (477 to 1865)
Type 2 Diabetes Mellitus at Baseline Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2152 participants	2152 participants	4304 participants
	Yes	1455 67.6%	1451 67.4%	2906 67.5%
	No	697 32.4%	701 32.6%	1398 32.5%

Outcome Measures

1.Primary Outcome


Title	Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death.
Description	End Stage Renal Disease (ESRD) is defined as: ...
Description	End Stage Renal Disease (ESRD) is defined as: Sustained eGFR <15 mL/min/1.73m2 or, Chronic dialysis treatment or, Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time Frame	Up to 38.2 months

Outcome Measure Data

Analysis Population Description

For the primary endpoint the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.


Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description:	Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...
Arm/Group Description:	Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
Overall Number of Participants Analyzed	2152	2152
Measure Type: Count of Participants Unit of Measure: Participants
	197 9.2%	312 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Stratified by randomization stratification of Type 2 Diabetes and urine albumin creatinine ratio and adjusting for baseline eGFR.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	95% 0.51 to 0.72
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or Renal Death.
Description	End Stage Renal Disease (ESRD) is defined as: ...
Description	End Stage Renal Disease (ESRD) is defined as: Sustained eGFR <15 mL/min/1.73m2 or, Chronic dialysis treatment or, Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time Frame	Up to 38.2 months

Outcome Measure Data

Analysis Population Description

For the secondary endpoints the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.


Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description:	Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...
Arm/Group Description:	Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
Overall Number of Participants Analyzed	2152	2152
Measure Type: Count of Participants Unit of Measure: Participants
	142 6.6%	243 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Stratified by randomization stratification of Type 2 Diabetes and urine albumin creatinine ratio and adjusting for baseline eGFR.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.56
	Confidence Interval	95% 0.45 to 0.68
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Time to the First Occurrence of Either of the Components of the Composite: CV Death or Hospitalization for Heart Failure.
Description	The proportional hazards Cox regression model takes into account the t...
Description	The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time Frame	Up to 38.2 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description:	Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...
Arm/Group Description:	Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
Overall Number of Participants Analyzed	2152	2152
Measure Type: Count of Participants Unit of Measure: Participants
	100 4.6%	138 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0089
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Stratified by randomization stratification of Type 2 Diabetes and urine albumin creatinine ratio and adjusting for baseline eGFR.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	95% 0.55 to 0.92
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Time to Death From Any Cause.
Description	The proportional hazards Cox regression model takes into account the t...
Description	The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time Frame	Up to 38.2 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description:	Dapagliflozin 10 mg, given once dai...	Placebo tablet to match dapaglifloz...
Arm/Group Description:	Dapagliflozin 10 mg, given once daily per oral use	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
Overall Number of Participants Analyzed	2152	2152
Measure Type: Count of Participants Unit of Measure: Participants
	101 4.7%	146 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0035
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Stratified by randomization stratification of Type 2 Diabetes and urine albumin creatinine ratio and adjusting for baseline eGFR.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	95% 0.53 to 0.88
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Up to 39.2 months
Adverse Event Reporting Description	For All Cause Mortality, the Full Analysis Set was used. This included all patients who were randomized to study drug. For analysis of Serious Adverse Events, Safety analysis set was used. Safety analysis set consisted of all randomized patients who received at least one dose of study drug.

Arm/Group Title	Dapa 10 mg		Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once dai...		Placebo tablet to match dapaglifloz...
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use		Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use
All-Cause Mortality
	Dapa 10 mg		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	107/2152 (4.97%)		159/2152 (7.39%)
Serious Adverse Events Serious Adverse Events
	Dapa 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	633/2149 (29.46%)		729/2149 (33.92%)
Blood and lymphatic system disorders
Anaemia ^† 1	7/2149 (0.33%)	8	8/2149 (0.37%)	8
Blood loss anaemia ^† 1	3/2149 (0.14%)	3	2/2149 (0.09%)	3
Bone marrow failure ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Febrile neutropenia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hypochromic anaemia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Iron deficiency anaemia ^† 1	1/2149 (0.05%)	1	6/2149 (0.28%)	6
Nephrogenic anaemia ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Cardiac disorders
Acute coronary syndrome ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Acute left ventricular failure ^† 1	5/2149 (0.23%)	5	10/2149 (0.47%)	12
Acute myocardial infarction ^† 1	32/2149 (1.49%)	35	46/2149 (2.14%)	56
Angina pectoris ^† 1	4/2149 (0.19%)	5	9/2149 (0.42%)	9
Angina unstable ^† 1	14/2149 (0.65%)	17	22/2149 (1.02%)	26
Aortic valve disease ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Aortic valve incompetence ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Arteriosclerosis coronary artery ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Atrial fibrillation ^† 1	8/2149 (0.37%)	8	17/2149 (0.79%)	18
Atrial flutter ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Atrioventricular block ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Atrioventricular block complete ^† 1	3/2149 (0.14%)	3	5/2149 (0.23%)	5
Atrioventricular block second degree ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Bradyarrhythmia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Bradycardia ^† 1	3/2149 (0.14%)	3	3/2149 (0.14%)	3
Bundle branch block left ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cardiac arrest ^† 1	4/2149 (0.19%)	4	10/2149 (0.47%)	10
Cardiac failure ^† 1	39/2149 (1.81%)	56	59/2149 (2.75%)	72
Cardiac failure acute ^† 1	4/2149 (0.19%)	5	7/2149 (0.33%)	8
Cardiac failure chronic ^† 1	3/2149 (0.14%)	4	5/2149 (0.23%)	5
Cardiac failure congestive ^† 1	13/2149 (0.60%)	17	22/2149 (1.02%)	29
Cardio-respiratory arrest ^† 1	5/2149 (0.23%)	5	3/2149 (0.14%)	4
Cardiogenic shock ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Cardiomyopathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cardiopulmonary failure ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Cardiorenal syndrome ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Chronic left ventricular failure ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Congestive cardiomyopathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Coronary artery disease ^† 1	4/2149 (0.19%)	4	10/2149 (0.47%)	10
Coronary artery stenosis ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Defect conduction intraventricular ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hypertensive heart disease ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	5
Ischaemic cardiomyopathy ^† 1	4/2149 (0.19%)	4	4/2149 (0.19%)	4
Left ventricular dysfunction ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Left ventricular failure ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Mitral valve incompetence ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Myocardial infarction ^† 1	11/2149 (0.51%)	11	6/2149 (0.28%)	7
Myocardial ischaemia ^† 1	6/2149 (0.28%)	6	6/2149 (0.28%)	7
Pericardial effusion ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Pericarditis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Prinzmetal angina ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Sinus bradycardia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Supraventricular tachycardia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Ventricular hypokinesia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Ventricular tachycardia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Ear and labyrinth disorders
Vertigo ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Vestibular disorder ^† 1	5/2149 (0.23%)	7	3/2149 (0.14%)	3
Endocrine disorders
Goitre ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hyperadrenocorticism ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hyperparathyroidism primary ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pituitary-dependent cushing's syndrome ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Toxic nodular goitre ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Eye disorders
Cataract ^† 1	8/2149 (0.37%)	12	6/2149 (0.28%)	8
Cataract subcapsular ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Diabetic retinal oedema ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Diabetic retinopathy ^† 1	4/2149 (0.19%)	4	1/2149 (0.05%)	1
Diplopia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Glaucoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Ocular hyperaemia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Ocular ischaemic syndrome ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Retinal detachment ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Retinal haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Vitreous disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Vitreous haemorrhage ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Gastrointestinal disorders
Abdominal hernia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Abdominal hernia obstructive ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Abdominal pain ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Abdominal wall haematoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Colitis ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Colitis ischaemic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Constipation ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Diabetic gastroparesis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Diarrhoea ^† 1	4/2149 (0.19%)	4	2/2149 (0.09%)	2
Diverticular perforation ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Diverticulum ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Diverticulum intestinal ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Diverticulum intestinal haemorrhagic ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	4
Duodenal ulcer ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Duodenal ulcer perforation ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Dysphagia ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Enteritis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Enterocolitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Erosive oesophagitis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Faecaloma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Food poisoning ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastric disorder ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Gastric ulcer ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Gastric ulcer haemorrhage ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Gastritis ^† 1	3/2149 (0.14%)	3	5/2149 (0.23%)	6
Gastritis hypertrophic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastroduodenal ulcer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal angiectasia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal haemorrhage ^† 1	5/2149 (0.23%)	5	6/2149 (0.28%)	7
Gastrointestinal motility disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal polyp haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal ulcer haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrooesophageal reflux disease ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Haemoperitoneum ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Haemorrhoidal haemorrhage ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Haemorrhoids ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Ileus ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Impaired gastric emptying ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Inguinal hernia ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Intestinal obstruction ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Large intestine polyp ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Lower gastrointestinal haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Mechanical ileus ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Mesenteric artery thrombosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Mesenteric vascular insufficiency ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Mesenteric vein thrombosis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Nausea ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Obstruction gastric ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Obstructive pancreatitis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Oesophageal stenosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Oesophageal ulcer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Palatal disorder ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pancreatic cyst ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pancreatitis ^† 1	3/2149 (0.14%)	3	2/2149 (0.09%)	2
Pancreatitis acute ^† 1	5/2149 (0.23%)	6	1/2149 (0.05%)	1
Pancreatitis chronic ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pancreatitis relapsing ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Peptic ulcer ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Small intestinal haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Small intestinal obstruction ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Thrombosis mesenteric vessel ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Upper gastrointestinal haemorrhage ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	4
Varices oesophageal ^† 1	1/2149 (0.05%)	2	0/2149 (0.00%)	0
Vomiting ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
General disorders
Asthenia ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	3
Cardiac death ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Catheter site haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Chest pain ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Death ^† 1	15/2149 (0.70%)	15	27/2149 (1.26%)	27
Fatigue ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Gait disturbance ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Generalised oedema ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Impaired healing ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Inflammation ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Medical device site discomfort ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Medical device site pain ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Multiple organ dysfunction syndrome ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Non-cardiac chest pain ^† 1	3/2149 (0.14%)	3	5/2149 (0.23%)	5
Oedema peripheral ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Pyrexia ^† 1	3/2149 (0.14%)	3	4/2149 (0.19%)	4
Stent-graft endoleak ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Sudden cardiac death ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Sudden death ^† 1	4/2149 (0.19%)	4	1/2149 (0.05%)	1
Systemic inflammatory response syndrome ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Hepatobiliary disorders
Bile duct obstruction ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Bile duct stenosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bile duct stone ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Biliary colic ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Cholangitis ^† 1	4/2149 (0.19%)	4	4/2149 (0.19%)	4
Cholangitis acute ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cholecystitis ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Cholecystitis acute ^† 1	3/2149 (0.14%)	3	5/2149 (0.23%)	5
Cholecystitis chronic ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Cholelithiasis ^† 1	3/2149 (0.14%)	3	0/2149 (0.00%)	0
Cirrhosis alcoholic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hepatic cirrhosis ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Hepatic failure ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hepatotoxicity ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Liver injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Immune system disorders
Hypersensitivity ^† 1	1/2149 (0.05%)	2	0/2149 (0.00%)	0
Sarcoidosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Transplant rejection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Infections and infestations
Abscess ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Abscess limb ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Acquired immunodeficiency syndrome ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Acute hepatitis b ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Anal abscess ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Appendicitis ^† 1	3/2149 (0.14%)	3	3/2149 (0.14%)	3
Appendicitis perforated ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Arthritis bacterial ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Arthritis infective ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Bacteraemia ^† 1	3/2149 (0.14%)	3	0/2149 (0.00%)	0
Bacterial sepsis ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Biliary sepsis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Bronchitis ^† 1	5/2149 (0.23%)	5	6/2149 (0.28%)	7
Bronchitis bacterial ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bronchitis viral ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bronchopulmonary aspergillosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Covid-19 ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Covid-19 pneumonia ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Candida infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cellulitis ^† 1	14/2149 (0.65%)	17	15/2149 (0.70%)	20
Cellulitis gangrenous ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cholecystitis infective ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Clostridium difficile colitis ^† 1	4/2149 (0.19%)	5	1/2149 (0.05%)	1
Clostridium difficile infection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Coronavirus infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cystitis ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Cytomegalovirus infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Dengue fever ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Dengue haemorrhagic fever ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Device related infection ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Device related sepsis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Diabetic foot infection ^† 1	5/2149 (0.23%)	8	5/2149 (0.23%)	6
Diabetic gangrene ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Diverticulitis ^† 1	5/2149 (0.23%)	5	5/2149 (0.23%)	5
Empyema ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Encephalitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Endocarditis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Erysipelas ^† 1	3/2149 (0.14%)	3	5/2149 (0.23%)	6
Escherichia bacteraemia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Escherichia sepsis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Escherichia urinary tract infection ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Fournier's gangrene ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Fungaemia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Fungal oesophagitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Furuncle ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Gangrene ^† 1	7/2149 (0.33%)	7	3/2149 (0.14%)	4
Gas gangrene ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Gastroenteritis ^† 1	10/2149 (0.47%)	11	9/2149 (0.42%)	9
Gastroenteritis salmonella ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Gastroenteritis viral ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal bacterial infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastrointestinal infection ^† 1	0/2149 (0.00%)	0	4/2149 (0.19%)	4
Herpes zoster ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Infected skin ulcer ^† 1	2/2149 (0.09%)	3	2/2149 (0.09%)	3
Infection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Infectious pleural effusion ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Influenza ^† 1	4/2149 (0.19%)	4	3/2149 (0.14%)	3
Inguinal hernia gangrenous ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Intestinal sepsis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Large intestine infection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Leishmaniasis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Liver abscess ^† 1	3/2149 (0.14%)	4	0/2149 (0.00%)	0
Localised infection ^† 1	3/2149 (0.14%)	3	8/2149 (0.37%)	8
Lower respiratory tract infection ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Mastoiditis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Mediastinitis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Meningitis bacterial ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Meningoencephalitis herpetic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Necrotising fasciitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Osteomyelitis ^† 1	10/2149 (0.47%)	12	12/2149 (0.56%)	13
Osteomyelitis chronic ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Otitis externa ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Otitis media ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Peritonitis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Peritonsillar abscess ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Pilonidal cyst ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Plasmodium falciparum infection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pneumocystis jirovecii pneumonia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pneumonia ^† 1	44/2149 (2.05%)	50	70/2149 (3.26%)	79
Pneumonia bacterial ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Pneumonia fungal ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pneumonia haemophilus ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pneumonia influenzal ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pneumonia legionella ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Post procedural infection ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Postoperative wound infection ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Pulmonary sepsis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pyelonephritis ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Pyelonephritis acute ^† 1	5/2149 (0.23%)	5	2/2149 (0.09%)	2
Pyonephrosis ^† 1	1/2149 (0.05%)	2	0/2149 (0.00%)	0
Respiratory tract infection ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Rocky mountain spotted fever ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Sepsis ^† 1	13/2149 (0.60%)	13	18/2149 (0.84%)	18
Septic shock ^† 1	11/2149 (0.51%)	11	11/2149 (0.51%)	11
Skin infection ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Soft tissue infection ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Splenic abscess ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Staphylococcal bacteraemia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Staphylococcal sepsis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Streptococcal bacteraemia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Streptococcal endocarditis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Subcutaneous abscess ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Superinfection viral ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Suspected covid-19 ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Tonsillitis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Tooth abscess ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Tuberculosis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Tuberculosis bladder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Upper respiratory tract infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Urinary tract infection ^† 1	20/2149 (0.93%)	22	15/2149 (0.70%)	21
Urinary tract infection bacterial ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Urogenital infection bacterial ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Urosepsis ^† 1	4/2149 (0.19%)	4	3/2149 (0.14%)	3
Varicella zoster virus infection ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Vestibular neuronitis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Viral upper respiratory tract infection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Vulval cellulitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Wound infection ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Injury, poisoning and procedural complications
Accidental overdose ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Ankle fracture ^† 1	3/2149 (0.14%)	3	2/2149 (0.09%)	2
Arteriovenous fistula site haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Arteriovenous fistula thrombosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Arteriovenous graft aneurysm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Burns third degree ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Carbon monoxide poisoning ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cervical vertebral fracture ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Chest injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Concussion ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Craniocerebral injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Fall ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Femoral neck fracture ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Femur fracture ^† 1	7/2149 (0.33%)	7	4/2149 (0.19%)	5
Foot fracture ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Forearm fracture ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Foreign body aspiration ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hand fracture ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Head injury ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Hip fracture ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Humerus fracture ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Inflammation of wound ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Injury ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Joint dislocation ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Joint injury ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Lenticular injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Ligament rupture ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Limb injury ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Limb traumatic amputation ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Lower limb fracture ^† 1	3/2149 (0.14%)	3	0/2149 (0.00%)	0
Meniscus injury ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Multiple fractures ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Multiple injuries ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Muscle strain ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Patella fracture ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Pelvic fracture ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Periprosthetic fracture ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Post procedural bile leak ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Post procedural complication ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Post procedural fever ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Post procedural haematoma ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Post procedural haematuria ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Post procedural haemorrhage ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Radiation proctitis ^† 1	1/2149 (0.05%)	3	0/2149 (0.00%)	0
Radius fracture ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Rib fracture ^† 1	5/2149 (0.23%)	5	2/2149 (0.09%)	2
Road traffic accident ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Scapula fracture ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Skin laceration ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Soft tissue injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Spinal column injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Spinal compression fracture ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Spinal fracture ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Subdural haematoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Tendon injury ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Tendon rupture ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Thermal burn ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Tibia fracture ^† 1	5/2149 (0.23%)	5	1/2149 (0.05%)	2
Toxicity to various agents ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Traumatic arthritis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Traumatic haemothorax ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Traumatic intracranial haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Upper limb fracture ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Vascular access malfunction ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Vascular pseudoaneurysm ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Wound evisceration ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Wrist fracture ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Investigations
Blood creatinine increased ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Blood glucose increased ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Blood parathyroid hormone increased ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Blood pressure increased ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Fibrin d dimer increased ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Glomerular filtration rate decreased ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Hepatic enzyme increased ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Oxygen saturation decreased ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Metabolism and nutrition disorders
Acidosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cachexia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Decreased appetite ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Dehydration ^† 1	3/2149 (0.14%)	3	7/2149 (0.33%)	9
Diabetes mellitus ^† 1	9/2149 (0.42%)	11	5/2149 (0.23%)	6
Diabetes mellitus inadequate control ^† 1	2/2149 (0.09%)	2	4/2149 (0.19%)	4
Diabetic ketoacidosis ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	3
Diabetic metabolic decompensation ^† 1	4/2149 (0.19%)	4	4/2149 (0.19%)	4
Electrolyte imbalance ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Fluid overload ^† 1	3/2149 (0.14%)	3	4/2149 (0.19%)	4
Gout ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Hyperglycaemia ^† 1	6/2149 (0.28%)	8	17/2149 (0.79%)	19
Hyperglycaemic hyperosmolar nonketotic syndrome ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Hyperinsulinaemic hypoglycaemia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hyperkalaemia ^† 1	6/2149 (0.28%)	6	12/2149 (0.56%)	12
Hypocalcaemia ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Hypoglycaemia ^† 1	9/2149 (0.42%)	9	18/2149 (0.84%)	19
Hyponatraemia ^† 1	3/2149 (0.14%)	3	2/2149 (0.09%)	2
Hypophagia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Hypovolaemia ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Lactic acidosis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Metabolic acidosis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Metabolic disorder ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Milk-alkali syndrome ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Obesity ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Shock hypoglycaemic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Type 2 diabetes mellitus ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Musculoskeletal and connective tissue disorders
Arthritis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Arthropathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Back pain ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Bone pain ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Bursitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Facet joint syndrome ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Fracture nonunion ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Gouty arthritis ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Intervertebral disc compression ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Intervertebral disc disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Intervertebral disc protrusion ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Lumbar spinal stenosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Muscle spasms ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Musculoskeletal chest pain ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Neuropathic arthropathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Osteoarthritis ^† 1	7/2149 (0.33%)	7	6/2149 (0.28%)	6
Osteochondrosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Osteolysis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Osteonecrosis ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Pain in extremity ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Polymyalgia rheumatica ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Rhabdomyolysis ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Rotator cuff syndrome ^† 1	0/2149 (0.00%)	0	3/2149 (0.14%)	4
Spinal osteoarthritis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Spinal stenosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Systemic lupus erythematosus ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Adenocarcinoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Adenocarcinoma gastric ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Adenocarcinoma of colon ^† 1	3/2149 (0.14%)	3	2/2149 (0.09%)	2
Adenocarcinoma pancreas ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Adrenal adenoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
B-cell lymphoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Basal cell carcinoma ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Benign biliary neoplasm ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bile duct cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bladder cancer ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Bone giant cell tumour malignant ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Breast cancer female ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Bronchial carcinoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Cancer pain ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Cholangiocarcinoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Clear cell renal cell carcinoma ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Colon adenoma ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Colon cancer ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Colon cancer metastatic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Craniopharyngioma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Diffuse large b-cell lymphoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Endometrial adenocarcinoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Endometrial cancer ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Endometrial cancer stage i ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Epithelioid mesothelioma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gallbladder cancer metastatic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Gastric adenoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Gastric cancer ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Hepatic cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hepatic cancer metastatic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hepatocellular carcinoma ^† 1	1/2149 (0.05%)	2	2/2149 (0.09%)	2
Intraductal papillary mucinous neoplasm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Laryngeal cancer ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Lip and/or oral cavity cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Lung adenocarcinoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Lung carcinoma cell type unspecified recurrent ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Lung neoplasm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Lung neoplasm malignant ^† 1	2/2149 (0.09%)	2	6/2149 (0.28%)	6
Lymphoplasmacytoid lymphoma/immunocytoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Malignant peritoneal neoplasm ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Malignant pleural effusion ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Mantle cell lymphoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Metastases to bladder ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Metastases to liver ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Neoplasm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Neoplasm skin ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Non-small cell lung cancer ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Ovarian cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pancreatic carcinoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Pancreatic carcinoma metastatic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pancreatic neoplasm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Papillary renal cell carcinoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Peripheral t-cell lymphoma unspecified recurrent ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Plasma cell myeloma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Prostate cancer ^† 1	10/2149 (0.47%)	10	6/2149 (0.28%)	6
Prostate cancer metastatic ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Prostate cancer stage ii ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Prostatic adenoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Rectal adenocarcinoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Rectal cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Rectosigmoid cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Renal cancer ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Renal cell carcinoma ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Renal cell carcinoma stage iv ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Renal hamartoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Renal neoplasm ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Salivary gland adenoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Schwannoma ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Small cell lung cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Soft tissue neoplasm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Squamous cell carcinoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Squamous cell carcinoma of skin ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Testicular germ cell cancer metastatic ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Transitional cell carcinoma ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Uterine leiomyoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Vaginal cancer ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Vocal cord neoplasm ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Nervous system disorders
Altered state of consciousness ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Basal ganglia haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Brain hypoxia ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Brain injury ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Brain oedema ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Brain stem haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Brain stem infarction ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Brain stem stroke ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Carotid arteriosclerosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Carotid artery aneurysm ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Carotid artery occlusion ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Carotid artery stenosis ^† 1	6/2149 (0.28%)	6	2/2149 (0.09%)	2
Carpal tunnel syndrome ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Cerebellar stroke ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cerebral haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Cerebral infarction ^† 1	8/2149 (0.37%)	8	3/2149 (0.14%)	4
Cerebral ischaemia ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Cerebral vasoconstriction ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Cerebrovascular accident ^† 1	10/2149 (0.47%)	10	8/2149 (0.37%)	8
Cerebrovascular disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Dementia ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Diabetic hyperosmolar coma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Dysarthria ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Embolic stroke ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Encephalopathy ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Epilepsy ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	4
Facial nerve disorder ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Facial paralysis ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Guillain-barre syndrome ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Haemorrhage intracranial ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Haemorrhagic stroke ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Headache ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hemiparesis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hepatic encephalopathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Intracranial aneurysm ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Intraventricular haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Ischaemic cerebral infarction ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Ischaemic stroke ^† 1	22/2149 (1.02%)	23	28/2149 (1.30%)	29
Lacunar stroke ^† 1	2/2149 (0.09%)	2	0/2149 (0.00%)	0
Lumbar radiculopathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Lumbosacral radiculopathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Metabolic encephalopathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Motor neurone disease ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Multiple sclerosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Neuropathy peripheral ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Normal pressure hydrocephalus ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Partial seizures ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Presyncope ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Putamen haemorrhage ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Radiculopathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Seizure ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Subarachnoid haemorrhage ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Syncope ^† 1	7/2149 (0.33%)	7	5/2149 (0.23%)	5
Tension headache ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Thalamic infarction ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Toxic encephalopathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Transient ischaemic attack ^† 1	11/2149 (0.51%)	11	9/2149 (0.42%)	10
Vascular encephalopathy ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Anembryonic gestation ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pre-eclampsia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Premature separation of placenta ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Product Issues
Device dislocation ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Device malfunction ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Device power source issue ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Psychiatric disorders
Completed suicide ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Confusional state ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Delirium ^† 1	0/2149 (0.00%)	0	4/2149 (0.19%)	4
Depression ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Hallucination, visual ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Post stroke depression ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Sleep disorder ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Suicidal ideation ^† 1	3/2149 (0.14%)	3	0/2149 (0.00%)	0
Suicide attempt ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	39/2149 (1.81%)	43	52/2149 (2.42%)	64
Bladder tamponade ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Chronic kidney disease ^† 1	20/2149 (0.93%)	24	31/2149 (1.44%)	34
Cystitis haemorrhagic ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Diabetic nephropathy ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
End stage renal disease ^† 1	26/2149 (1.21%)	27	36/2149 (1.68%)	39
Focal segmental glomerulosclerosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Glomerulonephritis chronic ^† 1	2/2149 (0.09%)	3	6/2149 (0.28%)	9
Glomerulonephritis rapidly progressive ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	6
Haematuria ^† 1	3/2149 (0.14%)	4	2/2149 (0.09%)	2
Hydronephrosis ^† 1	1/2149 (0.05%)	2	1/2149 (0.05%)	1
Iga nephropathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Intercapillary glomerulosclerosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Nephrolithiasis ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	4
Nephropathy ^† 1	2/2149 (0.09%)	2	3/2149 (0.14%)	3
Nephropathy toxic ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	4
Nephrosclerosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Nephrotic syndrome ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	5
Obstructive nephropathy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Prerenal failure ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	4
Renal amyloidosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Renal colic ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Renal failure ^† 1	6/2149 (0.28%)	6	10/2149 (0.47%)	11
Renal impairment ^† 1	14/2149 (0.65%)	15	15/2149 (0.70%)	15
Renal mass ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Tubulointerstitial nephritis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Urate nephropathy ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	3
Ureteric stenosis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Ureterolithiasis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Urethral dilatation ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Urethral stenosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Urinary incontinence ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Urinary retention ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	4
Urinary tract obstruction ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Vesical fistula ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Reproductive system and breast disorders
Balanoposthitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Benign prostatic hyperplasia ^† 1	6/2149 (0.28%)	6	4/2149 (0.19%)	4
Endometrial disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Menometrorrhagia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Prostatomegaly ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Seminal vesicular cyst ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Uterine haemorrhage ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Uterine polyp ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	2
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema ^† 1	4/2149 (0.19%)	4	4/2149 (0.19%)	4
Acute respiratory failure ^† 1	12/2149 (0.56%)	14	11/2149 (0.51%)	12
Asthma ^† 1	1/2149 (0.05%)	1	3/2149 (0.14%)	3
Atelectasis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	7/2149 (0.33%)	8	10/2149 (0.47%)	13
Dyspnoea ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Dyspnoea exertional ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Epistaxis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Haemothorax ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hypoxia ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Laryngeal oedema ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Nasal polyps ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Nasal septum deviation ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Obstructive airways disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pleural effusion ^† 1	1/2149 (0.05%)	1	4/2149 (0.19%)	6
Pleurisy ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pneumonia aspiration ^† 1	2/2149 (0.09%)	2	2/2149 (0.09%)	2
Pneumothorax ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Pulmonary congestion ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Pulmonary embolism ^† 1	8/2149 (0.37%)	8	7/2149 (0.33%)	7
Pulmonary fibrosis ^† 1	1/2149 (0.05%)	2	0/2149 (0.00%)	0
Pulmonary oedema ^† 1	5/2149 (0.23%)	5	8/2149 (0.37%)	8
Respiratory disorder ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Respiratory failure ^† 1	2/2149 (0.09%)	2	6/2149 (0.28%)	6
Sleep apnoea syndrome ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Skin and subcutaneous tissue disorders
Angioedema ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	3
Decubitus ulcer ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Diabetic foot ^† 1	6/2149 (0.28%)	6	7/2149 (0.33%)	10
Neuropathic ulcer ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Pyoderma gangrenosum ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Skin ulcer ^† 1	2/2149 (0.09%)	2	7/2149 (0.33%)	7
Vascular disorders
Aortic aneurysm ^† 1	0/2149 (0.00%)	0	2/2149 (0.09%)	2
Aortic aneurysm rupture ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Aortic dissection ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Aortic stenosis ^† 1	1/2149 (0.05%)	1	2/2149 (0.09%)	2
Arterial occlusive disease ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Arteriosclerosis ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Deep vein thrombosis ^† 1	6/2149 (0.28%)	6	6/2149 (0.28%)	6
Diabetic vascular disorder ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Dry gangrene ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Extremity necrosis ^† 1	3/2149 (0.14%)	3	0/2149 (0.00%)	0
Femoral artery embolism ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Granulomatosis with polyangiitis ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Haematoma ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Hypertension ^† 1	9/2149 (0.42%)	13	10/2149 (0.47%)	10
Hypertensive crisis ^† 1	6/2149 (0.28%)	6	5/2149 (0.23%)	5
Hypertensive emergency ^† 1	0/2149 (0.00%)	0	6/2149 (0.28%)	7
Hypertensive urgency ^† 1	2/2149 (0.09%)	2	1/2149 (0.05%)	1
Hypotension ^† 1	8/2149 (0.37%)	8	3/2149 (0.14%)	3
Hypovolaemic shock ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Iliac artery embolism ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Iliac artery stenosis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Orthostatic hypotension ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Peripheral arterial occlusive disease ^† 1	6/2149 (0.28%)	8	7/2149 (0.33%)	7
Peripheral artery occlusion ^† 1	0/2149 (0.00%)	0	1/2149 (0.05%)	1
Peripheral artery stenosis ^† 1	3/2149 (0.14%)	3	1/2149 (0.05%)	1
Peripheral artery thrombosis ^† 1	1/2149 (0.05%)	2	0/2149 (0.00%)	0
Peripheral ischaemia ^† 1	4/2149 (0.19%)	4	8/2149 (0.37%)	8
Peripheral vascular disorder ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Shock haemorrhagic ^† 1	1/2149 (0.05%)	1	1/2149 (0.05%)	1
Thrombophlebitis ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
Venous thrombosis limb ^† 1	1/2149 (0.05%)	1	0/2149 (0.00%)	0
1 Term from vocabulary, MedDRA 23.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Dapa 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	479/2149 (22.29%)		500/2149 (23.27%)
Gastrointestinal disorders
Diarrhoea ^† 1	45/2149 (2.09%)	56	41/2149 (1.91%)	46
General disorders
Oedema peripheral ^† 1	54/2149 (2.51%)	56	63/2149 (2.93%)	75
Infections and infestations
Nasopharyngitis ^† 1	92/2149 (4.28%)	136	81/2149 (3.77%)	118
Urinary tract infection ^† 1	78/2149 (3.63%)	102	79/2149 (3.68%)	96
Investigations
Glomerular filtration rate decreased ^† 1	39/2149 (1.81%)	45	61/2149 (2.84%)	67
Metabolism and nutrition disorders
Hyperkalaemia ^† 1	53/2149 (2.47%)	67	49/2149 (2.28%)	54
Hypoglycaemia ^† 1	74/2149 (3.44%)	119	70/2149 (3.26%)	96
Musculoskeletal and connective tissue disorders
Back pain ^† 1	44/2149 (2.05%)	46	50/2149 (2.33%)	52
Renal and urinary disorders
Acute kidney injury ^† 1	49/2149 (2.28%)	54	44/2149 (2.05%)	50
Renal impairment ^† 1	51/2149 (2.37%)	55	64/2149 (2.98%)	72
Vascular disorders
Hypertension ^† 1	62/2149 (2.89%)	63	60/2149 (2.79%)	66
1 Term from vocabulary, MedDRA 23.0 † Indicates events were collected by 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.

Results Point of Contact

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Name/Title:	AstraZeneca Clinical Study Information Center
Organization:	AstraZeneca
Phone:	+1-877-240-9479
EMail:	Information.center@astrazeneca.com

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

McEwan P, Darlington O, Miller R, McMurray JJV, Wheeler DC, Heerspink HJL, Briggs A, Bergenheim K, Garcia Sanchez JJ. Cost-Effectiveness of Dapagliflozin as a Treatment for Chronic Kidney Disease: A Health-Economic Analysis of DAPA-CKD. Clin J Am Soc Nephrol. 2022 Dec;17(12):1730-1741. doi: 10.2215/CJN.03790322. Epub 2022 Nov 2.

Jongs N, Chertow GM, Greene T, McMurray JJV, Langkilde AM, Correa-Rotter R, Kashihara N, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators; Members of the DAPA-CKD Trial Committees and Investigators. Correlates and Consequences of an Acute Change in eGFR in Response to the SGLT2 Inhibitor Dapagliflozin in Patients with CKD. J Am Soc Nephrol. 2022 Nov;33(11):2094-2107. doi: 10.1681/ASN.2022030306. Epub 2022 Aug 17.

Vart P, Correa-Rotter R, Hou FF, Jongs N, Chertow GM, Langkilde AM, McMurray JJV, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Douthat W, Escudero E, Isidto R, Khullar D, Bajaj HS, Wheeler DC, Heerspink HJL. Efficacy and Safety of Dapagliflozin in Patients With CKD Across Major Geographic Regions. Kidney Int Rep. 2022 Feb 2;7(4):699-707. doi: 10.1016/j.ekir.2022.01.1060. eCollection 2022 Apr.

Waijer SW, Vart P, Cherney DZI, Chertow GM, Jongs N, Langkilde AM, Mann JFE, Mosenzon O, McMurray JJV, Rossing P, Correa-Rotter R, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL. Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial. Diabetologia. 2022 Jul;65(7):1085-1097. doi: 10.1007/s00125-022-05694-6. Epub 2022 Apr 21.

Heerspink HJL, Jongs N, Chertow GM, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Greene T; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):743-754. doi: 10.1016/S2213-8587(21)00242-4. Epub 2021 Oct 4. Erratum In: Lancet Diabetes Endocrinol. 2022 Oct;10(10):e10.

Jongs N, Greene T, Chertow GM, McMurray JJV, Langkilde AM, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):755-766. doi: 10.1016/S2213-8587(21)00243-6. Epub 2021 Oct 4.

McMurray JJV, Wheeler DC, Stefansson BV, Jongs N, Postmus D, Correa-Rotter R, Chertow GM, Hou FF, Rossing P, Sjostrom CD, Solomon SD, Toto RD, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure. JACC Heart Fail. 2021 Nov;9(11):807-820. doi: 10.1016/j.jchf.2021.06.017. Epub 2021 Aug 23. Erratum In: JACC Heart Fail. 2022 Jun;10(6):446-447.

Persson F, Rossing P, Vart P, Chertow GM, Hou FF, Jongs N, McMurray JJV, Correa-Rotter R, Bajaj HS, Stefansson BV, Toto RD, Langkilde AM, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial. Diabetes Care. 2021 Aug;44(8):1894-1897. doi: 10.2337/dc21-0300. Epub 2021 Jun 28.

Wheeler DC, Stefansson BV, Jongs N, Chertow GM, Greene T, Hou FF, McMurray JJV, Correa-Rotter R, Rossing P, Toto RD, Sjostrom CD, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Jan;9(1):22-31. doi: 10.1016/S2213-8587(20)30369-7.

McMurray JJV, Wheeler DC, Stefansson BV, Jongs N, Postmus D, Correa-Rotter R, Chertow GM, Greene T, Held C, Hou FF, Mann JFE, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effect of Dapagliflozin on Clinical Outcomes in Patients With Chronic Kidney Disease, With and Without Cardiovascular Disease. Circulation. 2021 Feb 2;143(5):438-448. doi: 10.1161/CIRCULATIONAHA.120.051675. Epub 2020 Nov 13.

Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.

Wheeler DC, Stefansson BV, Batiushin M, Bilchenko O, Cherney DZI, Chertow GM, Douthat W, Dwyer JP, Escudero E, Pecoits-Filho R, Furuland H, Gorriz JL, Greene T, Haller H, Hou FF, Kang SW, Isidto R, Khullar D, Mark PB, McMurray JJV, Kashihara N, Nowicki M, Persson F, Correa-Rotter R, Rossing P, Toto RD, Umanath K, Van Bui P, Wittmann I, Lindberg M, Sjostrom CD, Langkilde AM, Heerspink HJL. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics. Nephrol Dial Transplant. 2020 Oct 1;35(10):1700-1711. doi: 10.1093/ndt/gfaa234.

Piperidou A, Loutradis C, Sarafidis P. SGLT-2 inhibitors and nephroprotection: current evidence and future perspectives. J Hum Hypertens. 2021 Jan;35(1):12-25. doi: 10.1038/s41371-020-00393-4. Epub 2020 Aug 10.

Sternlicht HK, Bakris GL. Reductions in albuminuria with SGLT2 inhibitors: a marker for improved renal outcomes in patients without diabetes? Lancet Diabetes Endocrinol. 2020 Jul;8(7):553-555. doi: 10.1016/S2213-8587(20)30185-6. No abstract available.

Gonzalez DE, Foresto RD, Ribeiro AB. SGLT-2 inhibitors in diabetes: a focus on renoprotection. Rev Assoc Med Bras (1992). 2020 Jan 13;66Suppl 1(Suppl 1):s17-s24. doi: 10.1590/1806-9282.66.S1.17.

Layout table for additonal information

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT03036150
Other Study ID Numbers:	D169AC00001 2016-003896-24 ( EudraCT Number )
First Submitted:	January 26, 2017
First Posted:	January 30, 2017
Results First Submitted:	April 19, 2021
Results First Posted:	July 7, 2021
Last Update Posted:	July 7, 2021

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