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Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

NCT ID: NCT02915198

Last Updated: 2024-12-30

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE4

Total Enrollment

7410 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-04-03

Study Completion Date

2029-03-31

Brief Summary

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This research will help us to learn if the medicine called metformin reduces the risk of death, heart attacks, and/or strokes in Veterans who have pre-diabetes and heart or blood vessel problems.

Detailed Description

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CSP #2002 is a multicenter, prospective, randomized, double blind, secondary prevention trial to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in Veterans with pre-diabetes and established atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by HbA1c, fasting blood glucose, or oral glucose tolerance test criteria; clinically evident coronary, cerebrovascular, or peripheral arterial atherosclerotic cardiovascular disease; and estimated glomerular filtration rate of at least 45 mL/min/1.73 m2; and do not fulfill any exclusion criteria. Patients who are eligible and agree to participate are randomly assigned to treatment with metformin XR (titrated to a maximum dose of 2000 mg daily based on safety and tolerability) or matching placebo. All patients receive counseling on therapeutic lifestyle recommendations.

CSP #2002 had a Pilot Phase trial from 2/2019 to 1/2021 and was approved for the full-scale trial, with Full-scale study launch in 04/2023.

Conditions

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Prediabetic State Atherosclerosis Metformin

Keywords

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Metformin Atherosclerosis Prediabetic State Hemoglobin A, Glycosylated Coronary Artery Disease Peripheral Arterial Disease Cerebrovascular Disorders

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Metformin

Participants receive initial treatment with metformin XR 500 mg 1 tablet daily, with stepwise titration to a maximum dose of 2000 mg (4 tablets) daily.

Group Type EXPERIMENTAL

Metformin XR

Intervention Type DRUG

The study medication dose may be increased by a step-wise fashion up to a maximum of 4 tablets per day.

Placebo

Participants receive initial treatment with 1 tablet daily of placebo (for metformin XR), with stepwise titration to a maximum of 4 tablets daily.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

For patients \< 80 years of age at the time of a study visit, and with most recent eGFR 45 mL/min/1.73 m2, study medication dose may be increased in a stepwise fashion to a maximum of 4 tablets daily, corresponding to metformin XR 2000 mg or matching placebo.

For patients 80 years of age or with most recent 30 eGFR \< 45 mL/min/1.73 m2, the maximum dose of study medication is 2 tablets daily, corresponding to metformin XR 1000 mg or matching placebo

Interventions

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Metformin XR

The study medication dose may be increased by a step-wise fashion up to a maximum of 4 tablets per day.

Intervention Type DRUG

Placebo

For patients \< 80 years of age at the time of a study visit, and with most recent eGFR 45 mL/min/1.73 m2, study medication dose may be increased in a stepwise fashion to a maximum of 4 tablets daily, corresponding to metformin XR 2000 mg or matching placebo.

For patients 80 years of age or with most recent 30 eGFR \< 45 mL/min/1.73 m2, the maximum dose of study medication is 2 tablets daily, corresponding to metformin XR 1000 mg or matching placebo

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Pre-diabetes: This condition is fulfilled by HbA1c of at least 5.7%, but less than 6.5%; or two measurements of fasting plasma glucose (on separate days) of 100-125 mg/dL; or a 2-hour plasma glucose level of 140-199 mg/dL following a 75 g glucose load oral glucose tolerance test.
2. Established atherosclerotic cardiovascular disease: Qualifying participants must have evidence of atherosclerotic disease in at least one of the following vascular beds: coronary, cerebrovascular, or peripheral arterial circulation.

Coronary artery disease is fulfilled by at least one of (1), (2), or (3):

1. History of myocardial infarction at least one month prior to randomization.
2. History of percutaneous coronary intervention or coronary artery bypass surgery at least one month prior to randomization.
3. Angiographic evidence of coronary stenosis of at least 50% in at least two major epicardial coronary arteries.

Cerebrovascular disease is fulfilled by at least one of criteria (1) through (4):

1. Documented prior ischemic stroke (at least one month prior to randomization),
2. Carotid artery stenosis 50% and history of transient ischemic attack or transient ischemic visual symptoms attributable to the identified lesion(s),
3. Asymptomatic carotid stenosis of at least 70% luminal diameter,
4. History of carotid revascularization (surgical or catheter-based).

Peripheral arterial disease: Fulfilled by at least one of the following:

1. History of aorto-iliac or peripheral artery intervention (surgical or catheter based) for limb ischemia, or amputation for limb ischemia,
2. Symptoms of intermittent claudication with ankle:brachial index less than or equal to 0.85.

3\. Renal function: Estimated glomerular filtration rate at least 45 mL/min/1.73 m2.

4\. Informed consent has been fully executed, and participant agrees to study procedures.

Exclusion Criteria

1. Treatment with metformin or other anti-diabetic medication within 12 months of randomization. Note: In the absence of a diagnosis of diabetes, inpatient treatment with insulin or treatment with an SGLT2 inhibitor (e.g., for heart failure) or a GLP-1 receptor agonist (e.g., for obesity) is not exclusionary.
2. Treatment with systemic glucocorticoids within 3 months of randomization
3. Fasting plasma glucose 140 mg/dL measured between screening and randomization visits, or any plasma glucose 200 mg/dL or HbA1c 7.0% measured within 12 months of randomization.
4. Total CO2 below the local laboratory lower limit of normal on most recent blood chemistry panel
5. Current treatment with cimetidine, vandetanib, or a systemic treatment with a carbonic anhydrase inhibitor.
6. Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin \> 2 times upper limit of normal
7. Binge or heavy alcohol consumption within 6 months of randomization
8. Severe anemia (hemoglobin \< 10 g/dL)
9. Prior history of intolerance to metformin
10. Myocardial infarction, coronary revascularization procedure, or stroke within 1 month of randomization
11. Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm Hg or diastolic blood pressure 110 mm Hg
12. Acute or decompensated congestive heart failure
13. Expected survival less than study duration
14. Participants considered to be unable, unwilling, or unreliable to meet protocol requirements
15. Impaired decision-making capacity, defined by any history of dementia or cognitive impairment
16. Concurrent participation in another research study involving a randomized comparison of drug or device treatments, unless specifically excepted.
17. Pregnant, intent to become pregnant during the trial, or lactating
18. Women of childbearing potential who are not using a highly effective method of contraception
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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VA Office of Research and Development

FED

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Gregory G. Schwartz, PhD MD

Role: STUDY_CHAIR

Rocky Mountain Regional VA Medical Center, Aurora, CO

Locations

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Phoenix VA Health Care System, Phoenix, AZ

Phoenix, Arizona, United States

Site Status ACTIVE_NOT_RECRUITING

Southern Arizona VA Health Care System, Tucson, AZ

Tucson, Arizona, United States

Site Status RECRUITING

Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR

Little Rock, Arkansas, United States

Site Status RECRUITING

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, United States

Site Status RECRUITING

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, United States

Site Status RECRUITING

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, United States

Site Status RECRUITING

VA San Diego Healthcare System, San Diego, CA

San Diego, California, United States

Site Status RECRUITING

VA Greater Los Angeles Healthcare System, West Los Angeles, CA

West Los Angeles, California, United States

Site Status RECRUITING

Rocky Mountain Regional VA Medical Center, Aurora, CO

Aurora, Colorado, United States

Site Status RECRUITING

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, United States

Site Status RECRUITING

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, United States

Site Status RECRUITING

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, United States

Site Status RECRUITING

Miami VA Healthcare System, Miami, FL

Miami, Florida, United States

Site Status RECRUITING

Atlanta VA Medical and Rehab Center, Decatur, GA

Decatur, Georgia, United States

Site Status RECRUITING

VA Pacific Islands Health Care System, Honolulu, HI

Honolulu, Hawaii, United States

Site Status RECRUITING

Jesse Brown VA Medical Center, Chicago, IL

Chicago, Illinois, United States

Site Status TERMINATED

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, United States

Site Status RECRUITING

Iowa City VA Health Care System, Iowa City, IA

Iowa City, Iowa, United States

Site Status RECRUITING

Lexington VA Medical Center, Lexington, KY

Lexington, Kentucky, United States

Site Status NOT_YET_RECRUITING

Rehabilitation R&D Service, Baltimore, MD

Baltimore, Maryland, United States

Site Status RECRUITING

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, United States

Site Status RECRUITING

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, United States

Site Status RECRUITING

Kansas City VA Medical Center, Kansas City, MO

Kansas City, Missouri, United States

Site Status RECRUITING

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Omaha, Nebraska, United States

Site Status RECRUITING

New Mexico VA Health Care System, Albuquerque, NM

Albuquerque, New Mexico, United States

Site Status RECRUITING

Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY

New York, New York, United States

Site Status RECRUITING

Durham VA Medical Center, Durham, NC

Durham, North Carolina, United States

Site Status RECRUITING

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, United States

Site Status RECRUITING

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, United States

Site Status RECRUITING

VA Portland Health Care System, Portland, OR

Portland, Oregon, United States

Site Status RECRUITING

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, United States

Site Status RECRUITING

Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC

Columbia, South Carolina, United States

Site Status RECRUITING

Memphis VA Medical Center, Memphis, TN

Memphis, Tennessee, United States

Site Status RECRUITING

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, United States

Site Status RECRUITING

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, United States

Site Status RECRUITING

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, United States

Site Status RECRUITING

Hunter Holmes McGuire VA Medical Center, Richmond, VA

Richmond, Virginia, United States

Site Status RECRUITING

Salem VA Medical Center, Salem, VA

Salem, Virginia, United States

Site Status RECRUITING

Huntington VA Medical Center, Huntington, WV

Huntington, West Virginia, United States

Site Status RECRUITING

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Gregory G Schwartz, PhD MD

Role: CONTACT

Phone: (720) 723-6070

Email: [email protected]

Facility Contacts

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Punit Goel, MD

Role: primary

Barry Uretsky, MD

Role: primary

Geir Frivold, MD

Role: primary

Anthony Vo, MD

Role: primary

Arlina Ahluwalia, MD

Role: primary

Paul Heidenreich, MD

Role: backup

Leda Felicio, MD

Role: primary

Tannaz Moin, MD

Role: primary

Sridharan Raghavan, MD PhD

Role: primary

Brian Malm, MD

Role: primary

Manjunath Harlapur, MD

Role: primary

Carsten Schmalfuss, MD

Role: primary

Ana Palacio, MD

Role: primary

Mary Rhee, MD

Role: primary

Kelsey Shikuma-Lee, MD

Role: primary

Amit Dayal, MD

Role: primary

David Katz, MD

Role: primary

Dennis Karounos, MD

Role: primary

Ilias Spanakis, MD

Role: primary

Scott Kinlay, MD

Role: primary

Selcuk Adabag, MD

Role: primary

Mariana Garcia-Touza, MD

Role: primary

Cyrus Desouza, MD

Role: primary

Michelle D Ratliff, MD

Role: primary

Binita Shah, MD

Role: primary

Matthew Crowley, MD

Role: primary

Hanan Kerr, MD

Role: primary

Laure Sayyed Kassem, MD

Role: primary

North Noelck, MD

Role: primary

Linda Humphrey, MD

Role: backup

Ashley Waring, MD

Role: primary

Subhashini Yaturu, MD

Role: primary

Richard D Childress, MD

Role: primary

Colleen Sam, MD

Role: primary

Arunima Misra, MD

Role: primary

Charles Lui, MD

Role: primary

Edward McFalls, MD

Role: primary

Ali Iranmanesh, MD

Role: primary

Tina Sias, MD

Role: primary

Cynthia Kay, MD

Role: primary

Other Identifiers

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2002

Identifier Type: -

Identifier Source: org_study_id