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

• ClinicalTrials.gov Identifier: NCT02915198
• Recruitment Status: Recruiting
• First Posted: September 26, 2016
• Last Update Posted: January 8, 2024
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Tracking Information

• First Submitted Date: September 13, 2016
• First Posted Date: September 26, 2016
• Last Update Posted Date: January 8, 2024
• Actual Study Start Date: April 3, 2023
• Estimated Primary Completion Date: March 31, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 4, 2019)

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.

Original Primary Outcome Measures (submitted: September 22, 2016)

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 in days 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.

Current Secondary Outcome Measures (submitted: April 20, 2022)

• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: September 22, 2016)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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 patients 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 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
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Prediabetic State
• Atherosclerosis
• Metformin

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.
• 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

Study Arms

• 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.
  Intervention: Drug: Metformin XR
• 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.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 20, 2022): 7410
• Original Estimated Enrollment (submitted: September 22, 2016): 7868
• Estimated Study Completion Date: March 31, 2029
• Estimated Primary Completion Date: March 31, 2029 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Gregory G Schwartz, PhD MD; (720) 723-6070; Gregory.Schwartz@va.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02915198
• Other Study ID Numbers: 2002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: VA Office of Research and Development
• Original Responsible Party: Same as current
• Current Study Sponsor: VA Office of Research and Development
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: VA Office of Research and Development
• Verification Date: January 2024