The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
Condition: Diabetes Mellitus, Non-Insulin-Dependent
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: insulin glargine (HOE901); omega-3 polyunsaturated fatty acids (PUFA); placebo; reusable pen device for insulin injection
Intervention description: Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection; Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration; Matching placebo gelatin capsules (containing olive oil) for oral administration
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Glargine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 12537.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Impaired Fasting Glucose (IFG); Impaired Glucose Tolerance (IGT)

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.
    

Eligibility 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).