Ranolazine Implantable Cardioverter-Defibrillator Trial

Heart Failure Clinical Trial

— RAID  

Official title:

Late Sodium Current Blockade in High-Risk ICD Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01215253
• Other study ID #: U01HL096607
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Cardiomyopathies
• Heart Failure
• Ischemic Cardiomyopathy
• Nonischemic Cardiomyopathy

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