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CSP #2002 VA-IMPACT

IMPACT (Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes) 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, and/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.

Ages Eligible for Study:  18 Years and older

Sexes Eligible for Study:  All

Accepts Healthy Volunteers:  No
 

Inclusion Criteria

Pre-diabetes: This condition is fulfilled by HbA1c of at least 5.7%, but less than 6.5%; two measurements of fasting blood glucose (on separate days) of 100-125 mg/dL; or a 2-hour blood glucose level of 140-199 mg/dL following a 75 g glucose load oral glucose tolerance test. These criteria must be met in the absence of diabetic treatment.

For a participant to qualify with pre-diabetes on the basis of HbA1c or oral glucose tolerance testing, the results must have been obtained within 5 months prior to the date of the screening visit, to ensure that the data are no more than 6 months prior to randomization. If HbA1c was measured more than once during this time period, an average value of at least 5.7%, but less than 6.5%, will determine qualification.

To qualify with pre-diabetes on the basis of two fasting blood glucose levels of 100-125 mg/dL, testing must be performed during the period beginning with the screening visit and prior to the randomization visit, with documentation of fasting (no caloric intake) for at least 8 hours prior to blood sampling. To qualify with pre-diabetes on the basis of two fasting blood glucose levels of 100-125 mg/dL, testing must be performed during the period beginning with the screening visit and prior to the randomization visit, with documentation of fasting (no caloric intake) for at least 8 hours prior to blood sampling. Any or all qualifying laboratory values may have been obtained in either a VA or a non-VA laboratory, but in either case the laboratory source documents, including date(s) of testing and test results must be available and data recorded on the appropriate case report form.

1. Pre-diabetes: This condition is fulfilled by HbA1c of at least 5.7%, but less than 6.5%; two measurements of fasting blood glucose (on separate days) of 100-125 mg/dL; or a 2-hour blood glucose level of 140-199 mg/dL following a 75 g glucose load oral glucose tolerance test. These criteria must be met in the absence of diabetic treatment. For a participant to qualify with pre-diabetes on the basis of HbA1c or oral glucose tolerance testing, the results must have been obtained within 5 months prior to the date of the screening visit, to ensure that the data are no more than 6 months prior to randomization. If HbA1c was measured more than once during this time period, an average value of at least 5.7%, but less than 6.5%, will determine qualification. To qualify with pre-diabetes on the basis of two fasting blood glucose levels of 100-125 mg/dL, testing must be performed during the period beginning with the screening visit and prior to the randomization visit, with documentation of fasting (no caloric intake) for at least 8 hours prior to blood sampling. To qualify with pre-diabetes on the basis of two fasting blood glucose levels of 100-125 mg/dL, testing must be performed during the period beginning with the screening visit and prior to the randomization visit, with documentation of fasting (no caloric intake) for at least 8 hours prior to blood sampling. Any or all qualifying laboratory values may have been obtained in either a VA or a non-VA laboratory, but in either case the laboratory source documents, including date(s) of testing and test results must be available and data recorded on the appropriate case report form.

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
  • History of myocardial infarction at least one month prior to randomization
  • Hospital summary or notes recording diagnosis of myocardial infarction 


3. Documented prior ischemic stroke (at least one month prior to randomization) based upon at least one of the following:

  • stroke documented in hospital discharge summary or neurologic consultation note, not including subarachnoid or subdural hemorrhage;
  • neuroimaging study consistent with prior ischemic stroke (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 70% (4) History of carotid revascularization (surgical or catheter-based)

4. Peripheral arterial disease: Fulfilled by (1), (2), or both:

  • History of aorto-iliac or peripheral artery intervention (surgical or catheter based) or amputation for limb ischemia
  • Symptoms of intermittent claudication with ankle: brachial index 0.85

5. Renal function: Estimated glomerular filtration rate (MDRD formula) at least 45 mL/min/1.73 m2.

6. Informed consent has been provided, and participant agrees to study procedures
 

Exclusion Criteria

1. Related to metabolic state:

  • Current treatment with anti-diabetic medication
  • Treatment with systemic glucocorticoids within 3 months of randomization (due to potential effect on blood glucose and HbA1c levels).
  • Screening fasting blood glucose 140 mg/dL or HbA1c 7.0%, or any non-fasting blood glucose 200/mg/dL recorded within the past year.


2. Related to safety, tolerability, or previous treatment with metformin:

  • Metabolic acidosis (total CO2 below the local laboratory lower limit of normal on most recent blood chemistry panel)
  • Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin >2 times upper limit of normal on most recent (screening) laboratory study
  • Binge or heavy alcohol consumption within the past 6 months. Binge drinking is defined by consumption of 5 or more alcoholic drinks for men or 4 for women within 2 hours. Heavy drinking is defined by consumption of 5 or more alcoholic drinks on one occasion, occurring 5 or more times in a month.
  • Severe anemia (<10 g/dL) at time of randomization
  • Prior history of intolerance to metformin
  • Treatment with metformin within the preceding year


3. Related to likelihood of non-modifiable events:

  • Uncontrolled hypertension (systolic blood pressure 180 mm Hg or diastolic blood pressure 110 mm Hg at the randomization visit, despite treatment
  • New York Heart Association Class III-IV congestive heart failure symptoms at the randomization visit, despite treatment


4. Related to prognosis, reliability, ethics, or data validity:

  • Expected survival less than study duration
  • Persons considered to be unable, unwilling, or unreliable to meet protocol requirements
  • Impaired decision-making capacity, defined by any history of dementia or cognitive impairment
  • Concurrent participation in another research study with evaluating drug or device treatments.


5. Female participants

  • Pregnant or intent to become pregnant during the trial
  • Lactating
  • Women of childbearing potential not using a highly effective method of contraception as specified in the Operations Manual
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