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CANVAS - CANagliflozin cardioVascular Assessment Study (CANVAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01032629
Recruitment Status : Completed
First Posted : December 15, 2009
Results First Posted : December 7, 2018
Last Update Posted : December 7, 2018
Sponsor:
Collaborator:
The George Institute for Global Health, Australia
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Diabetes Mellitus, Type 2
Cardiovascular Diseases
Risk Factors
Interventions Drug: Placebo
Drug: Canagliflozin (JNJ-28431754) 100 mg
Drug: Canagliflozin (JNJ-28431754) 300 mg
Enrollment 4330
Recruitment Details  
Pre-assignment Details No Text enterred
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Period Title: Overall Study
Started 1442 1445 1443
Treated 1441 1445 1441
Completed 1297 [1] 1344 [1] 1355 [1]
Not Completed 145 101 88
Reason Not Completed
Closed Site             21             18             16
Withdrawal by Subject             50             36             35
Lost to Follow-up             74             47             37
[1]
Participants who died on trial were considered completed
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg Total
Hide Arm/Group Description Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment. Total of all reporting groups
Overall Number of Baseline Participants 1442 1445 1443 4330
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
62.3  (7.94) 62.2  (8) 62.8  (8.13) 62.4  (8.02)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
Female
486
  33.7%
484
  33.5%
499
  34.6%
1469
  33.9%
Male
956
  66.3%
961
  66.5%
944
  65.4%
2861
  66.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
Hispanic or Latino
149
  10.3%
142
   9.8%
125
   8.7%
416
   9.6%
Not Hispanic or Latino
1288
  89.3%
1300
  90.0%
1317
  91.3%
3905
  90.2%
Unknown or Not Reported
5
   0.3%
3
   0.2%
1
   0.1%
9
   0.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
American Indian or Alaska Native
3
   0.2%
1
   0.1%
1
   0.1%
5
   0.1%
Asian
262
  18.2%
270
  18.7%
263
  18.2%
795
  18.4%
Native Hawaiian or Other Pacific Islander
1
   0.1%
2
   0.1%
3
   0.2%
6
   0.1%
Black or African American
35
   2.4%
32
   2.2%
38
   2.6%
105
   2.4%
White
1064
  73.8%
1060
  73.4%
1055
  73.1%
3179
  73.4%
More than one race
10
   0.7%
8
   0.6%
13
   0.9%
31
   0.7%
Unknown or Not Reported
67
   4.6%
72
   5.0%
70
   4.9%
209
   4.8%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
Asian
262
  18.2%
270
  18.7%
263
  18.2%
795
  18.4%
Black or African American
35
   2.4%
32
   2.2%
38
   2.6%
105
   2.4%
Hispanic or Latino
134
   9.3%
123
   8.5%
106
   7.3%
363
   8.4%
Other
82
   5.7%
86
   6.0%
88
   6.1%
256
   5.9%
White Non- Hispanic
929
  64.4%
934
  64.6%
948
  65.7%
2811
  64.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1442 participants 1445 participants 1443 participants 4330 participants
Argentina
57
   4.0%
48
   3.3%
55
   3.8%
160
   3.7%
Australia
57
   4.0%
60
   4.2%
60
   4.2%
177
   4.1%
Belgium
3
   0.2%
10
   0.7%
8
   0.6%
21
   0.5%
Canada
134
   9.3%
139
   9.6%
123
   8.5%
396
   9.1%
Colombia
4
   0.3%
1
   0.1%
2
   0.1%
7
   0.2%
Czech Republic
37
   2.6%
37
   2.6%
43
   3.0%
117
   2.7%
Estonia
19
   1.3%
13
   0.9%
12
   0.8%
44
   1.0%
Germany
47
   3.3%
62
   4.3%
66
   4.6%
175
   4.0%
Hungary
38
   2.6%
50
   3.5%
37
   2.6%
125
   2.9%
India
229
  15.9%
232
  16.1%
234
  16.2%
695
  16.1%
Israel
5
   0.3%
11
   0.8%
9
   0.6%
25
   0.6%
Luxembourg
1
   0.1%
0
   0.0%
0
   0.0%
1
   0.0%
Malaysia
32
   2.2%
24
   1.7%
17
   1.2%
73
   1.7%
Mexico
40
   2.8%
48
   3.3%
36
   2.5%
124
   2.9%
Netherlands
70
   4.9%
77
   5.3%
81
   5.6%
228
   5.3%
New Zealand
27
   1.9%
22
   1.5%
25
   1.7%
74
   1.7%
Norway
41
   2.8%
33
   2.3%
35
   2.4%
109
   2.5%
Poland
47
   3.3%
54
   3.7%
43
   3.0%
144
   3.3%
Russia
146
  10.1%
118
   8.2%
125
   8.7%
389
   9.0%
Spain
64
   4.4%
74
   5.1%
71
   4.9%
209
   4.8%
Sweden
23
   1.6%
26
   1.8%
22
   1.5%
71
   1.6%
Ukraine
50
   3.5%
39
   2.7%
58
   4.0%
147
   3.4%
United Kingdom
31
   2.1%
29
   2.0%
32
   2.2%
92
   2.1%
United States
240
  16.6%
238
  16.5%
249
  17.3%
727
  16.8%
1.Primary Outcome
Title Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke
Hide Description MACE, defined as a composite of CV death, non-fatal MI, and nonfatal stroke. Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of MACE are presented.
Time Frame Up to approximately 8 years
Hide Outcome Measure Data
Hide Analysis Population Description
The primary analysis was based on the intent-to-treat (ITT) analysis set for adjudicated MACE, and included all randomized participants. As per planned analysis, the results were reported separately and combined for both doses.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin (Total)
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 mg or 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1442 1445 1443 2888
Measure Type: Number
Unit of Measure: Events per 1000 patient-year
30.36 28.41 25.37 26.89
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.4576
Comments [Not Specified]
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.78 to 1.12
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.0467
Comments [Not Specified]
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.68 to 1.00
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin (Total)
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1120
Comments [Not Specified]
Method Cox proportional hazard method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.75 to 1.03
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT)
Hide Description The homeostatic model assessment (HOMA) quantifies insulin resistance and beta-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady-state beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100 percent.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) included subset of participants who were not receiving insulin at baseline and had at least one post-baseline HOMA2-%B measurement on-treatment prior to initiation of insulin.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 463 511 477
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of HOMA2
4.02  (1.611) 6.82  (1.533) 8.09  (1.587)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.210
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 2.79
Confidence Interval (2-Sided) 95%
-1.571 to 7.154
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.224
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.072
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 4.07
Confidence Interval (2-Sided) 95%
-0.368 to 8.504
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.261
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With Progression of Albuminuria at the End-of-Treatment
Hide Description Progression defined as the development of micro-albuminuria (albumin/creatinine ratio (ACR) greater than or equal to [>=] 30 milligram per gram (mg/g) and less than or equal to <= 300 mg/g) or macroalbuminuria (ACR of >300 mg/g) in a participant with baseline normoalbuminuria or the development of macro-albuminuria in a participant with baseline microalbuminuria. Percentage of participants with progression of albuminuria at the end-of-treatment were assessed.
Time Frame End of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were treated, had both baseline and post−baseline ACR measurements, and baseline ACR<=300 mg/g.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1286 1334 1298
Measure Type: Number
Unit of Measure: Percentage of participants
24.0 20.2 18.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.67 to 0.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.58 to 0.85
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment
Hide Description A raised proinsulin-to-insulin ratio due to impaired processing of proinsulin is an early marker of beta cell dysfunction. Beta-cell dysfunction was evaluated by calculating the PI/I ratio, which estimates the capacity of beta cells to convert proinsulin to insulin and may represent an acceptable method to indicate the degree of beta-cell secretion.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set: all randomized participants who received at least 1 dose of study drug. 'N' (number of participants analyzed): number of participants evaluable for this outcome measure, had both baseline and any post-baseline PI/I ratio measurements on-treatment prior to initiation of insulin and didn’t receive insulin through baseline.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 370 426 412
Least Squares Mean (Standard Error)
Unit of Measure: Picomole per milli international units
0.70  (0.150) 0.67  (0.140) 1.03  (0.142)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.03
Confidence Interval (2-Sided) 95%
-0.429 to 0.374
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.205
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.33
Confidence Interval (2-Sided) 95%
-0.079 to 0.731
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.206
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment
Hide Description Urinary Albumin/Creatinine Ratio is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine.
Time Frame Baseline and End of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and had both baseline and post-baseline ACR measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1377 1398 1384
Geometric Mean (95% Confidence Interval)
Unit of Measure: Milligram per gram (mg/g)
29.30
(27.66 to 31.03)
25.50
(24.09 to 27)
24.47
(23.11 to 25.91)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.800 to 0.940
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.770 to 0.910
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment
Hide Description Change from baseline in Estimated Glomerular Filtration Rate (eGFR) was assessed at end of treatment. GFR is a measure of the rate at which blood is filtered by the kidney. Modification of Diet in Renal Disease (MDRD) is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and sex. eGFR milliliters/minute/1.73 meters square (mL/min/1.73 m^2) = 175 * (serum creatinine) ^ 1.154 * (Age) ^-0.203 *(0.742 if female) * (1.21 if Black).
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who had both baseline and post-baseline eGFR measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1394 1412 1383
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73 m^2
-5.23  (0.390) -3.55  (0.388) -3.98  (0.392)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 1.68
Confidence Interval (2-Sided) 95%
0.599 to 2.755
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.550
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 1.24
Confidence Interval (2-Sided) 95%
0.160 to 2.328
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.553
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment
Hide Description Change from baseline in glycated hemoglobin (HbA1c) percentage (%) was assessed at end of treatment. Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the average glucose concentration in the blood.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who had both baseline and any post-baseline HbA1C measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1366 1392 1352
Least Squares Mean (Standard Error)
Unit of Measure: HbA1c (%)
0.01  (0.032) -0.26  (0.032) -0.31  (0.032)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.27
Confidence Interval (2-Sided) 95%
-0.355 to -0.177
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.045
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.32
Confidence Interval (2-Sided) 95%
-0.405 to -0.227
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.046
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment
Hide Description Change from baseline in the fasting plasma glucose levels at end-of-treatment was assessed.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and had both baseline and post-baseline fasting plasma glucose measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1392 1410 1377
Least Squares Mean (Standard Error)
Unit of Measure: Millimoles per liter (mmol/L)
0.16  (0.076) -0.42  (0.075) -0.57  (0.076)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.58
Confidence Interval (2-Sided) 95%
-0.794 to -0.374
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.107
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.73
Confidence Interval (2-Sided) 95%
-0.945 to -0.523
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.108
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Percent Change From Baseline in Body Weight at End-of-Treatment
Hide Description Percent change from baseline in body weight was assessed at the end of treatment.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline body weight.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1398 1415 1388
Least Squares Mean (Standard Error)
Unit of Measure: Percent change
-0.50  (0.184) -3.47  (0.183) -4.12  (0.185)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -2.96
Confidence Interval 95%
-3.472 to -2.454
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.260
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -3.61
Confidence Interval (2-Sided) 95%
-4.125 to -3.103
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.261
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment
Hide Description Change from baseline in systolic blood pressure and diastolic blood pressure was assessed.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who and had both baseline and post-baseline blood pressure measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1398 1415 1388
Least Squares Mean (Standard Error)
Unit of Measure: Millimeter of mercury (mmHg)
SBP(Change at end of treatment) -1.96  (0.377) -4.91  (0.375) -6.49  (0.378)
DBP (Change at end of treatment) -2.88  (0.223) -3.70  (0.221) -4.51  (0.223)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Statistical analysis (Systolic blood pressure) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -2.96
Confidence Interval (2-Sided) 95%
-3.998 to -1.914
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.532
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Statistical analysis (Systolic blood pressure) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -4.53
Confidence Interval (2-Sided) 95%
-5.579 to -3.484
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.534
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Statistical analysis (Diastolic blood pressure) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -0.82
Confidence Interval (2-Sided) 95%
-1.437 to -0.205
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.314
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Statistical analysis (Diastolic blood pressure) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value -1.63
Confidence Interval (2-Sided) 95%
-2.245 to -1.007
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.316
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline in Triglycerides Levels at End-of-Treatment
Hide Description Change from baseline in triglycerides levels was assessed.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1325 1371 1321
Mean (Standard Deviation)
Unit of Measure: mmol/L
0.05  (1.597) 0.13  (1.679) 0.09  (1.238)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehman Estimate
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.040 to 0.070
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehman Estimate
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.030 to 0.080
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment
Hide Description Change from baseline in cholesterol, high-density lipoprotein cholesterol and low density lipoprotein cholesterol levels were assessed.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1325 1371 1321
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
Cholesterol (change at EOT) -0.07  (0.028) 0.11  (0.027) 0.16  (0.028)
HDL-C (change at EOT) -0.01  (0.006) 0.04  (0.006) 0.05  (0.006)
LDL-C (change at EOT) -0.07  (0.022) 0.04  (0.022) 0.10  (0.023)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Statistical analysis (Cholesterol) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.18
Confidence Interval (2-Sided) 95%
0.105 to 0.259
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.039
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Statistical analysis (Cholesterol) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.23
Confidence Interval (2-Sided) 95%
0.152 to 0.307
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.039
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Statistical analysis (HDL-C)
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.05
Confidence Interval (2-Sided) 95%
0.031 to 0.065
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.009
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Statistical analysis (HDL-C) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
0.040 to 0.075
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.009
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments Statistical analysis (LDL-C) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.11
Confidence Interval (2-Sided) 95%
0.046 to 0.170
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.032
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments Statistical analysis (LDL-C) Comparison for canagliflozin versus placebo is reported here.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.16
Confidence Interval (2-Sided) 95%
0.102 to 0.226
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.032
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment
Hide Description Change from baseline in LDL-C to HDL-C ratio was assessed.
Time Frame Baseline and end of treatment (approximately 338 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description:
Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment.
Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
Overall Number of Participants Analyzed 1325 1371 1321
Least Squares Mean (Standard Error)
Unit of Measure: Ratio
-0.04  (0.021) -0.02  (0.021) 0.00  (0.021)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 100 mg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.040 to 0.076
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.030
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Canagliflozin 300 mg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of Least Square Mean
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.023 to 0.094
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.030
Estimation Comments [Not Specified]
Time Frame Approximately 8 years
Adverse Event Reporting Description On-treatment analysis set included all randomized participants who were treated and received at least 1 dose of study drug.
 
Arm/Group Title Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Hide Arm/Group Description Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment. Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment.
All-Cause Mortality
Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   74/1441 (5.14%)   68/1445 (4.71%)   66/1441 (4.58%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   584/1441 (40.53%)   601/1445 (41.59%)   606/1441 (42.05%) 
Blood and lymphatic system disorders       
Anaemia * 1  8/1441 (0.56%)  2/1445 (0.14%)  7/1441 (0.49%) 
Haemorrhagic Anaemia * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Hypochromic Anaemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Iron Deficiency Anaemia * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Microcytic Anaemia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Normochromic Normocytic Anaemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pancytopenia * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Pernicious Anaemia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Splenomegaly * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Thrombocytopenia * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Cardiac disorders       
Acute Coronary Syndrome * 1  8/1441 (0.56%)  3/1445 (0.21%)  3/1441 (0.21%) 
Acute Left Ventricular Failure * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Acute Myocardial Infarction * 1  10/1441 (0.69%)  10/1445 (0.69%)  8/1441 (0.56%) 
Adams-Stokes Syndrome * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Angina Pectoris * 1  24/1441 (1.67%)  15/1445 (1.04%)  30/1441 (2.08%) 
Angina Unstable * 1  20/1441 (1.39%)  24/1445 (1.66%)  28/1441 (1.94%) 
Anginal Equivalent * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Aortic Valve Incompetence * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Aortic Valve Stenosis * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Arrhythmia * 1  3/1441 (0.21%)  0/1445 (0.00%)  4/1441 (0.28%) 
Arteriosclerosis Coronary Artery * 1  1/1441 (0.07%)  1/1445 (0.07%)  3/1441 (0.21%) 
Atrial Fibrillation * 1  26/1441 (1.80%)  22/1445 (1.52%)  17/1441 (1.18%) 
Atrial Flutter * 1  6/1441 (0.42%)  6/1445 (0.42%)  8/1441 (0.56%) 
Atrioventricular Block * 1  2/1441 (0.14%)  0/1445 (0.00%)  1/1441 (0.07%) 
Atrioventricular Block Complete * 1  2/1441 (0.14%)  2/1445 (0.14%)  3/1441 (0.21%) 
Atrioventricular Block Second Degree * 1  3/1441 (0.21%)  2/1445 (0.14%)  2/1441 (0.14%) 
Bradycardia * 1  4/1441 (0.28%)  2/1445 (0.14%)  5/1441 (0.35%) 
Cardiac Arrest * 1  6/1441 (0.42%)  7/1445 (0.48%)  6/1441 (0.42%) 
Cardiac Disorder * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Cardiac Failure * 1  19/1441 (1.32%)  19/1445 (1.31%)  23/1441 (1.60%) 
Cardiac Failure Acute * 1  2/1441 (0.14%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cardiac Failure Chronic * 1  5/1441 (0.35%)  3/1445 (0.21%)  2/1441 (0.14%) 
Cardiac Failure Congestive * 1  20/1441 (1.39%)  15/1445 (1.04%)  14/1441 (0.97%) 
Cardio-Respiratory Arrest * 1  2/1441 (0.14%)  3/1445 (0.21%)  1/1441 (0.07%) 
Cardiogenic Shock * 1  0/1441 (0.00%)  2/1445 (0.14%)  4/1441 (0.28%) 
Cardiomyopathy * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cardiopulmonary Failure * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Cardiovascular Disorder * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Cor Pulmonale * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Coronary Artery Disease * 1  24/1441 (1.67%)  24/1445 (1.66%)  23/1441 (1.60%) 
Coronary Artery Insufficiency * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Coronary Artery Occlusion * 1  2/1441 (0.14%)  2/1445 (0.14%)  0/1441 (0.00%) 
Coronary Artery Stenosis * 1  5/1441 (0.35%)  5/1445 (0.35%)  7/1441 (0.49%) 
Coronary Artery Thrombosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Hypertensive Heart Disease * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Ischaemic Cardiomyopathy * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Left Ventricular Dysfunction * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Left Ventricular Failure * 1  2/1441 (0.14%)  1/1445 (0.07%)  2/1441 (0.14%) 
Mitral Valve Incompetence * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Myocardial Fibrosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Myocardial Infarction * 1  16/1441 (1.11%)  18/1445 (1.25%)  11/1441 (0.76%) 
Myocardial Ischaemia * 1  9/1441 (0.62%)  11/1445 (0.76%)  6/1441 (0.42%) 
Palpitations * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pericardial Effusion * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Pericarditis Constrictive * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Pulseless Electrical Activity * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Restrictive Cardiomyopathy * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Right Ventricular Failure * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Sinus Bradycardia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Sinus Node Dysfunction * 1  2/1441 (0.14%)  0/1445 (0.00%)  1/1441 (0.07%) 
Supraventricular Tachycardia * 1  6/1441 (0.42%)  1/1445 (0.07%)  1/1441 (0.07%) 
Tachycardia * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ventricular Arrhythmia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Ventricular Extrasystoles * 1  2/1441 (0.14%)  1/1445 (0.07%)  1/1441 (0.07%) 
Ventricular Fibrillation * 1  3/1441 (0.21%)  2/1445 (0.14%)  1/1441 (0.07%) 
Ventricular Tachycardia * 1  3/1441 (0.21%)  2/1445 (0.14%)  3/1441 (0.21%) 
Congenital, familial and genetic disorders       
Arteriovenous Malformation * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Developmental Hip Dysplasia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Hydrocele * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Phimosis * 1  0/1441 (0.00%)  2/1445 (0.14%)  4/1441 (0.28%) 
Vitello-Intestinal Duct Remnant * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Ear and labyrinth disorders       
Deafness Neurosensory * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hypoacusis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Vertigo * 1  2/1441 (0.14%)  2/1445 (0.14%)  3/1441 (0.21%) 
Vertigo Positional * 1  2/1441 (0.14%)  1/1445 (0.07%)  1/1441 (0.07%) 
Endocrine disorders       
Empty Sella Syndrome * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Goitre * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Hyperparathyroidism * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hyperparathyroidism Primary * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Inappropriate Antidiuretic Hormone Secretion * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Thyroiditis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Eye disorders       
Amaurosis Fugax * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Blindness Unilateral * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cataract * 1  8/1441 (0.56%)  8/1445 (0.55%)  10/1441 (0.69%) 
Cataract Diabetic * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Cataract Nuclear * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cataract Subcapsular * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Dacryostenosis Acquired * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Diabetic Retinopathy * 1  1/1441 (0.07%)  3/1445 (0.21%)  2/1441 (0.14%) 
Diplopia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Exophthalmos * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Eye Haemorrhage * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Eyelid Ptosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Glaucoma * 1  2/1441 (0.14%)  0/1445 (0.00%)  3/1441 (0.21%) 
Lens Dislocation * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Macular Degeneration * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Macular Fibrosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Macular Hole * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Maculopathy * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Ocular Myasthenia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Open Angle Glaucoma * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Optic Ischaemic Neuropathy * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Retinal Detachment * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Retinal Vascular Thrombosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Retinopathy Proliferative * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Ulcerative Keratitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Visual Impairment * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Vitreous Floaters * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Vitreous Haemorrhage * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Gastrointestinal disorders       
Abdominal Hernia * 1  3/1441 (0.21%)  2/1445 (0.14%)  5/1441 (0.35%) 
Abdominal Incarcerated Hernia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Abdominal Pain * 1  4/1441 (0.28%)  3/1445 (0.21%)  5/1441 (0.35%) 
Abdominal Pain Upper * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Abdominal Wall Haematoma * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Anal Fissure * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Anal Fistula * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ascites * 1  1/1441 (0.07%)  1/1445 (0.07%)  3/1441 (0.21%) 
Bowel Movement Irregularity * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Chronic Gastritis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Colitis * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Colitis Ischaemic * 1  1/1441 (0.07%)  2/1445 (0.14%)  0/1441 (0.00%) 
Colitis Microscopic * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Colitis Ulcerative * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Colon Dysplasia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Colonic Pseudo-Obstruction * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Constipation * 1  2/1441 (0.14%)  2/1445 (0.14%)  0/1441 (0.00%) 
Diarrhoea * 1  3/1441 (0.21%)  3/1445 (0.21%)  1/1441 (0.07%) 
Dieulafoy's Vascular Malformation * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Diverticulum Intestinal * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Diverticulum Intestinal Haemorrhagic * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Duodenal Ulcer * 1  4/1441 (0.28%)  0/1445 (0.00%)  2/1441 (0.14%) 
Dyspepsia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Dysphagia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Enteritis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Erosive Duodenitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Eructation * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Food Poisoning * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Gallstone Ileus * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gastric Mucosal Hypertrophy * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Gastric Perforation * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gastric Ulcer * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Gastric Ulcer Perforation * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gastritis * 1  1/1441 (0.07%)  2/1445 (0.14%)  2/1441 (0.14%) 
Gastrointestinal Erosion * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Gastrointestinal Haemorrhage * 1  2/1441 (0.14%)  0/1445 (0.00%)  4/1441 (0.28%) 
Gastrointestinal Necrosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gastrointestinal Obstruction * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Gastrooesophageal Reflux Disease * 1  1/1441 (0.07%)  2/1445 (0.14%)  1/1441 (0.07%) 
Haematemesis * 1  1/1441 (0.07%)  1/1445 (0.07%)  2/1441 (0.14%) 
Haemorrhoidal Haemorrhage * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Haemorrhoids * 1  1/1441 (0.07%)  3/1445 (0.21%)  0/1441 (0.00%) 
Hernial Eventration * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hiatus Hernia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Ileus * 1  1/1441 (0.07%)  3/1445 (0.21%)  0/1441 (0.00%) 
Ileus Paralytic * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Incarcerated Umbilical Hernia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Inguinal Hernia * 1  0/1441 (0.00%)  3/1445 (0.21%)  0/1441 (0.00%) 
Intestinal Haemorrhage * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Intestinal Ischaemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Intestinal Polyp * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Intra-Abdominal Haemorrhage * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Intussusception * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Large Intestine Perforation * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Large Intestine Polyp * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Lower Gastrointestinal Haemorrhage * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Mallory-Weiss Syndrome * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Oesophageal Achalasia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Oesophageal Obstruction * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Oesophageal Ulcer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Oesophageal Varices Haemorrhage * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Pancreatic Cyst * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pancreatic Pseudocyst * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pancreatitis * 1  1/1441 (0.07%)  3/1445 (0.21%)  2/1441 (0.14%) 
Pancreatitis Acute * 1  1/1441 (0.07%)  4/1445 (0.28%)  1/1441 (0.07%) 
Pancreatitis Haemorrhagic * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pancreatitis Necrotising * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Peptic Ulcer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Rectal Haemorrhage * 1  4/1441 (0.28%)  6/1445 (0.42%)  3/1441 (0.21%) 
Rectal Ulcer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Small Intestinal Obstruction * 1  0/1441 (0.00%)  2/1445 (0.14%)  3/1441 (0.21%) 
Tooth Disorder * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Umbilical Hernia * 1  3/1441 (0.21%)  0/1445 (0.00%)  1/1441 (0.07%) 
Upper Gastrointestinal Haemorrhage * 1  3/1441 (0.21%)  3/1445 (0.21%)  1/1441 (0.07%) 
Varices Oesophageal * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Vomiting * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
General disorders       
Adverse Drug Reaction * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Application Site Dermatitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Asthenia * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Chest Discomfort * 1  3/1441 (0.21%)  3/1445 (0.21%)  2/1441 (0.14%) 
Chest Pain * 1  23/1441 (1.60%)  26/1445 (1.80%)  13/1441 (0.90%) 
Complication Associated with Device * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Death * 1  8/1441 (0.56%)  8/1445 (0.55%)  8/1441 (0.56%) 
Drug Intolerance * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Facial Pain * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Fatigue * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Generalised Oedema * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Impaired Healing * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Ischaemic Ulcer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Medical Device Site Reaction * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Multiple Organ Dysfunction Syndrome * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Necrosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Non-Cardiac Chest Pain * 1  2/1441 (0.14%)  8/1445 (0.55%)  5/1441 (0.35%) 
Oedema Peripheral * 1  3/1441 (0.21%)  3/1445 (0.21%)  1/1441 (0.07%) 
Perforated Ulcer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Peripheral Swelling * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pyrexia * 1  3/1441 (0.21%)  3/1445 (0.21%)  3/1441 (0.21%) 
Strangulated Hernia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Sudden Cardiac Death * 1  5/1441 (0.35%)  0/1445 (0.00%)  9/1441 (0.62%) 
Sudden Death * 1  6/1441 (0.42%)  5/1445 (0.35%)  3/1441 (0.21%) 
Vascular Stent Occlusion * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Vascular Stent Restenosis * 1  2/1441 (0.14%)  3/1445 (0.21%)  1/1441 (0.07%) 
Hepatobiliary disorders       
Alcoholic Liver Disease * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Bile Duct Obstruction * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Bile Duct Stone * 1  1/1441 (0.07%)  2/1445 (0.14%)  1/1441 (0.07%) 
Cholangitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cholangitis Acute * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cholecystitis * 1  2/1441 (0.14%)  5/1445 (0.35%)  5/1441 (0.35%) 
Cholecystitis Acute * 1  4/1441 (0.28%)  6/1445 (0.42%)  3/1441 (0.21%) 
Cholecystitis Chronic * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Cholelithiasis * 1  11/1441 (0.76%)  9/1445 (0.62%)  7/1441 (0.49%) 
Cholestasis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Drug-Induced Liver Injury * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Gallbladder Disorder * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Gallbladder Pain * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Gallbladder Perforation * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Gallbladder Polyp * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Hepatic Cirrhosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Hepatic Failure * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hepatic Fibrosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hepatic Steatosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hepatomegaly * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Hepatorenal Syndrome * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Jaundice Cholestatic * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Liver Disorder * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Non-Alcoholic Steatohepatitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Portal Hypertension * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Portal Vein Thrombosis * 1  2/1441 (0.14%)  0/1445 (0.00%)  2/1441 (0.14%) 
Post Cholecystectomy Syndrome * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Immune system disorders       
Atopy * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Drug Hypersensitivity * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Food Allergy * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Infections and infestations       
Abdominal Abscess * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Abdominal Sepsis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Abscess Limb * 1  4/1441 (0.28%)  5/1445 (0.35%)  2/1441 (0.14%) 
Anal Abscess * 1  1/1441 (0.07%)  2/1445 (0.14%)  0/1441 (0.00%) 
Appendicitis * 1  2/1441 (0.14%)  3/1445 (0.21%)  6/1441 (0.42%) 
Appendicitis Perforated * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Arthritis Bacterial * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Arthritis Infective * 1  1/1441 (0.07%)  2/1445 (0.14%)  1/1441 (0.07%) 
Atypical Pneumonia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Bacteraemia * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Bacterial Sepsis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Biliary Sepsis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Bronchitis * 1  4/1441 (0.28%)  5/1445 (0.35%)  3/1441 (0.21%) 
Bronchitis Bacterial * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Bronchopulmonary Aspergillosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Burn Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Campylobacter Gastroenteritis * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Carbuncle * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Cellulitis * 1  19/1441 (1.32%)  15/1445 (1.04%)  15/1441 (1.04%) 
Cellulitis Gangrenous * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Cellulitis Staphylococcal * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cholecystitis Infective * 1  0/1441 (0.00%)  0/1445 (0.00%)  3/1441 (0.21%) 
Chronic Hepatitis B * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Chronic Sinusitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Clostridium Difficile Colitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Clostridium Difficile Infection * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Colon Gangrene * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Dengue Fever * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Device Related Infection * 1  1/1441 (0.07%)  1/1445 (0.07%)  2/1441 (0.14%) 
Diabetic Foot Infection * 1  1/1441 (0.07%)  2/1445 (0.14%)  6/1441 (0.42%) 
Diabetic Gangrene * 1  1/1441 (0.07%)  2/1445 (0.14%)  1/1441 (0.07%) 
Diverticulitis * 1  3/1441 (0.21%)  3/1445 (0.21%)  5/1441 (0.35%) 
Endocarditis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Enterococcal Bacteraemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Epiglottitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Erysipelas * 1  1/1441 (0.07%)  3/1445 (0.21%)  5/1441 (0.35%) 
Escherichia Urinary Tract Infection * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Eye Infection * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Eye Infection Fungal * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Gangrene * 1  4/1441 (0.28%)  15/1445 (1.04%)  6/1441 (0.42%) 
Gastroenteritis * 1  6/1441 (0.42%)  5/1445 (0.35%)  8/1441 (0.56%) 
Gastroenteritis Viral * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Gastrointestinal Infection * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Groin Abscess * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Groin Infection * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Haematoma Infection * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Helicobacter Infection * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hepatitis C * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Hepatitis E * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Herpes Zoster * 1  1/1441 (0.07%)  2/1445 (0.14%)  1/1441 (0.07%) 
Hiv Infection * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Infected Cyst * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Infected Dermal Cyst * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Infected Skin Ulcer * 1  2/1441 (0.14%)  2/1445 (0.14%)  3/1441 (0.21%) 
Infective Exacerbation of Bronchiectasis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Influenza * 1  0/1441 (0.00%)  3/1445 (0.21%)  2/1441 (0.14%) 
Intervertebral Discitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Klebsiella Infection * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Laryngitis * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Leptospirosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Liver Abscess * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Localised Infection * 1  1/1441 (0.07%)  4/1445 (0.28%)  10/1441 (0.69%) 
Lower Respiratory Tract Infection * 1  7/1441 (0.49%)  1/1445 (0.07%)  4/1441 (0.28%) 
Lung Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Lymphangitis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Malaria * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Medical Device Site Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Meningitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Meningitis Viral * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Necrotising Fasciitis * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Nosocomial Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Oesophageal Candidiasis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Oral Candidiasis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Orchitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Osteomyelitis * 1  7/1441 (0.49%)  11/1445 (0.76%)  12/1441 (0.83%) 
Osteomyelitis Chronic * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Otitis Externa * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Otitis Media * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Paronychia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pathogen Resistance * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pelvic Abscess * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Penile Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Perineal Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Perinephric Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Peritonitis * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Peritonsillar Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Pharyngitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Plasmodium Vivax Infection * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pneumonia * 1  36/1441 (2.50%)  31/1445 (2.15%)  26/1441 (1.80%) 
Pneumonia Bacterial * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Pneumonia Influenzal * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Post Procedural Cellulitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Post Procedural Infection * 1  1/1441 (0.07%)  2/1445 (0.14%)  3/1441 (0.21%) 
Postoperative Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Postoperative Wound Infection * 1  5/1441 (0.35%)  2/1445 (0.14%)  4/1441 (0.28%) 
Pseudomonal Bacteraemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Psoas Abscess * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pulmonary Sepsis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pulmonary Tuberculosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pyelonephritis * 1  3/1441 (0.21%)  3/1445 (0.21%)  0/1441 (0.00%) 
Pyelonephritis Acute * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Pyelonephritis Chronic * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pyoderma * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Renal Tuberculosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Respiratory Tract Infection * 1  3/1441 (0.21%)  2/1445 (0.14%)  0/1441 (0.00%) 
Respiratory Tract Infection Viral * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Sepsis * 1  10/1441 (0.69%)  12/1445 (0.83%)  4/1441 (0.28%) 
Septic Shock * 1  3/1441 (0.21%)  0/1445 (0.00%)  2/1441 (0.14%) 
Sialoadenitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Sinusitis * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Soft Tissue Infection * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Staphylococcal Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Staphylococcal Infection * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Staphylococcal Osteomyelitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Staphylococcal Sepsis * 1  0/1441 (0.00%)  2/1445 (0.14%)  2/1441 (0.14%) 
Streptococcal Bacteraemia * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Streptococcal Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Streptococcal Sepsis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Subcutaneous Abscess * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Superinfection Bacterial * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Testicular Abscess * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Tooth Infection * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Tracheobronchitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Typhoid Fever * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Upper Respiratory Tract Infection * 1  2/1441 (0.14%)  1/1445 (0.07%)  2/1441 (0.14%) 
Urinary Tract Infection * 1  16/1441 (1.11%)  15/1445 (1.04%)  6/1441 (0.42%) 
Urosepsis * 1  4/1441 (0.28%)  7/1445 (0.48%)  3/1441 (0.21%) 
Vestibular Neuronitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Viral Infection * 1  1/1441 (0.07%)  3/1445 (0.21%)  2/1441 (0.14%) 
Viral Pharyngitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Viral Upper Respiratory Tract Infection * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Vulval Abscess * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Wound Abscess * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Wound Infection * 1  2/1441 (0.14%)  0/1445 (0.00%)  3/1441 (0.21%) 
Injury, poisoning and procedural complications       
Accident * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Accidental Overdose * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Acetabulum Fracture * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Alcohol Poisoning * 1  3/1441 (0.21%)  0/1445 (0.00%)  0/1441 (0.00%) 
Anaesthetic Complication * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Animal Bite * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ankle Fracture * 1  0/1441 (0.00%)  6/1445 (0.42%)  5/1441 (0.35%) 
Arterial Bypass Occlusion * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Arterial Bypass Stenosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Bone Contusion * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Brain Contusion * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Cervical Vertebral Fracture * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Clavicle Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Concussion * 1  2/1441 (0.14%)  1/1445 (0.07%)  2/1441 (0.14%) 
Contusion * 1  2/1441 (0.14%)  2/1445 (0.14%)  1/1441 (0.07%) 
Coronary Artery Restenosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Craniocerebral Injury * 1  0/1441 (0.00%)  1/1445 (0.07%)  3/1441 (0.21%) 
Dural Tear * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Facial Bones Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Fall * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Femoral Neck Fracture * 1  0/1441 (0.00%)  4/1445 (0.28%)  4/1441 (0.28%) 
Femur Fracture * 1  1/1441 (0.07%)  1/1445 (0.07%)  7/1441 (0.49%) 
Fibula Fracture * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Foot Fracture * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Foreign Body * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Foreign Body in Eye * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Fracture Displacement * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Head Injury * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Heat Stroke * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Hip Fracture * 1  3/1441 (0.21%)  4/1445 (0.28%)  7/1441 (0.49%) 
Humerus Fracture * 1  2/1441 (0.14%)  4/1445 (0.28%)  8/1441 (0.56%) 
Joint Dislocation * 1  2/1441 (0.14%)  0/1445 (0.00%)  1/1441 (0.07%) 
Joint Injury * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Laceration * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ligament Rupture * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Ligament Sprain * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Limb Injury * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Lower Limb Fracture * 1  2/1441 (0.14%)  1/1445 (0.07%)  0/1441 (0.00%) 
Lumbar Vertebral Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Meniscus Injury * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Multiple Injuries * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Muscle Rupture * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Overdose * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Patella Fracture * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Pelvic Fracture * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Peripheral Artery Restenosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Post Concussion Syndrome * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Post Procedural Bile Leak * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Post Procedural Complication * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Post Procedural Haemorrhage * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Postoperative Renal Failure * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Postoperative Respiratory Failure * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Postoperative Thoracic Procedure Complication * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Postoperative Wound Complication * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Procedural Haemorrhage * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Procedural Nausea * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Procedural Pain * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Procedural Vomiting * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Pubis Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Radius Fracture * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Rib Fracture * 1  1/1441 (0.07%)  3/1445 (0.21%)  8/1441 (0.56%) 
Road Traffic Accident * 1  2/1441 (0.14%)  1/1445 (0.07%)  2/1441 (0.14%) 
Skin Injury * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Skull Fracture * 1  0/1441 (0.00%)  0/1445 (0.00%)  3/1441 (0.21%) 
Skull Fractured Base * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Spinal Compression Fracture * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Spinal Cord Injury * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Spinal Fracture * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Sternal Fracture * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Stomal Hernia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Subarachnoid Haemorrhage * 1  1/1441 (0.07%)  0/1445 (0.00%)  2/1441 (0.14%) 
Subcutaneous Haematoma * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Subdural Haematoma * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Subdural Haemorrhage * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Tendon Injury * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Tendon Rupture * 1  2/1441 (0.14%)  1/1445 (0.07%)  0/1441 (0.00%) 
Thermal Burn * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Thoracic Vertebral Fracture * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Tibia Fracture * 1  0/1441 (0.00%)  4/1445 (0.28%)  1/1441 (0.07%) 
Traumatic Haematoma * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Traumatic Intracranial Haemorrhage * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Ulna Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Upper Limb Fracture * 1  3/1441 (0.21%)  2/1445 (0.14%)  1/1441 (0.07%) 
Urinary Retention Postoperative * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Vascular Graft Complication * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Vascular Pseudoaneurysm * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Wound * 1  2/1441 (0.14%)  2/1445 (0.14%)  2/1441 (0.14%) 
Wound Complication * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Wound Necrosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Wrist Fracture * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Investigations       
Alanine Aminotransferase Increased * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Blood Creatinine Increased * 1  1/1441 (0.07%)  1/1445 (0.07%)  0/1441 (0.00%) 
Blood Glucose Abnormal * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Blood Glucose Increased * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Blood Pressure Abnormal * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Blood Pressure Decreased * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Blood Pressure Increased * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Cardiac Stress Test Abnormal * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Catheterisation Cardiac * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Clostridium Test Positive * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Colonoscopy * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Electrocardiogram Abnormal * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Electrocardiogram St Segment Depression * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Electrocardiogram St-T Segment Abnormal * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Exercise Test Abnormal * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gamma-Glutamyltransferase Increased * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Glomerular Filtration Rate Decreased * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Hepatic Enzyme Increased * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Intraocular Pressure Increased * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Liver Function Test Increased * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Precancerous Cells Present * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Renal Function Test Abnormal * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Troponin Increased * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Weight Decreased * 1  3/1441 (0.21%)  1/1445 (0.07%)  1/1441 (0.07%) 
Metabolism and nutrition disorders       
Acidosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Decreased Appetite * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Dehydration * 1  4/1441 (0.28%)  1/1445 (0.07%)  4/1441 (0.28%) 
Diabetes Mellitus * 1  10/1441 (0.69%)  6/1445 (0.42%)  6/1441 (0.42%) 
Diabetes Mellitus Inadequate Control * 1  7/1441 (0.49%)  3/1445 (0.21%)  3/1441 (0.21%) 
Diabetic Ketoacidosis * 1  1/1441 (0.07%)  4/1445 (0.28%)  3/1441 (0.21%) 
Fluid Overload * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Gout * 1  1/1441 (0.07%)  0/1445 (0.00%)  4/1441 (0.28%) 
Hypercalcaemia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Hyperglycaemia * 1  6/1441 (0.42%)  1/1445 (0.07%)  6/1441 (0.42%) 
Hyperkalaemia * 1  2/1441 (0.14%)  3/1445 (0.21%)  3/1441 (0.21%) 
Hyperosmolar Hyperglycaemic State * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Hypoglycaemia * 1  8/1441 (0.56%)  12/1445 (0.83%)  12/1441 (0.83%) 
Hypokalaemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Hyponatraemia * 1  3/1441 (0.21%)  3/1445 (0.21%)  0/1441 (0.00%) 
Hypoproteinaemia * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Hypovolaemia * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Ketoacidosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ketosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Lactic Acidosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Metabolic Acidosis * 1  2/1441 (0.14%)  1/1445 (0.07%)  2/1441 (0.14%) 
Metabolic Disorder * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Metabolic Syndrome * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Obesity * 1  3/1441 (0.21%)  5/1445 (0.35%)  0/1441 (0.00%) 
Type 2 Diabetes Mellitus * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Vitamin B12 Deficiency * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Musculoskeletal and connective tissue disorders       
Acquired Claw Toe * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Ankylosing Spondylitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Arthralgia * 1  3/1441 (0.21%)  5/1445 (0.35%)  2/1441 (0.14%) 
Arthritis * 1  2/1441 (0.14%)  3/1445 (0.21%)  1/1441 (0.07%) 
Arthropathy * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Back Pain * 1  3/1441 (0.21%)  5/1445 (0.35%)  4/1441 (0.28%) 
Bone Atrophy * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Bone Cyst * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Bursitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  3/1441 (0.21%) 
Chondromalacia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Chondropathy * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Costochondritis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Diabetic Arthropathy * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Dupuytren's Contracture * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Exostosis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Flank Pain * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Foot Deformity * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Gouty Arthritis * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Gouty Tophus * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Haemarthrosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Intervertebral Disc Compression * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Intervertebral Disc Degeneration * 1  0/1441 (0.00%)  2/1445 (0.14%)  0/1441 (0.00%) 
Intervertebral Disc Disorder * 1  2/1441 (0.14%)  0/1445 (0.00%)  0/1441 (0.00%) 
Intervertebral Disc Protrusion * 1  4/1441 (0.28%)  3/1445 (0.21%)  6/1441 (0.42%) 
Juvenile Idiopathic Arthritis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Lumbar Spinal Stenosis * 1  0/1441 (0.00%)  8/1445 (0.55%)  3/1441 (0.21%) 
Lupus-Like Syndrome * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Muscle Atrophy * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Musculoskeletal Chest Pain * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Musculoskeletal Pain * 1  0/1441 (0.00%)  1/1445 (0.07%)  2/1441 (0.14%) 
Myalgia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Neck Pain * 1  1/1441 (0.07%)  0/1445 (0.00%)  1/1441 (0.07%) 
Neuropathic Arthropathy * 1  0/1441 (0.00%)  2/1445 (0.14%)  1/1441 (0.07%) 
Osteitis * 1  0/1441 (0.00%)  1/1445 (0.07%)  1/1441 (0.07%) 
Osteoarthritis * 1  27/1441 (1.87%)  30/1445 (2.08%)  23/1441 (1.60%) 
Osteochondrosis * 1  1/1441 (0.07%)  1/1445 (0.07%)  1/1441 (0.07%) 
Osteonecrosis * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Pain in Extremity * 1  4/1441 (0.28%)  3/1445 (0.21%)  1/1441 (0.07%) 
Periarthritis * 1  0/1441 (0.00%)  3/1445 (0.21%)  0/1441 (0.00%) 
Polyarthritis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Polymyalgia Rheumatica * 1  2/1441 (0.14%)  0/1445 (0.00%)  1/1441 (0.07%) 
Psoriatic Arthropathy * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Rotator Cuff Syndrome * 1  2/1441 (0.14%)  2/1445 (0.14%)  2/1441 (0.14%) 
Senile Osteoporosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Spinal Column Stenosis * 1  6/1441 (0.42%)  4/1445 (0.28%)  3/1441 (0.21%) 
Spinal Osteoarthritis * 1  4/1441 (0.28%)  3/1445 (0.21%)  1/1441 (0.07%) 
Spinal Pain * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Spondyloarthropathy * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Spondylolisthesis * 1  2/1441 (0.14%)  2/1445 (0.14%)  0/1441 (0.00%) 
Synovial Cyst * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Tendon Disorder * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Tendonitis * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Tenosynovitis * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Vertebral Foraminal Stenosis * 1  0/1441 (0.00%)  0/1445 (0.00%)  2/1441 (0.14%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acute Leukaemia * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Adenocarcinoma Gastric * 1  0/1441 (0.00%)  0/1445 (0.00%)  4/1441 (0.28%) 
Adenocarcinoma of Colon * 1  2/1441 (0.14%)  3/1445 (0.21%)  1/1441 (0.07%) 
Adenolymphoma * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Adenosquamous Cell Lung Cancer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Adrenal Adenoma * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Anal Squamous Cell Carcinoma * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Appendix Adenoma * 1  0/1441 (0.00%)  0/1445 (0.00%)  1/1441 (0.07%) 
Basal Cell Carcinoma * 1  2/1441 (0.14%)  3/1445 (0.21%)  2/1441 (0.14%) 
Benign Neoplasm of Bladder * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Benign Neoplasm of Prostate * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Benign Peritoneal Neoplasm * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441 (0.00%) 
Bile Duct Cancer * 1  1/1441 (0.07%)  0/1445 (0.00%)  0/1441 (0.00%) 
Bladder Cancer * 1  5/1441 (0.35%)  4/1445 (0.28%)  0/1441 (0.00%) 
Bladder Cancer Stage 0, with Cancer in Situ * 1  0/1441 (0.00%)  1/1445 (0.07%)  0/1441