Ranolazine Implantable Cardioverter-Defibrillator Trial

NCT ID: NCT01215253

Last Updated: 2018-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1012 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2017-02-28

Brief 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.

Detailed 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.

Conditions

Ischemic Cardiomyopathy; Nonischemic Cardiomyopathy; Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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 end of first week. For patients on anti-arrhythmic therapy at the time of randomization, their ECG will be checked at end of first week on 500 mg dose and again at end of second week on 1000 mg dose. For patients with CrCl \<60ml/min prior to randomization, their CrCl will be checked again at 2 weeks and study drug discontinued if \<30ml/min. For patients with CrCl \<60ml/min at 2 weeks, their CrCl will be checked again at 4 weeks and study drug discontinued if \<30ml/min.

Group Type: ACTIVE_COMPARATOR

Ranolazine

Intervention Type: DRUG

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.

Placebo

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 end of first week. For patients on anti-arrhythmic therapy at the time of randomization, their ECG will be checked at end of first week on 500 mg dose and again at end of second week on 1000 mg dose. For patients with CrCl \<60ml/min prior to randomization, their CrCl will be checked again at 2 weeks and study drug discontinued if \<30ml/min. For patients with CrCl \<60ml/min at 2 weeks, their CrCl will be checked again at 4 weeks and study drug discontinued if \<30ml/min.

Group Type: PLACEBO_COMPARATOR

Ranolazine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Ranexa

Eligibility Criteria

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

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Rochester

OTHER

Sponsor Role: lead

Responsible Party

Wojciech Zareba

MD PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wojciech Zareba, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Locations

University of Arizona

Tucson, Arizona, United States

Arkansas Cardiology

Little Rock, Arkansas, United States

Sequoia Hospital

East Palo Alto, California, United States

Good Samaritan Hospital

Los Angeles, California, United States

Huntington Memorial Hospital

Pasadena, California, United States

Regional Cardiology Associates

Sacramento, California, United States

Delta Heart and Medical Clinic

Stockton, California, United States

University of Colorado Health - MHS

Colorado Springs, Colorado, United States

Bridgeport Hospital

Bridgeport, Connecticut, United States

Hartford Hospital

Hartford, Connecticut, United States

Washington Electrophysiology/Cardiovascular Research Institute

Washington D.C., District of Columbia, United States

Bay Area Cardiology Associates, P.A.

Brandon, Florida, United States

University of Florida/Cardiovascular Medicine

Gainesville, Florida, United States

University of Florida Health Science Center at Jacksonville

Jacksonville, Florida, United States

Watson Clincia Center for Research Inc.

Lakeland, Florida, United States

Florida Hospital

Orlando, Florida, United States

Tallahassee Research Institute, Inc.

Tallahassee, Florida, United States

Georgia Health Sciences University

Augusta, Georgia, United States

Georgia Arrhythmia Consultants

Macon, Georgia, United States

University of Chicago Hospital

Chicago, Illinois, United States

Peakview Research Center

Fort Wayne, Indiana, United States

LaPorte Hospital

Hobart, Indiana, United States

University of Iowa

Iowa City, Iowa, United States

Central Baptist Hospital

Lexington, Kentucky, United States

Louisiana State University Health Sciences Center- New Orleans

New Orleans, Louisiana, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

MedStar Southern Maryland Hospital Center

Clinton, Maryland, United States

Tufts-New England Medical Center

Boston, Massachusetts, United States

Lahey Clinic

Burlington, Massachusetts, United States

University of Massachusetts-Worchester

Worcester, Massachusetts, United States

Henry Ford Hospital

Detroit, Michigan, United States

William Beaumont Hospital - Royal Oak

Royal Oak, Michigan, United States

Michigan Heart

Ypsilanti, Michigan, United States

St. Luke's Hospital Association of Duluth

Duluth, Minnesota, United States

University of Minnesota

Minneapolis, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

University of Missouri

Columbia, Missouri, United States

Kansas City Heart Foundation

Kansas City, Missouri, United States

Cooper University Hospital

Camden, New Jersey, United States

Morristown Memorial Hospital- Gagnon Cardiovascular Institute

Morristown, New Jersey, United States

SUNY Downstate Medical Center

Brooklyn, New York, United States

New York Methodist Hospital

Brooklyn, New York, United States

Maimonides Medical Center

Brooklyn, New York, United States

Weill Cornell Medical College/New York Presbyterian Hospital

New York, New York, United States

St. Luke's-Roosevelt Hospital

New York, New York, United States

Hudson Valley Heart Center

Poughkeepsie, New York, United States

The Valley Hospital

Ridgewood, New York, United States

University of Rochester

Rochester, New York, United States

Stony Brook University Medical Center,

Stony Brook, New York, United States

Durham VA Medical Center

Durham, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, 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

The Toledo Hospital/Northwest Ohio Cardiology Consultants

Toledo, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Portland VA Medical Ctr

Portland, Oregon, United States

Abington Medical Specialists

Abington, Pennsylvania, United States

Doylestown Cardiology Associates - VIAA

Doylestown, Pennsylvania, United States

Doylestown Health Cardiology/Central Bucks

Doylestown, Pennsylvania, United States

Lancaster Heart & Stroke Foundation

Lancaster, Pennsylvania, 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

Lankenau Institute for Medical Research

Wynnewood, Pennsylvania, United States

Brigham and Women's Cardiovascular Associates

Warwick, Rhode Island, United States

The Stern Cardiovascular Center

Germantown, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Texas Cardiac Arrhythmia Research Foundation

Austin, Texas, United States

Cardiopulmonary Research Science and Technology Inst.

Dallas, Texas, United States

Medicus Alliance CRO, Inc

Houston, Texas, United States

University of Virginia Health System

Charlottesville, Virginia, United States

Cardiovascular Associates Ltd.

Chesapeake, Virginia, United States

Walter Reed NMMC

Portsmouth, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Kootenai Heart Clinics, LLC

Spokane, Washington, United States

Cardiac Study Center

Tacoma, Washington, United States

CAMC Institute

Charleston, West Virginia, United States

Marshfield Clinic

Marshfield, Wisconsin, United States

Aurora St. Luke's Medical Center

Milwaukee, Wisconsin, United States

Wheaton Franciscan All Saints

Racine, Wisconsin, United States

University of Calgary

Calgary, Alberta, Canada

Royal Alexandra Hospital

Edmonton, Alberta, Canada

Queen's University

Kingston, Ontario, Canada

Montreal Heart Institute

Montreal, Quebec, Canada

McGill University Health Centre

Montreal, Quebec, Canada

CHUS (Sherbrooke University)

Sherbrooke, Quebec, Canada

IUCPQ

Québec, , Canada

Countries

United States; Canada

References

Krzowski B, Kutyifa V, Vloka M, Huang DT, Attari M, Aktas M, Shah AH, Musat D, Rosenthal L, McNitt S, Polonsky B, Schuger C, Natale A, Ziv O, Beck C, Daubert JP, Goldenberg I, Zareba W. Sex-Related Differences in Ventricular Tachyarrhythmia Events in Patients With Implantable Cardioverter-Defibrillator and Prior Ventricular Tachyarrhythmias. JACC Clin Electrophysiol. 2024 Feb;10(2):284-294. doi: 10.1016/j.jacep.2023.09.028. Epub 2023 Nov 29.

Reference Type: DERIVED

PMID: 38032582 (View on PubMed)

Younis A, Goldenberg I, Farooq S, Yavin H, Daubert J, Raitt M, Mazur A, Huang DT, Mitchell BL, Rashtian MR, Winters S, Vloka M, Aktas M, Bernabei MA, Beck CA, McNitt S, Zareba W. Reduction in Ventricular Tachyarrhythmia Burden in Patients Enrolled in the RAID Trial. JACC Clin Electrophysiol. 2022 Jun;8(6):754-762. doi: 10.1016/j.jacep.2022.02.018. Epub 2022 Apr 27.

Reference Type: DERIVED

PMID: 35738852 (View on PubMed)

Zareba W, Daubert JP, Beck CA, Huang DT, Alexis JD, Brown MW, Pyykkonen K, McNitt S, Oakes D, Feng C, Aktas MK, Ayala-Parades F, Baranchuk A, Dubuc M, Haigney M, Mazur A, McPherson CA, Mitchell LB, Natale A, Piccini JP, Raitt M, Rashtian MY, Schuger C, Winters S, Worley SJ, Ziv O, Moss AJ; RAID Trial Investigators. Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial. J Am Coll Cardiol. 2018 Aug 7;72(6):636-645. doi: 10.1016/j.jacc.2018.04.086.

Reference Type: DERIVED

PMID: 30071993 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U01HL096607

Identifier Type: NIH

Identifier Source: org_study_id

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