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
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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.
No text entered.

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
Total Total of all reporting groups

Baseline Measures
    Insulin Glargine     Standard Care     Total  
Number of Participants  
[units: participants]
  6264     6273     12537  
Age  
[units: years]
Mean ± Standard Deviation
  63.5  ± 7.8     63.5  ± 7.9     63.5  ± 7.8  
Gender, Customized  
[units: participants]
     
Male     4181     3969     8150  
Female     2082     2304     4386  
Missing value     1     0     1  
Baseline Weight [1]
[units: kg]
Mean ± Standard Deviation
  83.33  ± 16.77     83.13  ± 17.28     83.23  ± 17.03  
Baseline Body Mass Index [2]
[units: kg/m²]
Mean ± Standard Deviation
  29.77  ± 5.17     29.88  ± 5.33     29.82  ± 5.25  
Any previous cardiovascular event  
[units: participants]
     
No     2552     2607     5159  
Yes     3712     3666     7378  
Diabetes diagnosis at time of screening [3]
[units: participants]
     
IFG and/or IGT     735     717     1452  
Newly diagnosed diabetic     365     395     760  
Established diabetes with no OAD treatment     1414     1467     2881  
Established diabetes with one OAD treatment     3748     3692     7440  
Unclear diabetes status     2     2     4  
Duration of diabetes for established diabetes patients [4]
[units: years]
Median ( Inter-Quartile Range )
  3.50  
  ( 1.50 to 7.50 )  
  3.50  
  ( 1.50 to 7.50 )  
  3.50  
  ( 1.50 to 7.50 )  
Glycated Hemoglobin A1c (HbA1c) [5]
[units: percent]
Median ( Inter-Quartile Range )
  6.41  
  ( 5.81 to 7.18 )  
  6.40  
  ( 5.81 to 7.16 )  
  6.40  
  ( 5.81 to 7.18 )  
Fasting Plasma Glucose [6]
[units: mmol/L]
Median ( Inter-Quartile Range )
  6.94  
  ( 6.05 to 8.20 )  
  6.90  
  ( 6.00 to 8.20 )  
  6.94  
  ( 6.05 to 8.20 )  
[1] Due to missing values, N=6256 for insulin glargine and N=6271 for standard care.
[2] Due to missing values, N=6251 for insulin glargine and N=6270 for standard care.
[3]

IFG = Impaired Fasting Glucose defined as a Postprandial Plasma Glucose (PPG) value ≥140 and <200 mg/dL (ie, ≥7.8 and <11.1 mmol/L), with a Fasting Plasma Glucose (FPG) <126 mg/dL (7.0 mmol/L)

IGT = Impaired Glucose Tolerance 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])

OAD = oral antidiabetic drug

[4] Population of patients with established diabetes. Due to missing values, N=5148 for insulin glargine and N=5141 for standard care.
[5] Due to missing values, N=6175 for insulin glargine and N=6189 for standard care.
[6] Due to missing values, N=6248 for insulin glargine and N=6266 for standard care.



  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) ]

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) ]

Measure Type Primary
Measure Title Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
Measure Description

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.

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), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)  
[units: participants]
   
Participants with a composite endpoint     1792     1727  
Endpoint's composition: CV death     350     339  
Endpoint's composition: nonfatal MI     257     238  
Endpoint's composition: nonfatal stroke     231     227  
Endpoint's composition: revascularization     763     717  
Endpoint's composition: hospitalization for HF     249     259  


Statistical Analysis 1 for Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.2692
Cox Proportional Hazard [4] 1.038
95% Confidence Interval ( 0.972 to 1.109 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  See above additional details provided for the analysis of the first coprimary outcome.
[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:
  The second coprimary outcome was tested at 1% (see above additional information for the first coprimary outcome).
[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.



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

Measure Type Secondary
Measure Title Total Mortality (All Causes)
Measure Description Number of deaths due to any cause
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, which was all randomized participants, regardless of compliance with the protocol.

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  
Total Mortality (All Causes)  
[units: participants]
  951     965  


Statistical Analysis 1 for Total Mortality (All Causes)
Groups [1] All groups
Cox Proportional Hazard [2] 0.983
95% Confidence Interval ( 0.899 to 1.076 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, with double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event as covariates.



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) ]

Measure Type Secondary
Measure Title Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
Measure Description

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]).
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 Diabetic Microvascular Outcome (Kidney or Eye Disease)  
[units: participants]
   
Participants with a composite endpoint     1323     1363  
Endpoint's composition: vitrectomy     24     25  
Endpoint's composition: laser therapy for DR     57     67  
Endpoint's composition: dialysis     18     28  
Endpoint's composition: renal transplant     0     0  
Endpoint's composition: serum creatinine doubled     82     88  
Endpoint's composition: death due to renal failure     4     3  
Endpoint's composition: albuminuria progression     1153     1171  


Statistical Analysis 1 for Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
Groups [1] All groups
Cox Proportional Hazard [2] 0.970
95% Confidence Interval ( 0.900 to 1.047 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  Hazard ratio (glargine/standard care) estimated by Cox regression model with treatment (glargine, standard care) as factor, with double-blind treatment (omega-3 PUFA, placebo), baseline diabetes diagnosis and previous CV event as covariates.



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) ]

Measure Type Secondary
Measure Title Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
Measure Description 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).
Time Frame from randomization until the last follow-up visit or last OGTT (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 subgroup of the intent-to-treat (ITT) population without diabetes at randomization.

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]
  737     719  
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG  
[units: percentage¬†of¬†patients]
  24.7     31.2  


Statistical Analysis 1 for Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
Groups [1] All groups
Odds Ratio (OR) [2] 0.72
95% Confidence Interval ( 0.58 to 0.91 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  Odds ratio estimated using Cochran-Mantel-Haenszel (CMH) test method stratified by double-blind treatment (omega-3 PUFA or placebo) and previous cardiovascular event (yes or no).



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) ]

Measure Type Other Pre-specified
Measure Title Number of Patients With Various Types of Symptomatic Hypoglycemia Events
Measure Description

Symptomatic hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia, based on data recorded in the participant’s diary. These were further categorized as confirmed (ie, with a concomitant home glucose reading ≤54 mg/dL [≤3.0 mmol/L]) or unconfirmed.

Severe hypoglycemia was defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following:

  • the event was associated with a documented self-measured or laboratory plasma glucose level ≤36 mg/dL (≤2.0 mmol/L), or
  • the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.
Time Frame on-treatment period (median duration of follow-up: 6.2 years)  
Safety Issue Yes  

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 population analyzed was the safety population consisting of all randomized and treated patients (who received at least one dose of study drug) for the insulin glargine group and of all randomized patients for the standard care group.

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]
  6231     6273  
Number of Patients With Various Types of Symptomatic Hypoglycemia Events  
[units: participants]
   
Patients with hypoglycemia events     3597     1624  
Patients with non-severe hypoglycemia     3533     1582  
Patients with confirmed non-severe hypoglycemia     2581     904  
Patients with severe hypoglycemia     352     113  

No statistical analysis provided for Number of Patients With Various Types of Symptomatic Hypoglycemia Events



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) ]

Measure Type Other Pre-specified
Measure Title Number of Patients With First Occurrence of Any Type of Cancer
Measure Description Data on cancers that occurred in association with hospitalizations were collected systematically in both groups from the start of the study. All reported cancers occurring during the trial (new or recurrent) were adjudicated by the Event Adjudication Committee.
Time Frame from randomization until study cut-off date (median duration of follow-up: 6.2 years)  
Safety Issue Yes  

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.

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  
Number of Patients With First Occurrence of Any Type of Cancer  
[units: participants]
  559     561  

No statistical analysis provided for Number of Patients With First Occurrence of Any Type of Cancer




  Serious Adverse Events


  Other Adverse Events


  More Information