Does Ranolazine Decrease Biomarkers of Myocardial Damage in Diabetics

Study Overview
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Brief Summary
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The purpose of this investigation is to compare subjects at high risk for silent myocardial ischemia in the placebo group to subjects at high risk for silent myocardial ischemia in the ranolazine group to determine if ranolazine can be used as a treatment to decrease silent myocardial ischemia (SMI). Subjects at high risk for silent myocardial ischemia are defined in this protocol as diabetics with stable ischemic heart disease. This study will look at the impact ranolazine treatment has on biomarkers that have been shown to be highly associated with increased risk of morbidity and mortality in relation to SMI. If the hypothesis is correct, further studies can be conducted to determine if treatment with ranolazine has impact on long-term outcomes such as hospitalizations, myocardial infarction, congestive heart failure or sudden cardiac death.

Official Title
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Does Ranolazine Decrease Biomarkers That Indicate Evidence of Myocardial Damage in Diabetics With Stable Ischemic Heart Disease? A Double-blinded, Randomized, Placebo Controlled Trial

Conditions
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Silent Myocardial Ischemia, Type 2 Diabetes

Intervention / Treatment
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* Drug: Ranolazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects at risk for silent myocardial ischemia as defined by: Stable ischemic heart disease as defined by: Obstruction of at least one epicardial vessel of > 50 percent by invasive or non-invasive coronary angiography, or Evidence of ischemia or infarct on SPECT imaging, or History of myocardial infarction > 3 months ago, or Stent placement (PCI) > 3 months ago, or Coronary artery bypass grafting (CABG) > 3 months ago AND Type 2 diabetics as defined by: HgbA1C ≥ 6.5 percent, or Fasting Blood Glucose > 125 mg/dL on two or more blood draws, or Random Blood Glucose of ≥ 200 mg/dL on a single blood draw, or Previous diagnosis of type 2 diabetes listed in the subject's medical record AND - On Optimal Medical Therapy as defined as being on ALL of the following at time of enrollment: Beta Blocker Aspirin Statin AND Females < 60 who have not been free of menstruation for 2 years (menopause diagnosed) or who do not have documented history of hysterectomy must be willing to use at least one form of birth control (including abstinence as an option) for the duration of the study. If condoms are the method chosen, they are strongly urged to use a second form of birth control in addition to condoms. AND Screening Criteria met: • hs cTnT > 0.014 ng/mL Exclusion Criteria: Percutaneous intervention/stent placement in the past 3 months Coronary artery bypass grafting in the past 3 months Treatment with ranolazine in the past 12 months Significant lung disease, COPD or use of supplemental oxygen Cirrhosis Estimated Glomerular Filtration Rate (GFR) < 30 Subject taking strong CYP3A inhibitors (ketoconazole, itraconazole, clarithryomycin, nefazodone, nelfinavir, ritonavir, indinavir and saquinavir) Subject taking strong CYP3A inducers (rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, St. John's wort) Subjects taking P-gp Inhibitors (cyclosporine) Subject is taking concurrent simvastatin in > 20 mg/day Subject is taking metformin > 1700 mg/day NYHA Class 3 or 4 Heart Failure (severe) Canadian Cardiovascular Society Grade 4 Angina Unstable angina defined as a new angina occurring after minimal exercise or at rest OR a significant increase in angina severity (≥ 2 CCS grades) occurring with minimal exertion, with high clinical suspicion of acute coronary syndrome. Planned PCI or Cardiac Surgery Pregnant females or females trying to become pregnant Breast-feeding females Subjects younger than age 30 or older than age 85 Lactose Intolerance (placebo has lactose monohydrate) Lactose/Milk allergy (placebo has lactose monohydrate) QTc > 500 msec

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranolazine<br>Subjects will take one 500mg tablet twice daily (500mg BID) for seven days and then increase to two 500mg tablets twice daily (1000mg BID) for the remainder of the study, for a total of 24 weeks. Subjects taking moderate CYP3A4 inhibitors will not participate in upward titration and will remain on 500mg tablet twice daily (500mg BID) for the duration of the trial. | Drug: Ranolazine<br>* 24 weeks of the assigned medication<br>|
| Placebo Comparator: Placebo<br>Subjects will take one placebo tablet (identical to the 500mg Ranolazine tablet) twice daily (500mg BID) for seven days and then increase to two 500mg tablets twice daily (1000mg BID) for the remainder of the study, for a total of 24 weeks. Subjects taking moderate CYP3A4 inhibitors will not participate in upward titration and will remain on 500mg tablet twice daily (500mg BID) for the duration of the trial. | Drug: Placebo<br>* Placebo for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hs cTnT | Does ranolazine decrease hs cTnT in subjects at high risk for silent myocardial ischemia? | 24 weeks | 
| NT-pro-BNP | Does ranolazine decrease NT-pro-BNP in subjects at high risk for silent myocardial ischemia? | 24 weeks | 
| hsCRP | Determine the degree of decrease of hs CRP in subjects in the ranolazine group. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| prevalence of hs cTnT > 99th percentile | Determine the prevalence of hs cTnT greater than the 99th percentile (0.014 ng/mL) in asymptomatic diabetic subjects with stable ischemic heart disease. | 24 weeks |