Clinical trial NCT02915198: Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes
Official title: CSP #2002 - Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Prediabetic State
Atherosclerosis
Metformin
Keywords: Metformin
Atherosclerosis
Prediabetic State
Hemoglobin A, Glycosylated
Coronary Artery Disease
Peripheral Arterial Disease
Cerebrovascular Disorders
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2016-09-26
Enrollment: 7410
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time in days to death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization
timeFrame: through study completion, an average of 4.5 years
Secondary outcomes:
measure: Time in days to Cardiovascular Outcomes
timeFrame: through study completion, an average of 4.5 years
measure: Time in days to Oncologic Outcome
timeFrame: through study completion, an average of 4.5 years
measure: Time in days to Diabetes Outcome
timeFrame: through study completion, an average of 4.5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson, AZ
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
state: Arkansas
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
city: West Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, West Los Angeles, CA
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Miami
country: United States
facility: Miami VA Healthcare System, Miami, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Honolulu
country: United States
facility: VA Pacific Islands Health Care System, Honolulu, HI
state: Hawaii
city: Chicago
country: United States
facility: Jesse Brown VA Medical Center, Chicago, IL
state: Illinois
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Iowa City
country: United States
facility: Iowa City VA Health Care System, Iowa City, IA
state: Iowa
city: Lexington
country: United States
facility: Lexington VA Medical Center, Lexington, KY
state: Kentucky
city: Baltimore
country: United States
facility: Rehabilitation R&D Service, Baltimore, MD
state: Maryland
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque, NM
state: New Mexico
city: New York
country: United States
facility: Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Columbia
country: United States
facility: Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
state: South Carolina
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center, Richmond, VA
state: Virginia
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
city: Huntington
country: United States
facility: Huntington VA Medical Center, Huntington, WV
state: West Virginia
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
Study officials:
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
name: Gregory G. Schwartz, PhD MD
role: STUDY_CHAIR
References: