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Sitagliptin Cardiovascular Outcomes Study (MK-0431-082) (TECOS)

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: NCT00790205
Recruitment Status : Completed
First Posted : November 13, 2008
Results First Posted : April 15, 2016
Last Update Posted : August 17, 2018
Sponsor:
Collaborator:
Duke Clinical Research Institute, Oxford Diabetes Trials Unit
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Sitagliptin
Drug: Placebo
Enrollment 14671
Recruitment Details  
Pre-assignment Details A total of 14,671 participants were randomized to treatment, provided consent and did not have any Good Clinical Practice (GCP) deviations.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Period Title: Overall Study
Started 7332 7339
Treated 7266 7274
Completed 6972 6905
Not Completed 360 434
Reason Not Completed
Lost to Follow-up             61             71
Withdrawal by Subject             299             363
Arm/Group Title Sitagliptin Placebo Total
Hide Arm/Group Description Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years Total of all reporting groups
Overall Number of Baseline Participants 7332 7339 14671
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7332 participants 7339 participants 14671 participants
Adults 18 - 64 years 3315 3301 6616
From 65 - 84 years 3813 3821 7634
85 years and over 46 55 101
Unknown age 158 162 320
[1]
Measure Description: Age is unknown for 320 participants
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7332 participants 7339 participants 14671 participants
Female
2134
  29.1%
2163
  29.5%
4297
  29.3%
Male
5198
  70.9%
5176
  70.5%
10374
  70.7%
Estimated Glomerular Filtration Rate (eGFR)   [1] 
Mean (Standard Deviation)
Unit of measure:  mL/min/1.73 m^2
Number Analyzed 7332 participants 7339 participants 14671 participants
74.9  (21.3) 74.9  (20.9) 74.9  (21.1)
[1]
Measure Description: Sitagliptin, n= 7254; Placebo, n= 7274; Total, n=14528
Hemoglobin A1c (HbA1c)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of HbA1c
Number Analyzed 7332 participants 7339 participants 14671 participants
7.2  (0.5) 7.2  (0.5) 7.2  (0.5)
[1]
Measure Description: Sitagliptin, n= 7330; Placebo, n= 7336; Total, n= 14666
Urine albumin creatinine ratio   [1] 
Mean (Standard Deviation)
Unit of measure:  G/mol Creatinine
Number Analyzed 7332 participants 7339 participants 14671 participants
8.6  (37.4) 8.4  (36.0) 8.5  (36.7)
[1]
Measure Description: Sitagliptin, n= 2606; Placebo, n= 2542; Total, n= 5148
1.Primary Outcome
Title Percentage of Participants With First Confirmed Cardiovascular (CV) Event of Major Adverse Cardiovascular Event (MACE) Plus (Per Protocol Population)
Hide Description Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7257 7266
Measure Type: Number
Unit of Measure: Percentage of participants
9.6 9.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Hazard Ratio of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV outcome measure was assessed by the hazard ratio between the sitagliptin and placebo groups. The confidence interval for the hazard ratio was computed and compared to 1.30, the non-inferiority margin.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.88 to 1.09
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentage of Participants With First Confirmed CV Event of Major Adverse Cardiovascular Event (MACE) Plus (Intent to Treat Population)
Hide Description Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7332 7339
Measure Type: Number
Unit of Measure: Percentage of participants
11.4 11.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Hazard Ratio of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV outcome measure was assessed by the hazard ratio between the sitagliptin and placebo groups. The confidence interval for the hazard ratio was computed and compared to 1.30, the non-inferiority margin.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.89 to 1.08
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With First Confirmed CV Event of MACE (Per Protocol Population)
Hide Description CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7257 7266
Measure Type: Number
Unit of Measure: Percentage of participants
8.4 8.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Hazard Ratio of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV outcome measure was assessed by the hazard ratio between the sitagliptin and placebo groups. The confidence interval for the hazard ratio was computed and compared to 1.30, the non-inferiority margin.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.89 to 1.11
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With First Confirmed CV Event of MACE (Intent to Treat Population)
Hide Description CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7332 7339
Measure Type: Number
Unit of Measure: Percentage of participants
10.2 10.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Hazard Ratio of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV outcome measure was assessed by the hazard ratio between the sitagliptin and placebo groups. The confidence interval for the hazard ratio was computed and compared to 1.30, the non-inferiority margin.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.89 to 1.10
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percent Incidence of All-cause Mortality (Per Protocol Population)
Hide Description Percent incidence of all-cause mortality is reported as the percentage of participants who died due to any cause.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7257 7266
Measure Type: Number
Unit of Measure: Percentage of participants
4.7 4.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in mortality due to all causes was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.435
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.91 to 1.24
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percent Incidence of All-cause Mortality (Intent to Treat Population)
Hide Description Percent incidence of all-cause mortality is reported as the percentage of participants who died due to any cause.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7332 7339
Measure Type: Number
Unit of Measure: Percentage of participants
7.5 7.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in mortality due to all causes was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.875
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.90 to 1.14
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Percent Incidence of Congestive Heart Failure (CHF) Requiring Hospitalization (Per Protocol Population)
Hide Description Percent incidence of CHF requiring hospitalization was reported as the percentage of participants who were admitted to the hospital for CHF.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7257 7266
Measure Type: Number
Unit of Measure: Percentage of participants
2.8 2.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in CHF cases requiring hospitalization was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.858
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group and history of CHF at baseline as explanatory variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.81 to 1.19
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Percent Incidence of CHF Requiring Hospitalization (Intent to Treat Population)
Hide Description Percent incidence of CHF requiring hospitalization was reported as the percentage of participants who were admitted to the hospital for CHF.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7332 7339
Measure Type: Number
Unit of Measure: Percentage of participants
3.1 3.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in CHF cases requiring hospitalization was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.983
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group and history of CHF at baseline as explanatory variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.83 to 1.20
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline in Renal Function Over Time (Per Protocol Population)
Hide Description Change in renal function based on estimated glomerular filtration rate [eGFR] using the Modification of Diet in Renal Disease [MDRD] method.
Time Frame Baseline and up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of participants analyzed consists of those participants with a baseline value.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7182 7203
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73 m^2
Month 4; Sitagliptin, n= 3859; Placebo, n= 3864 -1.9  (14.2) -0.8  (14.3)
Month 8; Sitagliptin, n= 3562; Placebo, n= 3501 -2.5  (14.9) -0.9  (15.1)
Month 12; Sitagliptin, n=4912, Placebo, n=4778 -1.8  (15.8) -0.5  (16.2)
Month 24; Sitagliptin, n=4782, Placebo, n=4637 -3.1  (17.9) -1.7  (17.5)
Month 36; Sitagliptin, n=2776, Placebo, n=2614 -3.7  (18.0) -1.6  (18.8)
Month 48; Sitagliptin, n=1096, Placebo, n=1056 -3.7  (18.3) -2.8  (18.4)
Month 60; Sitagliptin, n=79, Placebo, n=88 -3.5  (18.2) -6.4  (17.3)
10.Secondary Outcome
Title Change From Baseline in Renal Function Over Time (Intent to Treat Population)
Hide Description Change in renal function based on eGFR using the MDRD method.
Time Frame Baseline and up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of participants analyzed consists of those participants with a baseline value.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7254 7274
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73 m^2
Month 4; Sitagliptin, n=3949; Placebo, n=3977 -1.8  (14.3) -0.8  (14.3)
Month 8; Sitagliptin, n=3687; Placebo, n=3648 -2.4  (14.8) -0.9  (15.2)
Month 12; Sitagliptin, n=5082; Placebo, n=5015 -1.8  (15.8) -0.5  (16.3)
Month 24; Sitagliptin, n=5157; Placebo, n=5071 -3.2  (17.9) -1.7  (17.7)
Month 36; Sitagliptin, n=3037; Placebo, n=2942 -3.8  (18.1) -1.6  (18.7)
Month 48; Sitagliptin, n=1237; Placebo, n=1210 -4.0  (18.4) -2.8  (18.3)
Month 60; Sitagliptin, n=93; Placebo, n=106 -4.2  (17.4) -5.7  (17.2)
11.Secondary Outcome
Title Change From Baseline in HbA1c Over Time (Per Protocol Population)
Hide Description HbA1c is a measure of the percentage of glycated hemoglobin in the blood. Estimated mean difference between sitagliptin and placebo controlling for baseline HbA1c and region.
Time Frame Baseline and up to 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of participants analyzed consists of those participants with a baseline value.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7250 7258
Mean (Standard Deviation)
Unit of Measure: Percentage of HbA1c
Month 4; Sitagliptin, n=6632, Placebo, n=6588 -0.3  (0.8) 0.1  (0.9)
Month 8; Sitagliptin, n=6294, Placebo, n=6197 -0.3  (0.9) 0.1  (1.0)
Month 12; Sitagliptin, n=6217, Placebo, n=6092 -0.2  (1.0) 0.1  (1.0)
Month 24; Sitagliptin, n=5668, Placebo, n=5475 -0.1  (1.0) 0.2  (1.1)
Month 36; Sitagliptin, n=3227, Placebo, n=3083 -0.1  (1.1) 0.1  (1.1)
Month 48; Sitagliptin, n=1271, Placebo, n=1224 0.0  (1.1) 0.1  (1.2)
Month 60; Sitagliptin, n=106, Placebo, n=108 -0.1  (1.0) 0.0  (0.9)
12.Secondary Outcome
Title Change From Baseline in HbA1c Over Time (Intent to Treat Population)
Hide Description HbA1c is a measure of the percentage of glycated hemoglobin in the blood. Estimated mean difference between sitagliptin and placebo controlling for baseline HbA1c and region.
Time Frame Baseline and up to 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of participants analyzed consists of those participants in the intent to treat population with a baseline value.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7325 7331
Mean (Standard Deviation)
Unit of Measure: Percentage of HbA1c
Month 4: Sitagliptin, n= 6772; Placebo, n= 6738 -0.3  (0.8) 0.1  (0.9)
Month 8: Sitagliptin, n= 6478; Placebo, n= 6414 -0.2  (0.9) 0.1  (1.0)
Month 12: Sitagliptin, n= 6448; Placebo, n= 6384 -0.2  (1.0) 0.1  (1.0)
Month 24: Sitagliptin, n= 6105; Placebo, n= 5975 -0.1  (1.0) 0.1  (1.1)
Month 36: Sitagliptin, n= 3521; Placebo, n= 3439 -0.1  (1.1) 0.1  (1.1)
Month 48: Sitagliptin, n= 1432; Placebo, n= 1383 0.0  (1.1) 0.1  (1.2)
Month 60: Sitagliptin, n= 123; Placebo, n= 128 0.0  (1.0) 0.0  (1.0)
13.Secondary Outcome
Title Change From Baseline in Urine Albumin:Creatinine Ratio Over Time (Per Protocol Population)
Hide Description Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value.
Time Frame Baseline and up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of participants analyzed consists of those participants with a baseline value.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 2590 2522
Mean (Standard Deviation)
Unit of Measure: g/mol Creatinine
Month 4; Sitagliptin, n=664; Placebo, n=688 -2.2  (27.7) -1.4  (24.6)
Month 8; Sitagliptin, n=635; Placebo, n=597 1.7  (38.5) 0.2  (45.3)
Month 12; Sitagliptin, n=1126; Placebo, n=1059 0.8  (27.7) 1.2  (33.1)
Month 24; Sitagliptin, n=930; Placebo, n=892 0.7  (34.0) 3.2  (31.6)
Month 36; Sitagliptin, n=488; Placebo, n=513 2.5  (24.0) 4.0  (31.0)
Month 48; Sitagliptin, n=238; Placebo, n=233 1.3  (15.2) 1.5  (25.5)
Month 60; Sitagliptin, n=13; Placebo, n=17 -2.7  (10.1) 4.8  (15.4)
14.Secondary Outcome
Title Change From Baseline in Urine Albumin:Creatinine Ratio Over Time (Intent to Treat Population)
Hide Description Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value.
Time Frame Baseline and up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of participants analyzed consists of those participants in the intent to treat population with a baseline value for the outcome measure.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 2606 2542
Mean (Standard Deviation)
Unit of Measure: g/mol Creatinine
Month 4; n=677, n=713 -2.1  (27.5) -1.4  (24.1)
Month 8; n=658, n=624 2.1  (39.4) 0.5  (44.5)
Month 12; n=1167, n=1115 1.3  (30.2) 1.2  (32.3)
Month 24; n=1011, n=964 0.5  (33.1) 3.1  (30.7)
Month 36; n=537, n=553 2.6  (25.8) 3.9  (30.3)
Month 48; n=265, n=256 1.9  (16.3) 1.6  (24.5)
Month 60; n=14, n=18 -2.5  (9.7) 6.4  (16.4)
15.Secondary Outcome
Title Percentage of Participants Who Initiated Chronic Insulin Therapy (Per Protocol Population)
Hide Description Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 5554 5601
Measure Type: Number
Unit of Measure: Percentage of participants
8.6 11.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.61 to 0.77
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Percentage of Participants Who Initiated Chronic Insulin Therapy (Intent to Treat Population)
Hide Description Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 5608 5655
Measure Type: Number
Unit of Measure: Percentage of participants
9.7 13.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.63 to 0.79
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Percentage of Participants With Initiation of Co-interventional Agent (Per Protocol Population)
Hide Description In participants not receiving insulin at baseline, time to addition of first co-interventional agent (i.e., next oral antihyperglycemic agent [AHA] or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.)
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7257 7266
Measure Type: Number
Unit of Measure: Percentage of participants
18.9 24.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.65 to 0.75
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Percentage of Participants With Initiation of Co-interventional Agent (Intent to Treat Population)
Hide Description In participants not receiving insulin at baseline, time to addition of first co-interventional agent (i.e., next oral AHA or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.)
Time Frame Up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description:
Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
Overall Number of Participants Analyzed 7332 7339
Measure Type: Number
Unit of Measure: Percentage of participants
21.7 27.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cox proportional hazards model
Comments Model stratified by region with treatment group only as explanatory variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.68 to 0.77
Estimation Comments [Not Specified]
Time Frame Up to 68 months (including up to 28 days after last dose of study drug)
Adverse Event Reporting Description All participants as treated (APaT) population includes participants who received at least one dose of study drug.
 
Arm/Group Title Sitagliptin Placebo
Hide Arm/Group Description Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
All-Cause Mortality
Sitagliptin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Sitagliptin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   928/7266 (12.77%)      909/7274 (12.50%)    
Blood and lymphatic system disorders     
Anaemia  1  23/7266 (0.32%)  24 23/7274 (0.32%)  23
Anaemia vitamin B12 deficiency  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Autoimmune haemolytic anaemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Haemolytic anaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Haemorrhagic anaemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Iron deficiency anaemia  1  6/7266 (0.08%)  6 6/7274 (0.08%)  6
Lymphadenopathy mediastinal  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Microcytic anaemia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Neutropenia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Normochromic normocytic anaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Pernicious anaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Thrombocytopenia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Cardiac disorders     
Angina pectoris  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Atrioventricular block  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Bradycardia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Cor pulmonale  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Coronary artery thrombosis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Palpitations  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Pericardial effusion  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Sinus arrhythmia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Congenital, familial and genetic disorders     
Arteriovenous malformation  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hamartoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hydrocele  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Phimosis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Pyloric stenosis  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Syringomyelia  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Vitello-intestinal duct remnant  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Ear and labyrinth disorders     
Deafness bilateral  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hypoacusis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Meniere's disease  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Sudden hearing loss  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tinnitus  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Vertigo  1  4/7266 (0.06%)  4 2/7274 (0.03%)  2
Vertigo labyrinthine  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Vertigo positional  1  3/7266 (0.04%)  3 2/7274 (0.03%)  2
Vestibular disorder  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Endocrine disorders     
Adrenocortical insufficiency acute  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Goitre  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Hyperthyroidism  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hypothyroidism  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Inappropriate antidiuretic hormone secretion  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Eye disorders     
Amaurosis fugax  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Angle closure glaucoma  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Cataract  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Corneal degeneration  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Dacryostenosis acquired  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Optic ischaemic neuropathy  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Retinal detachment  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Visual acuity reduced  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Vitreous haemorrhage  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gastrointestinal disorders     
Abdominal discomfort  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Abdominal hernia  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Abdominal hernia obstructive  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Abdominal pain  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Abdominal pain upper  1  4/7266 (0.06%)  4 0/7274 (0.00%)  0
Abdominal wall haematoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Abnormal faeces  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Anal fissure  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Anal fistula  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Ascites  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Change of bowel habit  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Colitis  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Colitis ischaemic  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Colonic fistula  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Colonic pseudo-obstruction  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Constipation  1  4/7266 (0.06%)  4 1/7274 (0.01%)  1
Crohn's disease  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Diaphragmatic hernia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Diverticular perforation  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Diverticulum  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Diverticulum intestinal  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Diverticulum intestinal haemorrhagic  1  1/7266 (0.01%)  1 1/7274 (0.01%)  2
Duodenal polyp  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Duodenal ulcer  1  5/7266 (0.07%)  5 3/7274 (0.04%)  3
Duodenal ulcer haemorrhage  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Duodenitis  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Dyspepsia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Dysphagia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Enterovesical fistula  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Erosive oesophagitis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Faecaloma  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Gastric polyps  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastric ulcer  1  3/7266 (0.04%)  3 4/7274 (0.05%)  4
Gastric ulcer haemorrhage  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Gastritis  1  10/7266 (0.14%)  10 2/7274 (0.03%)  2
Gastritis erosive  1  0/7266 (0.00%)  0 4/7274 (0.05%)  4
Gastritis haemorrhagic  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Gastroduodenal ulcer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastroduodenitis haemorrhagic  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastrointestinal haemorrhage  1  11/7266 (0.15%)  11 12/7274 (0.16%)  14
Gastrointestinal necrosis  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Gastrointestinal ulcer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gastrointestinal ulcer haemorrhage  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gastrooesophageal reflux disease  1  9/7266 (0.12%)  10 0/7274 (0.00%)  0
Haematochezia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Haemorrhoids  1  4/7266 (0.06%)  4 5/7274 (0.07%)  5
Ileus  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Ileus paralytic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Inguinal hernia  1  12/7266 (0.17%)  12 11/7274 (0.15%)  12
Inguinal hernia, obstructive  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Intestinal haemorrhage  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Intestinal ischaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Intestinal obstruction  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Intestinal perforation  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Intestinal polyp  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Intussusception  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Jejunal perforation  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Large intestinal stenosis  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Large intestine perforation  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Large intestine polyp  1  6/7266 (0.08%)  6 2/7274 (0.03%)  2
Lower gastrointestinal haemorrhage  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Mallory-Weiss syndrome  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Melaena  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Obstruction gastric  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Oedema mouth  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Oesophageal achalasia  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Oesophageal food impaction  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Oesophageal motility disorder  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Oesophageal spasm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Oesophageal varices haemorrhage  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pancreatic pseudocyst  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Peptic ulcer  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Peptic ulcer perforation  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Periodontal disease  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pharyngo-oesophageal diverticulum  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Rectal haemorrhage  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Rectal polyp  1  0/7266 (0.00%)  0 3/7274 (0.04%)  3
Rectal prolapse  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Salivary gland calculus  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Small intestinal haemorrhage  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Small intestinal obstruction  1  8/7266 (0.11%)  8 6/7274 (0.08%)  8
Small intestinal perforation  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Small intestinal ulcer haemorrhage  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tongue disorder  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Umbilical hernia  1  4/7266 (0.06%)  4 2/7274 (0.03%)  2
Upper gastrointestinal haemorrhage  1  3/7266 (0.04%)  3 6/7274 (0.08%)  6
Varices oesophageal  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Volvulus  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
General disorders     
Adverse drug reaction  1  3/7266 (0.04%)  3 1/7274 (0.01%)  1
Asthenia  1  2/7266 (0.03%)  2 3/7274 (0.04%)  3
Chest pain  1  6/7266 (0.08%)  6 8/7274 (0.11%)  8
Device dislocation  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Device malfunction  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Drug intolerance  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Fat necrosis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Fatigue  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gait disturbance  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Generalised oedema  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Granuloma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hernia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Malaise  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Mucosal hyperaemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Multi-organ failure  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Non-cardiac chest pain  1  17/7266 (0.23%)  19 26/7274 (0.36%)  31
Puncture site haemorrhage  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Pyrexia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Spinal pain  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Submandibular mass  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatobiliary disorders     
Bile duct stone  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Biliary colic  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Biliary dyskinesia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Cholecystitis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Cholelithiasis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Drug-induced liver injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gallbladder polyp  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hepatic cirrhosis  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Hepatic congestion  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatic cyst  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatic failure  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatic function abnormal  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Hepatitis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatitis acute  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatitis toxic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Immune system disorders     
Corneal graft rejection  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Drug hypersensitivity  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Infections and infestations     
Abdominal abscess  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Acute hepatitis B  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Appendicitis  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Appendicitis perforated  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Bronchitis  1  2/7266 (0.03%)  3 4/7274 (0.05%)  4
Bursitis infective  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Dengue fever  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Diverticulitis  1  6/7266 (0.08%)  7 4/7274 (0.05%)  4
Gastroenteritis  1  3/7266 (0.04%)  3 2/7274 (0.03%)  2
Hepatitis C  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Hepatitis E  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Herpes simplex encephalitis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Herpes zoster  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Infected bites  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease  1  0/7266 (0.00%)  0 3/7274 (0.04%)  3
Influenza  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Laryngitis  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Liver abscess  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lower respiratory tract infection  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lyme disease  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Mycetoma mycotic  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Oesophageal candidiasis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Osteomyelitis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Otitis media  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Otitis media chronic  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Pneumonia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Postoperative wound infection  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pulmonary tuberculosis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pyelonephritis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Scrub typhus  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Sepsis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Sialoadenitis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Sinusitis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tooth abscess  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Typhoid fever  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Urosepsis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Viral infection  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Wound infection  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Injury, poisoning and procedural complications     
Abdominal wound dehiscence  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Accidental overdose  1  17/7266 (0.23%)  17 19/7274 (0.26%)  19
Acetabulum fracture  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Alcohol poisoning  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Ankle fracture  1  6/7266 (0.08%)  6 3/7274 (0.04%)  3
Arthropod bite  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Arthropod sting  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Avulsion fracture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Brain contusion  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Burns second degree  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Burns third degree  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Cervical vertebral fracture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Chemical burns of eye  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Comminuted fracture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Concussion  1  0/7266 (0.00%)  0 4/7274 (0.05%)  4
Contusion  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Craniocerebral injury  1  3/7266 (0.04%)  3 3/7274 (0.04%)  3
Delayed recovery from anaesthesia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Dislocation of vertebra  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Facial bones fracture  1  3/7266 (0.04%)  3 4/7274 (0.05%)  4
Fall  1  9/7266 (0.12%)  9 9/7274 (0.12%)  9
Femoral neck fracture  1  5/7266 (0.07%)  5 3/7274 (0.04%)  3
Femur fracture  1  7/7266 (0.10%)  7 11/7274 (0.15%)  11
Fibula fracture  1  3/7266 (0.04%)  3 1/7274 (0.01%)  1
Foot fracture  1  4/7266 (0.06%)  4 1/7274 (0.01%)  1
Forearm fracture  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Foreign body  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Fracture  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Fracture displacement  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastrointestinal stoma complication  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hand fracture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Head injury  1  5/7266 (0.07%)  5 2/7274 (0.03%)  2
Heat stroke  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hip fracture  1  5/7266 (0.07%)  5 6/7274 (0.08%)  6
Humerus fracture  1  4/7266 (0.06%)  5 9/7274 (0.12%)  9
Incisional hernia  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Intentional overdose  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Joint dislocation  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Laceration  1  4/7266 (0.06%)  4 2/7274 (0.03%)  2
Ligament injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Ligament rupture  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Ligament sprain  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Limb traumatic amputation  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lower limb fracture  1  4/7266 (0.06%)  4 2/7274 (0.03%)  2
Lumbar vertebral fracture  1  3/7266 (0.04%)  3 2/7274 (0.03%)  2
Meniscus injury  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Mouth injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Muscle injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Near drowning  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Overdose  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Patella fracture  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Pelvic fracture  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Periorbital haematoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Periprosthetic fracture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Periprosthetic osteolysis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Post procedural fistula  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Post procedural haemorrhage  1  2/7266 (0.03%)  2 3/7274 (0.04%)  3
Postoperative ileus  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Postoperative wound complication  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Prescribed overdose  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Procedural complication  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pubis fracture  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Pulmonary contusion  1  1/7266 (0.01%)  2 0/7274 (0.00%)  0
Radius fracture  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Renal haematoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Rib fracture  1  2/7266 (0.03%)  2 5/7274 (0.07%)  5
Road traffic accident  1  5/7266 (0.07%)  6 1/7274 (0.01%)  1
Skull fracture  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Soft tissue injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Spinal column injury  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Spinal compression fracture  1  5/7266 (0.07%)  6 4/7274 (0.05%)  5
Splinter  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Sternal fracture  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Subdural haematoma  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Subdural haemorrhage  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tendon rupture  1  1/7266 (0.01%)  1 5/7274 (0.07%)  5
Testicular injury  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Thermal burn  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Thoracic vertebral fracture  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tibia fracture  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Tongue injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Toxicity to various agents  1  5/7266 (0.07%)  5 0/7274 (0.00%)  0
Tracheal injury  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Traumatic intracranial haemorrhage  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Ulnar nerve injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Upper limb fracture  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Urinary bladder rupture  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Vascular pseudoaneurysm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Wrist fracture  1  4/7266 (0.06%)  4 0/7274 (0.00%)  0
Investigations     
Anticoagulation drug level increased  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Haemoglobin decreased  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatic enzyme abnormal  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hepatic enzyme increased  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
International normalised ratio increased  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Prostatic specific antigen increased  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
White blood cell count increased  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Metabolism and nutrition disorders     
Decreased appetite  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Dehydration  1  5/7266 (0.07%)  5 8/7274 (0.11%)  8
Electrolyte imbalance  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Failure to thrive  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Hyperkalaemia  1  8/7266 (0.11%)  9 5/7274 (0.07%)  5
Hypoalbuminaemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hypochloraemia  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Hypokalaemia  1  3/7266 (0.04%)  3 4/7274 (0.05%)  4
Hyponatraemia  1  8/7266 (0.11%)  9 21/7274 (0.29%)  21
Hypophagia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hypophosphataemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hypovolaemia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Obesity  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Musculoskeletal and connective tissue disorders     
Ankle impingement  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Arthralgia  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Arthritis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  2
Arthritis reactive  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Arthropathy  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Back pain  1  6/7266 (0.08%)  6 4/7274 (0.05%)  5
Bursitis  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Chondrocalcinosis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Compartment syndrome  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Dupuytren's contracture  1  1/7266 (0.01%)  1 3/7274 (0.04%)  4
Gouty arthritis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Haemarthrosis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Intervertebral disc compression  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Intervertebral disc disorder  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Intervertebral disc displacement  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Intervertebral disc protrusion  1  8/7266 (0.11%)  9 8/7274 (0.11%)  8
Joint effusion  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Joint swelling  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Lumbar spinal stenosis  1  13/7266 (0.18%)  14 5/7274 (0.07%)  5
Musculoskeletal chest pain  1  5/7266 (0.07%)  5 6/7274 (0.08%)  6
Musculoskeletal pain  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Myalgia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Osteitis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Osteoarthritis  1  52/7266 (0.72%)  54 35/7274 (0.48%)  37
Osteochondrosis  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Osteoporosis  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Pain in extremity  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Polymyalgia rheumatica  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Psoriatic arthropathy  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Rheumatoid arthritis  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Rotator cuff syndrome  1  6/7266 (0.08%)  6 7/7274 (0.10%)  7
Spinal column stenosis  1  4/7266 (0.06%)  4 3/7274 (0.04%)  3
Spinal osteoarthritis  1  7/7266 (0.10%)  7 5/7274 (0.07%)  5
Spondylolisthesis  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Synovial cyst  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Tenosynovitis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Tenosynovitis stenosans  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Trigger finger  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Abdominal neoplasm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Acute myeloid leukaemia  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Adenocarcinoma  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Adenocarcinoma gastric  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Adenocarcinoma of appendix  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Adenocarcinoma of colon  1  11/7266 (0.15%)  11 12/7274 (0.16%)  12
Adenocarcinoma of salivary gland  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Adenocarcinoma of the cervix  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Adenocarcinoma pancreas  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Adenoid cystic carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Adenolymphoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Anal cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Anal squamous cell carcinoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Anaplastic large-cell lymphoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Angioimmunoblastic T-cell lymphoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
B-cell lymphoma  1  0/7266 (0.00%)  0 4/7274 (0.05%)  5
Basal cell carcinoma  1  44/7266 (0.61%)  50 55/7274 (0.76%)  86
Basosquamous carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Benign gastric neoplasm  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Benign salivary gland neoplasm  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Bile duct cancer  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Bladder cancer  1  15/7266 (0.21%)  15 10/7274 (0.14%)  10
Bladder cancer recurrent  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Bladder neoplasm  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Bladder papilloma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Bladder transitional cell carcinoma  1  6/7266 (0.08%)  6 6/7274 (0.08%)  6
Bone cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Bone neoplasm  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Bone sarcoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Bowen's disease  1  4/7266 (0.06%)  4 2/7274 (0.03%)  2
Breast cancer  1  5/7266 (0.07%)  5 5/7274 (0.07%)  5
Breast cancer in situ  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Breast cancer metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Breast cancer recurrent  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Bronchial carcinoma  1  3/7266 (0.04%)  3 1/7274 (0.01%)  1
Carcinoid tumour of the small bowel  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Carcinoid tumour pulmonary  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Central nervous system lymphoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Cervix carcinoma  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Cholangiocarcinoma  1  1/7266 (0.01%)  1 4/7274 (0.05%)  4
Cholesteatoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Chronic lymphocytic leukaemia  1  4/7266 (0.06%)  4 3/7274 (0.04%)  3
Chronic lymphocytic leukaemia recurrent  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Chronic myeloid leukaemia  1  0/7266 (0.00%)  0 3/7274 (0.04%)  3
Clear cell renal cell carcinoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Colon adenoma  1  4/7266 (0.06%)  4 1/7274 (0.01%)  1
Colon cancer  1  11/7266 (0.15%)  11 14/7274 (0.19%)  14
Colon cancer metastatic  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Colon cancer stage I  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Colon cancer stage IV  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Colon neoplasm  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Colorectal adenocarcinoma  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Colorectal cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Diffuse large B-cell lymphoma  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Endometrial adenocarcinoma  1  1/7266 (0.01%)  1 5/7274 (0.07%)  5
Endometrial cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gallbladder cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastric adenoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastric cancer  1  5/7266 (0.07%)  5 2/7274 (0.03%)  2
Gastric cancer recurrent  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Gastric cancer stage IV  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastrointestinal cancer metastatic  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Gastrointestinal carcinoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Gastrointestinal tract adenoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Glioblastoma multiforme  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Glioma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Hepatic cancer  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Hepatic cancer metastatic  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Hepatic neoplasm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Hepatocellular carcinoma  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Intraductal papilloma of breast  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Intraductal proliferative breast lesion  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Intraocular melanoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Invasive ductal breast carcinoma  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Laryngeal cancer  1  0/7266 (0.00%)  0 4/7274 (0.05%)  4
Laryngeal squamous cell carcinoma  1  2/7266 (0.03%)  3 0/7274 (0.00%)  0
Leiomyosarcoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Leiomyosarcoma metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Lentigo maligna  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Leukaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lip and/or oral cavity cancer  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Lip squamous cell carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lipoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lung adenocarcinoma  1  6/7266 (0.08%)  6 4/7274 (0.05%)  4
Lung adenocarcinoma metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Lung adenocarcinoma stage I  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Lung adenocarcinoma stage IV  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lung cancer metastatic  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Lung carcinoma cell type unspecified stage IV  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Lung neoplasm  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Lung neoplasm malignant  1  12/7266 (0.17%)  12 12/7274 (0.16%)  12
Lung squamous cell carcinoma stage III  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Lymphocytic leukaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Malignant melanoma  1  10/7266 (0.14%)  10 6/7274 (0.08%)  7
Malignant melanoma in situ  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Malignant neoplasm of ampulla of Vater  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Malignant neoplasm of renal pelvis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Melanocytic naevus  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Meningeal neoplasm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Meningioma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Meningioma malignant  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Metastases to bone  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Metastases to central nervous system  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Metastases to liver  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Metastases to spine  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Metastatic bronchial carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Metastatic malignant melanoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Metastatic renal cell carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Metastatic squamous cell carcinoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Metastatic uterine cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Mucinous adenocarcinoma of appendix  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Myelodysplastic syndrome  1  3/7266 (0.04%)  3 1/7274 (0.01%)  1
Nasal cavity cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Nasopharyngeal cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Neoplasm recurrence  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Neuroendocrine carcinoma metastatic  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Neuroendocrine tumour  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Neurofibroma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Non-Hodgkin's lymphoma  1  6/7266 (0.08%)  6 1/7274 (0.01%)  1
Non-small cell lung cancer  1  2/7266 (0.03%)  2 2/7274 (0.03%)  2
Non-small cell lung cancer metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Oesophageal adenocarcinoma  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Oesophageal carcinoma  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Oesophageal squamous cell carcinoma  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Oropharyngeal squamous cell carcinoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Ovarian adenoma  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Ovarian cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Ovarian cancer metastatic  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Ovarian germ cell teratoma benign  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Ovarian granulosa-theca cell tumour  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Ovarian neoplasm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pancreatic carcinoma  1  8/7266 (0.11%)  8 7/7274 (0.10%)  7
Pancreatic carcinoma metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Papillary thyroid cancer  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Parathyroid tumour benign  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Penile cancer  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Penile squamous cell carcinoma  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Phaeochromocytoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pituitary tumour  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pituitary tumour benign  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Plasma cell myeloma  1  1/7266 (0.01%)  1 6/7274 (0.08%)  6
Plasmablastic lymphoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Plasmacytoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Pleomorphic liposarcoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Pleural mesothelioma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Polycythaemia vera  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Prostate cancer  1  36/7266 (0.50%)  36 45/7274 (0.62%)  45
Prostate cancer metastatic  1  5/7266 (0.07%)  5 5/7274 (0.07%)  5
Prostate cancer recurrent  1  3/7266 (0.04%)  3 2/7274 (0.03%)  2
Prostate cancer stage I  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Prostatic adenoma  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Rectal adenocarcinoma  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Rectal cancer  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Rectal cancer metastatic  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Rectosigmoid cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Renal cancer  1  7/7266 (0.10%)  7 3/7274 (0.04%)  3
Renal cancer metastatic  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Renal cell carcinoma  1  3/7266 (0.04%)  3 2/7274 (0.03%)  2
Renal cell carcinoma recurrent  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Renal cell carcinoma stage I  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Renal cell carcinoma stage III  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Renal neoplasm  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Renal oncocytoma  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Retroperitoneal cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Sarcoma  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Skin cancer  1  1/7266 (0.01%)  1 3/7274 (0.04%)  5
Small cell lung cancer  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Squamous cell carcinoma  1  26/7266 (0.36%)  38 38/7274 (0.52%)  44
Squamous cell carcinoma of head and neck  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Squamous cell carcinoma of lung  1  2/7266 (0.03%)  2 7/7274 (0.10%)  7
Squamous cell carcinoma of skin  1  12/7266 (0.17%)  13 20/7274 (0.27%)  23
Squamous cell carcinoma of the oral cavity  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Squamous cell carcinoma of the tongue  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
T-cell lymphoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
T-cell prolymphocytic leukaemia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Testis cancer  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Thymic cancer metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Thyroid adenoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Thyroid cancer  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Tongue cancer recurrent  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Tongue neoplasm malignant stage unspecified  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Tonsil cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tonsil cancer metastatic  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Tracheal cancer  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Tracheal neoplasm  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Transitional cell carcinoma  1  7/7266 (0.10%)  8 7/7274 (0.10%)  7
Urethral neoplasm  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Uterine cancer  1  1/7266 (0.01%)  1 4/7274 (0.05%)  4
Uterine leiomyoma  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Nervous system disorders     
Acoustic neuritis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Arachnoid cyst  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Ataxia  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Basal ganglia haemorrhage  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Brain injury  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Carpal tunnel syndrome  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Cauda equina syndrome  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Central nervous system lesion  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Cervical cord compression  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Cervical myelopathy  1  0/7266 (0.00%)  0 3/7274 (0.04%)  3
Cervical radiculopathy  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Cervicobrachial syndrome  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Cognitive disorder  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Complex partial seizures  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Convulsion  1  5/7266 (0.07%)  5 6/7274 (0.08%)  6
Cubital tunnel syndrome  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Dementia  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Dementia Alzheimer's type  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Dizziness  1  7/7266 (0.10%)  7 1/7274 (0.01%)  1
Dizziness postural  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Encephalopathy  1  0/7266 (0.00%)  0 2/7274 (0.03%)  3
Epilepsy  1  2/7266 (0.03%)  3 3/7274 (0.04%)  3
Facial paresis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Haemorrhage intracranial  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Headache  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Hypersomnia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Intracranial aneurysm  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Loss of consciousness  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Lumbar radiculopathy  1  3/7266 (0.04%)  3 1/7274 (0.01%)  1
Migraine  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Monoplegia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Myasthenia gravis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Myasthenia gravis crisis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Myelopathy  1  0/7266 (0.00%)  0 2/7274 (0.03%)  2
Nerve compression  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Nerve root compression  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Nervous system disorder  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Neuralgia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Neurological symptom  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Neuropathy peripheral  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Normal pressure hydrocephalus  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Parkinson's disease  1  2/7266 (0.03%)  2 3/7274 (0.04%)  3
Partial seizures  1  1/7266 (0.01%)  1 3/7274 (0.04%)  3
Peripheral sensorimotor neuropathy  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Petit mal epilepsy  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Piriformis syndrome  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Posterior reversible encephalopathy syndrome  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Postictal state  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Radiculitis lumbosacral  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Retrograde amnesia  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Sciatica  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Sensory disturbance  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Spinal cord disorder  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Subarachnoid haemorrhage  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Subdural effusion  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Syncope  1  1/7266 (0.01%)  1 1/7274 (0.01%)  1
Thoracic outlet syndrome  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Ulnar tunnel syndrome  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Vascular dementia  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Vertebrobasilar insufficiency  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Vertigo CNS origin  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Psychiatric disorders     
Alcohol abuse  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Anxiety  1  0/7266 (0.00%)  0 3/7274 (0.04%)  3
Delirium  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Depression  1  4/7266 (0.06%)  4 3/7274 (0.04%)  3
Dissociative disorder  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Drug abuse  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Drug dependence  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Major depression  1  2/7266 (0.03%)  2 3/7274 (0.04%)  4
Mental status changes  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Nicotine dependence  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Paranoid personality disorder  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Suicidal ideation  1  2/7266 (0.03%)  2 0/7274 (0.00%)  0
Suicide attempt  1  1/7266 (0.01%)  1 2/7274 (0.03%)  2
Renal and urinary disorders     
Bladder outlet obstruction  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Bladder stenosis  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Calculus bladder  1  1/7266 (0.01%)  2 1/7274 (0.01%)  1
Calculus ureteric  1  6/7266 (0.08%)  8 6/7274 (0.08%)  6
Calculus urinary  1  2/7266 (0.03%)  2 4/7274 (0.05%)  4
Haematuria  1  6/7266 (0.08%)  6 6/7274 (0.08%)  6
Hydronephrosis  1  3/7266 (0.04%)  3 0/7274 (0.00%)  0
Nephrolithiasis  1  10/7266 (0.14%)  10 9/7274 (0.12%)  11
Renal artery stenosis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Renal colic  1  4/7266 (0.06%)  4 4/7274 (0.05%)  5
Renal cyst  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Renal failure  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Renal failure acute  1  2/7266 (0.03%)  2 1/7274 (0.01%)  1
Renal impairment  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1
Renal tubular necrosis  1  1/7266 (0.01%)  1 0/7274 (0.00%)  0
Stag horn calculus  1  0/7266 (0.00%)  0 1/7274 (0.01%)  1