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Efficacy and Safety of BI 1356 in Combination With Metformin in Patients With Type 2 Diabetes

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00622284
First received: February 13, 2008
Last updated: December 11, 2013
Last verified: December 2013
Results First Received: November 30, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double-Blind;   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Type 2
Interventions: Drug: Placebo identical to BI 1356 5mg
Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg
Drug: BI 1356
Drug: Glimepiride

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were in total 1560 patients randomised in the study. Of these, 1 patient was not treated. The remaining 8 patients not accounted for in the treated set were removed from all study analyses (explained in trial report) due to major good-clinical-practice violations at the site, and the inability to verify the validity of any patient level data.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Linagliptin Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride Patients randomized to receive Glimepiride 1-4mg and metformin

Participant Flow:   Overall Study
    Linagliptin     Glimepiride  
STARTED     776 [1]   775 [2]
COMPLETED     587 [3]   604 [3]
NOT COMPLETED     189     171  
Lack of Efficacy                 45                 15  
Adverse Event                 61                 90  
Protocol Violation                 12                 5  
Lost to Follow-up                 11                 13  
Withdrawal by Subject                 27                 24  
Other reason (not specified)                 33                 24  
[1] Number who started treatment. One patient in the Linagliptin group was randomized but not treated.
[2] Number who started treatment.
[3] Number who completed treatment.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Linagliptin Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride Patients randomized to receive Glimepiride 1-4mg and metformin
Total Total of all reporting groups

Baseline Measures
    Linagliptin     Glimepiride     Total  
Number of Participants  
[units: participants]
  776     775     1551  
Age  
[units: Years]
Mean ± Standard Deviation
  59.8  ± 9.4     59.8  ± 9.4     59.8  ± 9.4  
Gender  
[units: Patients]
     
Female     314     304     618  
Male     462     471     933  
Body mass index (BMI) continuous  
[units: kg/m^2]
Mean ± Standard Deviation
  30.21  ± 4.77     30.31  ± 4.57     30.26  ± 4.67  
Weight  
[units: kg]
Mean ± Standard Deviation
  86.14  ± 17.57     86.77  ± 16.69     86.46  ± 17.14  
Glycosylated haemoglobin (HbA1c) [1]
[units: Percent]
Mean ± Standard Deviation
  7.69  ± 0.88     7.69  ± 0.86     7.69  ± 0.87  
Fasting blood plasma glucose (FPG) [2]
[units: mg/dL]
Mean ± Standard Deviation
  164.46  ± 42.83     166.09  ± 42.05     165.27  ± 42.43  
[1] Baseline HbA1c was available for 1519 patients in the Full Analysis Set (FAS), 764 treated with Linagliptin and 755 patients treated with Glimepiride.
[2] Baseline fasting plasma glucose (FPG) was available for 1475 patients in the FAS, 740 treated with Linagliptin and 735 patients treated with Glimepiride.



  Outcome Measures
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1.  Primary:   HbA1c Change From Baseline at Week 52   [ Time Frame: Baseline and week 52 ]

2.  Primary:   HbA1c Change From Baseline at Week 104   [ Time Frame: Baseline and week 104 ]

3.  Secondary:   Body Weight Change From Baseline at Week 52   [ Time Frame: Baseline and week 52 ]

4.  Secondary:   Body Weight Change From Baseline at Week 104   [ Time Frame: Baseline and week 104 ]

5.  Secondary:   Incidence of Hypoglycaemic Events up to 52 Weeks   [ Time Frame: Week 52 ]

6.  Secondary:   Incidence of Hypoglycaemic Events up to 104 Weeks   [ Time Frame: Week 104 ]

7.  Secondary:   Fasting Plasma Glucose (FPG) Change From Baseline at Week 52   [ Time Frame: Baseline and week 52 ]

8.  Secondary:   Fasting Plasma Glucose (FPG) Change From Baseline at Week 104   [ Time Frame: Baseline and week 104 ]

9.  Secondary:   Percentage of Patients With HbA1c <7.0% at Week 52   [ Time Frame: Week 52 ]

10.  Secondary:   Percentage of Patients With HbA1c <7.0% at Week 104   [ Time Frame: Week 104 ]

11.  Secondary:   Percentage of Patients With HbA1c <6.5% at Week 52   [ Time Frame: Week 52 ]

12.  Secondary:   Percentage of Patients With HbA1c <6.5% at Week 104   [ Time Frame: Week 104 ]

13.  Secondary:   Percentage of Patients With HbA1c Lowering by 0.5% at Week 104   [ Time Frame: Week 104 ]

14.  Secondary:   2 hr Postprandial Glucose (PPG) Change From Baseline at Week 104   [ Time Frame: Baseline and week 104 ]

15.  Secondary:   HbA1c Change at Week 4   [ Time Frame: Baseline and week 4 ]

16.  Secondary:   HbA1c Change at Week 8   [ Time Frame: Baseline and week 8 ]

17.  Secondary:   HbA1c Change at Week 12   [ Time Frame: Baseline and week 12 ]

18.  Secondary:   HbA1c Change at Week 16   [ Time Frame: Baseline and week 16 ]

19.  Secondary:   HbA1c Change at Week 28   [ Time Frame: Baseline and week 28 ]

20.  Secondary:   HbA1c Change at Week 40   [ Time Frame: Baseline and week 40 ]

21.  Secondary:   HbA1c Change at Week 52   [ Time Frame: Baseline and week 52 ]

22.  Secondary:   HbA1c Change at Week 65   [ Time Frame: Baseline and week 65 ]

23.  Secondary:   HbA1c Change at Week 78   [ Time Frame: Baseline and week 78 ]

24.  Secondary:   HbA1c Change at Week 91   [ Time Frame: Baseline and week 91 ]

25.  Secondary:   HbA1c Change at Week 104   [ Time Frame: Baseline and week 104 ]

26.  Secondary:   Change in Baseline Lipid Parameter Cholesterol at Week 104   [ Time Frame: Baseline and week 104 ]

27.  Secondary:   Change in Baseline Lipid Parameter HDL at Week 104   [ Time Frame: Baseline and week 104 ]

28.  Secondary:   Change in Baseline Lipid Parameter Low Density Lipoprotein (LDL) at Week 104   [ Time Frame: Baseline and week 104 ]

29.  Secondary:   Change in Baseline Lipid Parameter Triglyceride at Week 104   [ Time Frame: Baseline and week 104 ]


  Serious Adverse Events
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Time Frame From day of first dose until 7 days after last dose
Additional Description No text entered.

Reporting Groups
  Description
Linagliptin Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride Patients randomized to receive Glimepiride 1-4mg and metformin

Serious Adverse Events
    Linagliptin     Glimepiride  
Total, serious adverse events      
# participants affected / at risk     135/776 (17.40%)     162/775 (20.90%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     3/776 (0.39%)     1/775 (0.13%)  
Iron deficiency anaemia † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Lymphadenopathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Cardiac disorders      
Acute coronary syndrome † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Acute myocardial infarction † 1    
# participants affected / at risk     1/776 (0.13%)     4/775 (0.52%)  
Angina pectoris † 1    
# participants affected / at risk     5/776 (0.64%)     4/775 (0.52%)  
Angina unstable † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Aortic valve disease † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Aortic valve stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Arrhythmia † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Arteriosclerosis coronary artery † 1    
# participants affected / at risk     3/776 (0.39%)     1/775 (0.13%)  
Arteriospasm coronary † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Atrial fibrillation † 1    
# participants affected / at risk     3/776 (0.39%)     2/775 (0.26%)  
Atrial flutter † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Atrioventricular block † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Bradyarrhythmia † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Bradycardia † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Cardiac failure † 1    
# participants affected / at risk     3/776 (0.39%)     2/775 (0.26%)  
Cardio-respiratory arrest † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Congestive cardiomyopathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Coronary artery disease † 1    
# participants affected / at risk     5/776 (0.64%)     6/775 (0.77%)  
Coronary artery stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Ischaemic cardiomyopathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Mitral valve disease mixed † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Myocardial infarction † 1    
# participants affected / at risk     4/776 (0.52%)     6/775 (0.77%)  
Pericarditis constrictive † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Sinoatrial block † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Congenital, familial and genetic disorders      
Central nervous system dermoid tumour † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Hydrocele † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Ear and labyrinth disorders      
Hypoacusis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Vertigo † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Endocrine disorders      
Goitre † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Hyperthyroidism † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Eye disorders      
Cataract † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Glaucoma † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Optic disc haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Optic neuropathy † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Retinal degeneration † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Retinal haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Gastrointestinal disorders      
Abdominal pain upper † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Anal prolapse † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Colitis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Colonic polyp † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Colonic stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Constipation † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Diarrhoea † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Diverticulum intestinal † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Duodenal ulcer haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Gastric polyps † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Gastritis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Gastritis erosive † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Haemorrhoids † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Inguinal hernia † 1    
# participants affected / at risk     0/776 (0.00%)     3/775 (0.39%)  
Intestinal obstruction † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Lip swelling † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Oesophageal food impaction † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Rectal haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Rectal stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Umbilical hernia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
General disorders      
Chest pain † 1    
# participants affected / at risk     2/776 (0.26%)     1/775 (0.13%)  
Drowning † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Fatigue † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Mass † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Medical device complication † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Non-cardiac chest pain † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Sudden cardiac death † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Hepatobiliary disorders      
Cholangitis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Cholecystitis † 1    
# participants affected / at risk     2/776 (0.26%)     2/775 (0.26%)  
Cholelithiasis † 1    
# participants affected / at risk     3/776 (0.39%)     3/775 (0.39%)  
Gallbladder polyp † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Hepatic steatosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Immune system disorders      
Allergy to arthropod bite † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Anaphylactic reaction † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Sarcoidosis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Infections and infestations      
Abdominal infection † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Abscess intestinal † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Abscess limb † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Appendicitis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Arthritis bacterial † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Arthritis infective † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Balanitis candida † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Bronchitis † 1    
# participants affected / at risk     2/776 (0.26%)     1/775 (0.13%)  
Chronic sinusitis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Cystitis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Diverticulitis † 1    
# participants affected / at risk     0/776 (0.00%)     3/775 (0.39%)  
Erysipelas † 1    
# participants affected / at risk     2/776 (0.26%)     2/775 (0.26%)  
Escherichia sepsis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Gangrene † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Gastroenteritis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Klebsiella sepsis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Localised infection † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Lung infection † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Malaria † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Mastitis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Osteomyelitis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Otitis media chronic † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Peritonsillar abscess † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     5/776 (0.64%)     4/775 (0.52%)  
Pulmonary tuberculosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Pyelonephritis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Sepsis † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Sinusitis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Skin infection † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Soft tissue infection † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Subcutaneous abscess † 1    
# participants affected / at risk     0/776 (0.00%)     3/775 (0.39%)  
Tonsillitis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Urinary tract infection † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Injury, poisoning and procedural complications      
Accident † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Ankle fracture † 1    
# participants affected / at risk     2/776 (0.26%)     2/775 (0.26%)  
Arthropod bite † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Avulsion fracture † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Concussion † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Contusion † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Fall † 1    
# participants affected / at risk     3/776 (0.39%)     2/775 (0.26%)  
Femoral neck fracture † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Femoral nerve injury † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Fibula fracture † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Foot fracture † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Humerus fracture † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Joint sprain † 1    
# participants affected / at risk     3/776 (0.39%)     0/775 (0.00%)  
Lumbar vertebral fracture † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Meniscus lesion † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Post procedural complication † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Post procedural discharge † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Post procedural haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Road traffic accident † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Suture related complication † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Tendon rupture † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Ulna fracture † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Upper limb fracture † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Investigations      
Alanine aminotransferase increased † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Blood alkaline phosphatase increased † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Gamma-glutamyltransferase increased † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Metabolism and nutrition disorders      
Dehydration † 1    
# participants affected / at risk     2/776 (0.26%)     1/775 (0.13%)  
Gout † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Hyperglycaemia † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Hypoglycaemia † 1    
# participants affected / at risk     0/776 (0.00%)     3/775 (0.39%)  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     3/776 (0.39%)     2/775 (0.26%)  
Arthritis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Back pain † 1    
# participants affected / at risk     3/776 (0.39%)     0/775 (0.00%)  
Chondropathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Foot deformity † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Intervertebral disc disorder † 1    
# participants affected / at risk     0/776 (0.00%)     3/775 (0.39%)  
Intervertebral disc protrusion † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Musculoskeletal pain † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Osteoarthritis † 1    
# participants affected / at risk     5/776 (0.64%)     6/775 (0.77%)  
Periarthritis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Pseudarthrosis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Rotator cuff syndrome † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Spinal column stenosis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Spinal disorder † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Spinal osteoarthritis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Benign muscle neoplasm † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Breast cancer † 1    
# participants affected / at risk     3/776 (0.39%)     2/775 (0.26%)  
Breast cancer metastatic † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Breast cancer recurrent † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Bronchial carcinoma † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Carcinoid tumour pulmonary † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Cholesteatoma † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Colon cancer † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Endometrial cancer † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Gastrointestinal carcinoma † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Laryngeal cancer † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Metastases to abdominal cavity † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Metastases to bone † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Metastases to central nervous system † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Metastases to liver † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Metastases to lung † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Metastases to lymph nodes † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Metastases to pleura † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Metastatic bronchial carcinoma † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Osteoma † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Ovarian cancer recurrent † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Pancreatic carcinoma † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Pancreatic neoplasm † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Prostate cancer † 1    
# participants affected / at risk     6/776 (0.77%)     3/775 (0.39%)  
Prostatic adenoma † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Rectal cancer † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Renal cancer † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Small cell lung cancer stage unspecified † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Thyroid cancer † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Vulval cancer † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Nervous system disorders      
Agnosia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Amnesia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Carotid artery stenosis † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Cerebral haemorrhage † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Cerebral infarction † 1    
# participants affected / at risk     0/776 (0.00%)     4/775 (0.52%)  
Cerebral ischaemia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Cerebrovascular accident † 1    
# participants affected / at risk     2/776 (0.26%)     6/775 (0.77%)  
Cubital tunnel syndrome † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Diabetic neuropathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Dizziness † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Guillain-Barre syndrome † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Hepatic encephalopathy † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Hydrocephalus † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Hypoaesthesia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Ischaemic stroke † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Monoparesis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Myelopathy † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Nerve compression † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Parkinson's disease † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Sciatica † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Syncope † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Transient global amnesia † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Transient ischaemic attack † 1    
# participants affected / at risk     1/776 (0.13%)     5/775 (0.65%)  
VIIth nerve paralysis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Psychiatric disorders      
Confusional state † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Delirium tremens † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Depression † 1    
# participants affected / at risk     2/776 (0.26%)     2/775 (0.26%)  
Paranoia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Renal and urinary disorders      
Acute prerenal failure † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Calculus ureteric † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Calculus urinary † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Haematuria † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Hydronephrosis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Hypertonic bladder † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Nephrolithiasis † 1    
# participants affected / at risk     2/776 (0.26%)     3/775 (0.39%)  
Renal colic † 1    
# participants affected / at risk     1/776 (0.13%)     4/775 (0.52%)  
Renal failure † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Renal failure acute † 1    
# participants affected / at risk     1/776 (0.13%)     2/775 (0.26%)  
Stress urinary incontinence † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Ureteric stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Urinary incontinence † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Urinary retention † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Reproductive system and breast disorders      
Benign prostatic hyperplasia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Cystocele † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Endometrial hyperplasia † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Endometriosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Haemorrhagic ovarian cyst † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Menorrhagia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Ovarian mass † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Pelvic pain † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Penile curvature † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Postmenopausal haemorrhage † 1    
# participants affected / at risk     2/776 (0.26%)     0/775 (0.00%)  
Prostatism † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Prostatomegaly † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Urogenital prolapse † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Vaginal cyst † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Vaginal discharge † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Respiratory, thoracic and mediastinal disorders      
Asthma † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Chronic obstructive pulmonary disease † 1    
# participants affected / at risk     3/776 (0.39%)     0/775 (0.00%)  
Dyspnoea † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Hydrothorax † 1    
# participants affected / at risk     0/776 (0.00%)     2/775 (0.26%)  
Hypoxia † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Lung disorder † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Nasal septum deviation † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Nasal turbinate hypertrophy † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Pleural effusion † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Pulmonary embolism † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Pulmonary oedema † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Sleep apnoea syndrome † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Skin and subcutaneous tissue disorders      
Decubitus ulcer † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Diabetic ulcer † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Hypertrophic scar † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Pemphigoid † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Surgical and medical procedures      
Coronary artery bypass † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Hip arthroplasty † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Vascular disorders      
Aortic aneurysm † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Arterial occlusive disease † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Arterial stenosis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Blood pressure inadequately controlled † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Deep vein thrombosis † 1    
# participants affected / at risk     1/776 (0.13%)     1/775 (0.13%)  
Hypertensive crisis † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Hypotension † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Peripheral arterial occlusive disease † 1    
# participants affected / at risk     2/776 (0.26%)     2/775 (0.26%)  
Peripheral embolism † 1    
# participants affected / at risk     1/776 (0.13%)     0/775 (0.00%)  
Peripheral vascular disorder † 1    
# participants affected / at risk     0/776 (0.00%)     1/775 (0.13%)  
Events were collected by systematic assessment
1 Term from vocabulary, 13.1




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
With the exception of HbA1c<6.5% and HbA1c<7.0% at Week52, all other endpoints are presented in the Week52 repeated analysis within the final clinical trial report, where discrepancies between interim and final results are also explained.


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