RANOLAZINE STUDY: Speckle Tracking Derived Myocardial Strain

RANOLAZINE STUDY: The Effect of Ranolazine on Speckle Tracking Derived Myocardial Strain in Regions of Non-Revascularizable Ischemic Myocardium

The purpose of this study is to collect data to determine if the medication, Ranolazine, effects heart muscle function in patients who have areas of non-revascularizable heart muscle.

Study Overview

• Status: Withdrawn
• Conditions: Severe Coronary Artery Disease; Ischaemic Myocardial Dysfunction
• Intervention / Treatment: Drug: Ranolazine

Detailed Description

Many cardiac patients with severe coronary artery disease have areas of ischemic LV myocardium that cannot be revascularized (Non-R). The investigators propose to identify such patients via retrospective case review of CMRI data, as well as identify the exact regions which specify Non-R coronary anatomy. This selected study group will have a specific echocardiographic imaging protocol performed, which includes the known ischemic regions. All segments will be collected and analyzed as a pre-therapeutic baseline using specialized STE software to derive strain values. Following eight (8) weeks of ranolazine therapy, each subject will be re-interrogated with the same echocardiographic imaging protocol and have identical measurements of regional strain performed. Ranolazine will be added to the patients' usual medical therapy. Each patient will serve as their own control, from baseline to post therapeutic state.

It is the hypothesis of the investigators, that additional therapeutic dosing of ranolazine will improve regional and perhaps global myocardial function. Improvement in LV mechanical function (regional and global) will be quantitated and objectively elucidated by STE derived myocardial strain as described further in this document.

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Saint Thomas Heart at Saint Thomas West

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Study population will be either male or female, age 18 or greater with stable GDMT for 60 days prior to enrollment. They will be in normal sinus rhythm with coronary artery revascularization more than 60 days prior to enrollment, with a non-revascularizable area of myocardial ischemia as determined by stress MRI. They will be able to perform the bicycle stress echocardiogram and able to provide written informed consent.

Description

Inclusion Criteria:

• age > 18 Stable GDMT for 60 days prior to enrollment Normal sinus rhythm Coronary artery revascularization > 60 days prior to enrollment Non-revascularizable area of myocardial ischemia as determined by stress MRI Able to perform the bicycle stress echocardiograms Able to provide written, informed consent Women of childbearing potential with negative pregnancy test at the index visit, and consent to use effective contraception throughout the study period and up to at least 14 days following the last dose of study drug

Exclusion Criteria:

• More than 1+MR, aortic stenosis, aortic insufficiency, mitral stenosis Serious co-morbidities with predicted life expectancy <1 year Patients not in normal sinus rhythm (NSR) Patients who have undergone coronary artery revascularization (PCI, CABG) within 60 days Pregnant or unknown pregnancy status Liver cirrhosis Patients unwilling/unable to provide written, informed consent Concomitant use of QTc prolonging drugs, potassium channel variants resulting in a long QT interval, patients with a family history of (or congenital) long QT syndrome, and patients with known acquired QT interval prolongation Concomitant use of strong CYP3A inhibitors including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir Concomitant use of CYP3A4 inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort Breast feeding Atrial fibrillation or frequent atrial or ventricular ectopy Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) P-gp inhibitors (e.g., cyclosporine) which increase ranolazine exposure Renal failure. Patients with Creatinine clearance less than 30ml/min . Safety Considerations for patients with the following drugs/conditions CYP3A substrates: Limit simvastatin to 20 mg when used with ranolazine. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with ranolazine OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with ranolazine Renal failure: Patients with creatinine clearance less than 30ml/min are excluded from participation in this study. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min). If acute renal failure develops, discontinue ranolazine.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Selected group with cardiac ischemia; This selected study group will have a specific echocardiographic imaging protocol performed, which includes the known ischemic regions. All segments will be collected and analyzed as a pre-therapeutic baseline using specialized STE software to derive strain values. Following eight (8) weeks of ranolazine therapy, each subject will be re-interrogated with the same echocardiographic imaging protocol and have identical measurements of regional strain performed. Ranolazine will be added to the patients' usual medical therapy. Each patient will serve as their own control, from baseline to post therapeutic state.

Drug: Ranolazine; Study group will receive additional therapeutic dosing of drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of strain	Changes in 3D regional left ventricular myocardial strain assessed by speckle-tracking	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular function	2D global longitudinal strain and various other echo parameters of left ventricular function	8 weeks

Collaborators and Investigators

• Sponsor: Saint Thomas Health
• Investigators: Principal Investigator: Douglas J Pearce, MD, Saint Thomas Health

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2017
• Primary Completion (Actual): November 16, 2017
• Study Completion (Actual): February 16, 2018

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: August 18, 2017
• First Posted (Actual): August 22, 2017

Study Record Updates

• Last Update Posted (Actual): April 10, 2018
• Last Update Submitted That Met QC Criteria: April 6, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: STH 16-012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes