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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
History of Changes
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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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) ]
  Show Outcome Measure 1

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) ]
  Show Outcome Measure 2

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

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) ]
  Show Outcome Measure 4

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) ]
  Show Outcome Measure 5

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) ]
  Hide Outcome Measure 6

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) ]
  Hide Outcome Measure 7

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
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  Other Adverse Events
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
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
No text entered.  


Results Point of Contact:  
Name/Title: Trial Transparency Team
Organization: sanofi
e-mail: Contact_US@sanofi.com


Publications of Results:

Other Publications:


Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00069784     History of Changes
Other Study ID Numbers: LTS6035, HOE901/4032
Study First Received: October 1, 2003
Results First Received: December 18, 2012
Last Updated: January 24, 2013
Health Authority: United States: Food and Drug Administration