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Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE)

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ClinicalTrials.gov Identifier: NCT00968708
Recruitment Status : Completed
First Posted : August 31, 2009
Results First Posted : April 15, 2014
Last Update Posted : May 2, 2014
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Diabetes Mellitus, Type 2
Acute Coronary Syndrome
Interventions Drug: Alogliptin
Drug: Placebo
Enrollment 5380

Recruitment Details Participants took part in the study at 898 investigative sites worldwide from 24 September 2009 to 18 June 2013.
Pre-assignment Details Participants with a diagnosis of type 2 diabetes mellitus and acute coronary syndrome were enrolled equally in 1 of 2 treatment groups, once a day placebo or alogliptin, in addition to receiving standard of care for cardiovascular disease and diabetes.
Arm/Group Title Placebo Alogliptin
Hide Arm/Group Description Alogliptin placebo matching tablets, orally, once daily. Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines. Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min). Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.
Period Title: Overall Study
Started 2679 2701
Treated 2676 2698
Completed 2361 2403
Not Completed 318 298
Reason Not Completed
Adverse Event             169             150
Major Protocol Deviation             0             1
Lost to Follow-up             19             11
Voluntary Withdrawal             104             101
Investigator Discretion             0             1
Other             26             34
Arm/Group Title Placebo Alogliptin Total
Hide Arm/Group Description Alogliptin placebo matching tablets, orally, once daily. Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min). Total of all reporting groups
Overall Number of Baseline Participants 2679 2701 5380
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) - all randomized participants who signed informed consent.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2679 participants 2701 participants 5380 participants
60.7  (9.88) 61.0  (9.96) 60.9  (9.92)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Female
856
  32.0%
873
  32.3%
1729
  32.1%
Male
1823
  68.0%
1828
  67.7%
3651
  67.9%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
American Indian or Alaska Native 54 56 110
Asian 542 547 1089
Black or African American 115 101 216
Native Hawaiian or Other Pacific Islander 5 6 11
White 1943 1966 3909
More than one race 20 25 45
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Hispanic or Latino 764 773 1537
Non-Hispanic or Latino 1915 1928 3843
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Argentina 136 136 272
Australia 7 8 15
Austria 8 8 16
Belgium 11 12 23
Brazil 179 181 360
Bulgaria 41 41 82
Canada 54 55 109
Chile 51 55 106
Colombia 15 13 28
Croatia 38 39 77
Czech Republic 13 13 26
Denmark 3 3 6
Egypt 7 7 14
Finland 12 10 22
France 11 11 22
Germany 26 27 53
Greece 0 1 1
Guatemala 25 24 49
Hong Kong 11 12 23
Hungary 60 59 119
India 165 165 330
Israel 100 101 201
Italy 25 25 50
Japan 105 104 209
Kuwait 2 3 5
Latvia 6 6 12
Lithuania 16 20 36
Malaysia 39 42 81
Mexico 192 191 383
New Zealand 13 13 26
Peru 79 81 160
Philippines 52 50 102
Poland 121 118 239
Portugal 13 16 29
Puerto Rico 16 19 35
Korea, Republic Of 61 62 123
Romania 40 38 78
Russian Federation 153 151 304
Serbia 35 35 70
Slovakia 46 49 95
South Africa 39 41 80
Spain 21 22 43
Sweden 16 16 32
Taiwan, Province Of China 14 13 27
Thailand 57 58 115
Ukraine 138 138 276
United Arab Emirates 3 3 6
United Kingdom 32 34 66
United States 372 372 744
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 2679 participants 2701 participants 5380 participants
29.53  (5.758) 29.42  (5.422) 29.48  (5.591)
Duration of Type 2 Diabetes Mellitus  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2679 participants 2701 participants 5380 participants
9.18  (8.121) 9.13  (8.198) 9.16  (8.159)
Smoking History  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Never smoked 1144 1158 2302
Current smoker 383 351 734
Ex-smoker 1152 1192 2344
Estimated Glomerular Filtration Rate (eGFR)   [1] 
Mean (Standard Deviation)
Unit of measure:  mL/min/1.73 m^2
Number Analyzed 2679 participants 2701 participants 5380 participants
71.01  (21.541) 70.86  (21.297) 70.93  (21.417)
[1]
Measure Description: Calculated using the Modification of Diet in Renal Disease (MDRD) formula
Renal Impairment Category   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Normal Renal Function 440 399 839
Mild Renal Impairment 1446 1530 2976
Moderate Renal Impairment 714 694 1408
Severe Renal Impairment/End-Stage Renal Disease 79 78 157
[1]
Measure Description: Normal renal function: eGFR ≥90 mL/min/1.73 m^2; Mild renal impairment: eGFR ≥60 and <90 mL/min/1.73 m^2; Moderate renal impairment: eGFR ≥30 and <60 mL/min/1.73 m^2; Severe renal impairment: eGFR <30 mL/min/1.73 m^2; End-stage renal disease (ESRD): eGFR <15 mL/min/1.73 m^2
Index Acute Coronary Syndrome (ACS) Event Type   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2679 participants 2701 participants 5380 participants
Myocardial Infarction 2068 2084 4152
Unstable Angina 605 609 1214
[1]
Measure Description: Six participants in the placebo arm and 7 participants in the alogliptin arm are not included because they did not meet the ACS requirements for study inclusion.
Time From Index ACS Event to Randomization   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 2679 participants 2701 participants 5380 participants
48.0  (21.95) 47.6  (22.04) 47.8  (22.00)
[1]
Measure Description: Six participants in the placebo arm and 7 participants in the alogliptin arm are not included because they did not meet the ACS requirements for study inclusion.
1.Primary Outcome
Title Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)
Hide Description Primary Major Adverse Cardiac Events were defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.
Time Frame From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (all randomized participants)
Arm/Group Title Placebo Alogliptin
Hide Arm/Group Description:
Alogliptin placebo matching tablets, orally, once daily.
Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).
Overall Number of Participants Analyzed 2679 2701
Measure Type: Number
Unit of Measure: percentage of participants
11.8 11.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alogliptin
Comments Statistical analyses of the primary MACE composite endpoint was based on sequences of 1-sided repeated confidence intervals (CIs) to assess non-inferiority or statistical superiority with respect to the null hypotheses. Each sequence of repeated CIs was constructed using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%. Each sequence of 1-sided repeated CIs had a simultaneous coverage probability of 97.5%.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If after accrual of 550 participants with MACE events, the upper bound of a 1-sided repeated CI for the hazard ratio (alogliptin to placebo) was <1.0, superiority of alogliptin to placebo for the primary MACE composite would be concluded. If the upper bound of the 1-sided repeated CI for the hazard ratio of the primary MACE composite was <1.3 but ≥1.0 then non-inferiority but not superiority of alogliptin to placebo was to be concluded.
Statistical Test of Hypothesis P-Value 0.315
Comments [Not Specified]
Method Cox proportional hazards
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.962
Confidence Interval (1-Sided) 97.5%
1.160
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Alogliptin
Comments Stratified by endpoint renal function and geographic region
Type of Statistical Test Non-Inferiority or Equivalence
Comments If after accrual of 550 participants with MACE events, the upper bound of a 1-sided repeated CI for the hazard ratio (alogliptin to placebo) was <1.0, superiority of alogliptin to placebo for the primary MACE composite would be concluded. If the upper bound of the 1-sided repeated CI for the hazard ratio of the primary MACE composite was <1.3 but ≥1.0 then non-inferiority but not superiority of alogliptin to placebo was to be concluded.
Statistical Test of Hypothesis P-Value 0.332
Comments Stratified by endpoint renal function (defined as the last observed postbaseline renal function (normal renal function/mild renal impairment vs moderate/severe renal impairment including end-stage renal disease)) and geographic region.
Method Cox proportional hazards
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.965
Confidence Interval (1-Sided) 97.5%
1.169
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)
Hide Description Secondary MACE composite consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina; these events were adjudicated by an independent cardiovascular endpoint committee.
Time Frame From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months).
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Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Alogliptin
Hide Arm/Group Description:
Alogliptin placebo matching tablets, orally, once daily.
Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).
Overall Number of Participants Analyzed 2679 2701
Measure Type: Number
Unit of Measure: percentage of participants
13.4 12.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alogliptin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the upper bound of the confidence interval for the primary MACE composite was <1.0, then statistical superiority of alogliptin to placebo for the secondary MACE composite would be demonstrated.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.952
Confidence Interval (1-Sided) 97.5%
1.135
Estimation Comments [Not Specified]
Time Frame From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Placebo Alogliptin
Hide Arm/Group Description Alogliptin placebo matching tablets, orally, once daily. Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).
All-Cause Mortality
Placebo Alogliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Alogliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   952/2679 (35.54%)   907/2701 (33.58%) 
Blood and lymphatic system disorders     
Anaemia  1  17/2679 (0.63%)  16/2701 (0.59%) 
Iron deficiency anaemia  1  3/2679 (0.11%)  0/2701 (0.00%) 
Febrile neutropenia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Haemolytic anaemia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Leukocytosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Lymphopenia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Microcytic anaemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Neutropenia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Thrombocytopenia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cardiac disorders     
Angina unstable  1  142/2679 (5.30%)  117/2701 (4.33%) 
Acute myocardial infarction  1  104/2679 (3.88%)  125/2701 (4.63%) 
Angina pectoris  1  83/2679 (3.10%)  86/2701 (3.18%) 
Myocardial infarction  1  54/2679 (2.02%)  66/2701 (2.44%) 
Cardiac failure congestive  1  53/2679 (1.98%)  63/2701 (2.33%) 
Cardiac failure  1  56/2679 (2.09%)  45/2701 (1.67%) 
Coronary artery disease  1  34/2679 (1.27%)  35/2701 (1.30%) 
Acute coronary syndrome  1  29/2679 (1.08%)  27/2701 (1.00%) 
Myocardial ischaemia  1  19/2679 (0.71%)  20/2701 (0.74%) 
Atrial fibrillation  1  22/2679 (0.82%)  15/2701 (0.56%) 
Coronary artery stenosis  1  17/2679 (0.63%)  20/2701 (0.74%) 
Cardiac arrest  1  11/2679 (0.41%)  14/2701 (0.52%) 
Cardiogenic shock  1  5/2679 (0.19%)  14/2701 (0.52%) 
Cardio-respiratory arrest  1  9/2679 (0.34%)  6/2701 (0.22%) 
Ventricular tachycardia  1  10/2679 (0.37%)  5/2701 (0.19%) 
Cardiac failure acute  1  8/2679 (0.30%)  6/2701 (0.22%) 
Cardiac failure chronic  1  7/2679 (0.26%)  7/2701 (0.26%) 
Ischaemic cardiomyopathy  1  4/2679 (0.15%)  9/2701 (0.33%) 
Supraventricular tachycardia  1  4/2679 (0.15%)  7/2701 (0.26%) 
Ventricular fibrillation  1  6/2679 (0.22%)  5/2701 (0.19%) 
Atrial flutter  1  4/2679 (0.15%)  3/2701 (0.11%) 
Bradycardia  1  4/2679 (0.15%)  3/2701 (0.11%) 
Arrhythmia  1  4/2679 (0.15%)  2/2701 (0.07%) 
Atrioventricular block complete  1  0/2679 (0.00%)  6/2701 (0.22%) 
Cardiomyopathy  1  1/2679 (0.04%)  4/2701 (0.15%) 
Left ventricular failure  1  2/2679 (0.07%)  3/2701 (0.11%) 
Cardiopulmonary failure  1  1/2679 (0.04%)  3/2701 (0.11%) 
Mitral valve incompetence  1  2/2679 (0.07%)  1/2701 (0.04%) 
Silent myocardial infarction  1  2/2679 (0.07%)  1/2701 (0.04%) 
Tachycardia  1  3/2679 (0.11%)  0/2701 (0.00%) 
Acute left ventricular failure  1  0/2679 (0.00%)  2/2701 (0.07%) 
Arteriosclerosis coronary artery  1  1/2679 (0.04%)  1/2701 (0.04%) 
Atrial tachycardia  1  2/2679 (0.07%)  0/2701 (0.00%) 
Cardiac discomfort  1  2/2679 (0.07%)  0/2701 (0.00%) 
Cardiorenal syndrome  1  1/2679 (0.04%)  1/2701 (0.04%) 
Coronary artery insufficiency  1  0/2679 (0.00%)  2/2701 (0.07%) 
Left ventricular dysfunction  1  1/2679 (0.04%)  1/2701 (0.04%) 
Postinfarction angina  1  2/2679 (0.07%)  0/2701 (0.00%) 
Right ventricular failure  1  1/2679 (0.04%)  1/2701 (0.04%) 
Sick sinus syndrome  1  2/2679 (0.07%)  0/2701 (0.00%) 
Tricuspid valve incompetence  1  1/2679 (0.04%)  1/2701 (0.04%) 
Ventricular extrasystoles  1  1/2679 (0.04%)  1/2701 (0.04%) 
Aortic valve stenosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Arteriospasm coronary  1  0/2679 (0.00%)  1/2701 (0.04%) 
Atrioventricular block  1  0/2679 (0.00%)  1/2701 (0.04%) 
Atrioventricular block second degree  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bradyarrhythmia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cardiac asthma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cardiac valve disease  1  0/2679 (0.00%)  1/2701 (0.04%) 
Cardiovascular disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cardiovascular insufficiency  1  0/2679 (0.00%)  1/2701 (0.04%) 
Congestive cardiomyopathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cor pulmonale chronic  1  1/2679 (0.04%)  0/2701 (0.00%) 
Coronary artery dissection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Coronary artery occlusion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Coronary artery thrombosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Intracardiac thrombus  1  0/2679 (0.00%)  1/2701 (0.04%) 
Nodal rhythm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Palpitations  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pulseless electrical activity  1  1/2679 (0.04%)  0/2701 (0.00%) 
Sinus bradycardia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Trifascicular block  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ventricular arrhythmia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Ventricular dysfunction  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ventricular dyskinesia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Congenital, familial and genetic disorders     
Congenital megaureter  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pyloric stenosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ear and labyrinth disorders     
Vertigo  1  2/2679 (0.07%)  3/2701 (0.11%) 
Vertigo positional  1  2/2679 (0.07%)  3/2701 (0.11%) 
Endocrine disorders     
Goitre  1  0/2679 (0.00%)  1/2701 (0.04%) 
Hyperthyroidism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Eye disorders     
Cataract  1  6/2679 (0.22%)  5/2701 (0.19%) 
Diabetic retinopathy  1  1/2679 (0.04%)  1/2701 (0.04%) 
Vitreous haemorrhage  1  2/2679 (0.07%)  0/2701 (0.00%) 
Amaurosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cataract subcapsular  1  0/2679 (0.00%)  1/2701 (0.04%) 
Dacryostenosis acquired  1  0/2679 (0.00%)  1/2701 (0.04%) 
Open angle glaucoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Retinal detachment  1  0/2679 (0.00%)  1/2701 (0.04%) 
Retinopathy  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gastrointestinal disorders     
Gastrointestinal haemorrhage  1  10/2679 (0.37%)  9/2701 (0.33%) 
Diarrhoea  1  8/2679 (0.30%)  8/2701 (0.30%) 
Gastritis  1  7/2679 (0.26%)  3/2701 (0.11%) 
Pancreatitis  1  4/2679 (0.15%)  6/2701 (0.22%) 
Upper gastrointestinal haemorrhage  1  4/2679 (0.15%)  6/2701 (0.22%) 
Abdominal pain  1  3/2679 (0.11%)  6/2701 (0.22%) 
Gastritis erosive  1  4/2679 (0.15%)  2/2701 (0.07%) 
Pancreatitis acute  1  4/2679 (0.15%)  2/2701 (0.07%) 
Dyspepsia  1  3/2679 (0.11%)  2/2701 (0.07%) 
Gastric ulcer  1  3/2679 (0.11%)  2/2701 (0.07%) 
Gastrooesophageal reflux disease  1  1/2679 (0.04%)  4/2701 (0.15%) 
Haemorrhoids  1  2/2679 (0.07%)  2/2701 (0.07%) 
Constipation  1  3/2679 (0.11%)  0/2701 (0.00%) 
Diabetic gastroparesis  1  1/2679 (0.04%)  2/2701 (0.07%) 
Duodenal ulcer  1  2/2679 (0.07%)  1/2701 (0.04%) 
Impaired gastric emptying  1  0/2679 (0.00%)  3/2701 (0.11%) 
Inguinal hernia  1  1/2679 (0.04%)  2/2701 (0.07%) 
Oesophagitis  1  1/2679 (0.04%)  2/2701 (0.07%) 
Pancreatitis chronic  1  1/2679 (0.04%)  2/2701 (0.07%) 
Pancreatitis relapsing  1  0/2679 (0.00%)  3/2701 (0.11%) 
Peptic ulcer  1  2/2679 (0.07%)  1/2701 (0.04%) 
Rectal haemorrhage  1  1/2679 (0.04%)  2/2701 (0.07%) 
Vomiting  1  2/2679 (0.07%)  1/2701 (0.04%) 
Abdominal pain upper  1  1/2679 (0.04%)  1/2701 (0.04%) 
Diverticulum intestinal haemorrhagic  1  1/2679 (0.04%)  1/2701 (0.04%) 
Intestinal ischaemia  1  0/2679 (0.00%)  2/2701 (0.07%) 
Intestinal obstruction  1  1/2679 (0.04%)  1/2701 (0.04%) 
Lower gastrointestinal haemorrhage  1  2/2679 (0.07%)  0/2701 (0.00%) 
Small intestinal obstruction  1  0/2679 (0.00%)  2/2701 (0.07%) 
Abdominal discomfort  1  1/2679 (0.04%)  0/2701 (0.00%) 
Abdominal distension  1  1/2679 (0.04%)  0/2701 (0.00%) 
Abdominal pain lower  1  1/2679 (0.04%)  0/2701 (0.00%) 
Acute abdomen  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colitis ischaemic  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colitis ulcerative  1  0/2679 (0.00%)  1/2701 (0.04%) 
Crohn's disease  1  0/2679 (0.00%)  1/2701 (0.04%) 
Dental caries  1  0/2679 (0.00%)  1/2701 (0.04%) 
Diverticulitis intestinal haemorrhagic  1  0/2679 (0.00%)  1/2701 (0.04%) 
Duodenal ulcer haemorrhage  1  0/2679 (0.00%)  1/2701 (0.04%) 
Duodenitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Dysphagia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Enteritis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Enterocolitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Erosive duodenitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gastric haemorrhage  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gastric ulcer haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gastrointestinal angiodysplasia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gastrointestinal motility disorder  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gastrointestinal ulcer haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gingival bleeding  1  1/2679 (0.04%)  0/2701 (0.00%) 
Haemorrhoidal haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hernial eventration  1  1/2679 (0.04%)  0/2701 (0.00%) 
Inguinal hernia, obstructive  1  1/2679 (0.04%)  0/2701 (0.00%) 
Intestinal angina  1  0/2679 (0.00%)  1/2701 (0.04%) 
Intestinal infarction  1  0/2679 (0.00%)  1/2701 (0.04%) 
Irritable bowel syndrome  1  0/2679 (0.00%)  1/2701 (0.04%) 
Large intestinal obstruction  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lip haematoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Mallory-Weiss syndrome  1  0/2679 (0.00%)  1/2701 (0.04%) 
Oesophageal obstruction  1  1/2679 (0.04%)  0/2701 (0.00%) 
Oesophageal pain  1  0/2679 (0.00%)  1/2701 (0.04%) 
Oesophageal spasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pancreatic cyst  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pancreatic enlargement  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pancreatic mass  1  1/2679 (0.04%)  0/2701 (0.00%) 
Peptic ulcer haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Peritonitis sclerosing  1  0/2679 (0.00%)  1/2701 (0.04%) 
Retroperitoneal fibrosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Retroperitoneal haematoma  1  1/2679 (0.04%)  0/2701 (0.00%) 
General disorders     
Non-cardiac chest pain  1  54/2679 (2.02%)  40/2701 (1.48%) 
Chest pain  1  9/2679 (0.34%)  8/2701 (0.30%) 
Sudden cardiac death  1  8/2679 (0.30%)  8/2701 (0.30%) 
Sudden death  1  7/2679 (0.26%)  6/2701 (0.22%) 
Death  1  6/2679 (0.22%)  6/2701 (0.22%) 
Pyrexia  1  3/2679 (0.11%)  3/2701 (0.11%) 
Multi-organ failure  1  2/2679 (0.07%)  3/2701 (0.11%) 
Chest discomfort  1  3/2679 (0.11%)  1/2701 (0.04%) 
Device occlusion  1  2/2679 (0.07%)  2/2701 (0.07%) 
Oedema peripheral  1  1/2679 (0.04%)  3/2701 (0.11%) 
Asthenia  1  3/2679 (0.11%)  0/2701 (0.00%) 
Adverse drug reaction  1  0/2679 (0.00%)  2/2701 (0.07%) 
General physical health deterioration  1  0/2679 (0.00%)  2/2701 (0.07%) 
Cardiac death  1  1/2679 (0.04%)  0/2701 (0.00%) 
Device battery issue  1  1/2679 (0.04%)  0/2701 (0.00%) 
Device dislocation  1  0/2679 (0.00%)  1/2701 (0.04%) 
Device failure  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hyperpyrexia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Impaired healing  1  1/2679 (0.04%)  0/2701 (0.00%) 
Implant site pain  1  1/2679 (0.04%)  0/2701 (0.00%) 
Necrobiosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Oedema  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pseudoangina  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hepatobiliary disorders     
Cholelithiasis  1  9/2679 (0.34%)  7/2701 (0.26%) 
Cholecystitis  1  2/2679 (0.07%)  5/2701 (0.19%) 
Cholecystitis acute  1  2/2679 (0.07%)  4/2701 (0.15%) 
Cholecystitis chronic  1  3/2679 (0.11%)  0/2701 (0.00%) 
Bile duct stone  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hepatic cirrhosis  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hepatic function abnormal  1  0/2679 (0.00%)  2/2701 (0.07%) 
Jaundice cholestatic  1  0/2679 (0.00%)  2/2701 (0.07%) 
Acute hepatic failure  1  1/2679 (0.04%)  0/2701 (0.00%) 
Biliary colic  1  1/2679 (0.04%)  0/2701 (0.00%) 
Biliary tract disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cholangitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cholangitis acute  1  0/2679 (0.00%)  1/2701 (0.04%) 
Hepatitis acute  1  1/2679 (0.04%)  0/2701 (0.00%) 
Liver injury  1  1/2679 (0.04%)  0/2701 (0.00%) 
Post cholecystectomy syndrome  1  1/2679 (0.04%)  0/2701 (0.00%) 
Immune system disorders     
Anaphylactic reaction  1  3/2679 (0.11%)  1/2701 (0.04%) 
Infections and infestations     
Pneumonia  1  44/2679 (1.64%)  49/2701 (1.81%) 
Sepsis  1  19/2679 (0.71%)  11/2701 (0.41%) 
Bronchitis  1  10/2679 (0.37%)  14/2701 (0.52%) 
Urinary tract infection  1  14/2679 (0.52%)  10/2701 (0.37%) 
Cellulitis  1  15/2679 (0.56%)  7/2701 (0.26%) 
Gastroenteritis  1  10/2679 (0.37%)  7/2701 (0.26%) 
Septic shock  1  6/2679 (0.22%)  10/2701 (0.37%) 
Postoperative wound infection  1  5/2679 (0.19%)  4/2701 (0.15%) 
Gangrene  1  4/2679 (0.15%)  4/2701 (0.15%) 
Lower respiratory tract infection  1  5/2679 (0.19%)  3/2701 (0.11%) 
Abscess limb  1  6/2679 (0.22%)  1/2701 (0.04%) 
Pyelonephritis  1  2/2679 (0.07%)  5/2701 (0.19%) 
Diverticulitis  1  5/2679 (0.19%)  1/2701 (0.04%) 
Erysipelas  1  3/2679 (0.11%)  3/2701 (0.11%) 
Osteomyelitis  1  1/2679 (0.04%)  5/2701 (0.19%) 
Cystitis  1  4/2679 (0.15%)  1/2701 (0.04%) 
Localised infection  1  2/2679 (0.07%)  3/2701 (0.11%) 
Pyelonephritis acute  1  4/2679 (0.15%)  1/2701 (0.04%) 
Appendicitis  1  3/2679 (0.11%)  1/2701 (0.04%) 
Bacteraemia  1  2/2679 (0.07%)  2/2701 (0.07%) 
Bronchopneumonia  1  3/2679 (0.11%)  1/2701 (0.04%) 
Endocarditis  1  2/2679 (0.07%)  2/2701 (0.07%) 
Lobar pneumonia  1  3/2679 (0.11%)  1/2701 (0.04%) 
Subcutaneous abscess  1  2/2679 (0.07%)  2/2701 (0.07%) 
Wound infection  1  4/2679 (0.15%)  0/2701 (0.00%) 
Arthritis bacterial  1  1/2679 (0.04%)  2/2701 (0.07%) 
Gastroenteritis viral  1  2/2679 (0.07%)  1/2701 (0.04%) 
Herpes zoster  1  2/2679 (0.07%)  1/2701 (0.04%) 
Respiratory tract infection  1  2/2679 (0.07%)  1/2701 (0.04%) 
Urosepsis  1  2/2679 (0.07%)  1/2701 (0.04%) 
Viral infection  1  1/2679 (0.04%)  2/2701 (0.07%) 
Appendicitis perforated  1  1/2679 (0.04%)  1/2701 (0.04%) 
Atypical pneumonia  1  0/2679 (0.00%)  2/2701 (0.07%) 
Carbuncle  1  0/2679 (0.00%)  2/2701 (0.07%) 
Diarrhoea infectious  1  0/2679 (0.00%)  2/2701 (0.07%) 
Intestinal gangrene  1  1/2679 (0.04%)  1/2701 (0.04%) 
Mediastinitis  1  2/2679 (0.07%)  0/2701 (0.00%) 
Upper respiratory tract infection  1  0/2679 (0.00%)  2/2701 (0.07%) 
Wound infection staphylococcal  1  0/2679 (0.00%)  2/2701 (0.07%) 
Abdominal sepsis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Abdominal wall infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Acinetobacter bacteraemia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Acute hepatitis B  1  1/2679 (0.04%)  0/2701 (0.00%) 
Acute sinusitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Anal abscess  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bacterial diarrhoea  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bacterial pyelonephritis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Biliary tract infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Breast abscess  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cystitis escherichia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Dacryocanaliculitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Dengue fever  1  0/2679 (0.00%)  1/2701 (0.04%) 
Diabetic foot infection  1  0/2679 (0.00%)  1/2701 (0.04%) 
Diabetic gangrene  1  0/2679 (0.00%)  1/2701 (0.04%) 
Endocarditis bacterial  1  1/2679 (0.04%)  0/2701 (0.00%) 
Enterocolitis infectious  1  1/2679 (0.04%)  0/2701 (0.00%) 
Escherichia sepsis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Escherichia urinary tract infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Extradural abscess  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gas gangrene  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gastritis viral  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gastrointestinal infection  1  0/2679 (0.00%)  1/2701 (0.04%) 
Genital infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Groin abscess  1  1/2679 (0.04%)  0/2701 (0.00%) 
HIV infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Haematoma infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hepatitis B  1  1/2679 (0.04%)  0/2701 (0.00%) 
Incision site infection  1  0/2679 (0.00%)  1/2701 (0.04%) 
Infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Influenza  1  1/2679 (0.04%)  0/2701 (0.00%) 
Intervertebral discitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Korean haemorrhagic fever  1  0/2679 (0.00%)  1/2701 (0.04%) 
Liver abscess  1  0/2679 (0.00%)  1/2701 (0.04%) 
Malaria  1  0/2679 (0.00%)  1/2701 (0.04%) 
Meningitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Meningitis viral  1  1/2679 (0.04%)  0/2701 (0.00%) 
Orchitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Osteomyelitis acute  1  0/2679 (0.00%)  1/2701 (0.04%) 
Osteomyelitis chronic  1  1/2679 (0.04%)  0/2701 (0.00%) 
Periodontitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pharyngitis streptococcal  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pleural infection bacterial  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pneumonia bacterial  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pneumonia influenzal  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pneumonia staphylococcal  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pneumonia viral  1  0/2679 (0.00%)  1/2701 (0.04%) 
Post procedural cellulitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pseudomembranous colitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Respiratory tract infection viral  1  1/2679 (0.04%)  0/2701 (0.00%) 
Scrotal abscess  1  0/2679 (0.00%)  1/2701 (0.04%) 
Scrub typhus  1  0/2679 (0.00%)  1/2701 (0.04%) 
Serratia infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Staphylococcal infection  1  0/2679 (0.00%)  1/2701 (0.04%) 
Staphylococcal skin infection  1  1/2679 (0.04%)  0/2701 (0.00%) 
Thrombophlebitis septic  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tooth abscess  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tuberculosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Urethritis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Viraemia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Injury, poisoning and procedural complications     
Coronary artery restenosis  1  17/2679 (0.63%)  19/2701 (0.70%) 
Fall  1  6/2679 (0.22%)  3/2701 (0.11%) 
Femur fracture  1  8/2679 (0.30%)  1/2701 (0.04%) 
Laceration  1  3/2679 (0.11%)  2/2701 (0.07%) 
Road traffic accident  1  3/2679 (0.11%)  2/2701 (0.07%) 
Arterial restenosis  1  0/2679 (0.00%)  3/2701 (0.11%) 
Foot fracture  1  2/2679 (0.07%)  1/2701 (0.04%) 
Head injury  1  1/2679 (0.04%)  2/2701 (0.07%) 
Rib fracture  1  3/2679 (0.11%)  0/2701 (0.00%) 
Spinal compression fracture  1  0/2679 (0.00%)  3/2701 (0.11%) 
Toxicity to various agents  1  2/2679 (0.07%)  1/2701 (0.04%) 
Traumatic haematoma  1  3/2679 (0.11%)  0/2701 (0.00%) 
Alcohol poisoning  1  2/2679 (0.07%)  0/2701 (0.00%) 
Ankle fracture  1  0/2679 (0.00%)  2/2701 (0.07%) 
Femoral neck fracture  1  1/2679 (0.04%)  1/2701 (0.04%) 
Limb injury  1  2/2679 (0.07%)  0/2701 (0.00%) 
Lower limb fracture  1  0/2679 (0.00%)  2/2701 (0.07%) 
Muscle strain  1  0/2679 (0.00%)  2/2701 (0.07%) 
Overdose  1  1/2679 (0.04%)  1/2701 (0.04%) 
Post procedural haemorrhage  1  0/2679 (0.00%)  2/2701 (0.07%) 
Postoperative wound complication  1  0/2679 (0.00%)  2/2701 (0.07%) 
Pubis fracture  1  2/2679 (0.07%)  0/2701 (0.00%) 
Subdural haematoma  1  1/2679 (0.04%)  1/2701 (0.04%) 
Vascular graft complication  1  1/2679 (0.04%)  1/2701 (0.04%) 
Vascular graft occlusion  1  2/2679 (0.07%)  0/2701 (0.00%) 
Vascular pseudoaneurysm  1  1/2679 (0.04%)  1/2701 (0.04%) 
Wound dehiscence  1  1/2679 (0.04%)  1/2701 (0.04%) 
Accident  1  1/2679 (0.04%)  0/2701 (0.00%) 
Anaemia postoperative  1  1/2679 (0.04%)  0/2701 (0.00%) 
Arterial injury  1  0/2679 (0.00%)  1/2701 (0.04%) 
Arteriovenous fistula occlusion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Arteriovenous fistula site complication  1  0/2679 (0.00%)  1/2701 (0.04%) 
Chemical poisoning  1  0/2679 (0.00%)  1/2701 (0.04%) 
Chest injury  1  0/2679 (0.00%)  1/2701 (0.04%) 
Concussion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Contusion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Coronary artery reocclusion  1  0/2679 (0.00%)  1/2701 (0.04%) 
Craniocerebral injury  1  0/2679 (0.00%)  1/2701 (0.04%) 
Eyeball rupture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Fat embolism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gun shot wound  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hand fracture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Human bite  1  1/2679 (0.04%)  0/2701 (0.00%) 
Inflammation of wound  1  0/2679 (0.00%)  1/2701 (0.04%) 
Intentional overdose  1  1/2679 (0.04%)  0/2701 (0.00%) 
Joint dislocation  1  0/2679 (0.00%)  1/2701 (0.04%) 
Joint injury  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ligament injury  1  1/2679 (0.04%)  0/2701 (0.00%) 
Lumbar vertebral fracture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Multiple fractures  1  1/2679 (0.04%)  0/2701 (0.00%) 
Muscle rupture  1  0/2679 (0.00%)  1/2701 (0.04%) 
Open fracture  1  0/2679 (0.00%)  1/2701 (0.04%) 
Patella fracture  1  0/2679 (0.00%)  1/2701 (0.04%) 
Post procedural myocardial infarction  1  1/2679 (0.04%)  0/2701 (0.00%) 
Postoperative thoracic procedure complication  1  0/2679 (0.00%)  1/2701 (0.04%) 
Radius fracture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Repetitive strain injury  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tendon rupture  1  0/2679 (0.00%)  1/2701 (0.04%) 
Tibia fracture  1  0/2679 (0.00%)  1/2701 (0.04%) 
Tobacco poisoning  1  1/2679 (0.04%)  0/2701 (0.00%) 
Transfusion reaction  1  0/2679 (0.00%)  1/2701 (0.04%) 
Traumatic intracranial haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ulna fracture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Wound necrosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Investigations     
Haemoglobin decreased  1  3/2679 (0.11%)  0/2701 (0.00%) 
Lipase increased  1  2/2679 (0.07%)  1/2701 (0.04%) 
Amylase increased  1  0/2679 (0.00%)  2/2701 (0.07%) 
Blood glucose increased  1  2/2679 (0.07%)  0/2701 (0.00%) 
Cardiac enzymes increased  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hepatic enzyme increased  1  2/2679 (0.07%)  0/2701 (0.00%) 
Alanine aminotransferase increased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Aspartate aminotransferase increased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Blood creatine phosphokinase increased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Blood creatinine increased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Blood potassium increased  1  1/2679 (0.04%)  0/2701 (0.00%) 
Electrocardiogram ST segment depression  1  0/2679 (0.00%)  1/2701 (0.04%) 
Gamma-glutamyltransferase increased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Heart rate irregular  1  1/2679 (0.04%)  0/2701 (0.00%) 
International normalised ratio increased  1  1/2679 (0.04%)  0/2701 (0.00%) 
Liver function test abnormal  1  0/2679 (0.00%)  1/2701 (0.04%) 
Neutrophil count decreased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Oxygen saturation decreased  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pancreatic enzymes increased  1  1/2679 (0.04%)  0/2701 (0.00%) 
Transaminases increased  1  1/2679 (0.04%)  0/2701 (0.00%) 
Troponin increased  1  1/2679 (0.04%)  0/2701 (0.00%) 
Metabolism and nutrition disorders     
Hypoglycaemia  1  16/2679 (0.60%)  18/2701 (0.67%) 
Diabetes mellitus inadequate control  1  14/2679 (0.52%)  5/2701 (0.19%) 
Diabetes mellitus  1  11/2679 (0.41%)  6/2701 (0.22%) 
Hyperglycaemia  1  11/2679 (0.41%)  5/2701 (0.19%) 
Gout  1  4/2679 (0.15%)  3/2701 (0.11%) 
Hyperkalaemia  1  2/2679 (0.07%)  5/2701 (0.19%) 
Dehydration  1  4/2679 (0.15%)  1/2701 (0.04%) 
Fluid overload  1  2/2679 (0.07%)  1/2701 (0.04%) 
Electrolyte imbalance  1  1/2679 (0.04%)  1/2701 (0.04%) 
Hypertriglyceridaemia  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hypokalaemia  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hyponatraemia  1  0/2679 (0.00%)  2/2701 (0.07%) 
Metabolic acidosis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Obesity  1  1/2679 (0.04%)  1/2701 (0.04%) 
Diabetes complicating pregnancy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Diabetic ketoacidosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Failure to thrive  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hyperglycaemic hyperosmolar nonketotic syndrome  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hyperlipasaemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hyperosmolar state  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hypoalbuminaemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hypomagnesaemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hypophosphataemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hypovolaemia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Lactic acidosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal chest pain  1  14/2679 (0.52%)  16/2701 (0.59%) 
Back pain  1  1/2679 (0.04%)  5/2701 (0.19%) 
Osteoarthritis  1  3/2679 (0.11%)  3/2701 (0.11%) 
Spinal osteoarthritis  1  3/2679 (0.11%)  1/2701 (0.04%) 
Intervertebral disc disorder  1  1/2679 (0.04%)  2/2701 (0.07%) 
Intervertebral disc protrusion  1  2/2679 (0.07%)  0/2701 (0.00%) 
Myopathy  1  1/2679 (0.04%)  1/2701 (0.04%) 
Rotator cuff syndrome  1  1/2679 (0.04%)  1/2701 (0.04%) 
Arthralgia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Arthritis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bursitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Chondrocalcinosis pyrophosphate  1  1/2679 (0.04%)  0/2701 (0.00%) 
Costochondritis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Fibromyalgia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Flank pain  1  0/2679 (0.00%)  1/2701 (0.04%) 
Haemarthrosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lumbar spinal stenosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Muscle contracture  1  1/2679 (0.04%)  0/2701 (0.00%) 
Muscle haemorrhage  1  0/2679 (0.00%)  1/2701 (0.04%) 
Muscle spasms  1  0/2679 (0.00%)  1/2701 (0.04%) 
Muscle twitching  1  0/2679 (0.00%)  1/2701 (0.04%) 
Muscular weakness  1  1/2679 (0.04%)  0/2701 (0.00%) 
Musculoskeletal discomfort  1  0/2679 (0.00%)  1/2701 (0.04%) 
Musculoskeletal pain  1  0/2679 (0.00%)  1/2701 (0.04%) 
Myalgia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Myositis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Neuropathic arthropathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Psoriatic arthropathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Rhabdomyolysis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Rheumatoid arthritis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tendon disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tendonitis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Torticollis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Colon cancer  1  4/2679 (0.15%)  4/2701 (0.15%) 
Prostate cancer  1  3/2679 (0.11%)  4/2701 (0.15%) 
Breast cancer  1  2/2679 (0.07%)  3/2701 (0.11%) 
Bladder cancer  1  2/2679 (0.07%)  2/2701 (0.07%) 
Gastric cancer  1  1/2679 (0.04%)  2/2701 (0.07%) 
Renal cell carcinoma  1  1/2679 (0.04%)  2/2701 (0.07%) 
Squamous cell carcinoma  1  0/2679 (0.00%)  3/2701 (0.11%) 
Adenocarcinoma gastric  1  0/2679 (0.00%)  2/2701 (0.07%) 
Invasive ductal breast carcinoma  1  1/2679 (0.04%)  1/2701 (0.04%) 
Lung neoplasm  1  1/2679 (0.04%)  1/2701 (0.04%) 
Lung neoplasm malignant  1  0/2679 (0.00%)  2/2701 (0.07%) 
Oesophageal carcinoma  1  1/2679 (0.04%)  1/2701 (0.04%) 
Renal neoplasm  1  1/2679 (0.04%)  1/2701 (0.04%) 
Squamous cell carcinoma of lung  1  0/2679 (0.00%)  2/2701 (0.07%) 
Uterine leiomyoma  1  1/2679 (0.04%)  1/2701 (0.04%) 
Adenocarcinoma of colon  1  0/2679 (0.00%)  1/2701 (0.04%) 
Basal cell carcinoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Benign salivary gland neoplasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bladder papilloma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Breast cancer stage III  1  0/2679 (0.00%)  1/2701 (0.04%) 
Colon adenoma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colon cancer recurrent  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colon cancer stage II  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colon neoplasm  1  1/2679 (0.04%)  0/2701 (0.00%) 
Colorectal adenocarcinoma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Endometrial cancer  1  1/2679 (0.04%)  0/2701 (0.00%) 
Endometrial cancer stage I  1  1/2679 (0.04%)  0/2701 (0.00%) 
Fibroadenoma of breast  1  1/2679 (0.04%)  0/2701 (0.00%) 
Follicular thyroid cancer  1  1/2679 (0.04%)  0/2701 (0.00%) 
Gallbladder cancer  1  0/2679 (0.00%)  1/2701 (0.04%) 
Hepatic cancer  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hepatocellular carcinoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lentigo maligna  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lip neoplasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lip squamous cell carcinoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lung adenocarcinoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lung cancer metastatic  1  0/2679 (0.00%)  1/2701 (0.04%) 
Malignant melanoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Metastases to lymph nodes  1  1/2679 (0.04%)  0/2701 (0.00%) 
Metastatic neoplasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Non-Hodgkin's lymphoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Osteoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Ovarian neoplasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Plasma cell myeloma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Rectal adenocarcinoma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Rectal cancer  1  0/2679 (0.00%)  1/2701 (0.04%) 
Rectal cancer metastatic  1  0/2679 (0.00%)  1/2701 (0.04%) 
Rectosigmoid cancer  1  1/2679 (0.04%)  0/2701 (0.00%) 
Renal cancer  1  1/2679 (0.04%)  0/2701 (0.00%) 
Signet-ring cell carcinoma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Spinal cord neoplasm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Squamous cell carcinoma of skin  1  0/2679 (0.00%)  1/2701 (0.04%) 
Nervous system disorders     
Cerebrovascular accident  1  25/2679 (0.93%)  15/2701 (0.56%) 
Ischaemic stroke  1  7/2679 (0.26%)  15/2701 (0.56%) 
Syncope  1  9/2679 (0.34%)  9/2701 (0.33%) 
Transient ischaemic attack  1  7/2679 (0.26%)  5/2701 (0.19%) 
Convulsion  1  2/2679 (0.07%)  7/2701 (0.26%) 
Carotid artery stenosis  1  5/2679 (0.19%)  3/2701 (0.11%) 
Cerebral infarction  1  4/2679 (0.15%)  4/2701 (0.15%) 
Epilepsy  1  3/2679 (0.11%)  2/2701 (0.07%) 
Haemorrhagic stroke  1  4/2679 (0.15%)  0/2701 (0.00%) 
Presyncope  1  2/2679 (0.07%)  2/2701 (0.07%) 
Sciatica  1  2/2679 (0.07%)  2/2701 (0.07%) 
Carpal tunnel syndrome  1  2/2679 (0.07%)  1/2701 (0.04%) 
Dizziness  1  3/2679 (0.11%)  0/2701 (0.00%) 
Hypoxic-ischaemic encephalopathy  1  2/2679 (0.07%)  1/2701 (0.04%) 
Lacunar infarction  1  2/2679 (0.07%)  1/2701 (0.04%) 
Subarachnoid haemorrhage  1  1/2679 (0.04%)  2/2701 (0.07%) 
Carotid artery disease  1  0/2679 (0.00%)  2/2701 (0.07%) 
Cauda equina syndrome  1  1/2679 (0.04%)  1/2701 (0.04%) 
Cerebrovascular disorder  1  2/2679 (0.07%)  0/2701 (0.00%) 
Cervicobrachial syndrome  1  1/2679 (0.04%)  1/2701 (0.04%) 
Coma  1  2/2679 (0.07%)  0/2701 (0.00%) 
Headache  1  2/2679 (0.07%)  0/2701 (0.00%) 
Hemiparesis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Hypoglycaemic seizure  1  0/2679 (0.00%)  2/2701 (0.07%) 
Migraine  1  0/2679 (0.00%)  2/2701 (0.07%) 
Neuralgia  1  1/2679 (0.04%)  1/2701 (0.04%) 
Neuritis cranial  1  2/2679 (0.07%)  0/2701 (0.00%) 
Polyneuropathy  1  2/2679 (0.07%)  0/2701 (0.00%) 
Spinal claudication  1  1/2679 (0.04%)  1/2701 (0.04%) 
VIIth nerve paralysis  1  0/2679 (0.00%)  2/2701 (0.07%) 
Amyotrophic lateral sclerosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ataxia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Balance disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Brain hypoxia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Brain stem haemorrhage  1  0/2679 (0.00%)  1/2701 (0.04%) 
Brain stem stroke  1  1/2679 (0.04%)  0/2701 (0.00%) 
Carotid artery occlusion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Carotid sinus syndrome  1  1/2679 (0.04%)  0/2701 (0.00%) 
Central pain syndrome  1  0/2679 (0.00%)  1/2701 (0.04%) 
Cerebellar infarction  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cerebral arteriosclerosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cerebrovascular insufficiency  1  0/2679 (0.00%)  1/2701 (0.04%) 
Cognitive disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Diabetic ketoacidotic hyperglycaemic coma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Diabetic neuropathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Embolic stroke  1  1/2679 (0.04%)  0/2701 (0.00%) 
Encephalopathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Grand mal convulsion  1  0/2679 (0.00%)  1/2701 (0.04%) 
Haemorrhage intracranial  1  1/2679 (0.04%)  0/2701 (0.00%) 
Hypoaesthesia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Hypoglycaemic coma  1  0/2679 (0.00%)  1/2701 (0.04%) 
Ischaemic cerebral infarction  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lumbar radiculopathy  1  0/2679 (0.00%)  1/2701 (0.04%) 
Metabolic encephalopathy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Multiple sclerosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Petit mal epilepsy  1  0/2679 (0.00%)  1/2701 (0.04%) 
Senile dementia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Thrombotic cerebral infarction  1  0/2679 (0.00%)  1/2701 (0.04%) 
VIth nerve paralysis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Vascular dementia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Vertebrobasilar insufficiency  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  1/2679 (0.04%)  0/2701 (0.00%) 
Psychiatric disorders     
Major depression  1  1/2679 (0.04%)  2/2701 (0.07%) 
Anxiety disorder  1  1/2679 (0.04%)  1/2701 (0.04%) 
Completed suicide  1  2/2679 (0.07%)  0/2701 (0.00%) 
Stress  1  1/2679 (0.04%)  1/2701 (0.04%) 
Abnormal behaviour  1  1/2679 (0.04%)  0/2701 (0.00%) 
Agoraphobia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Alcohol abuse  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bipolar disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Confusional state  1  0/2679 (0.00%)  1/2701 (0.04%) 
Depression  1  1/2679 (0.04%)  0/2701 (0.00%) 
Mental status changes  1  1/2679 (0.04%)  0/2701 (0.00%) 
Mood altered  1  0/2679 (0.00%)  1/2701 (0.04%) 
Schizophrenia, paranoid type  1  0/2679 (0.00%)  1/2701 (0.04%) 
Renal and urinary disorders     
Renal failure acute  1  36/2679 (1.34%)  43/2701 (1.59%) 
Renal failure  1  13/2679 (0.49%)  12/2701 (0.44%) 
Renal failure chronic  1  13/2679 (0.49%)  9/2701 (0.33%) 
Renal impairment  1  7/2679 (0.26%)  8/2701 (0.30%) 
Haematuria  1  2/2679 (0.07%)  5/2701 (0.19%) 
Nephrolithiasis  1  2/2679 (0.07%)  4/2701 (0.15%) 
Urinary retention  1  0/2679 (0.00%)  6/2701 (0.22%) 
Calculus ureteric  1  3/2679 (0.11%)  2/2701 (0.07%) 
Azotaemia  1  3/2679 (0.11%)  1/2701 (0.04%) 
Renal colic  1  2/2679 (0.07%)  2/2701 (0.07%) 
Calculus urinary  1  2/2679 (0.07%)  1/2701 (0.04%) 
Diabetic nephropathy  1  2/2679 (0.07%)  1/2701 (0.04%) 
Acute prerenal failure  1  1/2679 (0.04%)  1/2701 (0.04%) 
Hydronephrosis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Nephropathy  1  1/2679 (0.04%)  1/2701 (0.04%) 
Prerenal failure  1  0/2679 (0.00%)  2/2701 (0.07%) 
Renal artery stenosis  1  2/2679 (0.07%)  0/2701 (0.00%) 
Renal tubular necrosis  1  2/2679 (0.07%)  0/2701 (0.00%) 
Urethral stenosis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Calculus bladder  1  0/2679 (0.00%)  1/2701 (0.04%) 
Cystitis haemorrhagic  1  0/2679 (0.00%)  1/2701 (0.04%) 
Incontinence  1  1/2679 (0.04%)  0/2701 (0.00%) 
Obstructive uropathy  1  0/2679 (0.00%)  1/2701 (0.04%) 
Renal embolism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Renal injury  1  0/2679 (0.00%)  1/2701 (0.04%) 
Renal mass  1  1/2679 (0.04%)  0/2701 (0.00%) 
Ureteric obstruction  1  1/2679 (0.04%)  0/2701 (0.00%) 
Urinary incontinence  1  0/2679 (0.00%)  1/2701 (0.04%) 
Urinary tract obstruction  1  0/2679 (0.00%)  1/2701 (0.04%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  6/2679 (0.22%)  1/2701 (0.04%) 
Vaginal haemorrhage  1  2/2679 (0.07%)  1/2701 (0.04%) 
Gynaecomastia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Menorrhagia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Prostatism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Prostatitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Scrotal mass  1  0/2679 (0.00%)  1/2701 (0.04%) 
Uterine prolapse  1  1/2679 (0.04%)  0/2701 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  15/2679 (0.56%)  24/2701 (0.89%) 
Chronic obstructive pulmonary disease  1  19/2679 (0.71%)  13/2701 (0.48%) 
Pulmonary oedema  1  15/2679 (0.56%)  13/2701 (0.48%) 
Respiratory failure  1  8/2679 (0.30%)  8/2701 (0.30%) 
Dyspnoea  1  8/2679 (0.30%)  7/2701 (0.26%) 
Pulmonary embolism  1  2/2679 (0.07%)  9/2701 (0.33%) 
Acute respiratory failure  1  2/2679 (0.07%)  7/2701 (0.26%) 
Pulmonary hypertension  1  4/2679 (0.15%)  4/2701 (0.15%) 
Pleural effusion  1  1/2679 (0.04%)  4/2701 (0.15%) 
Pulmonary fibrosis  1  3/2679 (0.11%)  2/2701 (0.07%) 
Interstitial lung disease  1  1/2679 (0.04%)  3/2701 (0.11%) 
Acute respiratory distress syndrome  1  1/2679 (0.04%)  2/2701 (0.07%) 
Asthma  1  2/2679 (0.07%)  1/2701 (0.04%) 
Epistaxis  1  2/2679 (0.07%)  1/2701 (0.04%) 
Pneumothorax  1  0/2679 (0.00%)  3/2701 (0.11%) 
Pulmonary mass  1  1/2679 (0.04%)  2/2701 (0.07%) 
Bronchiectasis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Haemoptysis  1  1/2679 (0.04%)  1/2701 (0.04%) 
Haemothorax  1  0/2679 (0.00%)  2/2701 (0.07%) 
Hypoxia  1  0/2679 (0.00%)  2/2701 (0.07%) 
Pneumonia aspiration  1  1/2679 (0.04%)  1/2701 (0.04%) 
Pulmonary congestion  1  2/2679 (0.07%)  0/2701 (0.00%) 
Asphyxia  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bronchial hyperreactivity  1  0/2679 (0.00%)  1/2701 (0.04%) 
Bronchospasm  1  1/2679 (0.04%)  0/2701 (0.00%) 
Bullous lung disease  1  0/2679 (0.00%)  1/2701 (0.04%) 
Chronic respiratory failure  1  1/2679 (0.04%)  0/2701 (0.00%) 
Cough  1  0/2679 (0.00%)  1/2701 (0.04%) 
Hydrothorax  1  1/2679 (0.04%)  0/2701 (0.00%) 
Laryngeal oedema  1  0/2679 (0.00%)  1/2701 (0.04%) 
Lung disorder  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pickwickian syndrome  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pleurisy  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pleuritic pain  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pneumonitis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Pulmonary arterial hypertension  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pulmonary sarcoidosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Respiratory arrest  1  0/2679 (0.00%)  1/2701 (0.04%) 
Respiratory distress  1  0/2679 (0.00%)  1/2701 (0.04%) 
Thoracic haemorrhage  1  1/2679 (0.04%)  0/2701 (0.00%) 
Tracheal stenosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Vocal cord polyp  1  0/2679 (0.00%)  1/2701 (0.04%) 
Skin and subcutaneous tissue disorders     
Diabetic foot  1  4/2679 (0.15%)  7/2701 (0.26%) 
Skin ulcer  1  0/2679 (0.00%)  4/2701 (0.15%) 
Angioedema  1  1/2679 (0.04%)  1/2701 (0.04%) 
Skin necrosis  1  0/2679 (0.00%)  2/2701 (0.07%) 
Cutaneous lupus erythematosus  1  1/2679 (0.04%)  0/2701 (0.00%) 
Decubitus ulcer  1  0/2679 (0.00%)  1/2701 (0.04%) 
Dermatitis contact  1  1/2679 (0.04%)  0/2701 (0.00%) 
Drug eruption  1  0/2679 (0.00%)  1/2701 (0.04%) 
Dry gangrene  1  0/2679 (0.00%)  1/2701 (0.04%) 
Erythema  1  1/2679 (0.04%)  0/2701 (0.00%) 
Erythema nodosum  1  1/2679 (0.04%)  0/2701 (0.00%) 
Pruritus  1  1/2679 (0.04%)  0/2701 (0.00%) 
Rash  1  0/2679 (0.00%)  1/2701 (0.04%) 
Surgical and medical procedures     
Hospitalisation  1  1/2679 (0.04%)  0/2701 (0.00%) 
Implantable defibrillator insertion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Vascular disorders     
Hypertension  1  16/2679 (0.60%)  8/2701 (0.30%) 
Peripheral arterial occlusive disease  1  9/2679 (0.34%)  9/2701 (0.33%) 
Hypertensive crisis  1  10/2679 (0.37%)  5/2701 (0.19%) 
Hypotension  1  7/2679 (0.26%)  6/2701 (0.22%) 
Peripheral artery stenosis  1  1/2679 (0.04%)  6/2701 (0.22%) 
Peripheral vascular disorder  1  4/2679 (0.15%)  3/2701 (0.11%) 
Deep vein thrombosis  1  2/2679 (0.07%)  3/2701 (0.11%) 
Hypertensive emergency  1  2/2679 (0.07%)  3/2701 (0.11%) 
Aortic stenosis  1  1/2679 (0.04%)  3/2701 (0.11%) 
Malignant hypertension  1  2/2679 (0.07%)  2/2701 (0.07%) 
Peripheral ischaemia  1  2/2679 (0.07%)  2/2701 (0.07%) 
Hypovolaemic shock  1  3/2679 (0.11%)  0/2701 (0.00%) 
Intermittent claudication  1  0/2679 (0.00%)  3/2701 (0.11%) 
Orthostatic hypotension  1  0/2679 (0.00%)  3/2701 (0.11%) 
Arterial occlusive disease  1  2/2679 (0.07%)  0/2701 (0.00%) 
Circulatory collapse  1  2/2679 (0.07%)  0/2701 (0.00%) 
Femoral artery occlusion  1  1/2679 (0.04%)  1/2701 (0.04%) 
Iliac artery occlusion  1  1/2679 (0.04%)  1/2701 (0.04%) 
Accelerated hypertension  1  1/2679 (0.04%)  0/2701 (0.00%) 
Angiodysplasia  1  1/2679 (0.04%)  0/2701 (0.00%) 
Angiopathy  1  0/2679 (0.00%)  1/2701 (0.04%) 
Aortic aneurysm  1  1/2679 (0.04%)  0/2701 (0.00%) 
Aortic occlusion  1  1/2679 (0.04%)  0/2701 (0.00%) 
Aortic thrombosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Arterial insufficiency  1  0/2679 (0.00%)  1/2701 (0.04%) 
Arterial stenosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Arteriosclerosis  1  1/2679 (0.04%)  0/2701 (0.00%) 
Arteriovenous fistula  1  1/2679 (0.04%)  0/2701 (0.00%) 
Femoral artery embolism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Haematoma  1  1/2679 (0.04%)  0/2701 (0.00%) 
Peripheral artery aneurysm  1  0/2679 (0.00%)  1/2701 (0.04%) 
Peripheral artery thrombosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Peripheral embolism  1  1/2679 (0.04%)  0/2701 (0.00%) 
Shock haemorrhagic  1  0/2679 (0.00%)  1/2701 (0.04%) 
Subclavian artery stenosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Thrombosis  1  0/2679 (0.00%)  1/2701 (0.04%) 
Venous insufficiency  1  0/2679 (0.00%)  1/2701 (0.04%) 
Venous occlusion  1  0/2679 (0.00%)  1/2701 (0.04%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo Alogliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   1493/2679 (55.73%)   1523/2701 (56.39%) 
Blood and lymphatic system disorders     
Anaemia  1  96/2679 (3.58%)  130/2701 (4.81%) 
Cardiac disorders     
Angina pectoris  1  133/2679 (4.96%)  122/2701 (4.52%) 
Gastrointestinal disorders     
Diarrhoea  1  99/2679 (3.70%)  122/2701 (4.52%) 
Constipation  1  66/2679 (2.46%)  70/2701 (2.59%) 
Nausea  1  53/2679 (1.98%)  56/2701 (2.07%) 
General disorders     
Oedema peripheral  1  104/2679 (3.88%)  101/2701 (3.74%) 
Infections and infestations     
Nasopharyngitis  1  120/2679 (4.48%)  112/2701 (4.15%) 
Urinary tract infection  1  94/2679 (3.51%)  102/2701 (3.78%) 
Upper respiratory tract infection  1  85/2679 (3.17%)  79/2701 (2.92%) 
Bronchitis  1  68/2679 (2.54%)  81/2701 (3.00%) 
Influenza  1  54/2679 (2.02%)  64/2701 (2.37%) 
Investigations     
Blood creatine phosphokinase increased  1  116/2679 (4.33%)  140/2701 (5.18%) 
Glomerular filtration rate decreased  1  116/2679 (4.33%)  132/2701 (4.89%) 
Lipase increased  1  83/2679 (3.10%)  81/2701 (3.00%) 
Blood creatinine increased  1  72/2679 (2.69%)  91/2701 (3.37%) 
Creatinine renal clearance decreased  1  47/2679 (1.75%)  59/2701 (2.18%) 
Metabolism and nutrition disorders     
Hypoglycaemia  1  159/2679 (5.94%)  167/2701 (6.18%) 
Hyperglycaemia  1  99/2679 (3.70%)  94/2701 (3.48%) 
Hyperkalaemia  1  70/2679 (2.61%)  81/2701 (3.00%) 
Hypertriglyceridaemia  1  71/2679 (2.65%)  55/2701 (2.04%) 
Diabetes mellitus  1  70/2679 (2.61%)  52/2701 (1.93%) 
Dyslipidaemia  1  49/2679 (1.83%)  56/2701 (2.07%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  84/2679 (3.14%)  79/2701 (2.92%) 
Arthralgia  1  64/2679 (2.39%)  68/2701 (2.52%) 
Pain in extremity  1  60/2679 (2.24%)  54/2701 (2.00%) 
Nervous system disorders     
Dizziness  1  68/2679 (2.54%)  81/2701 (3.00%) 
Headache  1  72/2679 (2.69%)  69/2701 (2.55%) 
Renal and urinary disorders     
Renal impairment  1  174/2679 (6.49%)  203/2701 (7.52%) 
Proteinuria  1  107/2679 (3.99%)  103/2701 (3.81%) 
Diabetic nephropathy  1  68/2679 (2.54%)  62/2701 (2.30%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  99/2679 (3.70%)  98/2701 (3.63%) 
Dyspnoea  1  74/2679 (2.76%)  70/2701 (2.59%) 
Vascular disorders     
Hypertension  1  198/2679 (7.39%)  193/2701 (7.15%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Name/Title: Medical Director
Organization: Takeda
Phone: 800-778-2860
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00968708     History of Changes
Other Study ID Numbers: SYR-322_402
U1111-1111-6825 ( Registry Identifier: WHO )
2009-011222-34 ( Registry Identifier: EudraCT )
JapicCTI-101246 ( Registry Identifier: JapicCTI )
DOH-27-0310-3047 ( Registry Identifier: SANCTR )
09/H0709/63 ( Registry Identifier: NRES )
CTRI/2010/091/000046 ( Registry Identifier: CTRI )
2009-011222-34 ( Registry Identifier: REPEC )
2009-011222-34 ( Registry Identifier: OsSC )
NMRR-09-872-4471 ( Registry Identifier: NMRR )
First Submitted: August 28, 2009
First Posted: August 31, 2009
Results First Submitted: March 8, 2014
Results First Posted: April 15, 2014
Last Update Posted: May 2, 2014