The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

This study has been completed.
Sponsor:
Collaborator:
Population Health Research Institute
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00069784
First received: October 1, 2003
Last updated: January 24, 2013
Last verified: January 2013
Results First Received: December 18, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: 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

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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 Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Participant Flow:   Overall Study
    Insulin Glargine     Standard Care  
STARTED     6264 [1]   6273 [1]
Safety Population (Treated)     6231 [2]   6273 [3]
COMPLETED     5052 [4]   6273 [5]
NOT COMPLETED     1212     0  
Adverse Event                 105                 0  
Withdrawal by Subject                 1090                 0  
Unknown                 17                 0  
[1] randomized participants = intent-to-treat (ITT) population
[2] randomized patients who received at least one dose of insulin glargine
[3] patients randomized to standard care arm
[4] completed study treatment
[5] not applicable (no treatment)



  Baseline Characteristics


  Outcome Measures
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1.  Primary:   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) ]
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Measure Type Primary
Measure Title Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Measure 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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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.


Reporting Groups
  Description
Insulin Glargine Treatment with Insulin Glargine with or without omega-3 polyunsaturated fatty acids
Standard Care Standard care with or without omega-3 polyunsaturated fatty acids

Measured Values
    Insulin Glargine     Standard Care  
Number of Participants Analyzed  
[units: participants]
  6264     6273  
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke  
[units: participants]
   
Participants with a composite endpoint     1041     1013  
Endpoint's composition: CV death     484     476  
Endpoint's composition: nonfatal MI     297     282  
Endpoint's composition: nonfatal stroke     261     256  


Statistical Analysis 1 for Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.6273
Cox Proportional Hazard [4] 1.022
95% Confidence Interval ( 0.937 to 1.114 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Log-rank test stratified by double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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).
[4] Other relevant estimation information:
  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.



2.  Primary:   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) ]

3.  Secondary:   Total Mortality (All Causes)   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]

4.  Secondary:   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) ]

5.  Secondary:   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) ]

6.  Other Pre-specified:   Number of Patients With Various Types of Symptomatic Hypoglycemia Events   [ Time Frame: on-treatment period (median duration of follow-up: 6.2 years) ]

7.  Other Pre-specified:   Number of Patients With First Occurrence of Any Type of Cancer   [ Time Frame: from randomization until study cut-off date (median duration of follow-up: 6.2 years) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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