Please select the eligibility criteria that correspond to the clinical trial below.
Title: Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes
Brief Summary: The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2400 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of less than 7.0% for all patients).

SPECIFIC AIMS

A. Primary Aim

The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2400 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity:

1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone;
2. Method of Glycemic Control Hypothesis: with a target HbA1c level of less than 7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared to a strategy of insulin provision.

B. Secondary Aims

The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression.


Options:
A: Inclusion Criteria:

* Diabetes type 1 or 2
* Painful symptoms of diabetic neuropathy in the lower extremities extremities for at least 6 months

Exclusion Criteria:

* Major Depression
* Uncontrolled diabetes
B: Inclusion Criteria:

* Outpatients who have completed double-blind treatment in study 322 (NCT01050218) for DPN. Subjects must have completed all scheduled evaluations, with no major protocol violations and no events that, in the opinion of the investigator, would preclude the subject's entry into the long-term open-label study.
* Women of childbearing potential must have a negative serum pregnancy test on day 91 of the short-term study. A woman of childbearing potential is one who is biologically capable of becoming pregnant. "Biologically capable" includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Sexually active women participating in the study who are biologically capable of becoming pregnant must use a medically acceptable form of contraception during the study and for at least 15 days after the last dose of test article. Medically acceptable forms of contraception include oral contraceptives, transdermal, injectable, or implantable methods, intrauterine devices, or properly used double-barrier contraception, eg, condom plus diaphragm.

Exclusion Criteria:

* Presence of any new and/or clinically important medical condition that might compromise subject safety (including, but not limited to, significant changes in glycemic control).
* Pregnancy, lactation, or plans to become pregnant during the study.
* Use of prohibited treatments.
* Meets any of the exclusion criteria listed for study 322 (NCT01050218).
C: Inclusion Criteria:

* Diagnosis of Type 2 diabetes mellitus
* Coronary arteriogram showing one or more vessels amenable to revascularization (greater than or equal to 50% stenosis)
* Objective documentation of ischemia OR subjectively documented typical angina with greater than or equal to 70% stenosis in at least one artery
* Suitability for coronary revascularization by at least one of the available methods (does not require the ability to achieve complete revascularization)
* Ability to perform all tasks related to glycemic control and risk factor management

Exclusion Criteria:

* Definite need for invasive intervention as determined by the attending cardiologist
* Prior bypass surgery (CABG) or prior catheter-based intervention within the 12 months before study entry
* Planned intervention for disease in bypass graft(s) if the patient is randomly assigned to a strategy of initial revascularization
* Class III or IV CHF
* Creatinine greater than 2.0 mg/dL
* HbA1c greater than 13%
* Need for major vascular surgery concomitant with revascularization (e.g., carotid endarterectomy)
* Left main stenosis greater than or equal to 50%
* Non-cardiac illness expected to limit survival
* Hepatic disease (ALT greater than 2 times the ULN)
* Fasting triglycerides greater than 1000 mg/dL in the presence of moderate glycemic control (HbA1c less than 9.0%)
* Current alcohol abuse
* Chronic steroid use judged to interfere with the control of diabetes, exceeding 10 mg of Prednisone per day or the equivalent
* Pregnancy, known, suspected, or planned in 5 years after study entry
* Geographically inaccessible or unable to return for follow-up
* Enrolled in a competing randomized trial or clinical study
* Unable to understand or cooperate with protocol requirements

Patients with Type 2 diabetes mellitus and CAD documented by coronary arteriography will be eligible for the trial if revascularization is not required for prompt control of severe or unstable angina. Diabetic patients who are being treated with insulin or oral hypoglycemic drugs will be eligible as well as diabetic patients treated with diet and exercise alone provided that a diagnosis of diabetes can be confirmed by record review or that a fasting plasma glucose (FPG) greater than 125/mg/dL (7.0 mmol/L) can be obtained. The determination of suitability for BARI 2D will be made by a physician-investigator at each participating institution on clinical grounds at the time of coronary angiography.

Significant CAD will be defined as at least one stenosis greater than 50%. Angina and ischemia will be assessed by use of patient self-report, physician examination, and appropriate diagnostic measures including exercise myocardial perfusion imaging, exercise echocardiography, exercise electrocardiography, and IV dipyridamole or adenosine myocardial perfusion imaging or invasively by doppler or pressure wire. Objective documentation of myocardial ischemia includes any of the following:

1. Exercise or pharmacologically-induced:

   1. Greater than or equal to 1 mm of horizontal or downsloping ST depression or elevation for greater than or equal to 60-80 milliseconds after the end of the QRS complex
   2. Myocardial perfusion defect
   3. Myocardial wall motion abnormality
2. Stabilized, prior acute coronary syndrome with CK-MB or troponin elevation or with new, greater than or equal to 0.5 mm ST depression or elevation, or T wave inversion of greater than or equal to 3 mm in 2 contiguous ECG leads
3. Doppler or pressure wire showing coronary flow reserve (CFR) less than 2.0 or fractional flow reserve (FFR) less than 0.75

Among patients without documented ischemia, only patients with stenosis greater than or equal to 70% presenting with classic anginal symptoms will be eligible for randomization.
D: Inclusion Criteria:

* Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.

Exclusion Criteria:

* Angina pectoris, Canadian Class I-II,
* congestive heart failure, Class III-IV,
* stroke, incapacitating or in last 6 months,
* Myocardial infarction (MI) or invasive cardiovascular procedure within the past six months,
* ongoing diabetic gangrene,
* BMI \> 40,
* hemoglobinopathy that interferes with A1c monitoring,
* serum creatinine \> 1.6 mg/dL,
* fasting C-peptide \< 0.21 pmol/ml,
* Alanine Amino Transaminase (ALT) \> 3 times normal or serum bilirubin \> 1.9 mg/dL,
* malignancy or noncardiac life-threatening diseases making life expectancy \< 5 years,
* autonomic neuropathy,
* symptomatic pancreatic insufficiency (endocrine or exocrine),
* recurrent seizures within the past year,
* hypopituitarism,
* pregnancy, lactation, or planning a pregnancy,
* active psychosis or substance abuse,
* lack of access to a person who can assist or be called in an emergency,
* underlying conditions that in the site PI's judgment may prevent adherence to protocol,
* current participation in another clinical trial

Answer: C