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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01215253
Other study ID # U01HL096607
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date September 2011
Est. completion date February 28, 2017

Study information

Verified date July 2018
Source University of Rochester
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The purpose of the study is to see how effective a drug called ranolazine is in reducing the risk of ventricular arrhythmia and death in people with implantable cardioverter-defibrillators (ICDs). This drug will be used with standard medications that is routinely prescribed in enrolled patients.


Description:

There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta-blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage.

Ranolazine is a novel drug with anti-ischemic and antiarrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The antiischemic and antiarrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients with ventricular arrhythmias.

We designed a randomized double-blind placebo-controlled clinical trial enrolling 1,440 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy to test the hypothesis that late sodium current blockade contributes to significant reduction in the risk of arrhythmic events or death in high-risk ICD/cardiac resynchronization therapy-D patients.


Recruitment information / eligibility

Status Completed
Enrollment 1012
Est. completion date February 28, 2017
Est. primary completion date February 28, 2017
Accepts healthy volunteers No
Gender All
Age group 21 Years and older
Eligibility Inclusion Criteria:

1,440 high-risk patients with ischemic/nonischemic cardiomyopathy who receive their ICDs as standard of care for primary or secondary prevention of mortality following approved indications for ICD therapy. High-risk patients will be defined as:

Secondary Prevention Patients Subjects with ischemic or nonischemic cardiomyopathy, qualified for or with existing ICD (or CRT-D) after documented VT/VF or cardiac arrest (secondary prevention of mortality). Secondary prevention subjects with existing implants are eligible regardless of when the implant was received (subjects could be recruited from outpatient clinics or from inpatient activity including during re-implant or other procedures).

Primary Prevention Patients

1. Patients with primary prevention indications for ischemic or non-ischemic cardiomyopathy with EF=35%, with existing devices (ICD/CRT-D), regardless of when the device was implanted, who have experienced at least ONE episode of VT/VF appropriately treated with ICD therapy (ATP or shock) or had untreated NSVT lasting at least 10 beats with heart rate of at least 170 bpm, documented by electrogram of their implanted device.

2. Patients with ischemic or non-ischemic cardiomyopathy with EF=35%, who have been implanted within the last 2 years (initial ICD/CRT-D implants, including upgrades from pacemakers) who have NOT experienced VT/VF treated with ICD therapy (ATP or shock), AND who have one of the following additional criteria: BUN=26 mg/dl or QRS>120ms or Atrial Fibrillation or NSVT documented by ECG/Holter or >500 Ventricular Premature Beats (VPBs)documented in a 24-hour Holter.

- Stable optimal pharmacologic therapy for the cardiac condition

- Age: equal to 21 years without upper limit

Exclusion Criteria:

- Patient receiving first device with coronary artery bypass graft surgery within the last 3 calendar months prior to date consent obtained

- Patients receiving first device with percutaneous coronary intervention within the last 1 calendar month prior to date consent obtained

- Patient receiving first device with enzyme-positive myocardial infarction with the past 3 calendar months prior to date consent obtained

- Patient receiving first device with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future

- Patient in NYHA Class IV

- Patients receiving prophylactic ablation of ventricular substrate

- Patients with preexisting QTc prolongation >550ms

- Patients on strong CYP3A inhibitors (including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir and saquinavir and moderate CYP3A inhibitors, including, diltiazem, verapamil, aprepitant, erythromycin, fluconazole and grapefruit juice or grapefruit-containing products.

- Patients on CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine and St.John's wort

- Patients with inherited arrhythmia disorders such as Brugada's, ARVD, LQTS or hypertrophic cardiomyopathy

- Patient who is pregnant or plans to become pregnant during the course of the trial (patients at child bearing age who use prescribed pharmaceutical contraceptives could be enrolled)

- Patient with irreversible brain damage from preexisting cerebral disease

- Patient with presence of any disease, other than the patient's cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia, liver failure, etc.

- Patient with chronic renal disease with creatinine >2.5 mg/dl or creatinine clearance <30 ml/min

- Patient participating in any other clinical trial

- Patient unwilling or unable to cooperate with the protocol

- Patient who lives at such a distance from the clinic that travel for follow-up visits would be unusually difficult

- Patient who does not anticipate being a resident of the area for the scheduled duration of the trial

- Patients who are decisionally impaired adults, those of questionable capacity, and those who cannot consent for themselves will not be recruited for this study.

- Patient unwilling to sign the consent for participation

Study Design


Intervention

Drug:
Ranolazine
At enrollment, patients will be randomized to ranolazine or placebo. In the active drug arm each patient will be started on a 500 mg twice a day dose for one week with subsequent increase to 1000 mg twice a day at beginning of second week.

Locations

Country Name City State
Canada University of Calgary Calgary Alberta
Canada Royal Alexandra Hospital Edmonton Alberta
Canada Queen's University Kingston Ontario
Canada McGill University Health Centre Montreal Quebec
Canada Montreal Heart Institute Montreal Quebec
Canada IUCPQ Quebec
Canada CHUS (Sherbrooke University) Sherbrooke Quebec
United States Abington Medical Specialists Abington Pennsylvania
United States Georgia Health Sciences University Augusta Georgia
United States Texas Cardiac Arrhythmia Research Foundation Austin Texas
United States Johns Hopkins University Baltimore Maryland
United States University of Maryland Medical Center Baltimore Maryland
United States Tufts-New England Medical Center Boston Massachusetts
United States Bay Area Cardiology Associates, P.A. Brandon Florida
United States Bridgeport Hospital Bridgeport Connecticut
United States Maimonides Medical Center Brooklyn New York
United States New York Methodist Hospital Brooklyn New York
United States SUNY Downstate Medical Center Brooklyn New York
United States Lahey Clinic Burlington Massachusetts
United States Cooper University Hospital Camden New Jersey
United States CAMC Institute Charleston West Virginia
United States University of Virginia Health System Charlottesville Virginia
United States Cardiovascular Associates Ltd. Chesapeake Virginia
United States University of Chicago Hospital Chicago Illinois
United States The Lindner Center for Research & Education Cincinnati Ohio
United States University of Cincinnati Cincinnati Ohio
United States The MetroHealth System - Heart and Vascular Dept. Cleveland Ohio
United States MedStar Southern Maryland Hospital Center Clinton Maryland
United States University of Colorado Health - MHS Colorado Springs Colorado
United States University of Missouri Columbia Missouri
United States Cardiopulmonary Research Science and Technology Inst. Dallas Texas
United States Henry Ford Hospital Detroit Michigan
United States Doylestown Cardiology Associates - VIAA Doylestown Pennsylvania
United States Doylestown Health Cardiology/Central Bucks Doylestown Pennsylvania
United States St. Luke's Hospital Association of Duluth Duluth Minnesota
United States Duke University Medical Center Durham North Carolina
United States Durham VA Medical Center Durham North Carolina
United States Sequoia Hospital East Palo Alto California
United States Peakview Research Center Fort Wayne Indiana
United States University of Florida/Cardiovascular Medicine Gainesville Florida
United States The Stern Cardiovascular Center Germantown Tennessee
United States Hartford Hospital Hartford Connecticut
United States LaPorte Hospital Hobart Indiana
United States Medicus Alliance CRO, Inc Houston Texas
United States University of Iowa Iowa City Iowa
United States University of Mississippi Medical Center Jackson Mississippi
United States University of Florida Health Science Center at Jacksonville Jacksonville Florida
United States Kansas City Heart Foundation Kansas City Missouri
United States Watson Clincia Center for Research Inc. Lakeland Florida
United States Lancaster Heart & Stroke Foundation Lancaster Pennsylvania
United States Central Baptist Hospital Lexington Kentucky
United States Arkansas Cardiology Little Rock Arkansas
United States Good Samaritan Hospital Los Angeles California
United States Georgia Arrhythmia Consultants Macon Georgia
United States Marshfield Clinic Marshfield Wisconsin
United States Aurora St. Luke's Medical Center Milwaukee Wisconsin
United States University of Minnesota Minneapolis Minnesota
United States Morristown Memorial Hospital- Gagnon Cardiovascular Institute Morristown New Jersey
United States Vanderbilt University Medical Center Nashville Tennessee
United States Louisiana State University Health Sciences Center- New Orleans New Orleans Louisiana
United States St. Luke's-Roosevelt Hospital New York New York
United States Weill Cornell Medical College/New York Presbyterian Hospital New York New York
United States Florida Hospital Orlando Florida
United States Huntington Memorial Hospital Pasadena California
United States Drexel University College of Medicine Philadelphia Pennsylvania
United States Thomas Jefferson University Philadelphia Pennsylvania
United States University of Pittsburgh Medical Center-Presbyterian Pittsburgh Pennsylvania
United States VA Pittsburgh Healthcare Center Pittsburgh Pennsylvania
United States Oregon Health & Science University Portland Oregon
United States Portland VA Medical Ctr Portland Oregon
United States Walter Reed NMMC Portsmouth Virginia
United States Hudson Valley Heart Center Poughkeepsie New York
United States Wheaton Franciscan All Saints Racine Wisconsin
United States Virginia Commonwealth University Richmond Virginia
United States The Valley Hospital Ridgewood New York
United States University of Rochester Rochester New York
United States William Beaumont Hospital - Royal Oak Royal Oak Michigan
United States Regional Cardiology Associates Sacramento California
United States Kootenai Heart Clinics, LLC Spokane Washington
United States Delta Heart and Medical Clinic Stockton California
United States Stony Brook University Medical Center, Stony Brook New York
United States Cardiac Study Center Tacoma Washington
United States Tallahassee Research Institute, Inc. Tallahassee Florida
United States The Toledo Hospital/Northwest Ohio Cardiology Consultants Toledo Ohio
United States University of Arizona Tucson Arizona
United States Brigham and Women's Cardiovascular Associates Warwick Rhode Island
United States Washington Electrophysiology/Cardiovascular Research Institute Washington District of Columbia
United States University of Massachusetts-Worchester Worcester Massachusetts
United States Lankenau Institute for Medical Research Wynnewood Pennsylvania
United States Michigan Heart Ypsilanti Michigan

Sponsors (1)

Lead Sponsor Collaborator
University of Rochester

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type Measure Description Time frame Safety issue
Other Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP) Number of patients whose first VT or VF required antitachycardia pacing (ATP) 2 years of follow-up on average
Other Number of Patients Whose First VT/VF Required ICD Shock number of patients whose first VT or VF required ICD shock 2 years of follow-up on average
Primary Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death Primary endpoint of the study will be defined as a composite endpoint consisting of Ventricular Tachycardia or Ventricular Fibrillation requiring antitachycardia pacing (ATP) therapy, implantable cardioverter-defibrillator (ICD) shock, or death, whichever occurs first. 2 years of follow-up on average
Secondary Number of Patients With VT or VF Requiring ICD Shock or Death Implantable cardioverter-defibrillator (ICD) shock for VT or VF or death, whichever occurs first. 2 years of follow-up on average
Secondary Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies Total number of recurrent ICD therapies requiring antitachycardia pacing (ATP) or shock will be analyzed, not just first event 2 years of follow-up on average
Secondary Number of Patients With First Inappropriate ICD Shock Number of patients with first inappropriate ICD shock for other reasons than VT or VF 2 years of follow-up on average
Secondary Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First. Number of patients with a composite endpoint of cardiovascular hospitalization or death, whichever occurred first. 2 years of follow-up on average
Secondary Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First Number of patients with a composite endpoint of heart failure hospitalization or death, whichever occurred first. 2 years of follow-up on average
Secondary Death Death as a safety endpoint of the trial 2 years of follow-up on average
Secondary Mean Meters Walked in 6 Minutes Exercise capacity measured by the 6-minute walk test 1 year of follow-up
Secondary Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a new, self-administered, 23-item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference and quality of life. The scale ranges from 0-100 with lower scores indicating worse outcomes. 1 year follow-up
Secondary Number of Recurrent Inappropriate ICD Shocks Number of recurrent inappropriate ICD shocks in all patients combined. 2 years of follow-up on average
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