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Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD (RAND-CFR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Brigham and Women's Hospital
Sponsor:
Information provided by (Responsible Party):
Marcelo F. Di Carli, MD, FACC, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT01754259
First received: December 12, 2012
Last updated: July 15, 2014
Last verified: July 2014

December 12, 2012
July 15, 2014
April 2013
December 2014   (final data collection date for primary outcome measure)
Change in post-exercise coronary vasodilator reserve [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization.
Same as current
Complete list of historical versions of study NCT01754259 on ClinicalTrials.gov Archive Site
  • Change in symptoms of exertional angina and/or dyspnea [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change in symptoms of exertional angina and/or dyspnea on the Seattle Angina Questionnaire and Rose Dyspnea Scale Questionnaire at 4 weeks post randomization;
  • Change in left ventricular systolic function [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in left ventricular systolic function, reflected primarily in LV global longitudinal strain, at 4 weeks post randomization
  • Change in post-exercise global myocardial blood flow [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in post-exercise global myocardial blood flow (in mL/min/g) at 4 weeks post randomization
  • Change in post-exercise global coronary vascular resistance [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in post-exercise global coronary vascular resistance (in mm Hg/mL/min/g) at 4 weeks post randomization
  • Change in serum biomarkers of myocardial strain [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change in serum biomarkers of myocardial strain (ultrasensitive troponin I (usTnI), N-terminal pro-B-type natriuretic peptide (NTproBNP), and the interleukin family member (ST2)), as well as glycosylated hemoglobin (A1c) at 4 weeks post randomization
  • Correlation between multimodality imaging parameters [ Time Frame: varies ] [ Designated as safety issue: No ]
    Correlation between multimodality imaging parameters (in PET, echo, and angiography) characterizing extent of coronary vascular reactivity, myocardial dysfunction and patterns of atherosclerotic disease
  • Change in LV diastolic function [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization
Same as current
Not Provided
Not Provided
 
Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD
Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Patients With Diabetes and Suspected or Known Coronary Artery Disease

Coronary vascular dysfunction is highly prevalent among patients with known or suspected Coronary Artery Disease (CAD)1, increases the severity of inducible myocardial ischemia (beyond the effects of upstream coronary obstruction)2, and identifies patients at high risk for serious adverse events, including cardiac death1, 3-5. Diabetic patients without known CAD with impaired coronary vascular function show a risk of cardiac death comparable to, and possibly higher, than that for non-diabetic patients with known CAD10. In the setting of increased oxygen demand, coronary vasodilator dysfunction can upset the supply-demand relationship and lead to myocardial ischemia, subclinical left ventricular dysfunction (diastolic and systolic), and symptoms.

The significance of microvascular coronary dysfunction is increasingly recognized as invasive and non-invasive (PET) methods of quantifying CFR become available.

Importantly, current treatment strategies for obstructive CAD, such as percutaneous coronary intervention with angioplasty and stenting, are not helpful in microvascular disease. Similarly, mortality-altering treatments for systolic heart failure, such as angiotensin converting enzyme inhibitors, have not been beneficial in treating diastolic dysfunction.

Ranolazine is a novel anti-anginal agent which inhibits the late sodium current in cardiomyocytes, decreasing sodium and calcium overload. In ischemia, excess of intracellular calcium may impair myocyte relaxation and contribute to ventricular diastolic stiffness, which in turn affects myocardial contractility and perfusion. Ranolazine is FDA-approved for treatment of chronic angina. In three randomized, placebo-controlled trials of patients with stable angina, it was shown to increase exercise time free of angina and ST-segment depression, increase exercise capacity and decrease angina when used in combination with established antianginal agents including diltiazem, amlodipine or atenolol, and reduce the frequency of angina on patients on maximum doses of amlodipine.Similarly, in a large population of patients with acute coronary syndromes, ranolazine also decreased exertional angina symptoms and incidence of arrhythmias, with no effect on mortality. Interestingly, in this same study, it significantly improved hemoglobin A1c and recurrent ischemia in patients with diabetes mellitus, and reduced the incidence of increased hemoglobin A1c in patients without known prior hyperglycemia.

Although the anti-ischemic effect of ranolazine is thought to be mediated in part by increased myocardial blood flow,there is currently limited evidence for such an effect on tissue perfusion. A previous study in women without overt CAD did not detect improved myocardial blood flow after treatment with ranolazine. In that study, however, coronary hyperemia was elicited with adenosine (which uncouples blood flow from cardiac work, and reflects predominantly endothelial-independent vasodilation) rather than exercise, which triggers a more complex interplay between metabolic demand, coronary hemodynamics, and vasodilator response. Thus, there is a need for additional investigation of whether the beneficial effects of ranolazine on exertional symptoms are directly related to improved global tissue perfusion. Such evidence would support the use of ranolazine as an anti-ischemic therapy in the challenging population of symptomatic patients with evidence of microvascular dysfunction without obstructive CAD.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
  • Diabetes, Type I
  • Diabetes, Type II
  • Angina
  • Coronary Artery Disease
  • Drug: Ranolazine
    Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
  • Drug: Placebo Pill
    Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
  • Experimental: Ranolazin
    subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
    Intervention: Drug: Ranolazine
  • Placebo Comparator: Placebo
    Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
    Intervention: Drug: Placebo Pill
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
70
Not Provided
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria

  1. type 1 or 2 diabetes mellitus
  2. anginal symptoms and/or exertional dyspnea;
  3. ability to exercise and achieve an exercise tolerance of at least 3 METS but not higher than 9 METS either on a treadmill or bicycle exercise tolerance test;
  4. perfusion sum stress score (SSS) ≤ 6, as assessed by initial PET

Exclusion Criteria

  1. patients not fulfilling inclusion criteria
  2. patients with evidence of unprotected left main coronary artery stenosis >50%
  3. patients with evidence of new obstructive CAD not on optimal medical therapy
  4. evidence of angiographic disease and/or inducible myocardial ischemia on stress testing planning to undergo revascularization within the following 3 months
  5. history of cardiomyopathy (LVEF <40%) or significant valvular heart disease
  6. uncontrolled hypertension (SBP >180 mm Hg at screening)
  7. gait instability, lower extremity amputations preventing exercise

9. significant liver dysfunction (LFTs >3x upper limits of normal), including cirrhosis 10. prolonged QT (QTc >450 and >470 ms for men and women, respectively) or concomitant use of drugs that prolong QT interval (including methadone and antiarrhythmics such as sotalol, amiodarone, and quinidine) 11. use of drugs that inhibit CYP3A such as ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, diltiazem, verapamil, nefazodone, nelfinavir, ritonavir, lopinavir, ritonavir, indinavir, and saquinavir 12. use of drugs that induce CYP3A such rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort 13. atrial fibrillation / inability to hold breath for ≥ 10 seconds (in patients in whom CTA will be performed) 14. eGFR < 50 ml/min or end stage renal disease on dialysis 15. allergy to intravenous contrast 16. pregnant or lactating women, or women of childbearing potential not using an acceptable form of birth control (negative pregnancy test also required) 17. inability to fit safely in PET/CT scanner

Both
18 Years to 90 Years
No
Contact: Marcelo Di Carli, MD 617-525-8322 mdicarli@partners.org
Contact: Masha Gaber, ALM 617-732-4237 mgaber@partners.org
United States
 
NCT01754259
2012P002537
Yes
Marcelo F. Di Carli, MD, FACC, Brigham and Women's Hospital
Brigham and Women's Hospital
Not Provided
Principal Investigator: Marcelo Di Carli, MD Brigham and Women's Hospital
Brigham and Women's Hospital
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP