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The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention) (ORIGIN)

This study has been completed.
Sponsor:
Collaborator:
Population Health Research Institute
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00069784
First received: October 1, 2003
Last updated: January 24, 2013
Last verified: January 2013
Results First Received: December 18, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Non-Insulin-Dependent
Interventions: Drug: insulin glargine (HOE901)
Drug: omega-3 polyunsaturated fatty acids (PUFA)
Drug: placebo
Device: reusable pen device for insulin injection

  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
This study was conducted at 575 sites in 40 countries between August 22, 2003 and December 19, 2011. Three sites were closed and data from these sites were not analyzed following site audits and in compliance with rulings from national health authorities.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The purpose of the factorial design was to efficiently answer two independent scientifically worthwhile questions regarding insulin glargine and omega-3 fatty acids within the context of a single clinical trial. Sample size was determined based on the insulin glargine study objective. Results reported below are those of the insulin glargine study.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Participant Flow:   Overall Study
    Insulin Glargine   Standard Care
STARTED   6264 [1]   6273 [1] 
Safety Population (Treated)   6231 [2]   6273 [3] 
COMPLETED   5052 [4]   6273 [5] 
NOT COMPLETED   1212   0 
Adverse Event                105                0 
Withdrawal by Subject                1090                0 
Other                17                0 
[1] randomized participants = intent-to-treat (ITT) population
[2] randomized patients who received at least one dose of insulin glargine
[3] patients randomized to standard care arm
[4] completed study treatment
[5] not applicable (no 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
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids
Total Total of all reporting groups

Baseline Measures
   Insulin Glargine   Standard Care   Total 
Overall Participants Analyzed 
[Units: Participants]
 6264   6273   12537 
Age 
[Units: Years]
Mean (Standard Deviation)
 63.5  (7.8)   63.5  (7.9)   63.5  (7.8) 
Gender, Customized 
[Units: Participants]
     
Male   4181   3969   8150 
Female   2082   2304   4386 
Missing value   1   0   1 
Baseline Weight [1] 
[Units: Kg]
Mean (Standard Deviation)
 83.33  (16.77)   83.13  (17.28)   83.23  (17.03) 
[1] Due to missing values, N=6256 for insulin glargine and N=6271 for standard care.
Baseline Body Mass Index [1] 
[Units: Kg/m²]
Mean (Standard Deviation)
 29.77  (5.17)   29.88  (5.33)   29.82  (5.25) 
[1] Due to missing values, N=6251 for insulin glargine and N=6270 for standard care.
Any previous cardiovascular event 
[Units: Participants]
     
No   2552   2607   5159 
Yes   3712   3666   7378 
Diabetes diagnosis at time of screening [1] 
[Units: Participants]
     
IFG and/or IGT   735   717   1452 
Newly diagnosed diabetic   365   395   760 
Established diabetes with no OAD treatment   1414   1467   2881 
Established diabetes with one OAD treatment   3748   3692   7440 
Unclear diabetes status   2   2   4 
[1]

IFG = Impaired Fasting Glucose defined as a Postprandial Plasma Glucose (PPG) value ≥140 and <200 mg/dL (ie, ≥7.8 and <11.1 mmol/L), with a Fasting Plasma Glucose (FPG) <126 mg/dL (7.0 mmol/L)

IGT = Impaired Glucose Tolerance defined as an FPG ≥110 and <126 mg/dL (≥6.1 and <7 mmol/L), without diabetes mellitus (PPG must be <200 mg/dL [11.1 mmol/L])

OAD = oral antidiabetic drug

Duration of diabetes for established diabetes patients [1] 
[Units: Years]
Median (Inter-Quartile Range)
 3.50 
 (1.50 to 7.50) 
 3.50 
 (1.50 to 7.50) 
 3.50 
 (1.50 to 7.50) 
[1] Population of patients with established diabetes. Due to missing values, N=5148 for insulin glargine and N=5141 for standard care.
Glycated Hemoglobin A1c (HbA1c) [1] 
[Units: Percent]
Median (Inter-Quartile Range)
 6.41 
 (5.81 to 7.18) 
 6.40 
 (5.81 to 7.16) 
 6.40 
 (5.81 to 7.18) 
[1] Due to missing values, N=6175 for insulin glargine and N=6189 for standard care.
Fasting Plasma Glucose [1] 
[Units: mmol/L]
Median (Inter-Quartile Range)
 6.94 
 (6.05 to 8.20) 
 6.90 
 (6.00 to 8.20) 
 6.94 
 (6.05 to 8.20) 
[1] Due to missing values, N=6248 for insulin glargine and N=6266 for standard care.


  Outcome Measures
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1.  Primary:   Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

2.  Primary:   Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

3.  Secondary:   Total Mortality (All Causes)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

4.  Secondary:   Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

5.  Secondary:   Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG   [ Time Frame: from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years) ]

6.  Other Pre-specified:   Number of Patients With Various Types of Symptomatic Hypoglycemia Events   [ Time Frame: on-treatment period (median duration of follow-up: 6.2 years) ]

7.  Other Pre-specified:   Number of Patients With First Occurrence of Any Type of Cancer   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]


  Serious Adverse Events
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Time Frame Adverse events (AEs) were assessed through the study. The median duration of follow-up was 6.2 years.
Additional Description Aside from hypoglycemia and cancer, serious AEs were only captured if the event was considered related to a study drug. Non-serious AEs were only captured if the event resulted in some modification (suspension, alteration or cessation) in the dose of a study drug. This creates a bias for the comparison between insulin glargine and standard care.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Serious Adverse Events
    Insulin Glargine   Standard Care
Total, serious adverse events     
# participants affected / at risk   303/6231 (4.86%)   232/6273 (3.70%) 
Blood and lymphatic system disorders     
Anaemia * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Coagulopathy * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hypochromic anaemia * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Idiopathic thrombocytopenic purpura * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Lymphadenopathy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cardiac disorders     
Myocardial infarction * 1     
# participants affected / at risk   10/6231 (0.16%)   9/6273 (0.14%) 
Angina unstable * 1     
# participants affected / at risk   9/6231 (0.14%)   11/6273 (0.18%) 
Acute myocardial infarction * 1     
# participants affected / at risk   8/6231 (0.13%)   4/6273 (0.06%) 
Cardiac failure congestive * 1     
# participants affected / at risk   6/6231 (0.10%)   6/6273 (0.10%) 
Arrhythmia supraventricular * 1     
# participants affected / at risk   3/6231 (0.05%)   1/6273 (0.02%) 
Atrial fibrillation * 1     
# participants affected / at risk   3/6231 (0.05%)   3/6273 (0.05%) 
Angina pectoris * 1     
# participants affected / at risk   2/6231 (0.03%)   3/6273 (0.05%) 
Cardiac arrest * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Cardiac failure * 1     
# participants affected / at risk   2/6231 (0.03%)   3/6273 (0.05%) 
Supraventricular tachycardia * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Acute coronary syndrome * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Arrhythmia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Bradycardia * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Ventricular extrasystoles * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Ventricular fibrillation * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Ventricular tachycardia * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Atrioventricular block * 1     
# participants affected / at risk   0/6231 (0.00%)   3/6273 (0.05%) 
Atrioventricular block second degree * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cardiac disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Coronary artery disease * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Coronary artery occlusion * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Myocardial ischaemia * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Pericardial disease * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Congenital, familial and genetic disorders     
Skull malformation * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Ear and labyrinth disorders     
Tinnitus * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Vertigo * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Inner ear disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Otosclerosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Eye disorders     
Vitreous haemorrhage * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Retinal haemorrhage * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Retinal oedema * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Visual impairment * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Blindness * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Diabetic retinopathy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Eversion of lacrimal punctum * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Retinal vein thrombosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Gastrointestinal disorders     
Gastrointestinal haemorrhage * 1     
# participants affected / at risk   5/6231 (0.08%)   0/6273 (0.00%) 
Abdominal pain * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Pancreatitis * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Rectal haemorrhage * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Abdominal pain upper * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Abdominal strangulated hernia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Colitis ulcerative * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Diarrhoea * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Duodenal varices * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Gastric ulcer * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Gastrointestinal ulcer haemorrhage * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Oesophagitis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Pancreatitis acute * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Peptic ulcer haemorrhage * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Abdominal distension * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Colitis ischaemic * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Constipation * 1     
# participants affected / at risk   0/6231 (0.00%)   2/6273 (0.03%) 
Dyspepsia * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Gastritis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Gastrointestinal ulcer * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Lower gastrointestinal haemorrhage * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Pancreatolithiasis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Upper gastrointestinal haemorrhage * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
General disorders     
Death * 1     
# participants affected / at risk   11/6231 (0.18%)   14/6273 (0.22%) 
Chest pain * 1     
# participants affected / at risk   6/6231 (0.10%)   2/6273 (0.03%) 
Non-cardiac chest pain * 1     
# participants affected / at risk   4/6231 (0.06%)   0/6273 (0.00%) 
Oedema peripheral * 1     
# participants affected / at risk   3/6231 (0.05%)   0/6273 (0.00%) 
Sudden death * 1     
# participants affected / at risk   3/6231 (0.05%)   1/6273 (0.02%) 
Cardiac death * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Device failure * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Pyrexia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Sudden cardiac death * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Hernia obstructive * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Hepatobiliary disorders     
Cholelithiasis * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Hepatic cirrhosis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hepatitis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Cholecystitis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cholecystitis acute * 1     
# participants affected / at risk   0/6231 (0.00%)   2/6273 (0.03%) 
Hepatitis toxic * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Liver disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Immune system disorders     
Drug hypersensitivity * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Hypersensitivity * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Infections and infestations     
Pneumonia * 1     
# participants affected / at risk   5/6231 (0.08%)   6/6273 (0.10%) 
Gastroenteritis * 1     
# participants affected / at risk   2/6231 (0.03%)   3/6273 (0.05%) 
Sepsis * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Urinary tract infection * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Abdominal abscess * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Anal abscess * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Diverticulitis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Herpes zoster * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Respiratory tract infection * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Bronchitis * 1     
# participants affected / at risk   0/6231 (0.00%)   4/6273 (0.06%) 
Cellulitis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
H1N1 influenza * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Pseudomonas infection * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Rectal abscess * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Wound infection * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Injury, poisoning and procedural complications     
Accidental overdose * 1     
# participants affected / at risk   5/6231 (0.08%)   0/6273 (0.00%) 
Fracture * 1     
# participants affected / at risk   3/6231 (0.05%)   3/6273 (0.05%) 
Toxicity to various agents * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Intentional overdose * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Radius fracture * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Splenic rupture * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Subdural haematoma * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Wrist fracture * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Fall * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Gun shot wound * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Hip fracture * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Joint dislocation * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Meniscus lesion * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Overdose * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Tendon injury * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Upper limb fracture * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Investigations     
Arteriogram coronary * 1     
# participants affected / at risk   4/6231 (0.06%)   1/6273 (0.02%) 
Weight increased * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Arteriogram carotid * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Biopsy lymph gland * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Colonoscopy * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Diagnostic procedure * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Ureteroscopy * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Cystoscopy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Investigation * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Liver function test abnormal * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Metabolism and nutrition disorders     
Hypoglycaemia * 1     
# participants affected / at risk   36/6231 (0.58%)   15/6273 (0.24%) 
Hypoglycaemic unconsciousness * 1     
# participants affected / at risk   21/6231 (0.34%)   0/6273 (0.00%) 
Hypoglycaemic seizure * 1     
# participants affected / at risk   7/6231 (0.11%)   0/6273 (0.00%) 
Hyperglycaemia * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Hypertriglyceridaemia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hypokalaemia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Lactic acidosis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Cachexia * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Diabetic foot * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Shock hypoglycaemic * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Musculoskeletal and connective tissue disorders     
Arthritis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Muscle spasms * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Osteoarthritis * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Osteoporotic fracture * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Spinal column stenosis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Chondrocalcinosis pyrophosphate * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Lumbar spinal stenosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Osteoporosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Rheumatoid arthritis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Spinal disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Spinal osteoarthritis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant * 1     
# participants affected / at risk   4/6231 (0.06%)   3/6273 (0.05%) 
Pancreatic carcinoma * 1     
# participants affected / at risk   4/6231 (0.06%)   5/6273 (0.08%) 
Prostate cancer * 1     
# participants affected / at risk   4/6231 (0.06%)   5/6273 (0.08%) 
Adenocarcinoma * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Adrenal adenoma * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Basal cell carcinoma * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Bladder cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Breast cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Chronic lymphocytic leukaemia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Colon cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   2/6273 (0.03%) 
Colon neoplasm * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Colorectal cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Endometrial cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Gastric cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Hepatic neoplasm malignant non-resectable * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Lymphoma * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Malignant melanoma stage I * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Multiple myeloma * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Myelodysplastic syndrome * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Neoplasm malignant * 1     
# participants affected / at risk   1/6231 (0.02%)   2/6273 (0.03%) 
Non-small cell lung cancer * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Pancreatic neoplasm * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Pituitary tumour benign * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Rectosigmoid cancer stage III * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Renal cell carcinoma * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Salivary gland neoplasm * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Transitional cell carcinoma * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Acute myeloid leukaemia * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Brain neoplasm * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Gallbladder cancer * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Hepatic neoplasm malignant * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Lymphoproliferative disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Mediastinum neoplasm * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Metastases to lung * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Metastatic neoplasm * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Metastatic squamous cell carcinoma * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Non-Hodgkin's lymphoma * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Pseudomyxoma peritonei * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Rectal cancer * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Renal cancer * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Uterine cancer * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Nervous system disorders     
Hypoglycaemic coma * 1     
# participants affected / at risk   18/6231 (0.29%)   2/6273 (0.03%) 
Cerebrovascular accident * 1     
# participants affected / at risk   8/6231 (0.13%)   5/6273 (0.08%) 
Syncope * 1     
# participants affected / at risk   4/6231 (0.06%)   1/6273 (0.02%) 
Cerebral haemorrhage * 1     
# participants affected / at risk   3/6231 (0.05%)   0/6273 (0.00%) 
Grand mal convulsion * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Cerebral infarction * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Cranial nerve palsies multiple * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Dementia * 1     
# participants affected / at risk   1/6231 (0.02%)   3/6273 (0.05%) 
Dizziness * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Ischaemic cerebral infarction * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Neurological symptom * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Subarachnoid haemorrhage * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
VIIth nerve paralysis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Cerebral artery embolism * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cerebrovascular disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cognitive disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Convulsion * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Diabetic neuropathy * 1     
# participants affected / at risk   0/6231 (0.00%)   2/6273 (0.03%) 
Haemorrhagic stroke * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Ischaemic stroke * 1     
# participants affected / at risk   0/6231 (0.00%)   2/6273 (0.03%) 
Lumbar radiculopathy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Neuropathy peripheral * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Polyneuropathy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Transient ischaemic attack * 1     
# participants affected / at risk   0/6231 (0.00%)   3/6273 (0.05%) 
Psychiatric disorders     
Abnormal behaviour * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hypomania * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Major depression * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Confusional state * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Renal and urinary disorders     
Nephrolithiasis * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Renal failure * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Urinary tract obstruction * 1     
# participants affected / at risk   2/6231 (0.03%)   0/6273 (0.00%) 
Haematuria * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Renal failure acute * 1     
# participants affected / at risk   1/6231 (0.02%)   2/6273 (0.03%) 
Nephropathy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Renal failure chronic * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Ureteric obstruction * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Urethral stenosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Urinary retention * 1     
# participants affected / at risk   0/6231 (0.00%)   2/6273 (0.03%) 
Reproductive system and breast disorders     
Postmenopausal haemorrhage * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Prostatism * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease * 1     
# participants affected / at risk   4/6231 (0.06%)   2/6273 (0.03%) 
Acute pulmonary oedema * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Asphyxia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Epistaxis * 1     
# participants affected / at risk   1/6231 (0.02%)   4/6273 (0.06%) 
Pleural effusion * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Pulmonary oedema * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Respiratory failure * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Acute respiratory failure * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Bronchospasm * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Pulmonary embolism * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Skin and subcutaneous tissue disorders     
Diabetic ulcer * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Erythema * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Erythema multiforme * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Ecchymosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Surgical and medical procedures     
Cardiac pacemaker insertion * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Coronary artery bypass * 1     
# participants affected / at risk   2/6231 (0.03%)   1/6273 (0.02%) 
Cholecystostomy * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hip arthroplasty * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Intestinal resection * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Urethral dilation procedure * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Vitrectomy * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Abdominal hernia repair * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Angioplasty * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Cholecystectomy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Colporrhaphy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Hospitalisation * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Parotidectomy * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Percutaneous coronary intervention * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Vascular disorders     
Hypotension * 1     
# participants affected / at risk   3/6231 (0.05%)   0/6273 (0.00%) 
Aortic aneurysm * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Embolism * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Femoral artery occlusion * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Hypertension * 1     
# participants affected / at risk   1/6231 (0.02%)   3/6273 (0.05%) 
Hypertensive emergency * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Iliac artery stenosis * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Intermittent claudication * 1     
# participants affected / at risk   1/6231 (0.02%)   1/6273 (0.02%) 
Ischaemia * 1     
# participants affected / at risk   1/6231 (0.02%)   0/6273 (0.00%) 
Accelerated hypertension * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Arterial occlusive disease * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Deep vein thrombosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Orthostatic hypotension * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Peripheral vascular disorder * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
Thrombosis * 1     
# participants affected / at risk   0/6231 (0.00%)   1/6273 (0.02%) 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 14.0




  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
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