The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

Phase 3

Completed

Conditions: Diabetes Mellitus, Non-Insulin-Dependent

Interventions: Drug: insulin glargine (HOE901)
Drug: omega-3 polyunsaturated fatty acids (PUFA)
Drug: placebo
Device: reusable pen device for insulin injection

Registration Number: NCT00069784

Lead Sponsor: Sanofi

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12537

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Insulin glargine + omega-3 polyunsaturated fatty acids	omega-3 polyunsaturated fatty acids (PUFA)	* 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 + omega-3 polyunsaturated fatty acids	insulin glargine (HOE901)	* 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	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
Insulin glargine + omega-3 polyunsaturated fatty acids	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	insulin glargine (HOE901)	* 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
Insulin glargine + placebo	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
Standard care + omega-3 polyunsaturated fatty acids	omega-3 polyunsaturated fatty acids (PUFA)	• One capsule of omega-3 polyunsaturated fatty acids once daily
Standard care + placebo	placebo	• One capsule of placebo once daily

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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).

Trial Locations

Locations (3): Makati City
🇻🇪
Caracas, Venezuela
Sanofi-Aventis Administrative Office
🇬🇧
Guildford, Surrey, United Kingdom
Sanofi-Aventis Aministrative Office
🇷🇺
Moscow, Russian Federation