Diabetes Mellitus, Non-Insulin-DependentPhase 3ORIGINNCT00069784
The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
A Phase 3 study testing insulin glargine (HOE901), omega-3 polyunsaturated fatty acids (PUFA) and reusable pen device for insulin injection in people with Diabetes Mellitus, Non-Insulin-Dependent, run by Sanofi at 40 sites in 40 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Diabetes Mellitus, Non-Insulin-Dependent
- What is being tested?
- insulin glargine (HOE901), omega-3 polyunsaturated fatty acids (PUFA) and reusable pen device for insulin injection
- Type of treatment
- Pill or oral medicine, Injection or infusion, Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12,537 participants
- Where
- 40 sitesin 40 countries
- Study dates
- Aug 2003to Dec 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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.
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- 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).
Trial locations and contacts
40 sites in 40 countries.
40 sites in 40 countries
United States1 site
Sanofi-Aventis Administrative Office
Bridgewater, New Jersey, 08807
Bermuda1 site
Sanofi-Aventis Administrative Office
Hamilton
United Kingdom1 site
Sanofi-Aventis Administrative Office
Guildford, Surrey
About this study
Official title: A Multicenter, International Randomized, 2x2 Factorial Design Study to Evaluate the Effects of Lantus (Insulin Glargine) Versus Standard Care, and of Omega-3 Fatty Acids Versus Placebo, in Reducing Cardiovascular Morbidity and Mortality in High Risk People With Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes Mellitus: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
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.
Read the 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.
- Conditions
- Diabetes Mellitus, Non-Insulin-Dependent
- Being tested
- insulin glargine (HOE901), omega-3 polyunsaturated fatty acids (PUFA), placebo, reusable pen device for insulin injection
- Keywords
- Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT)
- Medical subject headings
- Diabetes Mellitus, Type 2, Glucose Intolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
insulin glargine (HOE901)Drug
Also called Lantus®
Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection
omega-3 polyunsaturated fatty acids (PUFA)Drug
Also called Omacor®
Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration
placeboDrug
Matching placebo gelatin capsules (containing olive oil) for oral administration
reusable pen device for insulin injectionDevice
Also called OptiPen® Pro 1
| Study group | Role | What they receive |
|---|---|---|
| Insulin glargine + omega-3 polyunsaturated fatty acids | Experimental | * 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 Receives: Drug: insulin glargine (HOE901); Drug: omega-3 polyunsaturated fatty acids (PUFA); Device: reusable pen device for insulin injection |
| Insulin glargine + placebo | Experimental | * 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 Receives: Drug: insulin glargine (HOE901); Drug: placebo; Device: reusable pen device for insulin injection |
| Standard care + omega-3 polyunsaturated fatty acids | Experimental | • One capsule of omega-3 polyunsaturated fatty acids once daily Receives: Drug: omega-3 polyunsaturated fatty acids (PUFA) |
| Standard care + placebo | Placebo comparator | • One capsule of placebo once daily Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
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.
Measured: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
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.
Measured: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Secondary outcomes (3)
Total Mortality (All Causes)
Number of deaths due to any cause
Measured: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
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]).
Measured: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
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).
Measured: from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2003 (estimated)
- Study startAug 2003
- Primary completionDec 2011
- Study completionDec 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (38)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Non-Insulin-DependentStudies of the same condition, open and under way.
- More trials run by SanofiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 12,537 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sanofi
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Population Health Research Institute
- Responsible party
- Sponsor
- Investigators
- Clinical Sciences & Operations, Study director, SanofiHertzel Gerstein, M.D., Principal investigator, McMaster University and Hamilton Health SciencesSalim Yusuf, M.D., Principal investigator, McMaster University and Hamilton Health Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00069784
- Sponsor's protocol ID
- LTS6035
- Other IDs
- HOE901/4032
- Acronym
- ORIGIN
- Status last verified
- Jan 2013
- First submitted
- 1 Oct 2003
- Last updated
- 31 Jan 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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. doi: 10.1016/j.ahj.2007.09.009. Epub 2007 Nov 26.
PubMed 18082485Hanefeld 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.
PubMed 20546261Badings 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.
PubMed 21631894Ramachandran 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.
PubMed 22323416ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.
PubMed 22686416ORIGIN Trial Investigators; Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18. doi: 10.1056/NEJMoa1203859. Epub 2012 Jun 11.
PubMed 22686415Lee SF, Ramasundarahettige C, Gerstein HC, McIntyre WF, Eikelboom J, O'Donnell MJ, Zhou Y, Bangdiwala SI, Thabane L. Comparison of total event analysis and first event analysis in relation to heterogeneity in cardiovascular trials. BMC Med Res Methodol. 2025 Jun 9;25(1):159. doi: 10.1186/s12874-025-02593-3.
PubMed 40490702Mohammedi K, Hess S, McQueen M, Pigeyre M, Lee SF, Pare G, Gerstein HC. Determinants of serious health outcome-free status in middle-aged and older people with dysglycaemia: Exploratory analysis of the ORIGIN trial. Diabetes Obes Metab. 2024 Aug;26(8):3272-3280. doi: 10.1111/dom.15654. Epub 2024 May 15.
PubMed 38747213Pigeyre M, Gerstein H, Ahlqvist E, Hess S, Pare G. Identifying blood biomarkers for type 2 diabetes subtyping: a report from the ORIGIN trial. Diabetologia. 2023 Jun;66(6):1045-1051. doi: 10.1007/s00125-023-05887-7. Epub 2023 Mar 1.
PubMed 36854916Cukierman-Yaffe T, Lee SF, Pare G, McQueen M, Hess S, Gerstein HC. Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia: Data from the ORIGIN Trial. J Alzheimers Dis. 2022;87(3):1143-1150. doi: 10.3233/JAD-215195.
PubMed 35431237Shao H, Kianmehr H, Guo J, Li P, Fonseca V, Shi L. Efficacy of iGlarLixi on 5-year risk of diabetes-related complications: A simulation study. J Diabetes Complications. 2022 Mar;36(3):108132. doi: 10.1016/j.jdiacomp.2022.108132. Epub 2022 Jan 25.
PubMed 35101326Pigeyre M, Hess S, Gomez MF, Asplund O, Groop L, Pare G, Gerstein H. Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial. Diabetologia. 2022 Jan;65(1):206-215. doi: 10.1007/s00125-021-05567-4. Epub 2021 Oct 21.
PubMed 34676424Wang A, Gerstein HC, Lee SF, Hess S, Pare G, Ryden L, Mellbin LG. Testosterone and sex hormone-binding globulin in dysglycemic women at high cardiovascular risk: A report from the Outcome Reduction with an Initial Glargine Intervention trial. Diab Vasc Dis Res. 2021 Mar-Apr;18(2):14791641211002475. doi: 10.1177/14791641211002475.
PubMed 33752449Pigeyre M, Sjaarda J, Chong M, Hess S, Bosch J, Yusuf S, Gerstein H, Pare G. ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study. Diabetes Care. 2020 Apr;43(4):835-842. doi: 10.2337/dc19-1973. Epub 2020 Feb 4.
PubMed 32019855Theriault S, Sjaarda J, Chong M, Hess S, Gerstein H, Pare G. Identification of Circulating Proteins Associated With Blood Pressure Using Mendelian Randomization. Circ Genom Precis Med. 2020 Feb;13(1):e002605. doi: 10.1161/CIRCGEN.119.002605. Epub 2020 Jan 12.
PubMed 31928076
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, International Randomized, 2x2 Factorial Design Study to Evaluate the Effects of Lantus (Insulin Glargine) Versus Standard Care, and of Omega-3 Fatty Acids Versus Placebo, in Reducing Cardiovascular Morbidity and Mortality in High Risk People With Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes Mellitus: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
- ClinicalTrials.gov ID
- NCT00069784
- Acronym / sponsor ID
- ORIGIN / LTS6035
- Conditions
- Diabetes Mellitus, Non-Insulin-Dependent
- Keywords
- Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT)
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12,537 participants (actual)
- Lead sponsor
- SanofiIndustry (pharma, biotech, devices)
- Collaborators
- Population Health Research Institute
- Study start
- Aug 2003
- Primary completion
- Dec 2011 (actual)
- Study completion
- Dec 2011 (actual)
- First posted
- 6 Oct 2003 (estimated)
- Results
- Posted 25 Jan 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Insulin glargine + omega-3 polyunsaturated fatty acids | Experimental | Drug: insulin glargine (HOE901), Drug: omega-3 polyunsaturated fatty acids (PUFA), Device: reusable pen device for insulin injection* 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 |
| Insulin glargine + placebo | Experimental | Drug: insulin glargine (HOE901), Drug: placebo, Device: reusable pen device for insulin injection* 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 |
| Standard care + omega-3 polyunsaturated fatty acids | Experimental | Drug: omega-3 polyunsaturated fatty acids (PUFA)• One capsule of omega-3 polyunsaturated fatty acids once daily |
| Standard care + placebo | Placebo comparator | Drug: placebo• One capsule of placebo once daily |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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]).
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| insulin glargine (HOE901)Also: Lantus®Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection | Drug | Insulin glargine + omega-3 polyunsaturated fatty acids, Insulin glargine + placebo |
| omega-3 polyunsaturated fatty acids (PUFA)Also: Omacor®Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration | Drug | Insulin glargine + omega-3 polyunsaturated fatty acids, Standard care + omega-3 polyunsaturated fatty acids |
| placeboMatching placebo gelatin capsules (containing olive oil) for oral administration | Drug | Insulin glargine + placebo, Standard care + placebo |
| reusable pen device for insulin injectionAlso: OptiPen® Pro 1 | Device | Insulin glargine + omega-3 polyunsaturated fatty acids, Insulin glargine + placebo |
Primary outcome
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
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)
Time frame: 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.
3 secondary outcomes
Total Mortality (All Causes)
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
Time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
Time frame: from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18082485Origin 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. doi: 10.1016/j.ahj.2007.09.009. Epub 2007 Nov 26.
- Background: PubMed 20546261Hanefeld 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.
- Background: PubMed 21631894Badings 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.
- Background: PubMed 22323416Ramachandran 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.
- Results publication: PubMed 22686416ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.
- Results publication: PubMed 22686415ORIGIN Trial Investigators; Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18. doi: 10.1056/NEJMoa1203859. Epub 2012 Jun 11.
- Derived from this study: PubMed 40490702Lee SF, Ramasundarahettige C, Gerstein HC, McIntyre WF, Eikelboom J, O'Donnell MJ, Zhou Y, Bangdiwala SI, Thabane L. Comparison of total event analysis and first event analysis in relation to heterogeneity in cardiovascular trials. BMC Med Res Methodol. 2025 Jun 9;25(1):159. doi: 10.1186/s12874-025-02593-3.
- Derived from this study: PubMed 38747213Mohammedi K, Hess S, McQueen M, Pigeyre M, Lee SF, Pare G, Gerstein HC. Determinants of serious health outcome-free status in middle-aged and older people with dysglycaemia: Exploratory analysis of the ORIGIN trial. Diabetes Obes Metab. 2024 Aug;26(8):3272-3280. doi: 10.1111/dom.15654. Epub 2024 May 15.
- Derived from this study: PubMed 36854916Pigeyre M, Gerstein H, Ahlqvist E, Hess S, Pare G. Identifying blood biomarkers for type 2 diabetes subtyping: a report from the ORIGIN trial. Diabetologia. 2023 Jun;66(6):1045-1051. doi: 10.1007/s00125-023-05887-7. Epub 2023 Mar 1.
- Derived from this study: PubMed 35431237Cukierman-Yaffe T, Lee SF, Pare G, McQueen M, Hess S, Gerstein HC. Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia: Data from the ORIGIN Trial. J Alzheimers Dis. 2022;87(3):1143-1150. doi: 10.3233/JAD-215195.
- Derived from this study: PubMed 35101326Shao H, Kianmehr H, Guo J, Li P, Fonseca V, Shi L. Efficacy of iGlarLixi on 5-year risk of diabetes-related complications: A simulation study. J Diabetes Complications. 2022 Mar;36(3):108132. doi: 10.1016/j.jdiacomp.2022.108132. Epub 2022 Jan 25.
- Derived from this study: PubMed 34676424Pigeyre M, Hess S, Gomez MF, Asplund O, Groop L, Pare G, Gerstein H. Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial. Diabetologia. 2022 Jan;65(1):206-215. doi: 10.1007/s00125-021-05567-4. Epub 2021 Oct 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Sciences & Operations study director
Sanofi
Hertzel Gerstein, M.D. principal investigator
McMaster University and Hamilton Health Sciences
Salim Yusuf, M.D. principal investigator
McMaster University and Hamilton Health Sciences
40 sites in 40 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing insulin glargine (HOE901), omega-3 polyunsaturated fatty acids (PUFA) and reusable pen device for insulin injection in people with Diabetes Mellitus, Non-Insulin-Dependent, run by Sanofi at 40 sites in 40 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 40 sites in United States, Argentina, Australia, Austria, Belarus and 35 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jan 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke (time frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00069784, which also lists 38 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2013.