Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

Atherosclerosis Clinical Trial

— VA-IMPACT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02915198
• Other study ID #: 2002
• Status: Recruiting
• Phase: Phase 4
• Start date: April 3, 2023
• Est. completion date: March 31, 2029

Study information

• Verified date: January 2024
• Source: VA Office of Research and Development
• Contact: Gregory G Schwartz, PhD MD
• Phone: (720) 723-6070
• Email: Gregory.Schwartz[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 7410
• Est. completion date: March 31, 2029
• Est. primary completion date: March 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atherosclerosis
• Metformin
• Prediabetic State

Intervention

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
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

Locations

Country	Name	City	State
United States	New Mexico VA Health Care System, Albuquerque, NM	Albuquerque	New Mexico
United States	Rocky Mountain Regional VA Medical Center, Aurora, CO	Aurora	Colorado
United States	Rehabilitation R&D Service, Baltimore, MD	Baltimore	Maryland
United States	Bay Pines VA Healthcare System, Pay Pines, FL	Bay Pines	Florida
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
United States	Ralph H. Johnson VA Medical Center, Charleston, SC	Charleston	South Carolina
United States	Jesse Brown VA Medical Center, Chicago, IL	Chicago	Illinois
United States	Cincinnati VA Medical Center, Cincinnati, OH	Cincinnati	Ohio
United States	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio
United States	Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC	Columbia	South Carolina
United States	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas
United States	Atlanta VA Medical and Rehab Center, Decatur, GA	Decatur	Georgia
United States	Durham VA Medical Center, Durham, NC	Durham	North Carolina
United States	North Florida/South Georgia Veterans Health System, Gainesville, FL	Gainesville	Florida
United States	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois
United States	VA Pacific Islands Health Care System, Honolulu, HI	Honolulu	Hawaii
United States	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas
United States	Huntington VA Medical Center, Huntington, WV	Huntington	West Virginia
United States	Iowa City VA Health Care System, Iowa City, IA	Iowa City	Iowa
United States	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri
United States	Lexington VA Medical Center, Lexington, KY	Lexington	Kentucky
United States	Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR	Little Rock	Arkansas
United States	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California
United States	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California
United States	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee
United States	Miami VA Healthcare System, Miami, FL	Miami	Florida
United States	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York
United States	Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE	Omaha	Nebraska
United States	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California
United States	Phoenix VA Health Care System, Phoenix, AZ	Phoenix	Arizona
United States	VA Portland Health Care System, Portland, OR	Portland	Oregon
United States	Hunter Holmes McGuire VA Medical Center, Richmond, VA	Richmond	Virginia
United States	Salem VA Medical Center, Salem, VA	Salem	Virginia
United States	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah
United States	VA San Diego Healthcare System, San Diego, CA	San Diego	California
United States	Southern Arizona VA Health Care System, Tucson, AZ	Tucson	Arizona
United States	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut
United States	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time in days to death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization	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	Time in days to Cardiovascular Outcomes	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
Secondary	Time in days to Oncologic Outcome	Time to new or recurrent diagnosis of a malignancy or death from a malignancy	through study completion, an average of 4.5 years
Secondary	Time in days to Diabetes Outcome	Time to new diagnosis of type 2 diabetes	through study completion, an average of 4.5 years