Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD

NCT01754259 | Completed Phase 3 Results DMC

• 1 other identifier: 2012P002537
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes, Type I; Diabetes, Type II; Angina; Coronary Artery Disease

Keywords

type 1 diabetes; type 2 diabetes; exertion angina; suspected CAD; known CAD

Outcome Measures

Primary Outcomes (1)

• Change in Post-exercise Coronary Vasodilator Reserve

  Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization. Per-patient global coronary flow reserve (CFR) was calculated as the ratio of absolute MBF at stress over rest for the entire left ventricle. Quantitation of MBF was performed by two operators blinded to patient, treatment period and treatment order.

  4 weeks

Secondary Outcomes (1)

• Change in LV Diastolic Function

  4 weeks

Study Arms (2)

Ranolazine

EXPERIMENTAL

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Drug: Ranolazine

Placebo

PLACEBO COMPARATOR

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Drug: Placebo

Interventions

Ranolazine DRUG

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Also known as: Ranexa

Ranolazine

Placebo DRUG

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Also known as: Placebo pill

Placebo

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• type 1 or 2 diabetes mellitus
• anginal symptoms and/or exertional dyspnea;
• 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;
• perfusion sum stress score (SSS) ≤ 6, as assessed by initial PET

You may not qualify if:

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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Shah NR, Cheezum MK, Veeranna V, Horgan SJ, Taqueti VR, Murthy VL, Foster C, Hainer J, Daniels KM, Rivero J, Shah AM, Stone PH, Morrow DA, Steigner ML, Dorbala S, Blankstein R, Di Carli MF. Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function. J Am Heart Assoc. 2017 May 4;6(5):e005027. doi: 10.1161/JAHA.116.005027.

  PMID: 28473401 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Angina Pectoris; Coronary Artery Disease

Interventions

Ranolazine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Chest Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Coronary Disease; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The limitations for our study include a relatively small cohort size of 47 patients, that our mechanistic trial was not designed to assess clinical outcomes and that our experimental design allowed for inclusion of patients with non-obstructive CAD.

Results Point of Contact

• Title: Dr. Marcelo Di Carli
• Organization: Brigham and Women's Hospital

mdicarli@partners.org

617-732-6291

Study Officials

• Marcelo Di Carli, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Nuclear Medicine

Model Details: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Study Record Dates

• First Submitted: December 12, 2012
• First Posted: December 21, 2012
• Study Start: April 1, 2013
• Primary Completion: October 1, 2015
• Study Completion: December 1, 2015
• Last Updated: July 24, 2017
• Results First Posted: July 24, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)