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

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ClinicalTrials.gov Identifier: NCT00069784
Recruitment Status : Completed
First Posted : October 6, 2003
Results First Posted : January 25, 2013
Last Update Posted : January 31, 2013
Sponsor:
Collaborator:
Population Health Research Institute
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Factorial Assignment;   Masking: None (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
Enrollment 12537
Recruitment Details 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 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.
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids Standard care with or without omega-3 polyunsaturated fatty acids
Period Title: Overall Study
Started 6264 [1] 6273 [1]
Safety Population (Treated) 6231 [2] 6273 [3]
Completed 5052 [4] 6273 [5]
Not Completed 1212 0
Reason Not Completed
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)
Arm/Group Title Insulin Glargine Standard Care Total
Hide Arm/Group Description Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids Standard care with or without omega-3 polyunsaturated fatty acids Total of all reporting groups
Overall Number of Baseline Participants 6264 6273 12537
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6264 participants 6273 participants 12537 participants
63.5  (7.8) 63.5  (7.9) 63.5  (7.8)
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6264 participants 6273 participants 12537 participants
Male 4181 3969 8150
Female 2082 2304 4386
Missing value 1 0 1
Baseline Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 6264 participants 6273 participants 12537 participants
83.33  (16.77) 83.13  (17.28) 83.23  (17.03)
[1]
Measure Description: Due to missing values, N=6256 for insulin glargine and N=6271 for standard care.
Baseline Body Mass Index   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m²
Number Analyzed 6264 participants 6273 participants 12537 participants
29.77  (5.17) 29.88  (5.33) 29.82  (5.25)
[1]
Measure Description: Due to missing values, N=6251 for insulin glargine and N=6270 for standard care.
Any previous cardiovascular event  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6264 participants 6273 participants 12537 participants
No 2552 2607 5159
Yes 3712 3666 7378
Diabetes diagnosis at time of screening   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6264 participants 6273 participants 12537 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]
Measure Description:

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] 
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 6264 participants 6273 participants 12537 participants
3.50
(1.50 to 7.50)
3.50
(1.50 to 7.50)
3.50
(1.50 to 7.50)
[1]
Measure Description: 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] 
Median (Inter-Quartile Range)
Unit of measure:  Percent
Number Analyzed 6264 participants 6273 participants 12537 participants
6.41
(5.81 to 7.18)
6.40
(5.81 to 7.16)
6.40
(5.81 to 7.18)
[1]
Measure Description: Due to missing values, N=6175 for insulin glargine and N=6189 for standard care.
Fasting Plasma Glucose   [1] 
Median (Inter-Quartile Range)
Unit of measure:  mmol/L
Number Analyzed 6264 participants 6273 participants 12537 participants
6.94
(6.05 to 8.20)
6.90
(6.00 to 8.20)
6.94
(6.05 to 8.20)
[1]
Measure Description: Due to missing values, N=6248 for insulin glargine and N=6266 for standard care.
1.Primary Outcome
Title Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Hide Description

Number of participants with a first occurrence of one of the above events.

The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants.

Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of CV death, nonfatal MI or nonfatal stroke) is provided in the first row of the statistical table.

Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description

The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.

For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.

Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6264 6273
Measure Type: Number
Unit of Measure: participants
Participants with a composite endpoint 1041 1013
Endpoint's composition: CV death 484 476
Endpoint's composition: nonfatal MI 297 282
Endpoint's composition: nonfatal stroke 261 256
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine, Standard Care
Comments The total required number of first coprimary outcomes (2200) assumed that a hazard reduction of 14-16% was clinically significant and controlled the overall experiment-wise Type 1 error at 5% with a power of 80% for each outcome. The total number of participants needed to achieve this number of events within the planned enrollment and treatment periods was ultimately estimated to be 12 500 based on the CURE and HOPE study databases.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6273
Comments For the analysis of the two coprimary efficacy outcomes, the overall Type 1 error was partitioned. The first coprimary outcome was tested at 4.4%, whereas the second coprimary outcome was tested at 1% (weighted Hochberg procedure).
Method Log Rank
Comments Log-rank test stratified by double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.022
Confidence Interval (2-Sided) 95%
0.937 to 1.114
Estimation Comments Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, stratified by double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event.
2.Primary Outcome
Title Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
Hide Description

Number of participants with a first occurrence of one of the above events (revascularization procedures included coronary artery bypass graft, percutaneous transluminal coronary angioplasty (PTCA) i.e. balloon, PTCA with stent, other percutaneous intervention, carotid angioplasty with/without stent, carotid endarterectomy, peripheral angioplasty with or without stent, peripheral vascular surgery, and limb amputation due to vascular disease).

The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants.

Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of the events) is provided in the first row of the statistical table.

Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description

The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.

For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.

Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6264 6273
Measure Type: Number
Unit of Measure: participants
Participants with a composite endpoint 1792 1727
Endpoint's composition: CV death 350 339
Endpoint's composition: nonfatal MI 257 238
Endpoint's composition: nonfatal stroke 231 227
Endpoint's composition: revascularization 763 717
Endpoint's composition: hospitalization for HF 249 259
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine, Standard Care
Comments See above additional details provided for the analysis of the first coprimary outcome.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2692
Comments The second coprimary outcome was tested at 1% (see above additional information for the first coprimary outcome).
Method Log Rank
Comments Log-rank test stratified by double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.038
Confidence Interval (2-Sided) 95%
0.972 to 1.109
Estimation Comments Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, stratified by double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event.
3.Secondary Outcome
Title Total Mortality (All Causes)
Hide Description Number of deaths due to any cause
Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis was based on the intent-to-treat (ITT) population, which was all randomized participants, regardless of compliance with the protocol.
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6264 6273
Measure Type: Number
Unit of Measure: participants
951 965
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine, Standard Care
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.983
Confidence Interval (2-Sided) 95%
0.899 to 1.076
Estimation Comments Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, with double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event as covariates.
4.Secondary Outcome
Title Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
Hide Description

The composite outcome used to analyze microvascular disease progression contained components of clinical events:

  • the occurrence of laser surgery or vitrectomy for diabetic retinopathy (DR);
  • the development of blindness due to DR;
  • the occurrence of renal death or renal replacement therapy; as well as the following laboratory-based events:
  • doubling of serum creatinine; or
  • progression of albuminuria (from none to microalbuminuria [at least 30 mg/g creatinine], to macroalbuminuria [at least 300 mg/g creatinine]).
Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description

The analysis was based on the intent-to-treat (ITT) population i.e. all randomized participants.

For the endpoint's composition, the numbers only summarize the event when it was the first occurrence of the endpoint. A participant is counted only once within a category. The same participant may appear in different categories.

Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6264 6273
Measure Type: Number
Unit of Measure: participants
Participants with a composite endpoint 1323 1363
Endpoint's composition: vitrectomy 24 25
Endpoint's composition: laser therapy for DR 57 67
Endpoint's composition: dialysis 18 28
Endpoint's composition: renal transplant 0 0
Endpoint's composition: serum creatinine doubled 82 88
Endpoint's composition: death due to renal failure 4 3
Endpoint's composition: albuminuria progression 1153 1171
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine, Standard Care
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.970
Confidence Interval (2-Sided) 95%
0.900 to 1.047
Estimation Comments Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, with double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event as covariates.
5.Secondary Outcome
Title Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
Hide Description The incidence was determined by calculating the proportion of randomized participants without diabetes at randomization who either developed diabetes during the study or who were classified as having possible diabetes based on results of two oral glucose tolerance tests (OGTT) performed after the last follow-up visit (within 21-28 days for OGTT#1 and within 10-14 weeks for OGTT#2).
Time Frame from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis was based on the subgroup of the intent-to-treat (ITT) population without diabetes at randomization.
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 737 719
Measure Type: Number
Unit of Measure: percentage of patients
24.7 31.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine, Standard Care
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.58 to 0.91
Estimation Comments Odds ratio estimated using Cochran-Mantel-Haenszel (CMH) test method stratified by double-blind treatment (omega-3 PUFA or placebo) and previous cardiovascular event (yes or no).
6.Other Pre-specified Outcome
Title Number of Patients With Various Types of Symptomatic Hypoglycemia Events
Hide Description

Symptomatic hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia, based on data recorded in the participant’s diary. These were further categorized as confirmed (ie, with a concomitant home glucose reading ≤54 mg/dL [≤3.0 mmol/L]) or unconfirmed.

Severe hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following:

  • the event was associated with a documented self-measured or laboratory plasma glucose level ≤36 mg/dL (≤2.0 mmol/L), or
  • the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.
Time Frame on-treatment period (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The population analyzed was the safety population consisting of all randomized and treated patients (who received at least one dose of study drug) for the insulin glargine group and of all randomized patients for the standard care group.
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6231 6273
Measure Type: Number
Unit of Measure: participants
Patients with hypoglycemia events 3597 1624
Patients with non-severe hypoglycemia 3533 1582
Patients with confirmed non-severe hypoglycemia 2581 904
Patients with severe hypoglycemia 352 113
7.Other Pre-specified Outcome
Title Number of Patients With First Occurrence of Any Type of Cancer
Hide Description Data on cancers that occurred in association with hospitalizations were collected systematically in both groups from the start of the study. All reported cancers occurring during the trial (new or recurrent) were adjudicated by the Event Adjudication Committee.
Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis was based on the intent-to-treat (ITT) population.
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description:
Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard care with or without omega-3 polyunsaturated fatty acids
Overall Number of Participants Analyzed 6264 6273
Measure Type: Number
Unit of Measure: participants
559 561
Time Frame Adverse events (AEs) were assessed through the study. The median duration of follow-up was 6.2 years.
Adverse Event Reporting 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.
 
Arm/Group Title Insulin Glargine Standard Care
Hide Arm/Group Description Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids Standard care with or without omega-3 polyunsaturated fatty acids
All-Cause Mortality
Insulin Glargine Standard Care
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Insulin Glargine Standard Care
Affected / at Risk (%) Affected / at Risk (%)
Total   303/6231 (4.86%)   232/6273 (3.70%) 
Blood and lymphatic system disorders     
Anaemia * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Coagulopathy * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hypochromic anaemia * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Idiopathic thrombocytopenic purpura * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Lymphadenopathy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cardiac disorders     
Myocardial infarction * 1  10/6231 (0.16%)  9/6273 (0.14%) 
Angina unstable * 1  9/6231 (0.14%)  11/6273 (0.18%) 
Acute myocardial infarction * 1  8/6231 (0.13%)  4/6273 (0.06%) 
Cardiac failure congestive * 1  6/6231 (0.10%)  6/6273 (0.10%) 
Arrhythmia supraventricular * 1  3/6231 (0.05%)  1/6273 (0.02%) 
Atrial fibrillation * 1  3/6231 (0.05%)  3/6273 (0.05%) 
Angina pectoris * 1  2/6231 (0.03%)  3/6273 (0.05%) 
Cardiac arrest * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Cardiac failure * 1  2/6231 (0.03%)  3/6273 (0.05%) 
Supraventricular tachycardia * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Acute coronary syndrome * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Arrhythmia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Bradycardia * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Ventricular extrasystoles * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Ventricular fibrillation * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Ventricular tachycardia * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Atrioventricular block * 1  0/6231 (0.00%)  3/6273 (0.05%) 
Atrioventricular block second degree * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cardiac disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Coronary artery disease * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Coronary artery occlusion * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Myocardial ischaemia * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Pericardial disease * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Congenital, familial and genetic disorders     
Skull malformation * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Ear and labyrinth disorders     
Tinnitus * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Vertigo * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Inner ear disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Otosclerosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Eye disorders     
Vitreous haemorrhage * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Retinal haemorrhage * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Retinal oedema * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Visual impairment * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Blindness * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Diabetic retinopathy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Eversion of lacrimal punctum * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Retinal vein thrombosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Gastrointestinal disorders     
Gastrointestinal haemorrhage * 1  5/6231 (0.08%)  0/6273 (0.00%) 
Abdominal pain * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Pancreatitis * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Rectal haemorrhage * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Abdominal pain upper * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Abdominal strangulated hernia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Colitis ulcerative * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Diarrhoea * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Duodenal varices * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Gastric ulcer * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Gastrointestinal ulcer haemorrhage * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Oesophagitis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Pancreatitis acute * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Peptic ulcer haemorrhage * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Abdominal distension * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Colitis ischaemic * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Constipation * 1  0/6231 (0.00%)  2/6273 (0.03%) 
Dyspepsia * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Gastritis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Gastrointestinal ulcer * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Lower gastrointestinal haemorrhage * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Pancreatolithiasis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Upper gastrointestinal haemorrhage * 1  0/6231 (0.00%)  1/6273 (0.02%) 
General disorders     
Death * 1  11/6231 (0.18%)  14/6273 (0.22%) 
Chest pain * 1  6/6231 (0.10%)  2/6273 (0.03%) 
Non-cardiac chest pain * 1  4/6231 (0.06%)  0/6273 (0.00%) 
Oedema peripheral * 1  3/6231 (0.05%)  0/6273 (0.00%) 
Sudden death * 1  3/6231 (0.05%)  1/6273 (0.02%) 
Cardiac death * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Device failure * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Pyrexia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Sudden cardiac death * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Hernia obstructive * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Hepatobiliary disorders     
Cholelithiasis * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Hepatic cirrhosis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hepatitis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Cholecystitis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cholecystitis acute * 1  0/6231 (0.00%)  2/6273 (0.03%) 
Hepatitis toxic * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Liver disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Immune system disorders     
Drug hypersensitivity * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Hypersensitivity * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Infections and infestations     
Pneumonia * 1  5/6231 (0.08%)  6/6273 (0.10%) 
Gastroenteritis * 1  2/6231 (0.03%)  3/6273 (0.05%) 
Sepsis * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Urinary tract infection * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Abdominal abscess * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Anal abscess * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Diverticulitis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Herpes zoster * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Respiratory tract infection * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Bronchitis * 1  0/6231 (0.00%)  4/6273 (0.06%) 
Cellulitis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
H1N1 influenza * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Pseudomonas infection * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Rectal abscess * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Wound infection * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Injury, poisoning and procedural complications     
Accidental overdose * 1  5/6231 (0.08%)  0/6273 (0.00%) 
Fracture * 1  3/6231 (0.05%)  3/6273 (0.05%) 
Toxicity to various agents * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Intentional overdose * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Radius fracture * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Splenic rupture * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Subdural haematoma * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Wrist fracture * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Fall * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Gun shot wound * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Hip fracture * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Joint dislocation * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Meniscus lesion * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Overdose * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Tendon injury * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Upper limb fracture * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Investigations     
Arteriogram coronary * 1  4/6231 (0.06%)  1/6273 (0.02%) 
Weight increased * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Arteriogram carotid * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Biopsy lymph gland * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Colonoscopy * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Diagnostic procedure * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Ureteroscopy * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Cystoscopy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Investigation * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Liver function test abnormal * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Metabolism and nutrition disorders     
Hypoglycaemia * 1  36/6231 (0.58%)  15/6273 (0.24%) 
Hypoglycaemic unconsciousness * 1  21/6231 (0.34%)  0/6273 (0.00%) 
Hypoglycaemic seizure * 1  7/6231 (0.11%)  0/6273 (0.00%) 
Hyperglycaemia * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Hypertriglyceridaemia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hypokalaemia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Lactic acidosis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Cachexia * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Diabetic foot * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Shock hypoglycaemic * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Musculoskeletal and connective tissue disorders     
Arthritis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Muscle spasms * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Osteoarthritis * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Osteoporotic fracture * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Spinal column stenosis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Chondrocalcinosis pyrophosphate * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Lumbar spinal stenosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Osteoporosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Rheumatoid arthritis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Spinal disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Spinal osteoarthritis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant * 1  4/6231 (0.06%)  3/6273 (0.05%) 
Pancreatic carcinoma * 1  4/6231 (0.06%)  5/6273 (0.08%) 
Prostate cancer * 1  4/6231 (0.06%)  5/6273 (0.08%) 
Adenocarcinoma * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Adrenal adenoma * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Basal cell carcinoma * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Bladder cancer * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Breast cancer * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Chronic lymphocytic leukaemia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Colon cancer * 1  1/6231 (0.02%)  2/6273 (0.03%) 
Colon neoplasm * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Colorectal cancer * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Endometrial cancer * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Gastric cancer * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Hepatic neoplasm malignant non-resectable * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Lymphoma * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Malignant melanoma stage I * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Multiple myeloma * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Myelodysplastic syndrome * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Neoplasm malignant * 1  1/6231 (0.02%)  2/6273 (0.03%) 
Non-small cell lung cancer * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Pancreatic neoplasm * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Pituitary tumour benign * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Rectosigmoid cancer stage III * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Renal cell carcinoma * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Salivary gland neoplasm * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Transitional cell carcinoma * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Acute myeloid leukaemia * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Brain neoplasm * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Gallbladder cancer * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Hepatic neoplasm malignant * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Lymphoproliferative disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Mediastinum neoplasm * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Metastases to lung * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Metastatic neoplasm * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Metastatic squamous cell carcinoma * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Non-Hodgkin's lymphoma * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Pseudomyxoma peritonei * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Rectal cancer * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Renal cancer * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Uterine cancer * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Nervous system disorders     
Hypoglycaemic coma * 1  18/6231 (0.29%)  2/6273 (0.03%) 
Cerebrovascular accident * 1  8/6231 (0.13%)  5/6273 (0.08%) 
Syncope * 1  4/6231 (0.06%)  1/6273 (0.02%) 
Cerebral haemorrhage * 1  3/6231 (0.05%)  0/6273 (0.00%) 
Grand mal convulsion * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Cerebral infarction * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Cranial nerve palsies multiple * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Dementia * 1  1/6231 (0.02%)  3/6273 (0.05%) 
Dizziness * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Ischaemic cerebral infarction * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Neurological symptom * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Subarachnoid haemorrhage * 1  1/6231 (0.02%)  0/6273 (0.00%) 
VIIth nerve paralysis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Cerebral artery embolism * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cerebrovascular disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cognitive disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Convulsion * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Diabetic neuropathy * 1  0/6231 (0.00%)  2/6273 (0.03%) 
Haemorrhagic stroke * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Ischaemic stroke * 1  0/6231 (0.00%)  2/6273 (0.03%) 
Lumbar radiculopathy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Neuropathy peripheral * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Polyneuropathy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Transient ischaemic attack * 1  0/6231 (0.00%)  3/6273 (0.05%) 
Psychiatric disorders     
Abnormal behaviour * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hypomania * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Major depression * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Confusional state * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Renal and urinary disorders     
Nephrolithiasis * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Renal failure * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Urinary tract obstruction * 1  2/6231 (0.03%)  0/6273 (0.00%) 
Haematuria * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Renal failure acute * 1  1/6231 (0.02%)  2/6273 (0.03%) 
Nephropathy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Renal failure chronic * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Ureteric obstruction * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Urethral stenosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Urinary retention * 1  0/6231 (0.00%)  2/6273 (0.03%) 
Reproductive system and breast disorders     
Postmenopausal haemorrhage * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Prostatism * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease * 1  4/6231 (0.06%)  2/6273 (0.03%) 
Acute pulmonary oedema * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Asphyxia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Epistaxis * 1  1/6231 (0.02%)  4/6273 (0.06%) 
Pleural effusion * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Pulmonary oedema * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Respiratory failure * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Acute respiratory failure * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Bronchospasm * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Pulmonary embolism * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Skin and subcutaneous tissue disorders     
Diabetic ulcer * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Erythema * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Erythema multiforme * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Ecchymosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Surgical and medical procedures     
Cardiac pacemaker insertion * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Coronary artery bypass * 1  2/6231 (0.03%)  1/6273 (0.02%) 
Cholecystostomy * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hip arthroplasty * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Intestinal resection * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Urethral dilation procedure * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Vitrectomy * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Abdominal hernia repair * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Angioplasty * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Cholecystectomy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Colporrhaphy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Hospitalisation * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Parotidectomy * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Percutaneous coronary intervention * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Vascular disorders     
Hypotension * 1  3/6231 (0.05%)  0/6273 (0.00%) 
Aortic aneurysm * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Embolism * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Femoral artery occlusion * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Hypertension * 1  1/6231 (0.02%)  3/6273 (0.05%) 
Hypertensive emergency * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Iliac artery stenosis * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Intermittent claudication * 1  1/6231 (0.02%)  1/6273 (0.02%) 
Ischaemia * 1  1/6231 (0.02%)  0/6273 (0.00%) 
Accelerated hypertension * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Arterial occlusive disease * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Deep vein thrombosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Orthostatic hypotension * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Peripheral vascular disorder * 1  0/6231 (0.00%)  1/6273 (0.02%) 
Thrombosis * 1  0/6231 (0.00%)  1/6273 (0.02%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Insulin Glargine Standard Care
Affected / at Risk (%) Affected / at Risk (%)
Total   0/6231 (0.00%)   0/6273 (0.00%) 
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 Steering Committee will be responsible for preparing summaries of the study results for publication in the medical literature, and will have the right to submit such summaries for publication after a review by the sponsor. In such cases comments from the sponsor to the Steering Committee are to be provided within 15 working days. All comments will be carefully considered by the Steering Committee who nevertheless have the final decision on the content of the manuscript."
Results Point of Contact
Name/Title: Trial Transparency Team
Organization: sanofi
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00069784     History of Changes
Other Study ID Numbers: LTS6035
HOE901/4032 ( Other Identifier: previous Aventis study number )
First Submitted: October 1, 2003
First Posted: October 6, 2003
Results First Submitted: December 18, 2012
Results First Posted: January 25, 2013
Last Update Posted: January 31, 2013