Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)

January 5, 2024 updated by: VA Office of Research and Development

CSP #2002 - Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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 patients 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 projected full-scale launch in 10/2022.

Study Type

Interventional

Enrollment (Estimated)

7410

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85012
        • Recruiting
        • Phoenix VA Health Care System, Phoenix, AZ
        • Contact:
      • Tucson, Arizona, United States, 85723-0001
        • Recruiting
        • Southern Arizona VA Health Care System, Tucson, AZ
        • Contact:
    • Arkansas
      • Little Rock, Arkansas, United States, 72205-5484
        • Recruiting
        • Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
        • Contact:
    • California
      • Loma Linda, California, United States, 92357-1000
        • Recruiting
        • VA Loma Linda Healthcare System, Loma Linda, CA
        • Contact:
      • Long Beach, California, United States, 90822
        • Recruiting
        • VA Long Beach Healthcare System, Long Beach, CA
        • Contact:
      • Palo Alto, California, United States, 94304-1207
        • Recruiting
        • VA Palo Alto Health Care System, Palo Alto, CA
        • Contact:
        • Contact:
      • San Diego, California, United States, 92161-0002
        • Recruiting
        • VA San Diego Healthcare System, San Diego, CA
        • Contact:
      • West Los Angeles, California, United States, 90073-1003
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Rocky Mountain Regional VA Medical Center, Aurora, CO
        • Contact:
        • Study Chair:
          • Gregory G. Schwartz, PhD MD
    • Connecticut
      • West Haven, Connecticut, United States, 06516-2770
        • Recruiting
        • VA Connecticut Healthcare System West Haven Campus, West Haven, CT
        • Contact:
    • Florida
      • Bay Pines, Florida, United States, 33744-0000
        • Recruiting
        • Bay Pines VA Healthcare System, Pay Pines, FL
        • Contact:
      • Gainesville, Florida, United States, 32608-1135
        • Recruiting
        • North Florida/South Georgia Veterans Health System, Gainesville, FL
        • Contact:
      • Miami, Florida, United States, 33125
        • Recruiting
        • Miami VA Healthcare System, Miami, FL
        • Contact:
    • Georgia
      • Decatur, Georgia, United States, 30033-4004
        • Recruiting
        • Atlanta VA Medical and Rehab Center, Decatur, GA
        • Contact:
    • Hawaii
      • Honolulu, Hawaii, United States, 96819-1522
        • Recruiting
        • VA Pacific Islands Health Care System, Honolulu, HI
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Terminated
        • Jesse Brown VA Medical Center, Chicago, IL
      • Hines, Illinois, United States, 60141-3030
        • Recruiting
        • Edward Hines Jr. VA Hospital, Hines, IL
        • Contact:
    • Iowa
      • Iowa City, Iowa, United States, 52246-2292
        • Recruiting
        • Iowa City VA Health Care System, Iowa City, IA
        • Contact:
    • Kentucky
      • Lexington, Kentucky, United States, 40502-2235
        • Not yet recruiting
        • Lexington VA Medical Center, Lexington, KY
        • Contact:
    • Maryland
      • Baltimore, Maryland, United States, 21202
        • Recruiting
        • Rehabilitation R&D Service, Baltimore, MD
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02130-4817
        • Recruiting
        • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
        • Contact:
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417-2309
        • Recruiting
        • Minneapolis VA Health Care System, Minneapolis, MN
        • Contact:
    • Missouri
      • Kansas City, Missouri, United States, 64128-2226
        • Recruiting
        • Kansas City VA Medical Center, Kansas City, MO
        • Contact:
    • Nebraska
      • Omaha, Nebraska, United States, 68105-1850
        • Recruiting
        • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
        • Contact:
    • New Mexico
      • Albuquerque, New Mexico, United States, 87108-5153
        • Recruiting
        • New Mexico VA Health Care System, Albuquerque, NM
        • Contact:
    • New York
      • New York, New York, United States, 10010-5011
        • Recruiting
        • Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27705-3875
        • Recruiting
        • Durham VA Medical Center, Durham, NC
        • Contact:
    • Ohio
      • Cincinnati, Ohio, United States, 45220-2213
        • Recruiting
        • Cincinnati VA Medical Center, Cincinnati, OH
        • Contact:
      • Cleveland, Ohio, United States, 44106-1702
        • Recruiting
        • Louis Stokes VA Medical Center, Cleveland, OH
        • Contact:
    • Oregon
      • Portland, Oregon, United States, 97207-2964
        • Recruiting
        • VA Portland Health Care System, Portland, OR
        • Contact:
        • Contact:
    • South Carolina
      • Charleston, South Carolina, United States, 29401-5703
        • Recruiting
        • Ralph H. Johnson VA Medical Center, Charleston, SC
        • Contact:
      • Columbia, South Carolina, United States, 29209-1638
        • Recruiting
        • Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
        • Contact:
    • Tennessee
      • Memphis, Tennessee, United States, 38104-2127
        • Recruiting
        • Memphis VA Medical Center, Memphis, TN
        • Contact:
    • Texas
      • Dallas, Texas, United States, 75216-7167
        • Recruiting
        • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
        • Contact:
      • Houston, Texas, United States, 77030-4211
        • Recruiting
        • Michael E. DeBakey VA Medical Center, Houston, TX
        • Contact:
    • Utah
      • Salt Lake City, Utah, United States, 84148-0001
        • Recruiting
        • VA Salt Lake City Health Care System, Salt Lake City, UT
        • Contact:
    • Virginia
      • Richmond, Virginia, United States, 23249
        • Recruiting
        • Hunter Holmes McGuire VA Medical Center, Richmond, VA
        • Contact:
      • Salem, Virginia, United States, 24153-6404
        • Recruiting
        • Salem VA Medical Center, Salem, VA
        • Contact:
    • West Virginia
      • Huntington, West Virginia, United States, 25704-9300
        • Recruiting
        • Huntington VA Medical Center, Huntington, WV
        • Contact:
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53295-0001
        • Recruiting
        • Clement J. Zablocki VA Medical Center, Milwaukee, WI
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Metformin XR
The study medication dose may be increased by a step-wise fashion up to a maximum of 4 tablets per day.
Placebo Comparator: Placebo
Participants receive initial treatment with 1 tablet daily of placebo (for metformin XR), with stepwise titration to a maximum of 4 tablets daily.
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time in days to death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization
Time Frame: through study completion, an average of 4.5 years
The primary outcome measure is the time to first occurrence of death, non-fatal myocardial infarction or stroke, hospitalization for unstable angina with objective evidence of acute myocardial ischemia, or coronary revascularization driven by acute or progressive symptoms.
through study completion, an average of 4.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time in days to Cardiovascular Outcomes
Time Frame: through study completion, an average of 4.5 years
  • Time to first occurrence of death, myocardial infarction, or stroke
  • Time to first occurrence of a primary endpoint event, peripheral arterial disease event, or hospitalization for congestive heart failure
  • Cumulative incidence of all components of the primary endpoint, including recurrent or multiple events in the same participant
  • Cumulative incidence and time to first occurrence of each component of the primary outcome measure, peripheral arterial disease events, and hospitalization for congestive heart failure
through study completion, an average of 4.5 years
Time in days to Oncologic Outcome
Time Frame: through study completion, an average of 4.5 years
Time to new or recurrent diagnosis of a malignancy or death from a malignancy
through study completion, an average of 4.5 years
Time in days to Diabetes Outcome
Time Frame: through study completion, an average of 4.5 years
Time to new diagnosis of type 2 diabetes
through study completion, an average of 4.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Study Chair: Gregory G. Schwartz, PhD MD, Rocky Mountain Regional VA Medical Center, Aurora, CO

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 3, 2023

Primary Completion (Estimated)

March 31, 2029

Study Completion (Estimated)

March 31, 2029

Study Registration Dates

First Submitted

September 13, 2016

First Submitted That Met QC Criteria

September 22, 2016

First Posted (Estimated)

September 26, 2016

Study Record Updates

Last Update Posted (Actual)

January 8, 2024

Last Update Submitted That Met QC Criteria

January 5, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2002

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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