The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
Study Details
Study Description
Brief Summary
The primary objectives of the ORIGIN study were:
-
To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or early type 2 diabetes;
-
To determine whether omega-3 fatty acids can reduce cardiovascular mortality in people with IFG, IGT or early type 2 diabetes.
The secondary objectives of the insulin glargine study were to determine if insulin glargine-mediated normoglycemia can reduce:
-
total mortality (all causes);
-
the risk of diabetic microvascular outcomes;
-
the rate of progression of IGT or IFG to type 2 diabetes.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The ORIGIN study was conducted by the Population Health Research Institute in Hamilton, Ontario (Canada), working in conjunction with the sponsor, and an independent Steering Committee.
Routine visits were to occur at 2, 4, 8, and 16 weeks following randomization, then every four months for the rest of the study, for all participants
The duration of the study was based on the number of events observed (event-driven study) and was originally planned to be 5 years. In 2008-2009 ORIGIN's follow-up was extended by approximately 2 years, because of published literature of completed studies suggesting that a longer period of effective glycemic contrast between treatments might be needed to see an effect on cardiovascular events.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Insulin glargine + omega-3 polyunsaturated fatty acids Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L) One capsule of omega-3 polyunsaturated fatty acids once daily |
Drug: insulin glargine (HOE901)
Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection
Other Names:
Drug: omega-3 polyunsaturated fatty acids (PUFA)
Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration
Other Names:
Device: reusable pen device for insulin injection
Other Names:
|
| Experimental: Insulin glargine + placebo Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L) One capsule of placebo once daily |
Drug: insulin glargine (HOE901)
Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection
Other Names:
Drug: placebo
Matching placebo gelatin capsules (containing olive oil) for oral administration
Device: reusable pen device for insulin injection
Other Names:
|
| Experimental: Standard care + omega-3 polyunsaturated fatty acids • One capsule of omega-3 polyunsaturated fatty acids once daily |
Drug: omega-3 polyunsaturated fatty acids (PUFA)
Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration
Other Names:
|
| Placebo Comparator: Standard care + placebo • One capsule of placebo once daily |
Drug: placebo
Matching placebo gelatin capsules (containing olive oil) for oral administration
|
Outcome Measures
Primary Outcome Measures
- Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke [from randomization until study cut-off date (median duration of follow-up: 6.2 years)]
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.
- Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) [from randomization until study cut-off date (median duration of follow-up: 6.2 years)]
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.
Secondary Outcome Measures
- Total Mortality (All Causes) [from randomization until study cut-off date (median duration of follow-up: 6.2 years)]
Number of deaths due to any cause
- Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) [from randomization until study cut-off date (median duration of follow-up: 6.2 years)]
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]).
- Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG [from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)]
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).
Other Outcome Measures
- Number of Patients With Various Types of Symptomatic Hypoglycemia Events [on-treatment period (median duration of follow-up: 6.2 years)]
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.
- Number of Patients With First Occurrence of Any Type of Cancer [from randomization until study cut-off date (median duration of follow-up: 6.2 years)]
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.
Eligibility Criteria
Criteria
Inclusion criteria:
I1. Individuals with IFG and/or IGT, or early diabetes, as defined below.
Glucose tolerance status was determined by a 75 g oral glucose tolerance test (OGTT) that was performed fasting (ie, no consumption of food or beverage other than water for at least 8 hours) at the time of screening for all candidates who were not known to have diabetes. The qualifying OGTT could be obtained up to 4 weeks prior to screening provided that anti-diabetic therapy (if any) remained unchanged between the qualifying OGTT and the screening visit. Two plasma glucose values were drawn during the OGTT - a fasting value (FPG) and a value drawn two hours after the 75 g oral glucose load was administered (postprandial plasma glucose [PPG]).
- Impaired glucose tolerance (IGT), defined as a PPG value ≥140 and <200 mg/dL (ie, ≥7.8 and <11.1 mmol/L), with a FPG <126 mg/dL (7.0 mmol/L).
OR
- Impaired fasting glucose (IFG), 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]).
OR
-
Early type 2 diabetes, defined as a FPG ≥126 mg/dL (7.0 mmol/L) or a PPG of ≥200 mg/dL (11.1 mmol/L), or a previous diagnosis of diabetes, and either:
-
on no pharmacological treatment (while ambulatory) for at least 10 weeks prior to screening, with screening glycated hemoglobin <150% of the upper limit of normal (ULN) for the laboratory (eg, <9% if the ULN is 6%)
-
or taking one oral antidiabetic drug (OAD) from among sulfonylureas (SU), biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and meglitinides (MGTs) at a stable dose while ambulatory for at least 10 weeks at the time of screening (or for the 10 weeks prior to hospitalization if identified while hospitalized for a CV event), with screening glycated hemoglobin <133% of the ULN for the laboratory (eg, <8% if the ULN is 6%) if taking this medication at half-maximum dose or greater, and glycated hemoglobin <142% of the ULN for the laboratory (eg, <8.5% if the ULN is 6%) if taking this medication at less than half-maximum dose. Individuals taking combination products containing two or more OADs were not eligible.
I2. Men or women aged 50 years and older
I3. At least one of the following CV risk factors:
-
previous myocardial infarction (MI) (≥ 5 days prior to randomization)
-
previous stroke (≥ 5 days prior to randomization)
-
previous coronary, carotid or peripheral arterial revascularization
-
angina with documented ischemic changes (at least 2 mm ST segment depression on electrocardiogram during a Graded Exercise Test [GXT]; or with a cardiac imaging study positive for ischemia); or unstable angina with documented ischemic changes (either ST segment depression of at least 1 mm or an increase in troponin above the normal range but below the range diagnostic for acute myocardial infarction)
-
microalbuminuria or clinical albuminuria (an albumin: creatinine ratio ≥ 30 μg/mg in at least one or timed collection of urine with albumin excretion ≥20 μg/min or ≥30 mg/24 hours or total protein excretion ≥500 mg/24 hours)
-
left ventricular hypertrophy by electrocardiogram or echocardiogram
-
significant stenosis on angiography of coronary, carotid, or lower extremity arteries (ie, 50% or more stenosis)
-
ankle-brachial index < 0.9.
I4. Provision of signed and dated informed consent prior to any study procedures.
I5. Ability and willingness to complete study diaries and questionnaires.
I6. Demonstrated ability to use the self-glucose-monitoring device, and to self-inject insulin prior to randomization.
I7. A negative pregnancy test for all women of childbearing potential (ie, ovulating, pre- menopausal, and not surgically sterile) and the agreement of these women to use a reliable method of birth control to prevent pregnancy during the duration of the study .
I8. Willingness to discontinue prior omega-3 PUFA supplements for the duration of the study.
Exclusion criteria
E1. Type 1 diabetes.
E2. Requiring ambulatory insulin treatment or uncontrolled or symptomatic hyperglycemia that is likely to require the addition of ambulatory insulin therapy or a new antidiabetic agent either before or within 2 weeks after randomization.
E3. Known anti-glutamic acid decarboxylase antibody (anti-GAD Ab) positivity in the past.
E4. Screening glycated hemoglobin ≥150% of the ULN for the laboratory (eg, ≥9% if the ULN is 6%).
E5. Unwillingness to inject insulin or perform self-monitoring of blood glucose.
E6. Nonadherence to the run-in requirement to inject placebo insulin and do capillary glucose monitoring for at least 4 days prior to randomization.
E7. Coronary artery bypass grafting (CABG) either planned at the time of screening, or CABG within the 4 years prior to screening - however, participants with angina, MI, or stroke since a previous CABG will be eligible for randomization, even if the last CABG was within 4 years.
E8. Serum creatinine >2.0 mg/dL (176 μmol/L) at screening.
E9. Active liver disease, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times ULN at screening.
E10. Chronic or recurrent treatment with systemic corticosteroids, or niacin treatment for hyperlipidemia.
E11. Heart failure of New York Heart Association (NYHA) Functional Class III or IV.
E12. Expected survival of <3 years for non-CV causes such as cancer.
E13. Any other factor likely to limit protocol compliance or reporting of adverse events (AEs).
E14. Unwilling or unable to discontinue TZDs.
E15. Simultaneous participation in any other clinical trial of an active pharmacologic agent.
E16. Unwillingness to permit sites to contact their primary physicians to communicate information about the study and the participant's data and treatment assignment.
E17. History of hypersensitivity to the investigational products.
E18. Previous randomization in this study.
E19. A prior heart transplant, or awaiting a heart transplant.
E20. Known infection with human immunodeficiency virus (HIV).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sanofi-Aventis Administrative Office | Bridgewater | New Jersey | United States | 08807 |
| 2 | Sanofi-Aventis Administrative Office | Buenos Aires | Argentina | ||
| 3 | Sanofi-Aventis Administrative Office | Cove | New South Wales | Australia | |
| 4 | Sanofi-Aventis Administrative Office | Vienna | Austria | ||
| 5 | Sanofi-Aventis Administrative Office | Minsk | Belarus | ||
| 6 | Sanofi-Aventis Administrative Office | Hamilton | Bermuda | ||
| 7 | Sanofi-Aventis Administrative Office | Sao Paulo | Brazil | ||
| 8 | Sanofi-Aventis Administrative Office | Laval | Quebec | Canada | |
| 9 | Sanofi-Aventis Administrative Office | Santiago | Chile | ||
| 10 | Sanofi-Aventis Administrative Office | Beijing | China | ||
| 11 | Sanofi-Aventis Administrative Office | Cali | Colombia | ||
| 12 | Sanofi-Aventis Administrative Office | Zagreb | Croatia | ||
| 13 | Sanofi-Aventis Administrative Office | Horsholm | Denmark | ||
| 14 | Sanofi-Aventis Administrative Office | Tatari | Estonia | ||
| 15 | Sanofi-Aventis Administrative Office | Helsinki | Finland | ||
| 16 | Sanofi-Aventis Administrative Office | Paris | France | ||
| 17 | Sanofi-Aventis Administrative Office | Berlin | Germany | ||
| 18 | Sanofi-Aventis Administrative Office | Budapest | Hungary | ||
| 19 | Sanofi-Aventis Administrative Office | Mumbai | India | ||
| 20 | Makati City | Dublin | Ireland | ||
| 21 | Sanofi-Aventis Administrative Office | Netanya | Israel | ||
| 22 | Sanofi-Aventis Administrative Office | Milano | Italy | ||
| 23 | Sanofi-Aventis Administrative Office | Seoul | Korea, Republic of | ||
| 24 | Sanofi-Aventis Administrative Office | Riga | Latvia | ||
| 25 | Sanofi-Aventis Administrative Office | Vilnius | Lithuania | ||
| 26 | Sanofi-Aventis Administrative Office | Mexico | Mexico | ||
| 27 | Sanofi-Aventis Administrative Office | Gouda | Netherlands | ||
| 28 | Sanofi-Aventis Administrative Office | Lysaker | Norway | ||
| 29 | Sanofi-Aventis Administrative Office | Makati City | Philippines | ||
| 30 | Sanofi-Aventis Administrative Office | Warszawa | Poland | ||
| 31 | Sanofi-Aventis Administrative Office | Bucuresti | Romania | ||
| 32 | Sanofi-Aventis Aministrative Office | Moscow | Russian Federation | ||
| 33 | Sanofi-Aventis Administrative Office | Bratislava | Slovakia | ||
| 34 | Sanofi-Aventis Administrative Office | Midrand | South Africa | ||
| 35 | Sanofi-Aventis Administrative Office | Barcelona | Spain | ||
| 36 | Sanofi-Aventis Administrative Office | Bromma | Sweden | ||
| 37 | Sanofi-Aventis Administrative Office | Geneva | Switzerland | ||
| 38 | Sanofi-Aventis Administrative Office | Istanbul | Turkey | ||
| 39 | Sanofi-Aventis Administrative Office | Guildford | Surrey | United Kingdom | |
| 40 | Makati City | Caracas | Venezuela |
Sponsors and Collaborators
- Sanofi
- Population Health Research Institute
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
- Principal Investigator: Hertzel Gerstein, M.D., McMaster University and Hamilton Health Sciences
- Principal Investigator: Salim Yusuf, M.D., McMaster University and Hamilton Health Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
- Badings EA, Dyal L, Schoterman L, Lok DJ, Stoel I, Gerding MN, Gerstein HC, Tijssen JG. Strategies to detect abnormal glucose metabolism in people at high risk of cardiovascular disease from the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial population. J Diabetes. 2011 Sep;3(3):232-7. doi: 10.1111/j.1753-0407.2011.00124.x.
- Hanefeld M, Koehler C, Hoffmann C, Wilhelm K, Kamke W, Gerstein H. Effect of targeting normal fasting glucose levels with basal insulin glargine on glycaemic variability and risk of hypoglycaemia: a randomized, controlled study in patients with early Type 2 diabetes. Diabet Med. 2010 Feb;27(2):175-80. doi: 10.1111/j.1464-5491.2009.02915.x.
- Origin Trial Investigators, Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J. 2008 Jan;155(1):26-32, 32.e1-6. Epub 2007 Nov 26.
- Ramachandran A, Riddle MC, Kabali C, Gerstein HC; ORIGIN Investigators. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care. 2012 Apr;35(4):749-53. doi: 10.2337/dc11-1918. Epub 2012 Feb 8.
- LTS6035
- HOE901/4032
Study Results
Participant Flow
| 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 Detail | 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 |
|---|---|---|
| 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 | 6273 |
| Safety Population (Treated) | 6231 | 6273 |
| COMPLETED | 5052 | 6273 |
| NOT COMPLETED | 1212 | 0 |
Baseline Characteristics
| Arm/Group Title | Insulin Glargine | Standard Care | Total |
|---|---|---|---|
| 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 Participants | 6264 | 6273 | 12537 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
63.5
(7.8)
|
63.5
(7.9)
|
63.5
(7.8)
|
| Sex/Gender, Customized (participants) [Number] | |||
| Male |
4181
66.7%
|
3969
63.3%
|
8150
65%
|
| Female |
2082
33.2%
|
2304
36.7%
|
4386
35%
|
| Missing value |
1
0%
|
0
0%
|
1
0%
|
| Baseline Weight (kg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg] |
83.33
(16.77)
|
83.13
(17.28)
|
83.23
(17.03)
|
| Baseline Body Mass Index (kg/m²) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg/m²] |
29.77
(5.17)
|
29.88
(5.33)
|
29.82
(5.25)
|
| Any previous cardiovascular event (participants) [Number] | |||
| No |
2552
40.7%
|
2607
41.6%
|
5159
41.2%
|
| Yes |
3712
59.3%
|
3666
58.4%
|
7378
58.8%
|
| Diabetes diagnosis at time of screening (participants) [Number] | |||
| IFG and/or IGT |
735
11.7%
|
717
11.4%
|
1452
11.6%
|
| Newly diagnosed diabetic |
365
5.8%
|
395
6.3%
|
760
6.1%
|
| Established diabetes with no OAD treatment |
1414
22.6%
|
1467
23.4%
|
2881
23%
|
| Established diabetes with one OAD treatment |
3748
59.8%
|
3692
58.9%
|
7440
59.3%
|
| Unclear diabetes status |
2
0%
|
2
0%
|
4
0%
|
| Duration of diabetes for established diabetes patients (years) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [years] |
3.50
|
3.50
|
3.50
|
| Glycated Hemoglobin A1c (HbA1c) (percent) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [percent] |
6.41
|
6.40
|
6.40
|
| Fasting Plasma Glucose (mmol/L) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [mmol/L] |
6.94
|
6.90
|
6.94
|
Outcome Measures
| Title | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 6264 | 6273 |
| Participants with a composite endpoint |
1041
16.6%
|
1013
16.1%
|
| Endpoint's composition: CV death |
484
7.7%
|
476
7.6%
|
| Endpoint's composition: nonfatal MI |
297
4.7%
|
282
4.5%
|
| Endpoint's composition: nonfatal stroke |
261
4.2%
|
256
4.1%
|
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 | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| 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. | |
| Title | Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF) |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 6264 | 6273 |
| Participants with a composite endpoint |
1792
28.6%
|
1727
27.5%
|
| Endpoint's composition: CV death |
350
5.6%
|
339
5.4%
|
| Endpoint's composition: nonfatal MI |
257
4.1%
|
238
3.8%
|
| Endpoint's composition: nonfatal stroke |
231
3.7%
|
227
3.6%
|
| Endpoint's composition: revascularization |
763
12.2%
|
717
11.4%
|
| Endpoint's composition: hospitalization for HF |
249
4%
|
259
4.1%
|
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 | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| 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. | |
| Title | Total Mortality (All Causes) |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 6264 | 6273 |
| Number [participants] |
951
15.2%
|
965
15.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Standard Care |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Cox Proportional Hazard |
| Estimated Value | 0.983 | |
| Confidence Interval |
(2-Sided) 95% 0.899 to 1.076 |
|
| Parameter Dispersion |
Type: Value: |
|
| 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. | |
| Title | Composite Diabetic Microvascular Outcome (Kidney or Eye Disease) |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 6264 | 6273 |
| Participants with a composite endpoint |
1323
21.1%
|
1363
21.7%
|
| Endpoint's composition: vitrectomy |
24
0.4%
|
25
0.4%
|
| Endpoint's composition: laser therapy for DR |
57
0.9%
|
67
1.1%
|
| Endpoint's composition: dialysis |
18
0.3%
|
28
0.4%
|
| Endpoint's composition: renal transplant |
0
0%
|
0
0%
|
| Endpoint's composition: serum creatinine doubled |
82
1.3%
|
88
1.4%
|
| Endpoint's composition: death due to renal failure |
4
0.1%
|
3
0%
|
| Endpoint's composition: albuminuria progression |
1153
18.4%
|
1171
18.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Standard Care |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Cox Proportional Hazard |
| Estimated Value | 0.970 | |
| Confidence Interval |
(2-Sided) 95% 0.900 to 1.047 |
|
| Parameter Dispersion |
Type: Value: |
|
| 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. | |
| Title | Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 737 | 719 |
| Number [percentage of patients] |
24.7
|
31.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Standard Care |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.58 to 0.91 |
|
| Parameter Dispersion |
Type: Value: |
|
| 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). | |
| Title | Number of Patients With Various Types of Symptomatic Hypoglycemia Events |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 6231 | 6273 |
| Patients with hypoglycemia events |
3597
57.4%
|
1624
25.9%
|
| Patients with non-severe hypoglycemia |
3533
56.4%
|
1582
25.2%
|
| Patients with confirmed non-severe hypoglycemia |
2581
41.2%
|
904
14.4%
|
| Patients with severe hypoglycemia |
352
5.6%
|
113
1.8%
|
| Title | Number of Patients With First Occurrence of Any Type of Cancer |
|---|---|
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis was based on the intent-to-treat (ITT) population. |
| Arm/Group Title | Insulin Glargine | Standard Care |
|---|---|---|
| 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 |
| Measure Participants | 6264 | 6273 |
| Number [participants] |
559
8.9%
|
561
8.9%
|
Adverse Events
| 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 | ||
| 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 (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Insulin Glargine | Standard Care | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 303/6231 (4.9%) | 232/6273 (3.7%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 1/6231 (0%) | 1/6273 (0%) | ||
| Coagulopathy | 1/6231 (0%) | 0/6273 (0%) | ||
| Hypochromic anaemia | 0/6231 (0%) | 1/6273 (0%) | ||
| Idiopathic thrombocytopenic purpura | 0/6231 (0%) | 1/6273 (0%) | ||
| Lymphadenopathy | 0/6231 (0%) | 1/6273 (0%) | ||
| Cardiac disorders | ||||
| Myocardial infarction | 10/6231 (0.2%) | 9/6273 (0.1%) | ||
| Angina unstable | 9/6231 (0.1%) | 11/6273 (0.2%) | ||
| Acute myocardial infarction | 8/6231 (0.1%) | 4/6273 (0.1%) | ||
| Cardiac failure congestive | 6/6231 (0.1%) | 6/6273 (0.1%) | ||
| Arrhythmia supraventricular | 3/6231 (0%) | 1/6273 (0%) | ||
| Atrial fibrillation | 3/6231 (0%) | 3/6273 (0%) | ||
| Angina pectoris | 2/6231 (0%) | 3/6273 (0%) | ||
| Cardiac arrest | 2/6231 (0%) | 1/6273 (0%) | ||
| Cardiac failure | 2/6231 (0%) | 3/6273 (0%) | ||
| Supraventricular tachycardia | 2/6231 (0%) | 0/6273 (0%) | ||
| Acute coronary syndrome | 1/6231 (0%) | 0/6273 (0%) | ||
| Arrhythmia | 1/6231 (0%) | 0/6273 (0%) | ||
| Bradycardia | 1/6231 (0%) | 1/6273 (0%) | ||
| Ventricular extrasystoles | 1/6231 (0%) | 0/6273 (0%) | ||
| Ventricular fibrillation | 1/6231 (0%) | 0/6273 (0%) | ||
| Ventricular tachycardia | 1/6231 (0%) | 1/6273 (0%) | ||
| Atrioventricular block | 0/6231 (0%) | 3/6273 (0%) | ||
| Atrioventricular block second degree | 0/6231 (0%) | 1/6273 (0%) | ||
| Cardiac disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Coronary artery disease | 0/6231 (0%) | 1/6273 (0%) | ||
| Coronary artery occlusion | 0/6231 (0%) | 1/6273 (0%) | ||
| Myocardial ischaemia | 0/6231 (0%) | 1/6273 (0%) | ||
| Pericardial disease | 0/6231 (0%) | 1/6273 (0%) | ||
| Congenital, familial and genetic disorders | ||||
| Skull malformation | 0/6231 (0%) | 1/6273 (0%) | ||
| Ear and labyrinth disorders | ||||
| Tinnitus | 1/6231 (0%) | 0/6273 (0%) | ||
| Vertigo | 1/6231 (0%) | 1/6273 (0%) | ||
| Inner ear disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Otosclerosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Eye disorders | ||||
| Vitreous haemorrhage | 2/6231 (0%) | 0/6273 (0%) | ||
| Retinal haemorrhage | 1/6231 (0%) | 0/6273 (0%) | ||
| Retinal oedema | 1/6231 (0%) | 0/6273 (0%) | ||
| Visual impairment | 1/6231 (0%) | 0/6273 (0%) | ||
| Blindness | 0/6231 (0%) | 1/6273 (0%) | ||
| Diabetic retinopathy | 0/6231 (0%) | 1/6273 (0%) | ||
| Eversion of lacrimal punctum | 0/6231 (0%) | 1/6273 (0%) | ||
| Retinal vein thrombosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Gastrointestinal disorders | ||||
| Gastrointestinal haemorrhage | 5/6231 (0.1%) | 0/6273 (0%) | ||
| Abdominal pain | 2/6231 (0%) | 0/6273 (0%) | ||
| Pancreatitis | 2/6231 (0%) | 0/6273 (0%) | ||
| Rectal haemorrhage | 2/6231 (0%) | 0/6273 (0%) | ||
| Abdominal pain upper | 1/6231 (0%) | 0/6273 (0%) | ||
| Abdominal strangulated hernia | 1/6231 (0%) | 0/6273 (0%) | ||
| Colitis ulcerative | 1/6231 (0%) | 0/6273 (0%) | ||
| Diarrhoea | 1/6231 (0%) | 1/6273 (0%) | ||
| Duodenal varices | 1/6231 (0%) | 0/6273 (0%) | ||
| Gastric ulcer | 1/6231 (0%) | 0/6273 (0%) | ||
| Gastrointestinal ulcer haemorrhage | 1/6231 (0%) | 0/6273 (0%) | ||
| Oesophagitis | 1/6231 (0%) | 0/6273 (0%) | ||
| Pancreatitis acute | 1/6231 (0%) | 1/6273 (0%) | ||
| Peptic ulcer haemorrhage | 1/6231 (0%) | 0/6273 (0%) | ||
| Abdominal distension | 0/6231 (0%) | 1/6273 (0%) | ||
| Colitis ischaemic | 0/6231 (0%) | 1/6273 (0%) | ||
| Constipation | 0/6231 (0%) | 2/6273 (0%) | ||
| Dyspepsia | 0/6231 (0%) | 1/6273 (0%) | ||
| Gastritis | 0/6231 (0%) | 1/6273 (0%) | ||
| Gastrointestinal ulcer | 0/6231 (0%) | 1/6273 (0%) | ||
| Lower gastrointestinal haemorrhage | 0/6231 (0%) | 1/6273 (0%) | ||
| Pancreatolithiasis | 0/6231 (0%) | 1/6273 (0%) | ||
| Upper gastrointestinal haemorrhage | 0/6231 (0%) | 1/6273 (0%) | ||
| General disorders | ||||
| Death | 11/6231 (0.2%) | 14/6273 (0.2%) | ||
| Chest pain | 6/6231 (0.1%) | 2/6273 (0%) | ||
| Non-cardiac chest pain | 4/6231 (0.1%) | 0/6273 (0%) | ||
| Oedema peripheral | 3/6231 (0%) | 0/6273 (0%) | ||
| Sudden death | 3/6231 (0%) | 1/6273 (0%) | ||
| Cardiac death | 1/6231 (0%) | 1/6273 (0%) | ||
| Device failure | 1/6231 (0%) | 0/6273 (0%) | ||
| Pyrexia | 1/6231 (0%) | 0/6273 (0%) | ||
| Sudden cardiac death | 1/6231 (0%) | 1/6273 (0%) | ||
| Hernia obstructive | 0/6231 (0%) | 1/6273 (0%) | ||
| Hepatobiliary disorders | ||||
| Cholelithiasis | 2/6231 (0%) | 1/6273 (0%) | ||
| Hepatic cirrhosis | 1/6231 (0%) | 0/6273 (0%) | ||
| Hepatitis | 1/6231 (0%) | 0/6273 (0%) | ||
| Cholecystitis | 0/6231 (0%) | 1/6273 (0%) | ||
| Cholecystitis acute | 0/6231 (0%) | 2/6273 (0%) | ||
| Hepatitis toxic | 0/6231 (0%) | 1/6273 (0%) | ||
| Liver disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Immune system disorders | ||||
| Drug hypersensitivity | 2/6231 (0%) | 0/6273 (0%) | ||
| Hypersensitivity | 1/6231 (0%) | 1/6273 (0%) | ||
| Infections and infestations | ||||
| Pneumonia | 5/6231 (0.1%) | 6/6273 (0.1%) | ||
| Gastroenteritis | 2/6231 (0%) | 3/6273 (0%) | ||
| Sepsis | 2/6231 (0%) | 0/6273 (0%) | ||
| Urinary tract infection | 2/6231 (0%) | 1/6273 (0%) | ||
| Abdominal abscess | 1/6231 (0%) | 0/6273 (0%) | ||
| Anal abscess | 1/6231 (0%) | 0/6273 (0%) | ||
| Diverticulitis | 1/6231 (0%) | 0/6273 (0%) | ||
| Herpes zoster | 1/6231 (0%) | 0/6273 (0%) | ||
| Infective exacerbation of chronic obstructive airways disease | 1/6231 (0%) | 0/6273 (0%) | ||
| Respiratory tract infection | 1/6231 (0%) | 0/6273 (0%) | ||
| Bronchitis | 0/6231 (0%) | 4/6273 (0.1%) | ||
| Cellulitis | 0/6231 (0%) | 1/6273 (0%) | ||
| H1N1 influenza | 0/6231 (0%) | 1/6273 (0%) | ||
| Pseudomonas infection | 0/6231 (0%) | 1/6273 (0%) | ||
| Rectal abscess | 0/6231 (0%) | 1/6273 (0%) | ||
| Wound infection | 0/6231 (0%) | 1/6273 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Accidental overdose | 5/6231 (0.1%) | 0/6273 (0%) | ||
| Fracture | 3/6231 (0%) | 3/6273 (0%) | ||
| Toxicity to various agents | 2/6231 (0%) | 1/6273 (0%) | ||
| Intentional overdose | 1/6231 (0%) | 0/6273 (0%) | ||
| Radius fracture | 1/6231 (0%) | 0/6273 (0%) | ||
| Splenic rupture | 1/6231 (0%) | 0/6273 (0%) | ||
| Subdural haematoma | 1/6231 (0%) | 1/6273 (0%) | ||
| Wrist fracture | 1/6231 (0%) | 0/6273 (0%) | ||
| Fall | 0/6231 (0%) | 1/6273 (0%) | ||
| Gun shot wound | 0/6231 (0%) | 1/6273 (0%) | ||
| Hip fracture | 0/6231 (0%) | 1/6273 (0%) | ||
| Joint dislocation | 0/6231 (0%) | 1/6273 (0%) | ||
| Meniscus lesion | 0/6231 (0%) | 1/6273 (0%) | ||
| Overdose | 0/6231 (0%) | 1/6273 (0%) | ||
| Tendon injury | 0/6231 (0%) | 1/6273 (0%) | ||
| Upper limb fracture | 0/6231 (0%) | 1/6273 (0%) | ||
| Investigations | ||||
| Arteriogram coronary | 4/6231 (0.1%) | 1/6273 (0%) | ||
| Weight increased | 2/6231 (0%) | 0/6273 (0%) | ||
| Arteriogram carotid | 1/6231 (0%) | 0/6273 (0%) | ||
| Biopsy lymph gland | 1/6231 (0%) | 0/6273 (0%) | ||
| Colonoscopy | 1/6231 (0%) | 0/6273 (0%) | ||
| Diagnostic procedure | 1/6231 (0%) | 0/6273 (0%) | ||
| Ureteroscopy | 1/6231 (0%) | 0/6273 (0%) | ||
| Cystoscopy | 0/6231 (0%) | 1/6273 (0%) | ||
| Investigation | 0/6231 (0%) | 1/6273 (0%) | ||
| Liver function test abnormal | 0/6231 (0%) | 1/6273 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Hypoglycaemia | 36/6231 (0.6%) | 15/6273 (0.2%) | ||
| Hypoglycaemic unconsciousness | 21/6231 (0.3%) | 0/6273 (0%) | ||
| Hypoglycaemic seizure | 7/6231 (0.1%) | 0/6273 (0%) | ||
| Hyperglycaemia | 2/6231 (0%) | 0/6273 (0%) | ||
| Hypertriglyceridaemia | 1/6231 (0%) | 0/6273 (0%) | ||
| Hypokalaemia | 1/6231 (0%) | 0/6273 (0%) | ||
| Lactic acidosis | 1/6231 (0%) | 0/6273 (0%) | ||
| Cachexia | 0/6231 (0%) | 1/6273 (0%) | ||
| Diabetic foot | 0/6231 (0%) | 1/6273 (0%) | ||
| Shock hypoglycaemic | 0/6231 (0%) | 1/6273 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthritis | 1/6231 (0%) | 0/6273 (0%) | ||
| Muscle spasms | 1/6231 (0%) | 0/6273 (0%) | ||
| Osteoarthritis | 1/6231 (0%) | 1/6273 (0%) | ||
| Osteoporotic fracture | 1/6231 (0%) | 0/6273 (0%) | ||
| Spinal column stenosis | 1/6231 (0%) | 0/6273 (0%) | ||
| Chondrocalcinosis pyrophosphate | 0/6231 (0%) | 1/6273 (0%) | ||
| Lumbar spinal stenosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Osteoporosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Rheumatoid arthritis | 0/6231 (0%) | 1/6273 (0%) | ||
| Spinal disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Spinal osteoarthritis | 0/6231 (0%) | 1/6273 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Lung neoplasm malignant | 4/6231 (0.1%) | 3/6273 (0%) | ||
| Pancreatic carcinoma | 4/6231 (0.1%) | 5/6273 (0.1%) | ||
| Prostate cancer | 4/6231 (0.1%) | 5/6273 (0.1%) | ||
| Adenocarcinoma | 1/6231 (0%) | 1/6273 (0%) | ||
| Adrenal adenoma | 1/6231 (0%) | 0/6273 (0%) | ||
| Basal cell carcinoma | 1/6231 (0%) | 0/6273 (0%) | ||
| Bladder cancer | 1/6231 (0%) | 1/6273 (0%) | ||
| Breast cancer | 1/6231 (0%) | 0/6273 (0%) | ||
| Chronic lymphocytic leukaemia | 1/6231 (0%) | 0/6273 (0%) | ||
| Colon cancer | 1/6231 (0%) | 2/6273 (0%) | ||
| Colon neoplasm | 1/6231 (0%) | 0/6273 (0%) | ||
| Colorectal cancer | 1/6231 (0%) | 0/6273 (0%) | ||
| Endometrial cancer | 1/6231 (0%) | 0/6273 (0%) | ||
| Gastric cancer | 1/6231 (0%) | 1/6273 (0%) | ||
| Hepatic neoplasm malignant non-resectable | 1/6231 (0%) | 0/6273 (0%) | ||
| Lymphoma | 1/6231 (0%) | 0/6273 (0%) | ||
| Malignant melanoma stage I | 1/6231 (0%) | 0/6273 (0%) | ||
| Multiple myeloma | 1/6231 (0%) | 1/6273 (0%) | ||
| Myelodysplastic syndrome | 1/6231 (0%) | 1/6273 (0%) | ||
| Neoplasm malignant | 1/6231 (0%) | 2/6273 (0%) | ||
| Non-small cell lung cancer | 1/6231 (0%) | 0/6273 (0%) | ||
| Pancreatic neoplasm | 1/6231 (0%) | 0/6273 (0%) | ||
| Pituitary tumour benign | 1/6231 (0%) | 0/6273 (0%) | ||
| Rectosigmoid cancer stage III | 1/6231 (0%) | 0/6273 (0%) | ||
| Renal cell carcinoma | 1/6231 (0%) | 0/6273 (0%) | ||
| Salivary gland neoplasm | 1/6231 (0%) | 0/6273 (0%) | ||
| Transitional cell carcinoma | 1/6231 (0%) | 1/6273 (0%) | ||
| Acute myeloid leukaemia | 0/6231 (0%) | 1/6273 (0%) | ||
| Brain neoplasm | 0/6231 (0%) | 1/6273 (0%) | ||
| Gallbladder cancer | 0/6231 (0%) | 1/6273 (0%) | ||
| Hepatic neoplasm malignant | 0/6231 (0%) | 1/6273 (0%) | ||
| Lymphoproliferative disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Mediastinum neoplasm | 0/6231 (0%) | 1/6273 (0%) | ||
| Metastases to lung | 0/6231 (0%) | 1/6273 (0%) | ||
| Metastatic neoplasm | 0/6231 (0%) | 1/6273 (0%) | ||
| Metastatic squamous cell carcinoma | 0/6231 (0%) | 1/6273 (0%) | ||
| Non-Hodgkin's lymphoma | 0/6231 (0%) | 1/6273 (0%) | ||
| Pseudomyxoma peritonei | 0/6231 (0%) | 1/6273 (0%) | ||
| Rectal cancer | 0/6231 (0%) | 1/6273 (0%) | ||
| Renal cancer | 0/6231 (0%) | 1/6273 (0%) | ||
| Uterine cancer | 0/6231 (0%) | 1/6273 (0%) | ||
| Nervous system disorders | ||||
| Hypoglycaemic coma | 18/6231 (0.3%) | 2/6273 (0%) | ||
| Cerebrovascular accident | 8/6231 (0.1%) | 5/6273 (0.1%) | ||
| Syncope | 4/6231 (0.1%) | 1/6273 (0%) | ||
| Cerebral haemorrhage | 3/6231 (0%) | 0/6273 (0%) | ||
| Grand mal convulsion | 2/6231 (0%) | 0/6273 (0%) | ||
| Cerebral infarction | 1/6231 (0%) | 1/6273 (0%) | ||
| Cranial nerve palsies multiple | 1/6231 (0%) | 0/6273 (0%) | ||
| Dementia | 1/6231 (0%) | 3/6273 (0%) | ||
| Dizziness | 1/6231 (0%) | 0/6273 (0%) | ||
| Ischaemic cerebral infarction | 1/6231 (0%) | 0/6273 (0%) | ||
| Neurological symptom | 1/6231 (0%) | 0/6273 (0%) | ||
| Subarachnoid haemorrhage | 1/6231 (0%) | 0/6273 (0%) | ||
| VIIth nerve paralysis | 1/6231 (0%) | 0/6273 (0%) | ||
| Cerebral artery embolism | 0/6231 (0%) | 1/6273 (0%) | ||
| Cerebrovascular disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Cognitive disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Convulsion | 0/6231 (0%) | 1/6273 (0%) | ||
| Diabetic neuropathy | 0/6231 (0%) | 2/6273 (0%) | ||
| Haemorrhagic stroke | 0/6231 (0%) | 1/6273 (0%) | ||
| Ischaemic stroke | 0/6231 (0%) | 2/6273 (0%) | ||
| Lumbar radiculopathy | 0/6231 (0%) | 1/6273 (0%) | ||
| Neuropathy peripheral | 0/6231 (0%) | 1/6273 (0%) | ||
| Polyneuropathy | 0/6231 (0%) | 1/6273 (0%) | ||
| Transient ischaemic attack | 0/6231 (0%) | 3/6273 (0%) | ||
| Psychiatric disorders | ||||
| Abnormal behaviour | 1/6231 (0%) | 0/6273 (0%) | ||
| Hypomania | 1/6231 (0%) | 0/6273 (0%) | ||
| Major depression | 1/6231 (0%) | 1/6273 (0%) | ||
| Confusional state | 0/6231 (0%) | 1/6273 (0%) | ||
| Renal and urinary disorders | ||||
| Nephrolithiasis | 2/6231 (0%) | 0/6273 (0%) | ||
| Renal failure | 2/6231 (0%) | 1/6273 (0%) | ||
| Urinary tract obstruction | 2/6231 (0%) | 0/6273 (0%) | ||
| Haematuria | 1/6231 (0%) | 0/6273 (0%) | ||
| Renal failure acute | 1/6231 (0%) | 2/6273 (0%) | ||
| Nephropathy | 0/6231 (0%) | 1/6273 (0%) | ||
| Renal failure chronic | 0/6231 (0%) | 1/6273 (0%) | ||
| Ureteric obstruction | 0/6231 (0%) | 1/6273 (0%) | ||
| Urethral stenosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Urinary retention | 0/6231 (0%) | 2/6273 (0%) | ||
| Reproductive system and breast disorders | ||||
| Postmenopausal haemorrhage | 1/6231 (0%) | 0/6273 (0%) | ||
| Prostatism | 1/6231 (0%) | 0/6273 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Chronic obstructive pulmonary disease | 4/6231 (0.1%) | 2/6273 (0%) | ||
| Acute pulmonary oedema | 1/6231 (0%) | 0/6273 (0%) | ||
| Asphyxia | 1/6231 (0%) | 0/6273 (0%) | ||
| Epistaxis | 1/6231 (0%) | 4/6273 (0.1%) | ||
| Pleural effusion | 1/6231 (0%) | 0/6273 (0%) | ||
| Pulmonary oedema | 1/6231 (0%) | 1/6273 (0%) | ||
| Respiratory failure | 1/6231 (0%) | 1/6273 (0%) | ||
| Acute respiratory failure | 0/6231 (0%) | 1/6273 (0%) | ||
| Bronchospasm | 0/6231 (0%) | 1/6273 (0%) | ||
| Pulmonary embolism | 0/6231 (0%) | 1/6273 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Diabetic ulcer | 1/6231 (0%) | 1/6273 (0%) | ||
| Erythema | 1/6231 (0%) | 0/6273 (0%) | ||
| Erythema multiforme | 1/6231 (0%) | 0/6273 (0%) | ||
| Ecchymosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Surgical and medical procedures | ||||
| Cardiac pacemaker insertion | 2/6231 (0%) | 1/6273 (0%) | ||
| Coronary artery bypass | 2/6231 (0%) | 1/6273 (0%) | ||
| Cholecystostomy | 1/6231 (0%) | 0/6273 (0%) | ||
| Hip arthroplasty | 1/6231 (0%) | 0/6273 (0%) | ||
| Intestinal resection | 1/6231 (0%) | 0/6273 (0%) | ||
| Urethral dilation procedure | 1/6231 (0%) | 0/6273 (0%) | ||
| Vitrectomy | 1/6231 (0%) | 0/6273 (0%) | ||
| Abdominal hernia repair | 0/6231 (0%) | 1/6273 (0%) | ||
| Angioplasty | 0/6231 (0%) | 1/6273 (0%) | ||
| Cholecystectomy | 0/6231 (0%) | 1/6273 (0%) | ||
| Colporrhaphy | 0/6231 (0%) | 1/6273 (0%) | ||
| Hospitalisation | 0/6231 (0%) | 1/6273 (0%) | ||
| Parotidectomy | 0/6231 (0%) | 1/6273 (0%) | ||
| Percutaneous coronary intervention | 0/6231 (0%) | 1/6273 (0%) | ||
| Vascular disorders | ||||
| Hypotension | 3/6231 (0%) | 0/6273 (0%) | ||
| Aortic aneurysm | 1/6231 (0%) | 0/6273 (0%) | ||
| Embolism | 1/6231 (0%) | 0/6273 (0%) | ||
| Femoral artery occlusion | 1/6231 (0%) | 0/6273 (0%) | ||
| Hypertension | 1/6231 (0%) | 3/6273 (0%) | ||
| Hypertensive emergency | 1/6231 (0%) | 0/6273 (0%) | ||
| Iliac artery stenosis | 1/6231 (0%) | 0/6273 (0%) | ||
| Intermittent claudication | 1/6231 (0%) | 1/6273 (0%) | ||
| Ischaemia | 1/6231 (0%) | 0/6273 (0%) | ||
| Accelerated hypertension | 0/6231 (0%) | 1/6273 (0%) | ||
| Arterial occlusive disease | 0/6231 (0%) | 1/6273 (0%) | ||
| Deep vein thrombosis | 0/6231 (0%) | 1/6273 (0%) | ||
| Orthostatic hypotension | 0/6231 (0%) | 1/6273 (0%) | ||
| Peripheral vascular disorder | 0/6231 (0%) | 1/6273 (0%) | ||
| Thrombosis | 0/6231 (0%) | 1/6273 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Insulin Glargine | Standard Care | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6231 (0%) | 0/6273 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
"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 |
| Phone | |
| Contact_US@sanofi.com |
- LTS6035
- HOE901/4032