Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD)

• ClinicalTrials.gov Identifier: NCT02540993
• Recruitment Status: Completed
• First Posted: September 4, 2015
• Results First Posted: July 19, 2021
• Last Update Posted: July 24, 2023
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

• 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: Finerenone (BAY94-8862); Drug: Placebo
• Enrollment: 5734

Participant Flow

Recruitment Details

Study was conducted at multiple centers in 48 countries/regions between 17-SEP-2015 (first participant first visit) and 14-APR-2020 (last participant last visit).

Pre-assignment Details

Overall, 13911 participants were screened. Of them, 8177 participants were screening failures and 5734 participants were randomized to study treatment. 60 participants were prospectively excluded from the analyses because of Good Clinical Practice (GCP) violations, resulting in 5674 participants in the full analysis set (FAS). 16 participants did not take any study drug, resulting in 5658 participants who received study treatment.

Arm/Group Title	Finerenone	Placebo
Arm/Group Description	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Period Title: Overall Study
Started [1]	2866	2868
Included in FAS [2]	2833	2841
Treated	2827	2831
Completed [3]	2824	2832
Not Completed	42	36
Reason Not Completed
Lost to Follow-up	5	3
Withdrawal by Subject	4	6
GCP violations	33	27
[1] Randomized; [2] 60 participants were prospectively excluded from the analyses because of critical GCP violations; [3] Participants (except those with critical GCP violations) were followed up regardless of having started treatment or not, and study completion is independent of administration of study treatment. A participant included in the FAS was considered as having completed the study if there was a contact with the subject after the end-of-study (EOS) notification or if the subject died.

Baseline Characteristics

Arm/Group Title		Finerenone	Placebo	Total
Arm/Group Description		Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy	Total of all reporting groups
Overall Number of Baseline Participants		2833	2841	5674
Baseline Analysis Population Description		Full analysis set (FAS): the FAS comprised all randomized participants (except those with critical GCP violations)
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	2833 participants	2841 participants	5674 participants
		65.44 (8.94)	65.67 (9.16)	65.56 (9.05)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2833 participants	2841 participants	5674 participants
	Female	880 31.1%	811 28.5%	1691 29.8%
	Male	1953 68.9%	2030 71.5%	3983 70.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2833 participants	2841 participants	5674 participants
	Hispanic or Latino	447 15.8%	431 15.2%	878 15.5%
	Not Hispanic or Latino	2376 83.9%	2397 84.4%	4773 84.1%
	Unknown or Not Reported	10 0.4%	13 0.5%	23 0.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2833 participants	2841 participants	5674 participants
	American Indian or Alaska Native	78 2.8%	76 2.7%	154 2.7%
	Asian	717 25.3%	723 25.4%	1440 25.4%
	Native Hawaiian or Other Pacific Islander	11 0.4%	7 0.2%	18 0.3%
	Black or African American	140 4.9%	124 4.4%	264 4.7%
	White	1777 62.7%	1815 63.9%	3592 63.3%
	More than one race	101 3.6%	86 3.0%	187 3.3%
	Unknown or Not Reported	9 0.3%	10 0.4%	19 0.3%
Urinary albumin-to-creatinine ratio (UACR) [1]; Median (Inter-Quartile Range); Unit of measure: Milligram/gram (mg/g)
	Number Analyzed	2831 participants	2840 participants	5671 participants
		832.72; (441.00 to 1628.14)	867.01; (453.11 to 1644.58)	851.87; (446.24 to 1634.22)
		[1] Measure Analysis Population Description: Participants in FAS with evaluable data
Estimated glomerular filtration rate (eGFR) [1]; Mean (Standard Deviation); Unit of measure: mL/min/1.73m^2
	Number Analyzed	2832 participants	2840 participants	5672 participants
		44.36 (12.54)	44.32 (12.57)	44.34 (12.56)
		[1] Measure Analysis Population Description: Participants in FAS with evaluable data

Outcome Measures

1. Primary Outcome

Title	The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease of eGFR ≥40% From Baseline Over at Least 4 Weeks, or Renal Death
Description	Count of participants and time from randomization to the first occurrence of the primary renal composite outcome, onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time Frame	From randomization up until the first occurrence of the primary renal composite endpoint, or censoring at the end of the study, with an average follow-up time of 32 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2833	2841
Measure Type: Count of Participants; Unit of Measure: Participants
	504 17.8%	600 21.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.0014
	Comments	P-value from stratified log-rank test. Significance was considered to be achieved if p-value ≤ 0.03282695.
	Method	Log Rank
	Comments	Stratified log rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.825
	Confidence Interval	(2-Sided) 95%; 0.732 to 0.928
	Estimation Comments	A stratified Cox proportional hazards regression model was used to provide a point estimate of the hazard ratio and a corresponding two-sided 95% confidence interval.

2. Secondary Outcome

Title	The First Occurrence of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, or Hospitalization for Heart Failure
Description	Count of participants and time from randomization to the first occurrence of the key secondary cardiovascular (CV) composite outcome, CV death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for heart failure were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time Frame	From randomization up until the first occurrence of the key secondary CV composite endpoint, or censoring at the end of the study, with an average of 32 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2833	2841
Measure Type: Count of Participants; Unit of Measure: Participants
	367 13.0%	420 14.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.0339
	Comments	P-value from stratified log-rank test. Significance was considered to be achieved if p-value ≤ 0.04967388.
	Method	Log Rank
	Comments	Stratified log rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.860
	Confidence Interval	(2-Sided) 95%; 0.747 to 0.989
	Estimation Comments	A stratified Cox proportional hazards regression model was used to provide a point estimate of the hazard ratio and a corresponding two-sided 95% confidence interval.

3. Secondary Outcome

Title	All-cause Mortality
Description	Count of participants and time from randomization until death due to any cause were evaluated. Number of participants with outcome death is reported as descriptive result and hazard ratio is reported as statistical analysis. Number of participants with outcome death reported here includes deaths occurred after randomization until the end of the study visit. Deaths after end of study visit are not included in this table.
Time Frame	From randomization up until death due to any cause, or censoring at the end of the study visit, with an average of 32 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2833	2841
Measure Type: Count of Participants; Unit of Measure: Participants
	219 7.7%	244 8.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	If treatment effect on both primary and key secondary endpoint is significant, other secondary efficacy endpoints (i.e. all-cause mortality, all-cause hospitalization, change in UACR from baseline to Month 4, and secondary renal composite endpoint) will be tested hierarchically, starting with all-cause mortality. If treatment effect on all-cause mortality was not significant, all other endpoints would be tested in an exploratory manner.
Statistical Test of Hypothesis	P-Value	= 0.2348
	Comments	P-value from stratified log-rank test. Significance was considered to be achieved if p-value ≤ 0.04967388.
	Method	Log Rank
	Comments	Stratified log rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.895
	Confidence Interval	(2-Sided) 95%; 0.746 to 1.075
	Estimation Comments	A stratified Cox proportional hazards regression model was used to provide a point estimate of the hazard ratio and a corresponding two-sided 95% confidence interval.

4. Secondary Outcome

Title	All-cause Hospitalization
Description	Count of participants and time from randomization to the first occurrence of a hospitalization event were evaluated. Number of participants with the event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time Frame	From randomization up until the first occurrence of the hospitalization due to any cause, or censoring at the end of study, with an average of 32 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2833	2841
Measure Type: Count of Participants; Unit of Measure: Participants
	1263 44.6%	1321 46.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	If treatment effect on both primary and key secondary endpoint is significant, other secondary efficacy endpoints (i.e. all-cause mortality, all-cause hospitalization, change in UACR from baseline to Month 4, and secondary renal composite endpoint) will be tested hierarchically, starting with all-cause mortality. If treatment effect on all-cause mortality was not significant, all other endpoints would be tested in an exploratory manner.
Statistical Test of Hypothesis	P-Value	= 0.1623
	Comments	P-value from stratified log-rank test.
	Method	Log Rank
	Comments	Stratified log rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.946
	Confidence Interval	(2-Sided) 95%; 0.876 to 1.022
	Estimation Comments	A stratified Cox proportional hazards regression model was used to provide a point estimate of the hazard ratio and a corresponding two-sided 95% confidence interval.

5. Secondary Outcome

Title	Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline to Month 4
Description	First morning void urine samples were collected to evaluate the urinary albumin-to-creatinine ratio (UACR). Month 4 was the visit closest to day 120 within a time window of 120 ± 30 days after randomization. If no measurements were available in this time window, the participant was excluded from this analysis. Ratio of UACR at Month 4 to UACR at baseline is reported as the change.
Time Frame	From baseline up until Month 4

Outcome Measure Data

Analysis Population Description

Subjects in full analysis set with measurements available within the time window of Month 4

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2711	2705
Least Squares Mean (95% Confidence Interval); Unit of Measure: Ratio
	0.655; (0.637 to 0.673)	0.952; (0.927 to 0.979)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	If treatment effect on both primary and key secondary endpoint is significant, other secondary efficacy endpoints (i.e. all-cause mortality, all-cause hospitalization, change in UACR from baseline to Month 4, and secondary renal composite endpoint) will be tested hierarchically, starting with all-cause mortality. If treatment effect on all-cause mortality was not significant, all other endpoints would be tested in an exploratory manner.
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-value from F-test of equal means between the treatment groups.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of least squares means
	Estimated Value	0.688
	Confidence Interval	(2-Sided) 95%; 0.662 to 0.715
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease in eGFR of ≥57% From Baseline Over at Least 4 Weeks, or Renal Death
Description	Count of participants and time from randomization to the first occurrence of the secondary renal composite outcome, onset of kidney failure, a sustained decrease in eGFR of ≥57% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time Frame	From randomization up until the first occurrence of the composite primary endpoint, or censoring at the end of the study, with an average of 32 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Finerenone	Placebo
Arm/Group Description:	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy	Participants received matching placebo once daily in addition to standard of care therapy
Overall Number of Participants Analyzed	2833	2841
Measure Type: Count of Participants; Unit of Measure: Participants
	252 8.9%	326 11.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Finerenone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	If treatment effect on both primary and key secondary endpoint is significant, other secondary efficacy endpoints (i.e. all-cause mortality, all-cause hospitalization, change in UACR from baseline to Month 4, and secondary renal composite endpoint) will be tested hierarchically, starting with all-cause mortality. If treatment effect on all-cause mortality was not significant, all other endpoints would be tested in an exploratory manner.
Statistical Test of Hypothesis	P-Value	= 0.0012
	Comments	P-value from stratified log-rank test.
	Method	Log Rank
	Comments	Stratified log rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.763
	Confidence Interval	(2-Sided) 95%; 0.648 to 0.900
	Estimation Comments	A stratified Cox proportional hazards regression model was used to provide a point estimate of the hazard ratio and a corresponding two-sided 95% confidence interval.

Adverse Events

Time Frame	After the first dose of study drug up to 3 days after any temporary or permanent interruption of study drug, with an average treatment duration of 27 months
Adverse Event Reporting Description	Adverse events are reported for the safety analysis set (SAF) that comprised all randomized subjects who took at least 1 dose of study drug. Adverse event reporting for the all-cause mortality considers all deaths in full analysis set (FAS, comprised all randomized participants except those with critical GCP violations) that occurred at any time during the study after randomization, including deaths after end of study visit (with an average study duration of 32 months).
Arm/Group Title	Finerenone		Placebo
Arm/Group Description	Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy		Participants received matching placebo once daily in addition to standard of care therapy
All-Cause Mortality
	Finerenone		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	222/2833 (7.84%)		250/2841 (8.80%)
Serious Adverse Events
	Finerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	902/2827 (31.91%)		971/2831 (34.30%)
Blood and lymphatic system disorders
Anaemia * 1	14/2827 (0.50%)	14	19/2831 (0.67%)	21
Febrile neutropenia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Iron deficiency anaemia * 1	5/2827 (0.18%)	6	6/2831 (0.21%)	6
Lymphadenopathy * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Lymphadenopathy mediastinal * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Microcytic anaemia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Neutropenia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Normocytic anaemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pancytopenia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Thrombocytopenia * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Nephrogenic anaemia * 1	0/2827 (0.00%)	0	5/2831 (0.18%)	6
Blood loss anaemia * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Immune thrombocytopenia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cardiac disorders
Angina pectoris * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Angina unstable * 1	0/2827 (0.00%)	0	5/2831 (0.18%)	5
Aortic valve disease mixed * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Aortic valve stenosis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Arrhythmia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Arteriosclerosis coronary artery * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Atrial fibrillation * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Atrial flutter * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Atrioventricular block * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Bradycardia * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Cardiac arrest * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Cardiac asthma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cardiac failure * 1	1/2827 (0.04%)	1	10/2831 (0.35%)	10
Cardiac failure acute * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Cardiac failure chronic * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Cardiac failure congestive * 1	0/2827 (0.00%)	0	8/2831 (0.28%)	8
Cardio-respiratory arrest * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Cardiogenic shock * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cardiomyopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Coronary artery disease * 1	8/2827 (0.28%)	8	5/2831 (0.18%)	5
Hypertensive heart disease * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Left ventricular failure * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Myocardial ischaemia * 1	0/2827 (0.00%)	0	4/2831 (0.14%)	4
Atrial thrombosis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	3
Left ventricular dysfunction * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Aortic valve calcification * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Acute coronary syndrome * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Bifascicular block * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Mitral valve disease * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Acute left ventricular failure * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Stress cardiomyopathy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cardiorenal syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Sinus node dysfunction * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Ischaemic mitral regurgitation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Congenital, familial and genetic disorders
Dermoid cyst * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Factor VIII deficiency * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Phimosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Truncus arteriosus persistent * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ear and labyrinth disorders
Deafness neurosensory * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ear pain * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Tinnitus * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Tympanic membrane perforation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vertigo * 1	3/2827 (0.11%)	3	4/2831 (0.14%)	4
Vertigo positional * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Vestibular disorder * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Deafness unilateral * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Sudden hearing loss * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Endocrine disorders
Goitre * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hyperthyroidism * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pituitary-dependent Cushing's syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Thyroiditis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Thyroid mass * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Eye disorders
Blindness * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cataract * 1	19/2827 (0.67%)	22	12/2831 (0.42%)	15
Cataract diabetic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cataract subcapsular * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diabetic retinal oedema * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Diabetic retinopathy * 1	3/2827 (0.11%)	4	7/2831 (0.25%)	8
Ectropion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Eye disorder * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Eye haemorrhage * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Glaucoma * 1	6/2827 (0.21%)	10	1/2831 (0.04%)	1
Lens dislocation * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Macular oedema * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Open angle glaucoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Optic disc haemorrhage * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Papilloedema * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pterygium * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Retinal artery occlusion * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Retinal detachment * 1	4/2827 (0.14%)	7	2/2831 (0.07%)	3
Retinal haemorrhage * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Retinopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Visual impairment * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Vitreous haemorrhage * 1	6/2827 (0.21%)	8	7/2831 (0.25%)	9
Macular hole * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Ulcerative keratitis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Rhegmatogenous retinal detachment * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Macular fibrosis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Tractional retinal detachment * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Gastrointestinal disorders
Abdominal pain * 1	6/2827 (0.21%)	6	5/2831 (0.18%)	5
Abdominal pain upper * 1	2/2827 (0.07%)	2	4/2831 (0.14%)	5
Anal fistula * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Ascites * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Change of bowel habit * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Chronic gastritis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Colitis * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Colitis ischaemic * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	3
Constipation * 1	3/2827 (0.11%)	3	3/2831 (0.11%)	3
Dental caries * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Diarrhoea * 1	7/2827 (0.25%)	7	6/2831 (0.21%)	6
Diarrhoea haemorrhagic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diverticulum * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Diverticulum intestinal * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Diverticulum intestinal haemorrhagic * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Duodenal polyp * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Duodenal ulcer * 1	3/2827 (0.11%)	3	2/2831 (0.07%)	2
Duodenal ulcer haemorrhage * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Duodenal ulcer perforation * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Duodenitis haemorrhagic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Dyspepsia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Enterocolitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastric haemorrhage * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastric polyps * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastric ulcer haemorrhage * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Gastric ulcer perforation * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Gastritis * 1	2/2827 (0.07%)	3	3/2831 (0.11%)	3
Gastritis erosive * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastritis haemorrhagic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastrooesophageal reflux disease * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastroduodenal ulcer * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastrointestinal disorder * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastrointestinal haemorrhage * 1	13/2827 (0.46%)	16	7/2831 (0.25%)	9
Gastrointestinal necrosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Haematemesis * 1	2/2827 (0.07%)	3	1/2831 (0.04%)	1
Haematochezia * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Haemorrhoids * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Ileus * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Impaired gastric emptying * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Inguinal hernia * 1	1/2827 (0.04%)	1	4/2831 (0.14%)	4
Intestinal angina * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Intestinal ischaemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intestinal obstruction * 1	3/2827 (0.11%)	3	2/2831 (0.07%)	2
Intestinal perforation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Melaena * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Nausea * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Oesophageal achalasia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Oesophageal ulcer haemorrhage * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oesophagitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pancreatic cyst * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pancreatitis * 1	1/2827 (0.04%)	2	3/2831 (0.11%)	3
Pancreatitis acute * 1	7/2827 (0.25%)	8	8/2831 (0.28%)	8
Pancreatitis chronic * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Peptic ulcer haemorrhage * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Proctitis * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Rectal haemorrhage * 1	6/2827 (0.21%)	6	1/2831 (0.04%)	1
Rectal polyp * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Salivary gland calculus * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Small intestinal obstruction * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Umbilical hernia * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Upper gastrointestinal haemorrhage * 1	2/2827 (0.07%)	2	5/2831 (0.18%)	5
Vomiting * 1	3/2827 (0.11%)	3	2/2831 (0.07%)	2
Subileus * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lower gastrointestinal haemorrhage * 1	6/2827 (0.21%)	6	1/2831 (0.04%)	1
Large intestine polyp * 1	5/2827 (0.18%)	5	7/2831 (0.25%)	7
Chilaiditi's syndrome * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oedematous pancreatitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Small intestinal haemorrhage * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Abdominal strangulated hernia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Haemorrhoidal haemorrhage * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Varices oesophageal * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Faecaloma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Gastrointestinal ulcer haemorrhage * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Alcoholic pancreatitis * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Retroperitoneal haematoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Abdominal hernia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Gastric mucosal lesion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Gastrointestinal motility disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Incarcerated umbilical hernia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Pancreatic duct stenosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Haemorrhagic erosive gastritis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Functional gastrointestinal disorder * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Retroperitoneal mass * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Strangulated umbilical hernia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intra-abdominal fluid collection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Obstructive pancreatitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastrointestinal vascular malformation haemorrhagic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
General disorders
Asthenia * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Chest discomfort * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	3
Chest pain * 1	13/2827 (0.46%)	15	18/2831 (0.64%)	20
Death * 1	2/2827 (0.07%)	2	4/2831 (0.14%)	4
Fatigue * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Gait disturbance * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Generalised oedema * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Hypothermia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Malaise * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Mass * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oedema * 1	4/2827 (0.14%)	4	1/2831 (0.04%)	1
Oedema peripheral * 1	8/2827 (0.28%)	10	7/2831 (0.25%)	7
Pyrexia * 1	4/2827 (0.14%)	5	2/2831 (0.07%)	2
Soft tissue inflammation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Swelling face * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Peripheral swelling * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hernia pain * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
General physical health deterioration * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oedema due to renal disease * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	5
Inflammation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Non-cardiac chest pain * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Device intolerance * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vascular stent stenosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Multiple organ dysfunction syndrome * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hepatobiliary disorders
Bile duct stone * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Biliary colic * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Cholangitis * 1	2/2827 (0.07%)	3	4/2831 (0.14%)	4
Cholangitis acute * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	3
Cholecystitis * 1	4/2827 (0.14%)	4	3/2831 (0.11%)	3
Cholecystitis acute * 1	2/2827 (0.07%)	2	9/2831 (0.32%)	10
Cholecystitis chronic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cholelithiasis * 1	12/2827 (0.42%)	14	1/2831 (0.04%)	1
Cholestasis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hepatic cirrhosis * 1	1/2827 (0.04%)	1	5/2831 (0.18%)	5
Hepatic function abnormal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hepatitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hepatitis acute * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Hepatitis alcoholic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Jaundice cholestatic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Liver disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Bile duct obstruction * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Biliary dilatation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hepatic lesion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Drug-induced liver injury * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Immune system disorders
Drug hypersensitivity * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Infections and infestations
Abdominal wall abscess * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Appendicitis * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Appendicitis perforated * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Atypical pneumonia * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	3
Bacteraemia * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Bronchitis * 1	9/2827 (0.32%)	9	13/2831 (0.46%)	15
Campylobacter gastroenteritis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Carbuncle * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cellulitis * 1	26/2827 (0.92%)	30	22/2831 (0.78%)	23
Chronic sinusitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Clostridium difficile colitis * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Cystitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dengue fever * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diabetic gangrene * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Diverticulitis * 1	3/2827 (0.11%)	3	5/2831 (0.18%)	5
Ear infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Endocarditis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Endophthalmitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Epididymitis * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Epiglottitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Erysipelas * 1	11/2827 (0.39%)	11	14/2831 (0.49%)	16
Fournier's gangrene * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gangrene * 1	5/2827 (0.18%)	5	5/2831 (0.18%)	5
Gastroenteritis * 1	9/2827 (0.32%)	9	13/2831 (0.46%)	13
Gastroenteritis salmonella * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Gastroenteritis viral * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Hepatitis B * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hepatitis viral * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Herpes zoster * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Infected skin ulcer * 1	4/2827 (0.14%)	6	3/2831 (0.11%)	3
Infection * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Influenza * 1	7/2827 (0.25%)	8	3/2831 (0.11%)	3
Kidney infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Labyrinthitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Leptospirosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Liver abscess * 1	2/2827 (0.07%)	2	5/2831 (0.18%)	5
Localised infection * 1	7/2827 (0.25%)	7	2/2831 (0.07%)	2
Lower respiratory tract infection * 1	5/2827 (0.18%)	5	5/2831 (0.18%)	5
Mastoiditis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Oesophageal candidiasis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Orchitis * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Osteomyelitis * 1	14/2827 (0.50%)	14	12/2831 (0.42%)	12
Osteomyelitis chronic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Otitis externa * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Otitis media * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Paronychia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Periodontitis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Peritonitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pharyngitis streptococcal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pneumonia * 1	70/2827 (2.48%)	75	103/2831 (3.64%)	115
Pneumonia respiratory syncytial viral * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pneumonia streptococcal * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Postoperative wound infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Prostatic abscess * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pulmonary tuberculosis * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Pyelonephritis * 1	7/2827 (0.25%)	7	4/2831 (0.14%)	4
Pyelonephritis acute * 1	5/2827 (0.18%)	5	1/2831 (0.04%)	1
Pyelonephritis chronic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pyonephrosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Renal abscess * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Sepsis * 1	15/2827 (0.53%)	15	17/2831 (0.60%)	18
Septic shock * 1	3/2827 (0.11%)	3	5/2831 (0.18%)	5
Sinusitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Splenic abscess * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Subcutaneous abscess * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Tracheobronchitis * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Upper respiratory tract infection * 1	0/2827 (0.00%)	0	5/2831 (0.18%)	5
Urethritis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Urinary tract infection * 1	21/2827 (0.74%)	22	23/2831 (0.81%)	30
Viral infection * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Viral pericarditis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Viral tracheitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Wound infection * 1	4/2827 (0.14%)	4	3/2831 (0.11%)	3
Oral infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Urosepsis * 1	5/2827 (0.18%)	5	7/2831 (0.25%)	9
Anal abscess * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Rectal abscess * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Streptococcal sepsis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pyelocystitis * 1	2/2827 (0.07%)	3	0/2831 (0.00%)	0
Neutropenic sepsis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	2
Peritonsillitis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Groin abscess * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Abscess limb * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Burn infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Haematoma infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Chest wall abscess * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pulmonary sepsis * 1	5/2827 (0.18%)	5	1/2831 (0.04%)	1
Febrile infection * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Escherichia urinary tract infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Arthritis bacterial * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Peritoneal tuberculosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Enterococcal sepsis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Clostridium difficile infection * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Staphylococcal sepsis * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Enteritis infectious * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Klebsiella bacteraemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Viraemia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Acute hepatitis B * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Intervertebral discitis * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	4
Diabetic foot infection * 1	4/2827 (0.14%)	4	5/2831 (0.18%)	5
Abdominal abscess * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Pneumonia bacterial * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Borrelia infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Respiratory syncytial virus infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Herpes ophthalmic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Peritonitis bacterial * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Soft tissue infection * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Urinary tract infection staphylococcal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Respiratory tract infection * 1	3/2827 (0.11%)	3	4/2831 (0.14%)	5
Infective spondylitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Stoma site infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Dermo-hypodermitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Post procedural sepsis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Post procedural infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
H1N1 influenza * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Device related sepsis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Infective exacerbation of bronchiectasis * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	4
Infected seroma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Medical device site joint infection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Infected bite * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Large intestine infection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Nephritis bacterial * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bullous erysipelas * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Injury, poisoning and procedural complications
Accident * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Accidental overdose * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Acetabulum fracture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Alcohol poisoning * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Ankle fracture * 1	7/2827 (0.25%)	7	5/2831 (0.18%)	5
Back injury * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Burns second degree * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Clavicle fracture * 1	2/2827 (0.07%)	3	0/2831 (0.00%)	0
Concussion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dislocation of vertebra * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Facial bones fracture * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Fall * 1	2/2827 (0.07%)	2	6/2831 (0.21%)	6
Femoral neck fracture * 1	7/2827 (0.25%)	7	3/2831 (0.11%)	4
Femur fracture * 1	6/2827 (0.21%)	6	9/2831 (0.32%)	9
Fibula fracture * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Foot fracture * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Forearm fracture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hand fracture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Head injury * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Heat stroke * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hip fracture * 1	6/2827 (0.21%)	6	3/2831 (0.11%)	3
Humerus fracture * 1	4/2827 (0.14%)	4	7/2831 (0.25%)	8
Incisional hernia * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Injury * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intentional overdose * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Joint dislocation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Muscle rupture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Overdose * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Patella fracture * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Poisoning deliberate * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Radiation proctitis * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Radius fracture * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Rib fracture * 1	5/2827 (0.18%)	5	4/2831 (0.14%)	4
Road traffic accident * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Soft tissue injury * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Spinal cord injury cervical * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Spinal fracture * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Sternal fracture * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Subdural haematoma * 1	4/2827 (0.14%)	4	4/2831 (0.14%)	4
Subdural haemorrhage * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Tendon injury * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Tibia fracture * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Ulna fracture * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Wrist fracture * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Traumatic fracture * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Cervical vertebral fracture * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Lumbar vertebral fracture * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Thoracic vertebral fracture * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Muscle strain * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Contusion * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Post procedural haemorrhage * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Thermal burn * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Wound necrosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Inflammation of wound * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Arteriovenous fistula site complication * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Post concussion syndrome * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Skin laceration * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Incision site haematoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Joint injury * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Pelvic fracture * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Ligament injury * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Limb injury * 1	4/2827 (0.14%)	4	1/2831 (0.04%)	1
Skull fracture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Chest injury * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Upper limb fracture * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Postoperative wound complication * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Lower limb fracture * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Shunt malfunction * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Post procedural inflammation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Abdominal wound dehiscence * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Toxicity to various agents * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Craniocerebral injury * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Meniscus injury * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Cardiac contusion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Traumatic haemothorax * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Incarcerated incisional hernia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vascular access malfunction * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ocular procedural complication * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Investigations
Alanine aminotransferase increased * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Aspartate aminotransferase increased * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Biopsy kidney * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Blood creatine phosphokinase increased * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	3
Blood creatine phosphokinase MB increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Blood creatinine increased * 1	1/2827 (0.04%)	1	4/2831 (0.14%)	4
Blood glucose increased * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Blood potassium increased * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Blood pressure increased * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Colonoscopy * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Endoscopy small intestine * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Gamma-glutamyltransferase increased * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Glomerular filtration rate decreased * 1	5/2827 (0.18%)	5	4/2831 (0.14%)	4
Heart rate increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Weight decreased * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Ejection fraction decreased * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Protein urine present * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cardiac pacemaker evaluation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Computerised tomogram abdomen * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cardiac stress test abnormal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Troponin T increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Blood alkaline phosphatase increased * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Light chain analysis increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Anticoagulation drug level above therapeutic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hepatic enzyme increased * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Arteriogram * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Inflammatory marker increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Influenza A virus test positive * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cardiovascular examination * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Peripheral arteriogram * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Liver function test increased * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Angiocardiogram * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Metabolism and nutrition disorders
Dehydration * 1	7/2827 (0.25%)	7	5/2831 (0.18%)	5
Diabetes mellitus * 1	10/2827 (0.35%)	12	16/2831 (0.57%)	18
Diabetes mellitus inadequate control * 1	12/2827 (0.42%)	13	19/2831 (0.67%)	21
Diabetic ketoacidosis * 1	7/2827 (0.25%)	7	7/2831 (0.25%)	7
Fluid overload * 1	7/2827 (0.25%)	9	7/2831 (0.25%)	8
Fluid retention * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Gout * 1	1/2827 (0.04%)	1	7/2831 (0.25%)	8
Hypercalcaemia * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Hyperglycaemia * 1	17/2827 (0.60%)	20	23/2831 (0.81%)	26
Hyperkalaemia * 1	42/2827 (1.49%)	45	12/2831 (0.42%)	14
Hyperosmolar state * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Hypervolaemia * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Hypocalcaemia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Hypoglycaemia * 1	21/2827 (0.74%)	23	31/2831 (1.10%)	33
Hypoglycaemia unawareness * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hypokalaemia * 1	3/2827 (0.11%)	3	5/2831 (0.18%)	5
Hypomagnesaemia * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Hyponatraemia * 1	8/2827 (0.28%)	12	1/2831 (0.04%)	1
Hypoproteinaemia * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hypovolaemia * 1	3/2827 (0.11%)	4	2/2831 (0.07%)	2
Ketoacidosis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Metabolic acidosis * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Tumour lysis syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Calciphylaxis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metabolic disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Diabetic complication * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Malnutrition * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Decreased appetite * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hyperglycaemic hyperosmolar nonketotic syndrome * 1	2/2827 (0.07%)	2	4/2831 (0.14%)	4
Type 2 diabetes mellitus * 1	14/2827 (0.50%)	16	22/2831 (0.78%)	28
Diabetic metabolic decompensation * 1	12/2827 (0.42%)	15	14/2831 (0.49%)	15
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/2827 (0.00%)	0	5/2831 (0.18%)	5
Arthritis * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Back disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Back pain * 1	3/2827 (0.11%)	3	5/2831 (0.18%)	6
Bursitis * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Cervical spinal stenosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Costochondritis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Flank pain * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gouty arthritis * 1	5/2827 (0.18%)	6	2/2831 (0.07%)	2
Lumbar spinal stenosis * 1	4/2827 (0.14%)	5	7/2831 (0.25%)	10
Musculoskeletal pain * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neck pain * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neuropathic arthropathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Osteitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Osteoarthritis * 1	11/2827 (0.39%)	11	8/2831 (0.28%)	8
Osteoarthropathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Osteonecrosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pain in extremity * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Polymyalgia rheumatica * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Rhabdomyolysis * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Rheumatoid arthritis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	2
Rotator cuff syndrome * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Spinal osteoarthritis * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Tenosynovitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Musculoskeletal disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intervertebral disc protrusion * 1	7/2827 (0.25%)	7	13/2831 (0.46%)	16
Musculoskeletal chest pain * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Haematoma muscle * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Connective tissue inflammation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Foot deformity * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	3
Intervertebral disc degeneration * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Spondylitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Spondylolisthesis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Osteonecrosis of jaw * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Soft tissue necrosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Spinal instability * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Limb mass * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Spinal stenosis * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Adenocarcinoma * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Adenocarcinoma gastric * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Adenocarcinoma of colon * 1	2/2827 (0.07%)	2	4/2831 (0.14%)	4
Adenoma benign * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Adrenal adenoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
B-cell lymphoma stage IV * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Basal cell carcinoma * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	2
Benign salivary gland neoplasm * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bladder cancer * 1	2/2827 (0.07%)	2	5/2831 (0.18%)	5
Bladder cancer recurrent * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Bladder neoplasm * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Bladder squamous cell carcinoma stage unspecified * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Bladder transitional cell carcinoma * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Bowen's disease * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Breast cancer * 1	4/2827 (0.14%)	5	5/2831 (0.18%)	5
Breast neoplasm * 1	1/2827 (0.04%)	3	1/2831 (0.04%)	1
Cholangiocarcinoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Chronic lymphocytic leukaemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Colon cancer * 1	4/2827 (0.14%)	4	4/2831 (0.14%)	4
Colon cancer stage IV * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diffuse large B-cell lymphoma recurrent * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Endometrial adenocarcinoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Fibroadenoma of breast * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Fibrosarcoma * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Gastric cancer * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Gastrointestinal carcinoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Haemangioma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hypergammaglobulinaemia benign monoclonal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Laryngeal squamous cell carcinoma * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Lentigo maligna * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lipoma * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Lung adenocarcinoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lung carcinoma cell type unspecified stage IV * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Lung squamous cell carcinoma stage IV * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Lymphoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Malignant melanoma * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Malignant neoplasm of ampulla of Vater * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metastases to bone * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Metastases to liver * 1	0/2827 (0.00%)	0	4/2831 (0.14%)	4
Metastases to lung * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Metastases to lymph nodes * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Metastases to spine * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Metastatic malignant melanoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Myelodysplastic syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Nasal cavity cancer * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neoplasm * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	3
Neoplasm prostate * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neuroendocrine carcinoma of the skin * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oesophageal adenocarcinoma * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Oesophageal carcinoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oropharyngeal cancer * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	2
Pancreatic carcinoma * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Pancreatic carcinoma metastatic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Penile cancer * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Plasma cell myeloma * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Prostate cancer metastatic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Rectal adenocarcinoma * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Renal cancer * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Sarcoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Small cell lung cancer * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	3
Squamous cell carcinoma of lung * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Squamous cell carcinoma of skin * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	2
Squamous cell carcinoma of the oral cavity * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Squamous cell carcinoma of the tongue * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Superficial spreading melanoma stage unspecified * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Tongue neoplasm malignant stage unspecified * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Tonsil cancer * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Transitional cell carcinoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vulval cancer stage 0 * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Colon adenoma * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Lung cancer metastatic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metastatic renal cell carcinoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastrointestinal stromal tumour * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metastases to spleen * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Adenocarcinoma pancreas * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Rectal cancer metastatic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oesophageal cancer metastatic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Breast cancer metastatic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Infected neoplasm * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cancer pain * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gallbladder adenocarcinoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lung neoplasm malignant * 1	9/2827 (0.32%)	9	4/2831 (0.14%)	4
Metastases to central nervous system * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Pancreatic carcinoma stage IV * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Small cell lung cancer metastatic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Prostate cancer * 1	13/2827 (0.46%)	13	5/2831 (0.18%)	7
Monoclonal gammopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Benign pancreatic neoplasm * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Brain neoplasm * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Malignant urinary tract neoplasm * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Colorectal cancer * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Renal neoplasm * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Salivary gland neoplasm * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pituitary tumour benign * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pancreatic neoplasm * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lung neoplasm * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Tongue neoplasm * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Urethral neoplasm * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Renal cell carcinoma * 1	2/2827 (0.07%)	3	1/2831 (0.04%)	1
Sarcoma metastatic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Tumour rupture * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Malignant neoplasm of unknown primary site * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hepatocellular carcinoma * 1	3/2827 (0.11%)	3	3/2831 (0.11%)	3
Hepatobiliary cancer * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Intraductal proliferative breast lesion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Clear cell renal cell carcinoma * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Ductal adenocarcinoma of pancreas * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Angiomyofibroblastoma * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Adenocarcinoma metastatic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Nervous system disorders
Alcohol induced persisting dementia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Altered state of consciousness * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Aphasia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Brown-Sequard syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Carotid artery stenosis * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Carpal tunnel syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebral haemorrhage * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Cerebral infarction * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Cerebral ischaemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebrovascular accident * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebrovascular disorder * 1	4/2827 (0.14%)	4	0/2831 (0.00%)	0
Cervicobrachial syndrome * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Coma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cranial nerve palsies multiple * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Diabetic neuropathy * 1	6/2827 (0.21%)	7	3/2831 (0.11%)	4
Dizziness * 1	6/2827 (0.21%)	6	10/2831 (0.35%)	10
Drop attacks * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Dysarthria * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Epilepsy * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Facial paralysis * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Headache * 1	2/2827 (0.07%)	2	3/2831 (0.11%)	3
Hemiparesis * 1	0/2827 (0.00%)	0	3/2831 (0.11%)	3
Hepatic encephalopathy * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
IIIrd nerve paralysis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Lethargy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Loss of consciousness * 1	4/2827 (0.14%)	4	2/2831 (0.07%)	2
Migraine * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Myelopathy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Neuralgia * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Neuropathy peripheral * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Polyneuropathy * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Post herpetic neuralgia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Presyncope * 1	4/2827 (0.14%)	4	2/2831 (0.07%)	2
Radiculopathy * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Sciatica * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Seizure * 1	4/2827 (0.14%)	4	3/2831 (0.11%)	3
Subarachnoid haemorrhage * 1	3/2827 (0.11%)	3	2/2831 (0.07%)	3
Syncope * 1	12/2827 (0.42%)	12	22/2831 (0.78%)	22
Transient ischaemic attack * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Vertebrobasilar insufficiency * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Brain oedema * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Carotid artery occlusion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vertebral artery occlusion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Arachnoid cyst * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Balance disorder * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Lacunar infarction * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Facial paresis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Neurodegenerative disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebral disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neuroglycopenia * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Cerebrovascular insufficiency * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebral vasoconstriction * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ischaemic cerebral infarction * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Ischaemic stroke * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Mononeuropathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Vascular encephalopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebral arteriosclerosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Carotid arteriosclerosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Thrombotic cerebral infarction * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cerebral microangiopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dementia with Lewy bodies * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hypoxic-ischaemic encephalopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Secondary cerebellar degeneration * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Lumbosacral radiculopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cerebral vascular occlusion * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Post stroke epilepsy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hemianaesthesia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Angiopathic neuropathy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Product Issues
Device malfunction * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Device dislocation * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	3
Psychiatric disorders
Alcohol abuse * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Anxiety * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Confusional state * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Depression * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	4
Insomnia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Mania * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Suicide attempt * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Mental status changes * 1	1/2827 (0.04%)	2	3/2831 (0.11%)	4
Bipolar disorder * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Major depression * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Renal and urinary disorders
Azotaemia * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Calculus bladder * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Calculus urinary * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Chromaturia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cystitis ulcerative * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dysuria * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Glomerular vascular disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	2
Haematuria * 1	3/2827 (0.11%)	3	4/2831 (0.14%)	5
Hydronephrosis * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Intercapillary glomerulosclerosis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Nephrolithiasis * 1	6/2827 (0.21%)	8	1/2831 (0.04%)	1
Nephropathy * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	3
Nephropathy toxic * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Nephrosclerosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Nephrotic syndrome * 1	3/2827 (0.11%)	3	9/2831 (0.32%)	9
Nocturia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Proteinuria * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Renal artery stenosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Renal colic * 1	1/2827 (0.04%)	2	1/2831 (0.04%)	1
Renal cyst * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Renal failure * 1	7/2827 (0.25%)	7	7/2831 (0.25%)	7
Renal haemorrhage * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Renal tubular acidosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Urinary incontinence * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Urinary retention * 1	6/2827 (0.21%)	7	3/2831 (0.11%)	3
Tubulointerstitial nephritis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Urinary bladder polyp * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Hypertensive nephropathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Bladder cyst * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Urinary tract obstruction * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Diabetic nephropathy * 1	18/2827 (0.64%)	23	16/2831 (0.57%)	19
Renal mass * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Renal impairment * 1	8/2827 (0.28%)	8	8/2831 (0.28%)	10
Chronic kidney disease * 1	12/2827 (0.42%)	12	22/2831 (0.78%)	26
Urethral stenosis * 1	2/2827 (0.07%)	3	0/2831 (0.00%)	0
Acute kidney injury * 1	56/2827 (1.98%)	63	51/2831 (1.80%)	55
Bladder outlet obstruction * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Perinephritis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
End stage renal disease * 1	5/2827 (0.18%)	5	4/2831 (0.14%)	4
Ureterolithiasis * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Subcapsular renal haematoma * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Reproductive system and breast disorders
Balanoposthitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Benign prostatic hyperplasia * 1	5/2827 (0.18%)	5	10/2831 (0.35%)	10
Dysfunctional uterine bleeding * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Endometrial hyperplasia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metrorrhagia * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ovarian cyst * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Uterine haemorrhage * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Uterine polyp * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Vaginal haemorrhage * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Prostatomegaly * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Endometrial thickening * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Testicular mass * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema * 1	3/2827 (0.11%)	3	2/2831 (0.07%)	2
Acute respiratory failure * 1	6/2827 (0.21%)	6	15/2831 (0.53%)	18
Aspiration * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Asthma * 1	1/2827 (0.04%)	1	6/2831 (0.21%)	7
Bronchitis chronic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Chronic obstructive pulmonary disease * 1	14/2827 (0.50%)	21	12/2831 (0.42%)	13
Chronic respiratory failure * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Cough * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dyspnoea * 1	8/2827 (0.28%)	9	7/2831 (0.25%)	7
Dyspnoea at rest * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Dyspnoea exertional * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Emphysema * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Epistaxis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hypoxia * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Interstitial lung disease * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Laryngeal oedema * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Laryngeal stenosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pharyngeal oedema * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pleural effusion * 1	4/2827 (0.14%)	4	2/2831 (0.07%)	2
Pleurisy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pneumonia aspiration * 1	1/2827 (0.04%)	1	4/2831 (0.14%)	4
Pneumonitis * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Pneumothorax * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Pulmonary congestion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pulmonary embolism * 1	8/2827 (0.28%)	8	4/2831 (0.14%)	4
Pulmonary hypertension * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pulmonary oedema * 1	1/2827 (0.04%)	1	4/2831 (0.14%)	4
Respiratory distress * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Respiratory failure * 1	5/2827 (0.18%)	6	7/2831 (0.25%)	7
Sleep apnoea syndrome * 1	2/2827 (0.07%)	2	2/2831 (0.07%)	2
Vocal cord polyp * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Wheezing * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Restrictive pulmonary disease * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Vocal cord cyst * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bronchopneumopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pulmonary mass * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Laryngeal dysplasia * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Epiglottic cyst * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Laryngeal mass * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Pulmonary hilum mass * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Obstructive airways disorder * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Skin and subcutaneous tissue disorders
Actinic keratosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Angioedema * 1	3/2827 (0.11%)	3	1/2831 (0.04%)	1
Blister * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Decubitus ulcer * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dermal cyst * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dermatitis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dermatitis allergic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dermatitis bullous * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dermatitis herpetiformis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Drug eruption * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Ecchymosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Eczema * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	2
Hyperkeratosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Ingrowing nail * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Parapsoriasis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pemphigoid * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Purpura * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Rash * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Skin disorder * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Skin necrosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Skin ulcer * 1	9/2827 (0.32%)	10	16/2831 (0.57%)	19
Stasis dermatitis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Stevens-Johnson syndrome * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Neuropathic ulcer * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Diabetic foot * 1	13/2827 (0.46%)	16	18/2831 (0.64%)	22
Social circumstances
Social stay hospitalisation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Surgical and medical procedures
Aortic valve replacement * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Arteriovenous fistula operation * 1	3/2827 (0.11%)	3	3/2831 (0.11%)	3
Cardiac pacemaker insertion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cholecystectomy * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Coronary artery bypass * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Foot amputation * 1	1/2827 (0.04%)	1	3/2831 (0.11%)	3
Haemodialysis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Hip arthroplasty * 1	3/2827 (0.11%)	4	6/2831 (0.21%)	6
Hysterectomy * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Insertion of ambulatory peritoneal catheter * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Knee arthroplasty * 1	4/2827 (0.14%)	5	6/2831 (0.21%)	7
Leg amputation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Metatarsal excision * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Myomectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Nephrectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Parathyroidectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Physiotherapy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pterygium operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Rhinoplasty * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Spinal decompression * 1	2/2827 (0.07%)	2	0/2831 (0.00%)	0
Tenotomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Toe amputation * 1	4/2827 (0.14%)	5	4/2831 (0.14%)	4
Transurethral prostatectomy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Umbilical hernia repair * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Uterine prolapse repair * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Vitrectomy * 1	1/2827 (0.04%)	1	4/2831 (0.14%)	6
Lymphadenectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Cardiac pacemaker replacement * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Implantable defibrillator insertion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Coronary angioplasty * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Spinal fusion surgery * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Radical prostatectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diabetes mellitus management * 1	3/2827 (0.11%)	3	0/2831 (0.00%)	0
Transurethral bladder resection * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cardiac rehabilitation therapy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Continuous positive airway pressure * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Nephroureterectomy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Pancreaticosplenectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Polypectomy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Maxillofacial operation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Corneal transplant * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Meniscus operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Bladder neck operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Urethral dilation procedure * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intervertebral disc operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Rehabilitation therapy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Dialysis device insertion * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Skin neoplasm excision * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Foot operation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Amputation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Arthrodesis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Colectomy * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Colon operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Eye operation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Oophorectomy * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Prostatectomy * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Gastrectomy * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Gastric bypass * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hydrocele operation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intestinal operation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Nail operation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Skin graft * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Spinal operation * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Wound treatment * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bladder polypectomy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Cataract operation * 1	4/2827 (0.14%)	5	12/2831 (0.42%)	14
Aneurysm repair * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bowel preparation * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Retinopexy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Intraocular lens implant * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Vascular graft * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Internal fixation of spine * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Bile duct stent removal * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Gastric banding reversal * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Therapeutic nerve ablation * 1	1/2827 (0.04%)	2	0/2831 (0.00%)	0
Peripheral artery bypass * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Large intestinal polypectomy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Metabolic surgery * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Vascular disorders
Aortic aneurysm * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	4
Aortic dissection * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Aortic stenosis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Arteriovenous fistula * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Blood pressure fluctuation * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Circulatory collapse * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Embolism venous * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Haematoma * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Hypertension * 1	15/2827 (0.53%)	16	23/2831 (0.81%)	26
Hypertensive crisis * 1	4/2827 (0.14%)	4	7/2831 (0.25%)	7
Hypotension * 1	7/2827 (0.25%)	7	5/2831 (0.18%)	5
Hypovolaemic shock * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Intermittent claudication * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Lymphoedema * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Malignant hypertension * 1	0/2827 (0.00%)	0	2/2831 (0.07%)	2
Orthostatic hypotension * 1	4/2827 (0.14%)	4	2/2831 (0.07%)	3
Peripheral ischaemia * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Peripheral vascular disorder * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Temporal arteritis * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Thromboangiitis obliterans * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Thrombophlebitis * 1	1/2827 (0.04%)	1	2/2831 (0.07%)	2
Thrombophlebitis superficial * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Thrombosis * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Shock haemorrhagic * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Dry gangrene * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Deep vein thrombosis * 1	4/2827 (0.14%)	4	0/2831 (0.00%)	0
Peripheral artery aneurysm * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Peripheral artery occlusion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Hypertensive emergency * 1	2/2827 (0.07%)	3	4/2831 (0.14%)	5
Hypertensive urgency * 1	4/2827 (0.14%)	4	1/2831 (0.04%)	1
Venous occlusion * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Extremity necrosis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Peripheral embolism * 1	1/2827 (0.04%)	1	0/2831 (0.00%)	0
Diabetic vascular disorder * 1	2/2827 (0.07%)	2	1/2831 (0.04%)	1
Microangiopathy * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
Peripheral arterial occlusive disease * 1	0/2827 (0.00%)	0	6/2831 (0.21%)	6
Peripheral artery stenosis * 1	1/2827 (0.04%)	1	1/2831 (0.04%)	1
Peripheral artery thrombosis * 1	0/2827 (0.00%)	0	1/2831 (0.04%)	1
1 Term from vocabulary, MedDRA (23.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Finerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1602/2827 (56.67%)		1584/2831 (55.95%)
Blood and lymphatic system disorders
Anaemia * 1	201/2827 (7.11%)	218	177/2831 (6.25%)	196
Gastrointestinal disorders
Constipation * 1	128/2827 (4.53%)	146	162/2831 (5.72%)	179
Diarrhoea * 1	183/2827 (6.47%)	216	188/2831 (6.64%)	224
General disorders
Oedema peripheral * 1	183/2827 (6.47%)	216	303/2831 (10.70%)	359
Infections and infestations
Bronchitis * 1	127/2827 (4.49%)	140	142/2831 (5.02%)	188
Nasopharyngitis * 1	241/2827 (8.52%)	368	250/2831 (8.83%)	391
Upper respiratory tract infection * 1	181/2827 (6.40%)	274	185/2831 (6.53%)	262
Urinary tract infection * 1	168/2827 (5.94%)	215	185/2831 (6.53%)	259
Investigations
Glomerular filtration rate decreased * 1	177/2827 (6.26%)	225	130/2831 (4.59%)	146
Metabolism and nutrition disorders
Hyperkalaemia * 1	422/2827 (14.93%)	634	212/2831 (7.49%)	281
Hypoglycaemia * 1	137/2827 (4.85%)	212	173/2831 (6.11%)	299
Musculoskeletal and connective tissue disorders
Arthralgia * 1	142/2827 (5.02%)	163	145/2831 (5.12%)	157
Back pain * 1	175/2827 (6.19%)	187	170/2831 (6.00%)	182
Nervous system disorders
Dizziness * 1	143/2827 (5.06%)	165	147/2831 (5.19%)	162
Vascular disorders
Hypertension * 1	200/2827 (7.07%)	229	262/2831 (9.25%)	323
1 Term from vocabulary, MedDRA (23.0); * 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.

 

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: Bayer
• Phone: 1-888-8422937
• EMail: clinical-trials-contact@bayer.com

Publications of Results:

Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. Epub 2020 Oct 23.

Filippatos G, Anker SD, Agarwal R, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Schloemer P, Tornus I, Joseph A, Bakris GL; FIDELIO-DKD Investigators. Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes. Circulation. 2021 Feb 9;143(6):540-552. doi: 10.1161/CIRCULATIONAHA.120.051898. Epub 2020 Nov 16.

Other Publications:

Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Nowack C, Kolkhof P, Ferreira AC, Schloemer P, Filippatos G; on behalf of the FIDELIO-DKD study investigators; FIDELIO-DKD study investigators. Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial. Am J Nephrol. 2019;50(5):333-344. doi: 10.1159/000503713. Epub 2019 Oct 25.

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

Pitt B, Agarwal R, Anker SD, Ruilope LM, Rossing P, Ahlers C, Brinker M, Joseph A, Lambelet M, Lawatscheck R, Filippatos GS; FIDELIO-DKD and FIGARO-DKD Investigators. Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis. JAMA Netw Open. 2022 Oct 3;5(10):e2236123. doi: 10.1001/jamanetworkopen.2022.36123.

Ruilope LM, Agarwal R, Anker SD, Filippatos G, Pitt B, Rossing P, Sarafidis P, Schmieder RE, Joseph A, Rethemeier N, Nowack C, Bakris GL; FIDELIO-DKD Investigators. Blood Pressure and Cardiorenal Outcomes With Finerenone in Chronic Kidney Disease in Type 2 Diabetes. Hypertension. 2022 Dec;79(12):2685-2695. doi: 10.1161/HYPERTENSIONAHA.122.19744. Epub 2022 Oct 12.

Rossing P, Burgess E, Agarwal R, Anker SD, Filippatos G, Pitt B, Ruilope LM, Gillard P, MacIsaac RJ, Wainstein J, Joseph A, Brinker M, Roessig L, Scott C, Bakris GL; FIDELIO-DKD Investigators. Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes According to Baseline HbA1c and Insulin Use: An Analysis From the FIDELIO-DKD Study. Diabetes Care. 2022 Apr 1;45(4):888-897. doi: 10.2337/dc21-1944. Erratum In: Diabetes Care. 2023 Sep 1;46(9):1721.

Rossing P, Filippatos G, Agarwal R, Anker SD, Pitt B, Ruilope LM, Chan JCN, Kooy A, McCafferty K, Schernthaner G, Wanner C, Joseph A, Scheerer MF, Scott C, Bakris GL; FIDELIO-DKD Investigators. Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium-Glucose Cotransporter-2 Inhibitor Therapy. Kidney Int Rep. 2021 Oct 14;7(1):36-45. doi: 10.1016/j.ekir.2021.10.008. eCollection 2022 Jan.

Agarwal R, Anker SD, Filippatos G, Pitt B, Rossing P, Ruilope LM, Boletis J, Toto R, Umpierrez GE, Wanner C, Wada T, Scott C, Joseph A, Ogbaa I, Roberts L, Scheerer MF, Bakris GL. Effects of canagliflozin versus finerenone on cardiorenal outcomes: exploratory post hoc analyses from FIDELIO-DKD compared to reported CREDENCE results. Nephrol Dial Transplant. 2022 Jun 23;37(7):1261-1269. doi: 10.1093/ndt/gfab336.

Filippatos G, Bakris GL, Pitt B, Agarwal R, Rossing P, Ruilope LM, Butler J, Lam CSP, Kolkhof P, Roberts L, Tasto C, Joseph A, Anker SD; FIDELIO-DKD Investigators. Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes. J Am Coll Cardiol. 2021 Jul 13;78(2):142-152. doi: 10.1016/j.jacc.2021.04.079. Epub 2021 May 17.

Erraez S, Lopez-Mesa M, Gomez-Fernandez P. Mineralcorticoid receptor blockers in chronic kidney disease. Nefrologia (Engl Ed). 2021 May-Jun;41(3):258-275. doi: 10.1016/j.nefro.2020.10.001. Epub 2020 Dec 24. English, Spanish.

Agarwal R, Anker SD, Bakris G, Filippatos G, Pitt B, Rossing P, Ruilope L, Gebel M, Kolkhof P, Nowack C, Joseph A; FIDELIO-DKD and FIGARO-DKD Investigators. Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone. Nephrol Dial Transplant. 2022 May 25;37(6):1014-1023. doi: 10.1093/ndt/gfaa294.

Chung EY, Ruospo M, Natale P, Bolignano D, Navaneethan SD, Palmer SC, Strippoli GF. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 27;10(10):CD007004. doi: 10.1002/14651858.CD007004.pub4.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02540993
• Other Study ID Numbers: 16244; 2015-000990-11 ( EudraCT Number )
• First Submitted: September 2, 2015
• First Posted: September 4, 2015
• Results First Submitted: April 5, 2021
• Results First Posted: July 19, 2021
• Last Update Posted: July 24, 2023