The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention) (ORIGIN)

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; 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
Other	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

Overall Participants Analyzed
[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

Baseline Weight ^[1]
[Units: Kg]
Mean (Standard Deviation)

83.33 (16.77)

83.13 (17.28)

83.23 (17.03)

^[1]	Due to missing values, N=6256 for insulin glargine and N=6271 for standard care.

Baseline Body Mass Index ^[1]
[Units: Kg/m²]
Mean (Standard Deviation)

29.77 (5.17)

29.88 (5.33)

29.82 (5.25)

^[1]	Due to missing values, N=6251 for insulin glargine and N=6270 for standard care.

Any previous cardiovascular event
[Units: Participants]

2552

2607

5159

Yes

3712

3666

7378

Diabetes diagnosis at time of screening ^[1]
[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

^[1]

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

Duration of diabetes for established diabetes patients ^[1]
[Units: Years]
Median (Inter-Quartile Range)

3.50
(1.50 to 7.50)

^[1]	Population of patients with established diabetes. Due to missing values, N=5148 for insulin glargine and N=5141 for standard care.

Glycated Hemoglobin A1c (HbA1c) ^[1]
[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)

^[1]	Due to missing values, N=6175 for insulin glargine and N=6189 for standard care.

Fasting Plasma Glucose ^[1]
[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=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) ]

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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)

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.

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
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
Statistical Test Type ^[2]	Superiority or Other
Cox Proportional Hazard ^[3]	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]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	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) ]

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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) ]

Show Outcome Measure 6

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) ]

Show Outcome Measure 7

Serious Adverse Events

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Other Adverse Events

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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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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: "The Steering Committee will be responsible for preparing summaries of the study results for publication in the medical literature, and will have the right to submit such summaries for publication after a review by the sponsor. In such cases comments from the sponsor to the Steering Committee are to be provided within 15 working days. All comments will be carefully considered by the Steering Committee who nevertheless have the final decision on the content of the manuscript."

Results Point of Contact:

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

Publications of Results:

ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.

ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18. doi: 10.1056/NEJMoa1203859. Epub 2012 Jun 11.

Other Publications:

Origin Trial Investigators, Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J. 2008 Jan;155(1):26-32, 32.e1-6. Epub 2007 Nov 26.

Hanefeld M, Koehler C, Hoffmann C, Wilhelm K, Kamke W, Gerstein H. Effect of targeting normal fasting glucose levels with basal insulin glargine on glycaemic variability and risk of hypoglycaemia: a randomized, controlled study in patients with early Type 2 diabetes. Diabet Med. 2010 Feb;27(2):175-80. doi: 10.1111/j.1464-5491.2009.02915.x.

Badings EA, Dyal L, Schoterman L, Lok DJ, Stoel I, Gerding MN, Gerstein HC, Tijssen JG. Strategies to detect abnormal glucose metabolism in people at high risk of cardiovascular disease from the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial population. J Diabetes. 2011 Sep;3(3):232-7. doi: 10.1111/j.1753-0407.2011.00124.x.

Ramachandran A, Riddle MC, Kabali C, Gerstein HC; ORIGIN Investigators. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care. 2012 Apr;35(4):749-53. doi: 10.2337/dc11-1918. Epub 2012 Feb 8.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gerstein HC, Paré G, McQueen MJ, Haenel H, Lee SF, Pogue J, Maggioni AP, Yusuf S, Hess S; Outcome Reduction With Initial Glargine Intervention Trial Investigators. Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia. Circulation. 2015 Dec 15;132(24):2297-304. doi: 10.1161/CIRCULATIONAHA.115.015744. Epub 2015 Oct 30.

Cukierman-Yaffe T, Bosch J, Diaz R, Dyal L, Hancu N, Hildebrandt P, Lanas F, Lewis BS, Marre M, Yale JF, Yusuf S, Gerstein HC; ORIGIN Investigators. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol. 2014 Jul;2(7):562-72. doi: 10.1016/S2213-8587(14)70062-2. Epub 2014 Jun 2.

ORIGIN trial investigators, Gilbert RE, Mann JF, Hanefeld M, Spinas G, Bosch J, Yusuf S, Gerstein HC. Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. Diabetologia. 2014 Jul;57(7):1325-31. doi: 10.1007/s00125-014-3238-4. Epub 2014 Apr 26.

Lopez-Jaramillo P, Cohen DD, Gómez-Arbeláez D, Bosch J, Dyal L, Yusuf S, Gerstein HC; ORIGIN Trial Investigators. Association of handgrip strength to cardiovascular mortality in pre-diabetic and diabetic patients: a subanalysis of the ORIGIN trial. Int J Cardiol. 2014 Jun 15;174(2):458-61. doi: 10.1016/j.ijcard.2014.04.013. Epub 2014 Apr 13.

Lamy A, Tong W, Jung H, Gafni A, Singh K, Tyrwhitt J, Yusuf S, Gerstein HC; ORIGIN Investigators. Cost implications of the use of basal insulin glargine in people with early dysglycemia: the ORIGIN trial. J Diabetes Complications. 2014 Jul-Aug;28(4):553-8. doi: 10.1016/j.jdiacomp.2014.02.012. Epub 2014 Mar 2.

Bordeleau L, Yakubovich N, Dagenais GR, Rosenstock J, Probstfield J, Chang Yu P, Ryden LE, Pirags V, Spinas GA, Birkeland KI, Ratner RE, Marin-Neto JA, Keltai M, Riddle MC, Bosch J, Yusuf S, Gerstein HC; ORIGIN Trial Investigators. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care. 2014;37(5):1360-6. doi: 10.2337/dc13-1468. Epub 2014 Feb 26.

ORIGIN Trial Investigators, Mellbin LG, Rydén L, Riddle MC, Probstfield J, Rosenstock J, Díaz R, Yusuf S, Gerstein HC. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013 Oct;34(40):3137-44. doi: 10.1093/eurheartj/eht332. Epub 2013 Sep 2.

ORIGIN Trial Investigators. Characteristics associated with maintenance of mean A1C<6.5% in people with dysglycemia in the ORIGIN trial. Diabetes Care. 2013 Oct;36(10):2915-22. doi: 10.2337/dc12-2238. Epub 2013 May 8.

Lonn EM, Bosch J, Diaz R, Lopez-Jaramillo P, Ramachandran A, Hâncu N, Hanefeld M, Krum H, Ryden L, Smith S, McQueen MJ, Dyal L, Yusuf S, Gerstein HC; GRACE and ORIGIN Investigators. Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE). Diabetes Care. 2013 Sep;36(9):2466-74. doi: 10.2337/dc12-2129. Epub 2013 Apr 5.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT00069784 History of Changes
Other Study ID Numbers:	LTS6035 HOE901/4032 ( Other Identifier: previous Aventis study number )
Study First Received:	October 1, 2003
Results First Received:	December 18, 2012
Last Updated:	January 24, 2013

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