Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00069784




Registration number
NCT00069784
Ethics application status
Date submitted
1/10/2003
Date registered
6/10/2003
Date last updated
31/01/2013

Titles & IDs
Public title
The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)
Scientific 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)
Secondary ID [1] 0 0
HOE901/4032
Secondary ID [2] 0 0
LTS6035
Universal Trial Number (UTN)
Trial acronym
ORIGIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus, Non-Insulin-Dependent 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - insulin glargine (HOE901)
Treatment: Drugs - omega-3 polyunsaturated fatty acids (PUFA)
Treatment: Drugs - placebo

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

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

Experimental: Standard care + omega-3 polyunsaturated fatty acids - • One capsule of omega-3 polyunsaturated fatty acids once daily

Placebo comparator: Standard care + placebo - • One capsule of placebo once daily


Treatment: Drugs: insulin glargine (HOE901)
Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection

Treatment: Drugs: omega-3 polyunsaturated fatty acids (PUFA)
Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration

Treatment: Drugs: placebo
Matching placebo gelatin capsules (containing olive oil) for oral administration
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Timepoint [1] 0 0
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Primary outcome [2] 0 0
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
Timepoint [2] 0 0
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Secondary outcome [1] 0 0
Total Mortality (All Causes)
Timepoint [1] 0 0
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Secondary outcome [2] 0 0
Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
Timepoint [2] 0 0
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Secondary outcome [3] 0 0
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
Timepoint [3] 0 0
from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)

Eligibility
Key inclusion 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.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/08/2003
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/12/2011
Sample size
Target
Accrual to date
Final
12537
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Sanofi-Aventis Administrative Office - Cove
Recruitment postcode(s) [1] 0 0
- Cove
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
New Jersey
Country [2] 0 0
Argentina
State/province [2] 0 0
Buenos Aires
Country [3] 0 0
Austria
State/province [3] 0 0
Vienna
Country [4] 0 0
Belarus
State/province [4] 0 0
Minsk
Country [5] 0 0
Bermuda
State/province [5] 0 0
Hamilton
Country [6] 0 0
Brazil
State/province [6] 0 0
Sao Paulo
Country [7] 0 0
Canada
State/province [7] 0 0
Quebec
Country [8] 0 0
Chile
State/province [8] 0 0
Santiago
Country [9] 0 0
China
State/province [9] 0 0
Beijing
Country [10] 0 0
Colombia
State/province [10] 0 0
Cali
Country [11] 0 0
Croatia
State/province [11] 0 0
Zagreb
Country [12] 0 0
Denmark
State/province [12] 0 0
Horsholm
Country [13] 0 0
Estonia
State/province [13] 0 0
Tatari
Country [14] 0 0
Finland
State/province [14] 0 0
Helsinki
Country [15] 0 0
France
State/province [15] 0 0
Paris
Country [16] 0 0
Germany
State/province [16] 0 0
Berlin
Country [17] 0 0
Hungary
State/province [17] 0 0
Budapest
Country [18] 0 0
India
State/province [18] 0 0
Mumbai
Country [19] 0 0
Ireland
State/province [19] 0 0
Dublin
Country [20] 0 0
Israel
State/province [20] 0 0
Netanya
Country [21] 0 0
Italy
State/province [21] 0 0
Milano
Country [22] 0 0
Korea, Republic of
State/province [22] 0 0
Seoul
Country [23] 0 0
Latvia
State/province [23] 0 0
Riga
Country [24] 0 0
Lithuania
State/province [24] 0 0
Vilnius
Country [25] 0 0
Mexico
State/province [25] 0 0
Mexico
Country [26] 0 0
Netherlands
State/province [26] 0 0
Gouda
Country [27] 0 0
Norway
State/province [27] 0 0
Lysaker
Country [28] 0 0
Philippines
State/province [28] 0 0
Makati City
Country [29] 0 0
Poland
State/province [29] 0 0
Warszawa
Country [30] 0 0
Romania
State/province [30] 0 0
Bucuresti
Country [31] 0 0
Russian Federation
State/province [31] 0 0
Moscow
Country [32] 0 0
Slovakia
State/province [32] 0 0
Bratislava
Country [33] 0 0
South Africa
State/province [33] 0 0
Midrand
Country [34] 0 0
Spain
State/province [34] 0 0
Barcelona
Country [35] 0 0
Sweden
State/province [35] 0 0
Bromma
Country [36] 0 0
Switzerland
State/province [36] 0 0
Geneva
Country [37] 0 0
Turkey
State/province [37] 0 0
Istanbul
Country [38] 0 0
United Kingdom
State/province [38] 0 0
Surrey
Country [39] 0 0
Venezuela
State/province [39] 0 0
Caracas

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Sanofi
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Population Health Research Institute
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Sciences & Operations
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents


Results are available at https://clinicaltrials.gov/study/NCT00069784