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CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes

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: NCT01243424
Recruitment Status : Completed
First Posted : November 18, 2010
Results First Posted : January 7, 2020
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: linagliptin
Drug: glimepiride
Drug: linagliptin placebo
Drug: glimepiride placebo
Enrollment 6103
Recruitment Details This multicentre, multinational, randomised, double-blind, double-dummy, parallel group,comparator-controlled trial compared Linagliptin versus (vs.) Glimepiride, predominantly on metformin background treatment in participants with type 2 diabetes mellitus (T2DM) at elevated cardiovascular (CV) risk receiving usual care.
Pre-assignment Details All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Period Title: Discontinuation From Study (Treated Set)
Started [1] 3028 3014
Patient Died (Other Cause Than CV Death) 123 146
Treated 3023 3010
Completed [2] 2899 2895
Not Completed 129 119
Reason Not Completed
Consent Withdrawn (Status Alive)             49             37
Consent Withdrawn (Status Unknown)             14             12
Site Closure (Status Alive)             15             22
Site Closure (Status Unknown)             0             1
LostToFollowUpfor3P-MACE(StatusAlive)             38             35
LostToFollowUpfor3P-MACE(StatusUnknown)             8             8
Not treated             5             4
[1]
Started are entered/ randomised
[2]
Completed regarding MACE status or died
Period Title: Discontinuation From Treatment
Started [1] 3028 3014
Treated 3023 3010
Completed [2] 1896 1832
Not Completed 1132 1182
Reason Not Completed
Not treated             5             4
Adverse Event             457             523
Lack of Efficacy             61             41
Protocol Violation             46             47
Lost to Follow-up             24             28
Withdrawal by Subject             309             328
Other than listed above             230             211
[1]
Started are entered/ randomised
[2]
Not prematurely discontinued from trial medication
Arm/Group Title Linagliptin Glimepiride Total
Hide Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Total of all reporting groups
Overall Number of Baseline Participants 3023 3010 6033
Hide Baseline Analysis Population Description
Treated set (TS): All patients treated with at least one dose of trial drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3023 participants 3010 participants 6033 participants
63.9  (9.5) 64.2  (9.5) 64.0  (9.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3023 participants 3010 participants 6033 participants
Female
1185
  39.2%
1229
  40.8%
2414
  40.0%
Male
1838
  60.8%
1781
  59.2%
3619
  60.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3023 participants 3010 participants 6033 participants
Hispanic or Latino
519
  17.2%
513
  17.0%
1032
  17.1%
Not Hispanic or Latino
2495
  82.5%
2487
  82.6%
4982
  82.6%
Unknown or Not Reported
9
   0.3%
10
   0.3%
19
   0.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3023 participants 3010 participants 6033 participants
American Indian or Alaska Native
106
   3.5%
108
   3.6%
214
   3.5%
Asian
531
  17.6%
530
  17.6%
1061
  17.6%
Native Hawaiian or Other Pacific Islander
5
   0.2%
3
   0.1%
8
   0.1%
Black or African American
155
   5.1%
169
   5.6%
324
   5.4%
White
2217
  73.3%
2190
  72.8%
4407
  73.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
9
   0.3%
10
   0.3%
19
   0.3%
1.Primary Outcome
Title The First 3-point Major Adverse Cardiovascular Events (3P-MACE)
Hide Description The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented.
Time Frame From randomization until individual day of trial completion, up to 432 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS): All patients treated with at least one dose of trial drug.
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Unit of Measure: Events/ 1000 patients-years
20.7 21.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments This was the first step in a pre-defined hierarchical testing approach. The upper bound of the confidence interval (CI) of the Hazard ratio (HR) of linagliptin vs. glimepiride was compared with this noninferiority margin for the testing of non-inferiority. All non-inferiority tests were based on a margin of 1.3.
Statistical Test of Hypothesis P-Value <0.0001
Comments P-values derived from Wald´s Chi-square test for non-inferiority were calculated.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95.47%
0.84 to 1.14
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This was the second step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis P-Value 0.3813
Comments P-values derived from Wald´s Chi-square test.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95.47%
0.84 to 1.14
Estimation Comments [Not Specified]
2.Secondary Outcome
Title The First 4-point (4P)- MACE
Hide Description The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris.
Time Frame From randomization until individual day of trial completion, up to 432 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Unit of Measure: Events/ 1000 patients-years
23.4 23.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This was the third step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis P-Value 0.4334
Comments P-values derived from Wald´s Chi-square test for non-inferiority.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95.47%
0.86 to 1.14
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase
Hide Description The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase.
Time Frame From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
TS without duplicates (TS w/o duplicates), patients who are off-drug or died prior to regular study stop were handled as non-completers considered failure (NCF).
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3014 3000
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
16.0
(14.7 to 17.3)
10.2
(9.1 to 11.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments p-value derived from logistic regression.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.68
Confidence Interval (2-Sided) 95.47%
1.43 to 1.96
Estimation Comments Odds ratio and confidence interval are based on logistic regression with factor for treatment.
4.Secondary Outcome
Title Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase
Hide Description The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase.
Time Frame From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates (NCF)
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3014 3000
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
17.4
(16.1 to 18.8)
14.1
(12.9 to 15.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments p-value derived from logistic regression.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.29
Confidence Interval (2-Sided) 95.47%
1.11 to 1.48
Estimation Comments Odds ratio and confidence interval are based on logistic regression with factor for treatment.
5.Secondary Outcome
Title Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE
Hide Description Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.
Time Frame From randomization until individual day of trial completion, up to 432 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
11.8
(10.7 to 13.0)
12.0
(10.9 to 13.2)
6.Secondary Outcome
Title Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE
Hide Description Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.
Time Frame From randomization until individual day of trial completion, up to 432 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
13.2
(12.0 to 14.4)
13.3
(12.2 to 14.6)
7.Secondary Outcome
Title Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Hide Description

Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of:

  • CV death (including fatal stroke and fatal MI)
  • non-fatal MI
  • non-fatal stroke
  • hospitalisation for unstable angina pectoris
  • TIA
  • hospitalisation for heart failure
  • hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
17.1
(15.8 to 18.5)
17.8
(16.4 to 19.2)
8.Secondary Outcome
Title Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Hide Description

Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of:

  • CV death (including fatal stroke and fatal MI)
  • non-fatal MI
  • non-fatal stroke
  • hospitalisation for unstable angina pectoris
  • Transient ischaemic attack (TIA)
  • hospitalisation for heart failure
  • hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3023 3010
Measure Type: Number
Unit of Measure: Events/ 1000 patients-years
31.1 32.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5249
Comments p-value derived from Wald´s chi-square test.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.85 to 1.09
Estimation Comments Hazard ratio and confidence interval derived from Cox regression with factor treatment.
9.Secondary Outcome
Title Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c)
Hide Description Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates considering all available data
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2951 2949
Least Squares Mean (Standard Error)
Unit of Measure: Percentage glycosylated hemoglobin (%)
0.06  (0.02) 0.15  (0.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments [Not Specified]
Method ANCOVA
Comments The Analysis of Covariance (ANCOVA) model includes the fixed categorical effect of treatment and the continuous covariate of baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.09
Confidence Interval (2-Sided) 95%
-0.15 to -0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.03
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
10.Secondary Outcome
Title Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG)
Hide Description Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates considering all available data
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2996 2949
Least Squares Mean (Standard Error)
Unit of Measure: Milligram/ deciliter (mg/dL)
12.4  (0.9) 19.7  (0.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline FPG.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.3
Confidence Interval (2-Sided) 95%
-9.7 to -4.8
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.2
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
11.Secondary Outcome
Title Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol
Hide Description Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3014 3000
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
LDL cholesterol Number Analyzed 2688 participants 2660 participants
-6.1  (0.6) -6.5  (0.6)
HDL cholesterol Number Analyzed 2783 participants 2751 participants
0.7  (0.2) 0.3  (0.2)
Total cholesterol Number Analyzed 2788 participants 2762 participants
-5.4  (0.7) -0.5  (0.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments LDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6400
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline LDL cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95.47%
-1.3 to 2.1
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.9
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments HDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0497
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline HDL cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
0.0 to 1.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments Total cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6823
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline total cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-2.4 to 1.6
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.0
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
12.Secondary Outcome
Title Change From Baseline to Final Visit in Triglycerides
Hide Description Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2788 2762
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
1.7  (2.2) 5.2  (2.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2678
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline FPG.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-9.6 to 2.7
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.1
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
13.Secondary Outcome
Title Change From Baseline to Final Visit in Creatinine
Hide Description Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2917 2898
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
0.08  (0.01) 0.09  (0.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5165
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline creatinine.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.03 to 0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.01
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
14.Secondary Outcome
Title Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR)
Hide Description Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2917 2898
Least Squares Mean (Standard Error)
Unit of Measure: mL/minute/1.73 meter^2
-4.0  (0.3) -5.0  (0.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5165
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline eGFR.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
0.2 to 1.8
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.4
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
15.Secondary Outcome
Title Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR)
Hide Description Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 2904 2880
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mg/ gcrea
1.52
(1.83%)
1.57
(1.83%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2921
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline UACR.
Method of Estimation Estimation Parameter geometric mean (gMean) ratio (%)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.91 to 1.03
Estimation Comments gMean ration= Linagliptin mean/ Glimepiride mean
16.Secondary Outcome
Title Percentage of Participants With Transition in Albuminuria Classes
Hide Description Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.
Time Frame Baseline and week 432
Hide Outcome Measure Data
Hide Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 3014 3000
Measure Type: Number
Unit of Measure: Percentage of participants (%)
Base (<30mg/gcrea) LVOT (<30mg/gcrea) 58.4 57.7
Base(<30mg/gcrea)LVOT(>=30 to<=300mg/gcrea) 14.1 16.0
Base (<30 mg/gcrea) LVOT (>300 mg/gcrea) 1.4 1.4
Base (>=30 to <=300 mg/gcrea) LVOT(<30mg/gcrea) 5.4 5.1
Base(>=30to<=300mg/gcrea)LVOT(>=30to<=300mg/gcrea) 12.7 12.1
Base (>=30 to <=300 mg/gcrea) LVOT(>300 mg/gcrea) 3.5 3.7
Base (>300 mg/gcrea) LVOT (<30 mg/gcrea) 0.1 0.3
Base (>300 mg/gcrea) LVOT(>=30 to<=300mg/gcrea) 0.8 0.9
Base (>300 mg/gcrea) LVOT(>300 mg/gcrea) 3.4 2.7
17.Secondary Outcome
Title Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks
Hide Description The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint.
Time Frame Baseline and week 208
Hide Outcome Measure Data
Hide Analysis Population Description
Meal tolerance test(MTT) last observation carried forward(LOCF) set: Randomised and treated patients with one dose of study drug and signed the sub-study Informed Consent with valid baseline and on-treatment MTT. If values taken after rescue medication intake will be set to missing, last observed on-treatment value was carry forwarded.
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 40 48
Mean (Standard Error)
Unit of Measure: Picomol/ minute/meter^2 (pmol/min/m²)
11.07  (15.07) 6.95  (13.76)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis P-Value 0.8402
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effects of treatment and the continuous covariate of baseline ISR.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 4.13
Confidence Interval (2-Sided) 95%
-36.46 to 44.71
Estimation Comments Mean difference= Linagliptin mean- Glimepiride mean
18.Secondary Outcome
Title Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up
Hide Description Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint.
Time Frame 433 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set cognition(FAS-COG): Randomised and treated patients with one dose of study drug, baseline assessment (the z-scores, A&E or Mini-mental state examination(MMSE) can be calculated), years of formal education with baseline MMSE≥24 and at least one on-treatment assessment (of which at least one of the RBI scores can be calculated).
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 1618 1545
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
27.8
(25.6 to 30.0)
27.6
(25.4 to 29.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9112
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic regression model with terms for treatment as a fixed effect with Wald confidence Interval was used.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.86 to 1.18
Estimation Comments Linagliptin vs. Glimepiride odds is presented.
19.Secondary Outcome
Title Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study
Hide Description Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
Arm/Group Title All Participants
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose or 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. All doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 44
Mean (Standard Deviation)
Unit of Measure: Milligrams/ deciliter (mg/ dL)
44.2  (12.6)
20.Secondary Outcome
Title CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study
Hide Description Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
Arm/Group Title All Participants
Hide Arm/Group Description:
After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose or 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. All doses were administered once daily orally up to an estimated 432 weeks treatment period.
Overall Number of Participants Analyzed 44
Mean (Standard Deviation)
Unit of Measure: Millimoles/ Litre (mmol/L)
2.45  (0.7)
Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Linagliptin Glimepiride
Hide Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
All-Cause Mortality
Linagliptin Glimepiride
Affected / at Risk (%) Affected / at Risk (%)
Total   308/3023 (10.19%)   336/3010 (11.16%) 
Hide Serious Adverse Events
Linagliptin Glimepiride
Affected / at Risk (%) Affected / at Risk (%)
Total   1403/3023 (46.41%)   1448/3010 (48.11%) 
Blood and lymphatic system disorders     
Anaemia  1  14/3023 (0.46%)  18/3010 (0.60%) 
Anaemia macrocytic  1  0/3023 (0.00%)  1/3010 (0.03%) 
Coagulopathy  1  1/3023 (0.03%)  0/3010 (0.00%) 
Febrile neutropenia  1  2/3023 (0.07%)  0/3010 (0.00%) 
Haemorrhagic anaemia  1  6/3023 (0.20%)  1/3010 (0.03%) 
Haemorrhagic diathesis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Increased tendency to bruise  1  1/3023 (0.03%)  0/3010 (0.00%) 
Iron deficiency anaemia  1  1/3023 (0.03%)  3/3010 (0.10%) 
Leukocytosis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Lymphadenopathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Normocytic anaemia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pancytopenia  1  5/3023 (0.17%)  1/3010 (0.03%) 
Splenic haematoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Splenic vein thrombosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cardiac disorders     
Acute coronary syndrome  1  18/3023 (0.60%)  12/3010 (0.40%) 
Acute left ventricular failure  1  2/3023 (0.07%)  1/3010 (0.03%) 
Acute myocardial infarction  1  52/3023 (1.72%)  56/3010 (1.86%) 
Adams-Stokes syndrome  1  0/3023 (0.00%)  1/3010 (0.03%) 
Angina pectoris  1  37/3023 (1.22%)  40/3010 (1.33%) 
Angina unstable  1  54/3023 (1.79%)  65/3010 (2.16%) 
Aortic valve disease  1  1/3023 (0.03%)  2/3010 (0.07%) 
Aortic valve incompetence  1  1/3023 (0.03%)  1/3010 (0.03%) 
Aortic valve stenosis  1  5/3023 (0.17%)  4/3010 (0.13%) 
Arrhythmia  1  4/3023 (0.13%)  5/3010 (0.17%) 
Arteriosclerosis coronary artery  1  4/3023 (0.13%)  4/3010 (0.13%) 
Atrial fibrillation  1  39/3023 (1.29%)  48/3010 (1.59%) 
Atrial flutter  1  23/3023 (0.76%)  14/3010 (0.47%) 
Atrial tachycardia  1  2/3023 (0.07%)  2/3010 (0.07%) 
Atrioventricular block  1  1/3023 (0.03%)  1/3010 (0.03%) 
Atrioventricular block complete  1  10/3023 (0.33%)  8/3010 (0.27%) 
Atrioventricular block first degree  1  1/3023 (0.03%)  0/3010 (0.00%) 
Atrioventricular block second degree  1  3/3023 (0.10%)  3/3010 (0.10%) 
Bradyarrhythmia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bradycardia  1  6/3023 (0.20%)  7/3010 (0.23%) 
Bundle branch block  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bundle branch block left  1  1/3023 (0.03%)  3/3010 (0.10%) 
Cardiac aneurysm  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardiac arrest  1  4/3023 (0.13%)  8/3010 (0.27%) 
Cardiac asthma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardiac disorder  1  3/3023 (0.10%)  1/3010 (0.03%) 
Cardiac failure  1  58/3023 (1.92%)  53/3010 (1.76%) 
Cardiac failure acute  1  7/3023 (0.23%)  6/3010 (0.20%) 
Cardiac failure chronic  1  9/3023 (0.30%)  12/3010 (0.40%) 
Cardiac failure congestive  1  37/3023 (1.22%)  45/3010 (1.50%) 
Cardiac perforation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardiac valve disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardio-respiratory arrest  1  4/3023 (0.13%)  2/3010 (0.07%) 
Cardiogenic shock  1  2/3023 (0.07%)  4/3010 (0.13%) 
Cardiomegaly  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cardiomyopathy  1  1/3023 (0.03%)  2/3010 (0.07%) 
Cardiopulmonary failure  1  1/3023 (0.03%)  1/3010 (0.03%) 
Cardiovascular disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardiovascular insufficiency  1  1/3023 (0.03%)  0/3010 (0.00%) 
Conduction disorder  1  0/3023 (0.00%)  1/3010 (0.03%) 
Congestive cardiomyopathy  1  1/3023 (0.03%)  2/3010 (0.07%) 
Cor pulmonale  1  0/3023 (0.00%)  3/3010 (0.10%) 
Coronary artery disease  1  43/3023 (1.42%)  42/3010 (1.40%) 
Coronary artery dissection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Coronary artery insufficiency  1  2/3023 (0.07%)  1/3010 (0.03%) 
Coronary artery occlusion  1  3/3023 (0.10%)  2/3010 (0.07%) 
Coronary artery stenosis  1  4/3023 (0.13%)  12/3010 (0.40%) 
Diastolic dysfunction  1  1/3023 (0.03%)  0/3010 (0.00%) 
Extrasystoles  1  0/3023 (0.00%)  1/3010 (0.03%) 
Heart valve incompetence  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ischaemic cardiomyopathy  1  4/3023 (0.13%)  2/3010 (0.07%) 
Left ventricular dysfunction  1  2/3023 (0.07%)  0/3010 (0.00%) 
Left ventricular failure  1  2/3023 (0.07%)  4/3010 (0.13%) 
Left ventricular hypertrophy  1  1/3023 (0.03%)  0/3010 (0.00%) 
Long QT syndrome  1  0/3023 (0.00%)  1/3010 (0.03%) 
Mitral valve incompetence  1  1/3023 (0.03%)  2/3010 (0.07%) 
Mitral valve stenosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Myocardial infarction  1  49/3023 (1.62%)  64/3010 (2.13%) 
Myocardial ischaemia  1  14/3023 (0.46%)  9/3010 (0.30%) 
Myocardial rupture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Palpitations  1  2/3023 (0.07%)  2/3010 (0.07%) 
Pericardial effusion  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pericarditis  1  1/3023 (0.03%)  3/3010 (0.10%) 
Postinfarction angina  1  1/3023 (0.03%)  1/3010 (0.03%) 
Prinzmetal angina  1  1/3023 (0.03%)  1/3010 (0.03%) 
Pulmonary valve stenosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Right ventricular dysfunction  1  0/3023 (0.00%)  1/3010 (0.03%) 
Right ventricular failure  1  1/3023 (0.03%)  1/3010 (0.03%) 
Silent myocardial infarction  1  5/3023 (0.17%)  5/3010 (0.17%) 
Sinoatrial block  1  1/3023 (0.03%)  0/3010 (0.00%) 
Sinus arrest  1  0/3023 (0.00%)  1/3010 (0.03%) 
Sinus arrhythmia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Sinus bradycardia  1  1/3023 (0.03%)  1/3010 (0.03%) 
Sinus node dysfunction  1  4/3023 (0.13%)  5/3010 (0.17%) 
Sinus tachycardia  1  2/3023 (0.07%)  1/3010 (0.03%) 
Stress cardiomyopathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Supraventricular tachyarrhythmia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Supraventricular tachycardia  1  1/3023 (0.03%)  7/3010 (0.23%) 
Tachyarrhythmia  1  2/3023 (0.07%)  1/3010 (0.03%) 
Tachycardia  1  5/3023 (0.17%)  2/3010 (0.07%) 
Tachycardia paroxysmal  1  0/3023 (0.00%)  2/3010 (0.07%) 
Thyrotoxic cardiomyopathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tricuspid valve incompetence  1  0/3023 (0.00%)  1/3010 (0.03%) 
Trifascicular block  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ventricular arrhythmia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ventricular extrasystoles  1  4/3023 (0.13%)  2/3010 (0.07%) 
Ventricular fibrillation  1  0/3023 (0.00%)  2/3010 (0.07%) 
Ventricular hypokinesia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Ventricular tachycardia  1  4/3023 (0.13%)  1/3010 (0.03%) 
Wolff-Parkinson-White syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Congenital, familial and genetic disorders     
Adenomatous polyposis coli  1  0/3023 (0.00%)  1/3010 (0.03%) 
Arteriovenous malformation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Choledochal cyst  1  1/3023 (0.03%)  0/3010 (0.00%) 
Congenital cystic kidney disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Corneal dystrophy  1  1/3023 (0.03%)  0/3010 (0.00%) 
Developmental hip dysplasia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Exomphalos  1  1/3023 (0.03%)  0/3010 (0.00%) 
Fibrous dysplasia of bone  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hereditary haemochromatosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hydrocele  1  2/3023 (0.07%)  3/3010 (0.10%) 
Hypertrophic cardiomyopathy  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ichthyosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Left ventricle outflow tract obstruction  1  0/3023 (0.00%)  1/3010 (0.03%) 
Phimosis  1  3/3023 (0.10%)  6/3010 (0.20%) 
Porokeratosis  1  1/3023 (0.03%)  2/3010 (0.07%) 
Stargardt's disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Urachal abnormality  1  0/3023 (0.00%)  1/3010 (0.03%) 
Ear and labyrinth disorders     
Acute vestibular syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Aural polyp  1  1/3023 (0.03%)  0/3010 (0.00%) 
Conductive deafness  1  1/3023 (0.03%)  0/3010 (0.00%) 
Deafness  1  7/3023 (0.23%)  2/3010 (0.07%) 
Deafness neurosensory  1  3/3023 (0.10%)  6/3010 (0.20%) 
Deafness unilateral  1  0/3023 (0.00%)  4/3010 (0.13%) 
Ear canal stenosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hypoacusis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Inner ear disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Meniere's disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Mixed deafness  1  0/3023 (0.00%)  1/3010 (0.03%) 
Sudden hearing loss  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tympanic membrane perforation  1  1/3023 (0.03%)  1/3010 (0.03%) 
Vertigo  1  9/3023 (0.30%)  12/3010 (0.40%) 
Vestibular disorder  1  0/3023 (0.00%)  1/3010 (0.03%) 
Endocrine disorders     
Adrenal insufficiency  1  0/3023 (0.00%)  1/3010 (0.03%) 
Basedow's disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Goitre  1  3/3023 (0.10%)  4/3010 (0.13%) 
Hyperparathyroidism  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hyperthyroidism  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hypoparathyroidism  1  0/3023 (0.00%)  1/3010 (0.03%) 
Inappropriate antidiuretic hormone secretion  1  1/3023 (0.03%)  1/3010 (0.03%) 
Thyroid mass  1  1/3023 (0.03%)  0/3010 (0.00%) 
Eye disorders     
Age-related macular degeneration  1  0/3023 (0.00%)  1/3010 (0.03%) 
Amaurosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Amaurosis fugax  1  2/3023 (0.07%)  3/3010 (0.10%) 
Angle closure glaucoma  1  4/3023 (0.13%)  1/3010 (0.03%) 
Aphakia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Blepharitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Blindness  1  1/3023 (0.03%)  0/3010 (0.00%) 
Blindness transient  1  0/3023 (0.00%)  1/3010 (0.03%) 
Blindness unilateral  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cataract  1  16/3023 (0.53%)  21/3010 (0.70%) 
Chalazion  1  0/3023 (0.00%)  1/3010 (0.03%) 
Detachment of retinal pigment epithelium  1  0/3023 (0.00%)  1/3010 (0.03%) 
Diabetic retinopathy  1  1/3023 (0.03%)  2/3010 (0.07%) 
Diplopia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Dry age-related macular degeneration  1  0/3023 (0.00%)  2/3010 (0.07%) 
Endocrine ophthalmopathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Eye haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Eye swelling  1  1/3023 (0.03%)  0/3010 (0.00%) 
Eyelid ptosis  1  1/3023 (0.03%)  2/3010 (0.07%) 
Eyelid rash  1  1/3023 (0.03%)  0/3010 (0.00%) 
Glaucoma  1  29/3023 (0.96%)  31/3010 (1.03%) 
Iris neovascularisation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Keratitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Lens dislocation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Macular degeneration  1  12/3023 (0.40%)  11/3010 (0.37%) 
Macular fibrosis  1  5/3023 (0.17%)  6/3010 (0.20%) 
Macular hole  1  2/3023 (0.07%)  0/3010 (0.00%) 
Neovascular age-related macular degeneration  1  0/3023 (0.00%)  1/3010 (0.03%) 
Open angle glaucoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Panophthalmitis  1  2/3023 (0.07%)  0/3010 (0.00%) 
Pterygium  1  0/3023 (0.00%)  1/3010 (0.03%) 
Retinal artery embolism  1  2/3023 (0.07%)  1/3010 (0.03%) 
Retinal artery occlusion  1  3/3023 (0.10%)  0/3010 (0.00%) 
Retinal degeneration  1  2/3023 (0.07%)  0/3010 (0.00%) 
Retinal detachment  1  6/3023 (0.20%)  7/3010 (0.23%) 
Retinal tear  1  2/3023 (0.07%)  2/3010 (0.07%) 
Retinal vein occlusion  1  2/3023 (0.07%)  2/3010 (0.07%) 
Retinopathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Ulcerative keratitis  1  1/3023 (0.03%)  3/3010 (0.10%) 
Uveitic glaucoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Vision blurred  1  1/3023 (0.03%)  0/3010 (0.00%) 
Visual impairment  1  1/3023 (0.03%)  1/3010 (0.03%) 
Vitreous adhesions  1  1/3023 (0.03%)  0/3010 (0.00%) 
Vitreous degeneration  1  0/3023 (0.00%)  1/3010 (0.03%) 
Vitreous detachment  1  0/3023 (0.00%)  1/3010 (0.03%) 
Vitreous haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastrointestinal disorders     
Abdominal adhesions  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abdominal discomfort  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abdominal distension  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abdominal hernia  1  2/3023 (0.07%)  2/3010 (0.07%) 
Abdominal incarcerated hernia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abdominal pain  1  7/3023 (0.23%)  7/3010 (0.23%) 
Abdominal pain lower  1  1/3023 (0.03%)  1/3010 (0.03%) 
Abdominal pain upper  1  1/3023 (0.03%)  1/3010 (0.03%) 
Abdominal tenderness  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abdominal wall haematoma  1  1/3023 (0.03%)  1/3010 (0.03%) 
Acute abdomen  1  1/3023 (0.03%)  0/3010 (0.00%) 
Anal fissure  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anal fistula  1  1/3023 (0.03%)  2/3010 (0.07%) 
Appendiceal mucocoele  1  0/3023 (0.00%)  1/3010 (0.03%) 
Ascites  1  1/3023 (0.03%)  3/3010 (0.10%) 
Barrett's oesophagus  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bezoar  1  1/3023 (0.03%)  0/3010 (0.00%) 
Colitis  1  6/3023 (0.20%)  2/3010 (0.07%) 
Colitis ischaemic  1  2/3023 (0.07%)  1/3010 (0.03%) 
Colon dysplasia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Constipation  1  4/3023 (0.13%)  3/3010 (0.10%) 
Crohn's disease  1  1/3023 (0.03%)  0/3010 (0.00%) 
Dental necrosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Diarrhoea  1  5/3023 (0.17%)  5/3010 (0.17%) 
Diverticulum  1  1/3023 (0.03%)  2/3010 (0.07%) 
Diverticulum intestinal  1  1/3023 (0.03%)  2/3010 (0.07%) 
Diverticulum intestinal haemorrhagic  1  2/3023 (0.07%)  0/3010 (0.00%) 
Duodenal polyp  1  1/3023 (0.03%)  0/3010 (0.00%) 
Duodenal ulcer  1  3/3023 (0.10%)  2/3010 (0.07%) 
Duodenal ulcer haemorrhage  1  2/3023 (0.07%)  4/3010 (0.13%) 
Duodenitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Dyspepsia  1  1/3023 (0.03%)  1/3010 (0.03%) 
Dysphagia  1  0/3023 (0.00%)  2/3010 (0.07%) 
Enteritis  1  3/3023 (0.10%)  0/3010 (0.00%) 
Enterovesical fistula  1  0/3023 (0.00%)  1/3010 (0.03%) 
Erosive duodenitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Faecaloma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Food poisoning  1  1/3023 (0.03%)  1/3010 (0.03%) 
Gastric haemorrhage  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gastric polyps  1  1/3023 (0.03%)  1/3010 (0.03%) 
Gastric ulcer  1  4/3023 (0.13%)  3/3010 (0.10%) 
Gastric ulcer haemorrhage  1  3/3023 (0.10%)  0/3010 (0.00%) 
Gastric ulcer perforation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastritis  1  5/3023 (0.17%)  6/3010 (0.20%) 
Gastritis erosive  1  0/3023 (0.00%)  3/3010 (0.10%) 
Gastritis haemorrhagic  1  1/3023 (0.03%)  1/3010 (0.03%) 
Gastroduodenal haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastroduodenitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastrointestinal disorder  1  1/3023 (0.03%)  1/3010 (0.03%) 
Gastrointestinal haemorrhage  1  16/3023 (0.53%)  10/3010 (0.33%) 
Gastrointestinal obstruction  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gastrointestinal ulcer  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gastrointestinal ulcer haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastrooesophageal reflux disease  1  1/3023 (0.03%)  2/3010 (0.07%) 
Gingival bleeding  1  0/3023 (0.00%)  1/3010 (0.03%) 
Haematemesis  1  1/3023 (0.03%)  3/3010 (0.10%) 
Haematochezia  1  1/3023 (0.03%)  1/3010 (0.03%) 
Haemorrhoidal haemorrhage  1  2/3023 (0.07%)  1/3010 (0.03%) 
Haemorrhoids  1  3/3023 (0.10%)  2/3010 (0.07%) 
Hiatus hernia  1  1/3023 (0.03%)  2/3010 (0.07%) 
Ileus  1  3/3023 (0.10%)  1/3010 (0.03%) 
Ileus paralytic  1  0/3023 (0.00%)  4/3010 (0.13%) 
Impaired gastric emptying  1  0/3023 (0.00%)  1/3010 (0.03%) 
Incarcerated inguinal hernia  1  0/3023 (0.00%)  2/3010 (0.07%) 
Inguinal hernia  1  18/3023 (0.60%)  14/3010 (0.47%) 
Intestinal haematoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Intestinal haemorrhage  1  2/3023 (0.07%)  0/3010 (0.00%) 
Intestinal mass  1  1/3023 (0.03%)  0/3010 (0.00%) 
Intestinal obstruction  1  3/3023 (0.10%)  4/3010 (0.13%) 
Intestinal perforation  1  0/3023 (0.00%)  1/3010 (0.03%) 
Intra-abdominal haematoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Irritable bowel syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Jejunal perforation  1  0/3023 (0.00%)  1/3010 (0.03%) 
Large intestinal haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Large intestine perforation  1  0/3023 (0.00%)  1/3010 (0.03%) 
Large intestine polyp  1  6/3023 (0.20%)  9/3010 (0.30%) 
Lip swelling  1  0/3023 (0.00%)  1/3010 (0.03%) 
Lower gastrointestinal haemorrhage  1  2/3023 (0.07%)  3/3010 (0.10%) 
Lumbar hernia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Malignant bowel obstruction  1  1/3023 (0.03%)  0/3010 (0.00%) 
Melaena  1  3/3023 (0.10%)  4/3010 (0.13%) 
Mesenteric artery thrombosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Nausea  1  1/3023 (0.03%)  5/3010 (0.17%) 
Obstructive pancreatitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Oesophageal fistula  1  1/3023 (0.03%)  0/3010 (0.00%) 
Oesophageal obstruction  1  1/3023 (0.03%)  0/3010 (0.00%) 
Oesophageal ulcer  1  1/3023 (0.03%)  0/3010 (0.00%) 
Oesophageal varices haemorrhage  1  0/3023 (0.00%)  1/3010 (0.03%) 
Oesophagitis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Pancreatic failure  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pancreatic mass  1  0/3023 (0.00%)  1/3010 (0.03%) 
Pancreatitis  1  10/3023 (0.33%)  11/3010 (0.37%) 
Pancreatitis acute  1  8/3023 (0.26%)  8/3010 (0.27%) 
Pancreatitis chronic  1  5/3023 (0.17%)  2/3010 (0.07%) 
Pancreatitis necrotising  1  1/3023 (0.03%)  0/3010 (0.00%) 
Paraesthesia oral  1  0/3023 (0.00%)  1/3010 (0.03%) 
Peptic ulcer perforation  1  0/3023 (0.00%)  1/3010 (0.03%) 
Proctitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Rectal haemorrhage  1  3/3023 (0.10%)  2/3010 (0.07%) 
Rectal polyp  1  1/3023 (0.03%)  0/3010 (0.00%) 
Retroperitoneal fibrosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Salivary gland calculus  1  1/3023 (0.03%)  0/3010 (0.00%) 
Salivary gland mass  1  1/3023 (0.03%)  0/3010 (0.00%) 
Small intestinal haemorrhage  1  1/3023 (0.03%)  1/3010 (0.03%) 
Small intestinal obstruction  1  5/3023 (0.17%)  1/3010 (0.03%) 
Subileus  1  1/3023 (0.03%)  0/3010 (0.00%) 
Swollen tongue  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tongue oedema  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tongue ulceration  1  0/3023 (0.00%)  1/3010 (0.03%) 
Umbilical hernia  1  4/3023 (0.13%)  3/3010 (0.10%) 
Upper gastrointestinal haemorrhage  1  7/3023 (0.23%)  4/3010 (0.13%) 
Vomiting  1  3/3023 (0.10%)  4/3010 (0.13%) 
General disorders     
Adhesion  1  1/3023 (0.03%)  0/3010 (0.00%) 
Adverse drug reaction  1  1/3023 (0.03%)  0/3010 (0.00%) 
Asthenia  1  3/3023 (0.10%)  7/3010 (0.23%) 
Cardiac death  1  7/3023 (0.23%)  3/3010 (0.10%) 
Chest discomfort  1  3/3023 (0.10%)  6/3010 (0.20%) 
Chest pain  1  50/3023 (1.65%)  52/3010 (1.73%) 
Chills  1  0/3023 (0.00%)  1/3010 (0.03%) 
Condition aggravated  1  0/3023 (0.00%)  1/3010 (0.03%) 
Death  1  20/3023 (0.66%)  20/3010 (0.66%) 
Discomfort  1  1/3023 (0.03%)  0/3010 (0.00%) 
Exercise tolerance decreased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Fatigue  1  0/3023 (0.00%)  3/3010 (0.10%) 
Fibrosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
General physical health deterioration  1  3/3023 (0.10%)  4/3010 (0.13%) 
Hernia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hyperthermia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Impaired healing  1  0/3023 (0.00%)  1/3010 (0.03%) 
Implant site extravasation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Implant site haematoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Malaise  1  3/3023 (0.10%)  2/3010 (0.07%) 
Mass  1  1/3023 (0.03%)  0/3010 (0.00%) 
Multi-organ disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Multiple organ dysfunction syndrome  1  1/3023 (0.03%)  7/3010 (0.23%) 
Non-cardiac chest pain  1  8/3023 (0.26%)  8/3010 (0.27%) 
Oedema peripheral  1  2/3023 (0.07%)  1/3010 (0.03%) 
Puncture site haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pyrexia  1  7/3023 (0.23%)  8/3010 (0.27%) 
Retention cyst  1  0/3023 (0.00%)  1/3010 (0.03%) 
Sudden cardiac death  1  3/3023 (0.10%)  1/3010 (0.03%) 
Sudden death  1  9/3023 (0.30%)  4/3010 (0.13%) 
Swelling  1  1/3023 (0.03%)  0/3010 (0.00%) 
Vascular stent stenosis  1  3/3023 (0.10%)  1/3010 (0.03%) 
Hepatobiliary disorders     
Acute hepatic failure  1  0/3023 (0.00%)  2/3010 (0.07%) 
Bile duct obstruction  1  2/3023 (0.07%)  0/3010 (0.00%) 
Bile duct stenosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bile duct stone  1  6/3023 (0.20%)  1/3010 (0.03%) 
Biliary colic  1  1/3023 (0.03%)  1/3010 (0.03%) 
Biliary dyskinesia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cholangitis  1  2/3023 (0.07%)  1/3010 (0.03%) 
Cholangitis acute  1  1/3023 (0.03%)  1/3010 (0.03%) 
Cholecystitis  1  20/3023 (0.66%)  16/3010 (0.53%) 
Cholecystitis acute  1  9/3023 (0.30%)  5/3010 (0.17%) 
Cholecystitis chronic  1  3/3023 (0.10%)  0/3010 (0.00%) 
Cholelithiasis  1  20/3023 (0.66%)  14/3010 (0.47%) 
Cholestasis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cholestatic liver injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cirrhosis alcoholic  1  0/3023 (0.00%)  1/3010 (0.03%) 
Drug-induced liver injury  1  2/3023 (0.07%)  0/3010 (0.00%) 
Gallbladder disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gallbladder necrosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gallbladder polyp  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hepatic cirrhosis  1  3/3023 (0.10%)  6/3010 (0.20%) 
Hepatic cyst  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hepatic failure  1  1/3023 (0.03%)  1/3010 (0.03%) 
Hepatic fibrosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hepatic lesion  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hepatic mass  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hepatic steatosis  1  6/3023 (0.20%)  5/3010 (0.17%) 
Hepatitis acute  1  2/3023 (0.07%)  0/3010 (0.00%) 
Hepatocellular injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hydrocholecystis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Hypertransaminasaemia  1  2/3023 (0.07%)  0/3010 (0.00%) 
Ischaemic hepatitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Jaundice  1  1/3023 (0.03%)  1/3010 (0.03%) 
Jaundice cholestatic  1  2/3023 (0.07%)  0/3010 (0.00%) 
Liver disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Liver injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Portal vein thrombosis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Immune system disorders     
Allergy to vaccine  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anaphylactic reaction  1  1/3023 (0.03%)  1/3010 (0.03%) 
Hypersensitivity  1  2/3023 (0.07%)  1/3010 (0.03%) 
Infections and infestations     
Abdominal abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Abdominal infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Abscess intestinal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Abscess jaw  1  1/3023 (0.03%)  0/3010 (0.00%) 
Abscess limb  1  3/3023 (0.10%)  3/3010 (0.10%) 
Abscess neck  1  1/3023 (0.03%)  0/3010 (0.00%) 
Acarodermatitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Actinomycotic pulmonary infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Acute hepatitis C  1  0/3023 (0.00%)  1/3010 (0.03%) 
Administration site cellulitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anal abscess  1  1/3023 (0.03%)  2/3010 (0.07%) 
Appendiceal abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Appendicitis  1  5/3023 (0.17%)  5/3010 (0.17%) 
Appendicitis perforated  1  1/3023 (0.03%)  0/3010 (0.00%) 
Arthritis bacterial  1  1/3023 (0.03%)  4/3010 (0.13%) 
Arthritis infective  1  1/3023 (0.03%)  1/3010 (0.03%) 
Atypical pneumonia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bacteraemia  1  4/3023 (0.13%)  1/3010 (0.03%) 
Bacterial sepsis  1  1/3023 (0.03%)  2/3010 (0.07%) 
Biliary sepsis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Body tinea  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bronchitis  1  15/3023 (0.50%)  11/3010 (0.37%) 
Campylobacter gastroenteritis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Candida sepsis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cellulitis  1  17/3023 (0.56%)  18/3010 (0.60%) 
Cellulitis staphylococcal  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cholecystitis infective  1  1/3023 (0.03%)  1/3010 (0.03%) 
Chronic tonsillitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Clostridium difficile infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Colon gangrene  1  1/3023 (0.03%)  1/3010 (0.03%) 
Conjunctivitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Creutzfeldt-Jakob disease  1  0/3023 (0.00%)  2/3010 (0.07%) 
Cystitis  1  0/3023 (0.00%)  3/3010 (0.10%) 
Cystitis escherichia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Dengue fever  1  0/3023 (0.00%)  3/3010 (0.10%) 
Device related infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Device related sepsis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Diabetic foot infection  1  2/3023 (0.07%)  0/3010 (0.00%) 
Diabetic gangrene  1  1/3023 (0.03%)  1/3010 (0.03%) 
Diarrhoea infectious  1  1/3023 (0.03%)  1/3010 (0.03%) 
Diverticulitis  1  6/3023 (0.20%)  6/3010 (0.20%) 
Empyema  1  0/3023 (0.00%)  2/3010 (0.07%) 
Encephalitis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Endocarditis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Endocarditis bacterial  1  1/3023 (0.03%)  0/3010 (0.00%) 
Enteritis infectious  1  2/3023 (0.07%)  0/3010 (0.00%) 
Enterococcal sepsis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Epididymitis  1  2/3023 (0.07%)  2/3010 (0.07%) 
Epiglottitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Erysipelas  1  3/3023 (0.10%)  11/3010 (0.37%) 
Escherichia sepsis  1  1/3023 (0.03%)  0/3010 (0.00%) 
External ear cellulitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Febrile infection  1  1/3023 (0.03%)  1/3010 (0.03%) 
Fungal infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gallbladder abscess  1  2/3023 (0.07%)  1/3010 (0.03%) 
Gangrene  1  3/3023 (0.10%)  4/3010 (0.13%) 
Gastric ulcer helicobacter  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastroenteritis  1  17/3023 (0.56%)  17/3010 (0.56%) 
Gastroenteritis clostridial  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastroenteritis norovirus  1  2/3023 (0.07%)  0/3010 (0.00%) 
Gastroenteritis viral  1  3/3023 (0.10%)  2/3010 (0.07%) 
Gastrointestinal infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gingival abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Graft infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Groin abscess  1  2/3023 (0.07%)  0/3010 (0.00%) 
Haematoma infection  1  1/3023 (0.03%)  1/3010 (0.03%) 
Haemophilus infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Helicobacter gastritis  1  2/3023 (0.07%)  1/3010 (0.03%) 
Hepatitis A  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hepatitis C  1  1/3023 (0.03%)  1/3010 (0.03%) 
Herpes simplex  1  1/3023 (0.03%)  0/3010 (0.00%) 
Herpes zoster  1  1/3023 (0.03%)  9/3010 (0.30%) 
Infected bite  1  1/3023 (0.03%)  0/3010 (0.00%) 
Infected dermal cyst  1  0/3023 (0.00%)  1/3010 (0.03%) 
Infected skin ulcer  1  2/3023 (0.07%)  0/3010 (0.00%) 
Infection  1  1/3023 (0.03%)  3/3010 (0.10%) 
Infectious colitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Infectious pleural effusion  1  0/3023 (0.00%)  2/3010 (0.07%) 
Infective exacerbation of chronic obstructive airways disease  1  2/3023 (0.07%)  1/3010 (0.03%) 
Infective spondylitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Influenza  1  2/3023 (0.07%)  8/3010 (0.27%) 
Intervertebral discitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Kidney infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Klebsiella bacteraemia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Labyrinthitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Liver abscess  1  1/3023 (0.03%)  2/3010 (0.07%) 
Localised infection  1  2/3023 (0.07%)  1/3010 (0.03%) 
Lower respiratory tract infection  1  4/3023 (0.13%)  4/3010 (0.13%) 
Lung infection  1  1/3023 (0.03%)  2/3010 (0.07%) 
Lymphangitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Mediastinitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Medical device site infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Meningitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Meningitis aseptic  1  0/3023 (0.00%)  1/3010 (0.03%) 
Meningitis bacterial  1  1/3023 (0.03%)  1/3010 (0.03%) 
Meningitis viral  1  1/3023 (0.03%)  0/3010 (0.00%) 
Meningoencephalitis viral  1  0/3023 (0.00%)  1/3010 (0.03%) 
Morganella infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Nasopharyngitis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Necrotising fasciitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Nosocomial infection  1  1/3023 (0.03%)  0/3010 (0.00%) 
Oesophageal candidiasis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Orchitis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Osteomyelitis  1  8/3023 (0.26%)  3/3010 (0.10%) 
Osteomyelitis chronic  1  1/3023 (0.03%)  0/3010 (0.00%) 
Osteomyelitis fungal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Otitis media  1  1/3023 (0.03%)  0/3010 (0.00%) 
Otitis media chronic  1  0/3023 (0.00%)  1/3010 (0.03%) 
Parotitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Pelvic abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Perichondritis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Periodontitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Peritonitis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Peritonsillar abscess  1  0/3023 (0.00%)  2/3010 (0.07%) 
Pneumonia  1  83/3023 (2.75%)  83/3010 (2.76%) 
Pneumonia bacterial  1  3/3023 (0.10%)  0/3010 (0.00%) 
Pneumonia necrotising  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pneumonia pneumococcal  1  2/3023 (0.07%)  0/3010 (0.00%) 
Pneumonia viral  1  0/3023 (0.00%)  1/3010 (0.03%) 
Post procedural cellulitis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Post procedural infection  1  1/3023 (0.03%)  3/3010 (0.10%) 
Postoperative abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Postoperative wound infection  1  3/3023 (0.10%)  4/3010 (0.13%) 
Pseudomembranous colitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Purulence  1  0/3023 (0.00%)  1/3010 (0.03%) 
Pyelitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pyelonephritis  1  8/3023 (0.26%)  4/3010 (0.13%) 
Pyelonephritis acute  1  4/3023 (0.13%)  2/3010 (0.07%) 
Pyelonephritis fungal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pyonephrosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Respiratory tract infection  1  2/3023 (0.07%)  7/3010 (0.23%) 
Respiratory tract infection viral  1  0/3023 (0.00%)  1/3010 (0.03%) 
Retroperitoneal abscess  1  0/3023 (0.00%)  1/3010 (0.03%) 
Rotavirus infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Salmonellosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Scrotal abscess  1  0/3023 (0.00%)  1/3010 (0.03%) 
Scrub typhus  1  1/3023 (0.03%)  0/3010 (0.00%) 
Sepsis  1  17/3023 (0.56%)  24/3010 (0.80%) 
Septic arthritis streptococcal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Septic shock  1  6/3023 (0.20%)  7/3010 (0.23%) 
Sialoadenitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Sinusitis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Small intestine gangrene  1  0/3023 (0.00%)  1/3010 (0.03%) 
Soft tissue infection  1  1/3023 (0.03%)  1/3010 (0.03%) 
Staphylococcal bacteraemia  1  0/3023 (0.00%)  2/3010 (0.07%) 
Staphylococcal infection  1  1/3023 (0.03%)  1/3010 (0.03%) 
Subcutaneous abscess  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tooth abscess  1  1/3023 (0.03%)  2/3010 (0.07%) 
Tooth infection  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tracheobronchitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Tuberculosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Upper respiratory tract infection  1  5/3023 (0.17%)  3/3010 (0.10%) 
Ureteritis  1  2/3023 (0.07%)  0/3010 (0.00%) 
Urethritis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Urinary tract infection  1  30/3023 (0.99%)  31/3010 (1.03%) 
Urinary tract infection bacterial  1  1/3023 (0.03%)  0/3010 (0.00%) 
Urinary tract infection enterococcal  1  0/3023 (0.00%)  1/3010 (0.03%) 
Urinary tract infection fungal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Urosepsis  1  7/3023 (0.23%)  6/3010 (0.20%) 
Varicella  1  0/3023 (0.00%)  1/3010 (0.03%) 
Vestibular neuronitis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Viral infection  1  1/3023 (0.03%)  2/3010 (0.07%) 
Vulval abscess  1  1/3023 (0.03%)  0/3010 (0.00%) 
Wound infection  1  2/3023 (0.07%)  4/3010 (0.13%) 
Injury, poisoning and procedural complications     
Accident  1  1/3023 (0.03%)  3/3010 (0.10%) 
Anaemia postoperative  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anaesthetic complication cardiac  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anastomotic leak  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ankle fracture  1  6/3023 (0.20%)  11/3010 (0.37%) 
Arterial restenosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Arthropod sting  1  0/3023 (0.00%)  1/3010 (0.03%) 
Back injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bladder injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bone contusion  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bone fragmentation  1  1/3023 (0.03%)  0/3010 (0.00%) 
Brain contusion  1  2/3023 (0.07%)  1/3010 (0.03%) 
Brain herniation  1  0/3023 (0.00%)  1/3010 (0.03%) 
Burns second degree  1  0/3023 (0.00%)  1/3010 (0.03%) 
Carbon monoxide poisoning  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cardiac valve replacement complication  1  0/3023 (0.00%)  1/3010 (0.03%) 
Carotid artery restenosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cartilage injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cervical vertebral fracture  1  2/3023 (0.07%)  0/3010 (0.00%) 
Chemical burn  1  0/3023 (0.00%)  1/3010 (0.03%) 
Chest injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Comminuted fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Concussion  1  1/3023 (0.03%)  3/3010 (0.10%) 
Conjunctival laceration  1  0/3023 (0.00%)  1/3010 (0.03%) 
Contusion  1  4/3023 (0.13%)  5/3010 (0.17%) 
Coronary artery reocclusion  1  0/3023 (0.00%)  1/3010 (0.03%) 
Coronary artery restenosis  1  0/3023 (0.00%)  3/3010 (0.10%) 
Craniocerebral injury  1  5/3023 (0.17%)  1/3010 (0.03%) 
Crush injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Extradural haematoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Eye contusion  1  1/3023 (0.03%)  0/3010 (0.00%) 
Face injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Facial bones fracture  1  1/3023 (0.03%)  2/3010 (0.07%) 
Fall  1  31/3023 (1.03%)  44/3010 (1.46%) 
Femoral neck fracture  1  4/3023 (0.13%)  4/3010 (0.13%) 
Femur fracture  1  9/3023 (0.30%)  6/3010 (0.20%) 
Fibula fracture  1  1/3023 (0.03%)  2/3010 (0.07%) 
Foot fracture  1  1/3023 (0.03%)  4/3010 (0.13%) 
Forearm fracture  1  1/3023 (0.03%)  1/3010 (0.03%) 
Fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Fracture displacement  1  0/3023 (0.00%)  3/3010 (0.10%) 
Fracture of penis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Graft thrombosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hand fracture  1  2/3023 (0.07%)  2/3010 (0.07%) 
Head injury  1  5/3023 (0.17%)  4/3010 (0.13%) 
Hip fracture  1  7/3023 (0.23%)  16/3010 (0.53%) 
Humerus fracture  1  1/3023 (0.03%)  6/3010 (0.20%) 
Ilium fracture  1  1/3023 (0.03%)  0/3010 (0.00%) 
Impacted fracture  1  1/3023 (0.03%)  1/3010 (0.03%) 
Incarcerated incisional hernia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Incisional hernia  1  3/3023 (0.10%)  1/3010 (0.03%) 
Inflammation of wound  1  0/3023 (0.00%)  1/3010 (0.03%) 
Injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Injury corneal  1  0/3023 (0.00%)  1/3010 (0.03%) 
Intentional overdose  1  1/3023 (0.03%)  0/3010 (0.00%) 
Jaw fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Joint dislocation  1  6/3023 (0.20%)  6/3010 (0.20%) 
Laceration  1  1/3023 (0.03%)  0/3010 (0.00%) 
Ligament rupture  1  5/3023 (0.17%)  0/3010 (0.00%) 
Ligament sprain  1  1/3023 (0.03%)  4/3010 (0.13%) 
Limb injury  1  2/3023 (0.07%)  3/3010 (0.10%) 
Limb traumatic amputation  1  1/3023 (0.03%)  1/3010 (0.03%) 
Lower limb fracture  1  7/3023 (0.23%)  5/3010 (0.17%) 
Lumbar vertebral fracture  1  3/3023 (0.10%)  2/3010 (0.07%) 
Meniscus injury  1  6/3023 (0.20%)  4/3010 (0.13%) 
Multiple fractures  1  1/3023 (0.03%)  1/3010 (0.03%) 
Multiple injuries  1  1/3023 (0.03%)  0/3010 (0.00%) 
Muscle rupture  1  1/3023 (0.03%)  2/3010 (0.07%) 
Muscle strain  1  0/3023 (0.00%)  1/3010 (0.03%) 
Overdose  1  4/3023 (0.13%)  1/3010 (0.03%) 
Patella fracture  1  2/3023 (0.07%)  0/3010 (0.00%) 
Pelvic fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Pneumoconiosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Post procedural bile leak  1  1/3023 (0.03%)  0/3010 (0.00%) 
Post procedural fistula  1  0/3023 (0.00%)  1/3010 (0.03%) 
Post procedural haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Post procedural inflammation  1  1/3023 (0.03%)  1/3010 (0.03%) 
Post procedural urine leak  1  0/3023 (0.00%)  1/3010 (0.03%) 
Postoperative ileus  1  1/3023 (0.03%)  0/3010 (0.00%) 
Postoperative renal failure  1  0/3023 (0.00%)  1/3010 (0.03%) 
Postpericardiotomy syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Procedural haemorrhage  1  1/3023 (0.03%)  0/3010 (0.00%) 
Procedural pain  1  0/3023 (0.00%)  1/3010 (0.03%) 
Procedural pneumothorax  1  0/3023 (0.00%)  1/3010 (0.03%) 
Pubis fracture  1  2/3023 (0.07%)  1/3010 (0.03%) 
Pulmonary contusion  1  1/3023 (0.03%)  0/3010 (0.00%) 
Radius fracture  1  2/3023 (0.07%)  6/3010 (0.20%) 
Rib fracture  1  5/3023 (0.17%)  4/3010 (0.13%) 
Road traffic accident  1  13/3023 (0.43%)  7/3010 (0.23%) 
Scar  1  0/3023 (0.00%)  1/3010 (0.03%) 
Shunt occlusion  1  1/3023 (0.03%)  0/3010 (0.00%) 
Skin abrasion  1  0/3023 (0.00%)  1/3010 (0.03%) 
Skull fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Soft tissue injury  1  0/3023 (0.00%)  2/3010 (0.07%) 
Spinal compression fracture  1  8/3023 (0.26%)  1/3010 (0.03%) 
Spinal cord injury cervical  1  1/3023 (0.03%)  0/3010 (0.00%) 
Spinal fracture  1  2/3023 (0.07%)  4/3010 (0.13%) 
Splenic injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Stab wound  1  1/3023 (0.03%)  0/3010 (0.00%) 
Sternal fracture  1  0/3023 (0.00%)  1/3010 (0.03%) 
Subarachnoid haemorrhage  1  5/3023 (0.17%)  5/3010 (0.17%) 
Subdural haematoma  1  5/3023 (0.17%)  7/3010 (0.23%) 
Subdural haemorrhage  1  5/3023 (0.17%)  1/3010 (0.03%) 
Tendon injury  1  0/3023 (0.00%)  1/3010 (0.03%) 
Tendon rupture  1  6/3023 (0.20%)  3/3010 (0.10%) 
Thoracic vertebral fracture  1  2/3023 (0.07%)  0/3010 (0.00%) 
Tibia fracture  1  3/3023 (0.10%)  1/3010 (0.03%) 
Toxicity to various agents  1  0/3023 (0.00%)  2/3010 (0.07%) 
Transplant dysfunction  1  0/3023 (0.00%)  1/3010 (0.03%) 
Traumatic arthritis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Traumatic intracranial haemorrhage  1  2/3023 (0.07%)  0/3010 (0.00%) 
Ulna fracture  1  1/3023 (0.03%)  3/3010 (0.10%) 
Upper limb fracture  1  2/3023 (0.07%)  2/3010 (0.07%) 
Urethral injury  1  1/3023 (0.03%)  0/3010 (0.00%) 
Vascular graft occlusion  1  1/3023 (0.03%)  1/3010 (0.03%) 
Vascular pseudoaneurysm  1  1/3023 (0.03%)  0/3010 (0.00%) 
Wound  1  2/3023 (0.07%)  2/3010 (0.07%) 
Wound dehiscence  1  2/3023 (0.07%)  0/3010 (0.00%) 
Wound necrosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Wrist fracture  1  1/3023 (0.03%)  1/3010 (0.03%) 
Investigations     
Alanine aminotransferase increased  1  6/3023 (0.20%)  7/3010 (0.23%) 
Amylase increased  1  3/3023 (0.10%)  0/3010 (0.00%) 
Anticoagulation drug level below therapeutic  1  0/3023 (0.00%)  1/3010 (0.03%) 
Arteriogram coronary  1  1/3023 (0.03%)  0/3010 (0.00%) 
Aspartate aminotransferase increased  1  6/3023 (0.20%)  7/3010 (0.23%) 
Blood alkaline phosphatase increased  1  0/3023 (0.00%)  2/3010 (0.07%) 
Blood bilirubin increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Blood creatine phosphokinase MB increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Blood creatinine increased  1  12/3023 (0.40%)  11/3010 (0.37%) 
Blood pressure decreased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Blood pressure increased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Body temperature increased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cardiac stress test abnormal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Computerised tomogram head abnormal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Electrocardiogram QT prolonged  1  2/3023 (0.07%)  0/3010 (0.00%) 
Electrocardiogram ST segment depression  1  1/3023 (0.03%)  0/3010 (0.00%) 
Electrocardiogram T wave inversion  1  2/3023 (0.07%)  2/3010 (0.07%) 
Electrocardiogram abnormal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Electrocardiogram ambulatory abnormal  1  1/3023 (0.03%)  0/3010 (0.00%) 
Full blood count decreased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gamma-glutamyltransferase increased  1  7/3023 (0.23%)  7/3010 (0.23%) 
Glomerular filtration rate decreased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Haemoglobin decreased  1  0/3023 (0.00%)  2/3010 (0.07%) 
Heart rate decreased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Hepatic enzyme increased  1  2/3023 (0.07%)  1/3010 (0.03%) 
Hepatitis C virus test  1  1/3023 (0.03%)  0/3010 (0.00%) 
International normalised ratio decreased  1  1/3023 (0.03%)  1/3010 (0.03%) 
International normalised ratio increased  1  3/3023 (0.10%)  0/3010 (0.00%) 
Lipase increased  1  3/3023 (0.10%)  1/3010 (0.03%) 
Liver function test abnormal  1  0/3023 (0.00%)  2/3010 (0.07%) 
Liver function test increased  1  1/3023 (0.03%)  1/3010 (0.03%) 
Myelocyte count increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Positron emission tomogram abnormal  1  0/3023 (0.00%)  1/3010 (0.03%) 
Prostatic specific antigen increased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Transaminases increased  1  1/3023 (0.03%)  0/3010 (0.00%) 
Troponin increased  1  4/3023 (0.13%)  1/3010 (0.03%) 
Urine albumin/creatinine ratio increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Weight decreased  1  1/3023 (0.03%)  1/3010 (0.03%) 
Weight increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
White blood cell count increased  1  0/3023 (0.00%)  1/3010 (0.03%) 
Metabolism and nutrition disorders     
Acidosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Decreased appetite  1  2/3023 (0.07%)  0/3010 (0.00%) 
Dehydration  1  13/3023 (0.43%)  10/3010 (0.33%) 
Diabetes mellitus  1  3/3023 (0.10%)  2/3010 (0.07%) 
Diabetes mellitus inadequate control  1  2/3023 (0.07%)  3/3010 (0.10%) 
Diabetic metabolic decompensation  1  0/3023 (0.00%)  2/3010 (0.07%) 
Fluid overload  1  2/3023 (0.07%)  2/3010 (0.07%) 
Gout  1  4/3023 (0.13%)  1/3010 (0.03%) 
Hypercholesterolaemia  1  2/3023 (0.07%)  0/3010 (0.00%) 
Hyperglycaemia  1  6/3023 (0.20%)  8/3010 (0.27%) 
Hyperglycaemic hyperosmolar nonketotic syndrome  1  1/3023 (0.03%)  1/3010 (0.03%) 
Hyperkalaemia  1  7/3023 (0.23%)  4/3010 (0.13%) 
Hypocalcaemia  1  0/3023 (0.00%)  2/3010 (0.07%) 
Hypochloraemia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hypoglycaemia  1  3/3023 (0.10%)  29/3010 (0.96%) 
Hypokalaemia  1  4/3023 (0.13%)  1/3010 (0.03%) 
Hypomagnesaemia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Hyponatraemia  1  6/3023 (0.20%)  4/3010 (0.13%) 
Hypophagia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Lactic acidosis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Malnutrition  1  1/3023 (0.03%)  1/3010 (0.03%) 
Metabolic acidosis  1  4/3023 (0.13%)  1/3010 (0.03%) 
Metabolic disorder  1  0/3023 (0.00%)  1/3010 (0.03%) 
Obesity  1  0/3023 (0.00%)  5/3010 (0.17%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  6/3023 (0.20%)  9/3010 (0.30%) 
Arthritis  1  6/3023 (0.20%)  4/3010 (0.13%) 
Arthritis reactive  1  1/3023 (0.03%)  0/3010 (0.00%) 
Arthropathy  1  4/3023 (0.13%)  1/3010 (0.03%) 
Back pain  1  6/3023 (0.20%)  8/3010 (0.27%) 
Bone atrophy  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bursitis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Cervical spinal stenosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Compartment syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Costochondritis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Dupuytren's contracture  1  1/3023 (0.03%)  0/3010 (0.00%) 
Facet joint syndrome  1  1/3023 (0.03%)  0/3010 (0.00%) 
Fibromyalgia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Flank pain  1  0/3023 (0.00%)  1/3010 (0.03%) 
Foot deformity  1  3/3023 (0.10%)  1/3010 (0.03%) 
Gouty arthritis  1  4/3023 (0.13%)  0/3010 (0.00%) 
Groin pain  1  0/3023 (0.00%)  1/3010 (0.03%) 
Haemarthrosis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Intervertebral disc degeneration  1  1/3023 (0.03%)  3/3010 (0.10%) 
Intervertebral disc disorder  1  2/3023 (0.07%)  1/3010 (0.03%) 
Intervertebral disc protrusion  1  8/3023 (0.26%)  12/3010 (0.40%) 
Joint effusion  1  1/3023 (0.03%)  1/3010 (0.03%) 
Joint swelling  1  1/3023 (0.03%)  1/3010 (0.03%) 
Limb deformity  1  0/3023 (0.00%)  1/3010 (0.03%) 
Lumbar spinal stenosis  1  11/3023 (0.36%)  7/3010 (0.23%) 
Mobility decreased  1  1/3023 (0.03%)  2/3010 (0.07%) 
Muscle haemorrhage  1  0/3023 (0.00%)  1/3010 (0.03%) 
Muscular weakness  1  1/3023 (0.03%)  3/3010 (0.10%) 
Musculoskeletal chest pain  1  2/3023 (0.07%)  1/3010 (0.03%) 
Musculoskeletal pain  1  4/3023 (0.13%)  1/3010 (0.03%) 
Myalgia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Neck pain  1  0/3023 (0.00%)  2/3010 (0.07%) 
Osteoarthritis  1  49/3023 (1.62%)  63/3010 (2.09%) 
Osteolysis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Osteonecrosis  1  0/3023 (0.00%)  3/3010 (0.10%) 
Osteoporosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Pain in extremity  1  3/3023 (0.10%)  1/3010 (0.03%) 
Pathological fracture  1  2/3023 (0.07%)  1/3010 (0.03%) 
Periarthritis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Polyarthritis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Polymyalgia rheumatica  1  9/3023 (0.30%)  13/3010 (0.43%) 
Pseudarthrosis  1  0/3023 (0.00%)  1/3010 (0.03%) 
Psoriatic arthropathy  1  0/3023 (0.00%)  1/3010 (0.03%) 
Rhabdomyolysis  1  4/3023 (0.13%)  3/3010 (0.10%) 
Rheumatoid arthritis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Rotator cuff syndrome  1  7/3023 (0.23%)  5/3010 (0.17%) 
Scoliosis  1  1/3023 (0.03%)  1/3010 (0.03%) 
Sjogren's syndrome  1  1/3023 (0.03%)  1/3010 (0.03%) 
Spinal column stenosis  1  4/3023 (0.13%)  12/3010 (0.40%) 
Spinal disorder  1  0/3023 (0.00%)  1/3010 (0.03%) 
Spinal ligament ossification  1  1/3023 (0.03%)  0/3010 (0.00%) 
Spinal osteoarthritis  1  5/3023 (0.17%)  8/3010 (0.27%) 
Spinal pain  1  2/3023 (0.07%)  2/3010 (0.07%) 
Spondylitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Spondylolisthesis  1  3/3023 (0.10%)  2/3010 (0.07%) 
Synovial cyst  1  1/3023 (0.03%)  1/3010 (0.03%) 
Systemic lupus erythematosus  1  1/3023 (0.03%)  0/3010 (0.00%) 
Tendon disorder  1  1/3023 (0.03%)  0/3010 (0.00%) 
Tenosynovitis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Trigger finger  1  1/3023 (0.03%)  0/3010 (0.00%) 
Vertebral foraminal stenosis  1  0/3023 (0.00%)  2/3010 (0.07%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute leukaemia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Acute lymphocytic leukaemia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Acute promyelocytic leukaemia  1  0/3023 (0.00%)  1/3010 (0.03%) 
Adenocarcinoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Adenocarcinoma gastric  1  1/3023 (0.03%)  0/3010 (0.00%) 
Adenocarcinoma of appendix  1  1/3023 (0.03%)  0/3010 (0.00%) 
Adenocarcinoma of colon  1  8/3023 (0.26%)  7/3010 (0.23%) 
Adenocarcinoma pancreas  1  2/3023 (0.07%)  1/3010 (0.03%) 
Adenoma benign  1  1/3023 (0.03%)  1/3010 (0.03%) 
Adrenal neoplasm  1  0/3023 (0.00%)  1/3010 (0.03%) 
Anal cancer  1  0/3023 (0.00%)  1/3010 (0.03%) 
Angiosarcoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
B-cell lymphoma  1  1/3023 (0.03%)  1/3010 (0.03%) 
Basal cell carcinoma  1  39/3023 (1.29%)  33/3010 (1.10%) 
Basosquamous carcinoma of skin  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bile duct cancer  1  1/3023 (0.03%)  1/3010 (0.03%) 
Bladder cancer  1  4/3023 (0.13%)  8/3010 (0.27%) 
Bladder cancer recurrent  1  0/3023 (0.00%)  2/3010 (0.07%) 
Bladder papilloma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bladder transitional cell carcinoma  1  2/3023 (0.07%)  8/3010 (0.27%) 
Bladder transitional cell carcinoma recurrent  1  0/3023 (0.00%)  1/3010 (0.03%) 
Bowen's disease  1  5/3023 (0.17%)  5/3010 (0.17%) 
Brain neoplasm  1  0/3023 (0.00%)  2/3010 (0.07%) 
Brain neoplasm benign  1  1/3023 (0.03%)  0/3010 (0.00%) 
Breast cancer  1  12/3023 (0.40%)  9/3010 (0.30%) 
Breast cancer metastatic  1  1/3023 (0.03%)  1/3010 (0.03%) 
Breast cancer stage IV  1  1/3023 (0.03%)  0/3010 (0.00%) 
Breast neoplasm  1  1/3023 (0.03%)  0/3010 (0.00%) 
Bronchial carcinoma  1  0/3023 (0.00%)  2/3010 (0.07%) 
Carcinoid tumour pulmonary  1  0/3023 (0.00%)  1/3010 (0.03%) 
Carcinoma in situ of skin  1  1/3023 (0.03%)  0/3010 (0.00%) 
Central nervous system lymphoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cervix carcinoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Cholangiocarcinoma  1  2/3023 (0.07%)  1/3010 (0.03%) 
Chronic lymphocytic leukaemia  1  2/3023 (0.07%)  3/3010 (0.10%) 
Chronic myeloid leukaemia  1  1/3023 (0.03%)  1/3010 (0.03%) 
Colon adenoma  1  2/3023 (0.07%)  1/3010 (0.03%) 
Colon cancer  1  12/3023 (0.40%)  5/3010 (0.17%) 
Colon cancer metastatic  1  0/3023 (0.00%)  2/3010 (0.07%) 
Colon neoplasm  1  0/3023 (0.00%)  1/3010 (0.03%) 
Colorectal adenocarcinoma  1  2/3023 (0.07%)  0/3010 (0.00%) 
Colorectal cancer  1  1/3023 (0.03%)  0/3010 (0.00%) 
Conjunctival melanoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Cutaneous lymphoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Diffuse large B-cell lymphoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Dysplastic naevus  1  2/3023 (0.07%)  0/3010 (0.00%) 
Enchondromatosis  1  1/3023 (0.03%)  0/3010 (0.00%) 
Endometrial adenocarcinoma  1  2/3023 (0.07%)  0/3010 (0.00%) 
Endometrial cancer  1  2/3023 (0.07%)  2/3010 (0.07%) 
Ependymoma benign  1  1/3023 (0.03%)  0/3010 (0.00%) 
Essential thrombocythaemia  1  1/3023 (0.03%)  0/3010 (0.00%) 
Fibrous histiocytoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gallbladder adenocarcinoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gallbladder cancer  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gastric adenoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastric cancer  1  6/3023 (0.20%)  3/3010 (0.10%) 
Gastrointestinal carcinoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastrointestinal melanoma  1  0/3023 (0.00%)  1/3010 (0.03%) 
Gastrointestinal stromal tumour  1  0/3023 (0.00%)  2/3010 (0.07%) 
Gastrointestinal tract adenoma  1  1/3023 (0.03%)  0/3010 (0.00%) 
Gastrooesophageal cancer  1  0/3023 (0.00%)  1/3010 (0.03%) 
Glioblastoma  1  1/3023 (0.03%)  0/3010 (0.00%)