Clinical trial NCT01215253: Ranolazine Implantable Cardioverter-Defibrillator Trial
Official title: Late Sodium Current Blockade in High-Risk ICD Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemic Cardiomyopathy
Nonischemic Cardiomyopathy
Heart Failure
Keywords: Sudden Death
Ranolazine
Heart failure
Ventricular tachycardia
Ventricular fibrillation
Implantable cardioverter-defibrillator
Lead sponsor: University of Rochester
Sponsor class: OTHER
First posted: 2010-10-06
Enrollment: 1012
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death
timeFrame: 2 years of follow-up on average
Secondary outcomes:
measure: Number of Patients With VT or VF Requiring ICD Shock or Death
timeFrame: 2 years of follow-up on average
measure: Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies
timeFrame: 2 years of follow-up on average
measure: Number of Patients With First Inappropriate ICD Shock
timeFrame: 2 years of follow-up on average
measure: Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First.
timeFrame: 2 years of follow-up on average
measure: Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First
timeFrame: 2 years of follow-up on average
measure: Death
timeFrame: 2 years of follow-up on average
measure: Mean Meters Walked in 6 Minutes
timeFrame: 1 year of follow-up
measure: Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: 1 year follow-up
measure: Number of Recurrent Inappropriate ICD Shocks
timeFrame: 2 years of follow-up on average
Other outcomes:
measure: Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP)
timeFrame: 2 years of follow-up on average
measure: Number of Patients Whose First VT/VF Required ICD Shock
timeFrame: 2 years of follow-up on average
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Cardiology
state: Arkansas
city: East Palo Alto
country: United States
facility: Sequoia Hospital
state: California
city: Los Angeles
country: United States
facility: Good Samaritan Hospital
state: California
city: Pasadena
country: United States
facility: Huntington Memorial Hospital
state: California
city: Sacramento
country: United States
facility: Regional Cardiology Associates
state: California
city: Stockton
country: United States
facility: Delta Heart and Medical Clinic
state: California
city: Colorado Springs
country: United States
facility: University of Colorado Health - MHS
state: Colorado
city: Bridgeport
country: United States
facility: Bridgeport Hospital
state: Connecticut
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Washington
country: United States
facility: Washington Electrophysiology/Cardiovascular Research Institute
state: District of Columbia
city: Brandon
country: United States
facility: Bay Area Cardiology Associates, P.A.
state: Florida
city: Gainesville
country: United States
facility: University of Florida/Cardiovascular Medicine
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health Science Center at Jacksonville
state: Florida
city: Lakeland
country: United States
facility: Watson Clincia Center for Research Inc.
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Tallahassee
country: United States
facility: Tallahassee Research Institute, Inc.
state: Florida
city: Augusta
country: United States
facility: Georgia Health Sciences University
state: Georgia
city: Macon
country: United States
facility: Georgia Arrhythmia Consultants
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Peakview Research Center
state: Indiana
city: Hobart
country: United States
facility: LaPorte Hospital
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: Central Baptist Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Louisiana State University Health Sciences Center- New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Clinton
country: United States
facility: MedStar Southern Maryland Hospital Center
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts-Worchester
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak
state: Michigan
city: Ypsilanti
country: United States
facility: Michigan Heart
state: Michigan
city: Duluth
country: United States
facility: St. Luke's Hospital Association of Duluth
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Heart Foundation
state: Missouri
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Morristown
country: United States
facility: Morristown Memorial Hospital- Gagnon Cardiovascular Institute
state: New Jersey
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: Brooklyn
country: United States
facility: Maimonides Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College/New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: St. Luke's-Roosevelt Hospital
state: New York
city: Poughkeepsie
country: United States
facility: Hudson Valley Heart Center
state: New York
city: Ridgewood
country: United States
facility: The Valley Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center,
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Center for Research & Education
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: The MetroHealth System - Heart and Vascular Dept.
state: Ohio
city: Toledo
country: United States
facility: The Toledo Hospital/Northwest Ohio Cardiology Consultants
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Portland
country: United States
facility: Portland VA Medical Ctr
state: Oregon
city: Abington
country: United States
facility: Abington Medical Specialists
state: Pennsylvania
city: Doylestown
country: United States
facility: Doylestown Cardiology Associates - VIAA
state: Pennsylvania
city: Doylestown
country: United States
facility: Doylestown Health Cardiology/Central Bucks
state: Pennsylvania
city: Lancaster
country: United States
facility: Lancaster Heart & Stroke Foundation
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center-Presbyterian
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare Center
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Institute for Medical Research
state: Pennsylvania
city: Warwick
country: United States
facility: Brigham and Women's Cardiovascular Associates
state: Rhode Island
city: Germantown
country: United States
facility: The Stern Cardiovascular Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Texas Cardiac Arrhythmia Research Foundation
state: Texas
city: Dallas
country: United States
facility: Cardiopulmonary Research Science and Technology Inst.
state: Texas
city: Houston
country: United States
facility: Medicus Alliance CRO, Inc
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Chesapeake
country: United States
facility: Cardiovascular Associates Ltd.
state: Virginia
city: Portsmouth
country: United States
facility: Walter Reed NMMC
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Spokane
country: United States
facility: Kootenai Heart Clinics, LLC
state: Washington
city: Tacoma
country: United States
facility: Cardiac Study Center
state: Washington
city: Charleston
country: United States
facility: CAMC Institute
state: West Virginia
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Racine
country: United States
facility: Wheaton Franciscan All Saints
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Kingston
country: Canada
facility: Queen's University
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: CHUS (Sherbrooke University)
state: Quebec
city: Quebec
country: Canada
facility: IUCPQ
Study officials:
affiliation: University of Rochester
name: Wojciech Zareba, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.