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

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ClinicalTrials.gov Identifier: NCT02915198
Recruitment Status : Recruiting
First Posted : September 26, 2016
Last Update Posted : March 5, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Prediabetic State Atherosclerosis Metformin Drug: Metformin XR Drug: Placebo Phase 4

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, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7868 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: CSP #2002 - Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)
Actual Study Start Date : February 21, 2019
Estimated Primary Completion Date : August 21, 2024
Estimated Study Completion Date : August 21, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prediabetes

Arm Intervention/treatment
Experimental: Metformin
Participants are randomly assigned in a 1:1 ratio to treatment with metformin XR 500 mg or matching placebo.
Drug: Metformin XR

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.

Other Name: Glucophage XR

Placebo Comparator: Placebo
Participants are randomly assigned in a 1:1 ratio to treatment with metformin XR 500 mg or matching placebo.
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





Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. At least one of these criteria must be met in the absence of diabetic treatment. For a participant to qualify with pre-diabetes on basis of one of these criteria, the results must have been obtained per the allowable time intervals indicated in Table 2. Any or all qualifying laboratory values may have been obtained either in 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.

    1. Coronary artery disease: Fulfilled by at least one of (1), (2), or (3):

      1. History of myocardial infarction at least one month prior to Randomization: Fulfilled by (a), (b), or both:

        (a) Hospital summary or notes recording diagnosis of myocardial infarction (b) At least two of the following:

    i) pathologic Q-waves (and/or pathologic R wave in lead V1) consistent with myocardial infarction; ii) myocardial perfusion abnormality consistent with infarction; or iii) regional wall motion abnormality consistent with infarction. (2) History of percutaneous coronary intervention or coronary artery bypass surgery at least one month prior to Randomization (3) Angiographic evidence of significant coronary stenosis: At least 50% luminal stenosis in at least two major epicardial coronary arteries and/or their major branches (left main, left anterior descending and/or principal diagonal branches, left circumflex and/or principal obtuse marginal branches, or right and/or posterior descending or posterolateral branch).

    b) Cerebrovascular disease: Fulfilled by at least one of criteria (1) through (4):

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

    1. stroke documented in hospital discharge summary or neurologic consultation note, not including subarachnoid or subdural hemorrhage;
    2. 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)

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

  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 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. Related to glucometabolic state:

    a) Treatment with metformin or other anti-diabetic medication within 12 months of randomization.

    b) Treatment with systemic glucocorticoids within 3 months of randomization (due to potential effect on plasma glucose and HbA1c levels).

    c) 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.

  2. Related to safety or tolerability:

    a) Metabolic acidosis (total CO2 below the local laboratory lower limit of normal on most recent blood chemistry panel)

    b) Current treatment with cimetidine, vandetanib, or a systemic carbonic anhydrase inhibitor (topiramate, acetazolamide, methazolamide, dichlorphenamide, or zonisamide). Use of ophthalmic carbonic anhydrase inhibitors is not exclusionary.

    c) Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin > 2 times upper limit of normal on most recent laboratory study

    d) Binge or heavy alcohol consumption within 6 months of randomization. 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.

    e) Severe anemia (hemoglobin < 10 g/dL) on screening or most recent laboratory testing

    f) Prior history of intolerance to metformin

  3. Related to likelihood of non-modifiable events:

    a) Myocardial infarction, coronary revascularization procedure (PCI or CABG), or stroke within 1 month of randomization

    b) Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm Hg or diastolic blood pressure 110 mm Hg

    c) Acute or decompensated congestive heart failure

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

    1. Expected survival less than study duration
    2. Participants considered to be unable, unwilling, or unreliable to meet protocol requirements
    3. Impaired decision-making capacity, defined by any history of dementia or cognitive impairment
    4. Concurrent participation in another research study involving a randomized comparison of drug or device treatments, unless specifically excepted by CSP.
  5. Female participants

    1. Pregnant or intent to become pregnant during the trial
    2. Lactating
    3. Women of childbearing potential who are not using a highly effective method of contraception

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02915198


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

Locations
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United States, Arizona
Phoenix VA Health Care System, Phoenix, AZ Recruiting
Phoenix, Arizona, United States, 85012
Contact: Peter Reaven, MD    602-277-5551 ext 6875    Peter.Reaven@va.gov   
United States, California
VA Loma Linda Healthcare System, Loma Linda, CA Recruiting
Loma Linda, California, United States, 92357
Contact: Alan Jacobson, MD    909-583-6050    alan.jacobson@va.gov   
VA Long Beach Healthcare System, Long Beach, CA Recruiting
Long Beach, California, United States, 90822
Contact: Anthony Vo, MD    562-826-3497    Anthony.Vo@va.gov   
VA Palo Alto Health Care System, Palo Alto, CA Recruiting
Palo Alto, California, United States, 94304-1290
Contact: Arlina Ahluwalia, MD    650-493-5000 ext 61755    Arlina.Ahluwalia@va.gov   
Contact: Paul Heidenreich, MD    6504935000 ext 64069    Paul.Heidenreich@va.gov   
VA Greater Los Angeles Healthcare System, West Los Angeles, CA Recruiting
West Los Angeles, California, United States, 90073
Contact: Tannaz Moin, MD    310-478-3711 ext 48380    Tannaz.Moin@va.gov; tmoin@mednet.ucla.edu   
United States, Colorado
Rocky Mountain Regional VA Medical Center, Aurora, CO Recruiting
Aurora, Colorado, United States, 80045
Contact: Allan V Prochazka, MD MSc    720-723-3256    Allan.Prochazka@va.gov   
Study Chair: Gregory G. Schwartz, PhD MD         
United States, Florida
North Florida/South Georgia Veterans Health System, Gainesville, FL Recruiting
Gainesville, Florida, United States, 32608
Contact: Carsten Schmalfuss, MD    352-376-1611 ext 6052    Carsten.Schmalfuss@va.gov   
Miami VA Healthcare System, Miami, FL Recruiting
Miami, Florida, United States, 33125
Contact: Ana Palacio, MD    305-926-3780    Ana.Palacio@va.gov   
United States, Oregon
VA Portland Health Care System, Portland, OR Recruiting
Portland, Oregon, United States, 97239
Contact: North Noelck, MD    503-220-8262 ext 56426    North.Noelck2@va.gov   
Contact: Linda Humphrey, MD    5032208262 ext 57176    Linda.Humphrey@va.gov   
United States, Utah
VA Salt Lake City Health Care System, Salt Lake City, UT Recruiting
Salt Lake City, Utah, United States, 84148
Contact: Charles Lui, MD    801-582-1565    Charles.Lui@va.gov   
United States, Virginia
Salem VA Medical Center, Salem, VA Recruiting
Salem, Virginia, United States, 24153
Contact: Ali Iranmanesh, MD    540-983-1071    Ali.Iranmanesh@va.gov   
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Study Chair: Gregory G. Schwartz, PhD MD Rocky Mountain Regional VA Medical Center, Aurora, CO

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02915198     History of Changes
Other Study ID Numbers: 2002
First Posted: September 26, 2016    Key Record Dates
Last Update Posted: March 5, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by VA Office of Research and Development:
Metformin
Atherosclerosis
Prediabetic State
Hemoglobin A, Glycosylated
Coronary Artery Disease
Peripheral Arterial Disease
Cerebrovascular Disorders

Additional relevant MeSH terms:
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Atherosclerosis
Prediabetic State
Glucose Intolerance
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperglycemia
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs