Ranolazine Implantable Cardioverter-Defibrillator Trial (RAID)

• ClinicalTrials.gov Identifier: NCT01215253
• Recruitment Status: Completed
• First Posted: October 6, 2010
• Results First Posted: June 15, 2018
• Last Update Posted: August 27, 2018
• Sponsor: University of Rochester
• Information provided by (Responsible Party): Wojciech Zareba, University of Rochester

Tracking Information

• First Submitted Date: September 30, 2010
• First Posted Date: October 6, 2010
• Results First Submitted Date: May 24, 2018
• Results First Posted Date: June 15, 2018
• Last Update Posted Date: August 27, 2018
• Study Start Date: September 2011
• Actual Primary Completion Date: February 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 27, 2018)

Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death [ Time Frame: 2 years of follow-up on average ]

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.

Original Primary Outcome Measures (submitted: October 4, 2010)

Ventricular Tachycardia or Ventricular Fibrillation or Death [ Time Frame: 2 years of follow-up on average ]

Primary endpoint of the study will be defined as a composite endpoint consisting of VT/VF requiring ICD shock or death, whichever occurs first.

Current Secondary Outcome Measures (submitted: July 27, 2018)

• Number of Patients With VT or VF Requiring ICD Shock or Death [ Time Frame: 2 years of follow-up on average ]
  Implantable cardioverter-defibrillator (ICD) shock for VT or VF or death, whichever occurs first.
• Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies [ Time Frame: 2 years of follow-up on average ]
  Total number of recurrent ICD therapies requiring antitachycardia pacing (ATP) or shock will be analyzed, not just first event
• Number of Patients With First Inappropriate ICD Shock [ Time Frame: 2 years of follow-up on average ]
  Number of patients with first inappropriate ICD shock for other reasons than VT or VF
• Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First. [ Time Frame: 2 years of follow-up on average ]
  Number of patients with a composite endpoint of cardiovascular hospitalization or death, whichever occurred first.
• Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First [ Time Frame: 2 years of follow-up on average ]
  Number of patients with a composite endpoint of heart failure hospitalization or death, whichever occurred first.
• Death [ Time Frame: 2 years of follow-up on average ]
  Death as a safety endpoint of the trial
• Mean Meters Walked in 6 Minutes [ Time Frame: 1 year of follow-up ]
  Exercise capacity measured by the 6-minute walk test
• Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: 1 year follow-up ]
  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.
• Number of Recurrent Inappropriate ICD Shocks [ Time Frame: 2 years of follow-up on average ]
  Number of recurrent inappropriate ICD shocks in all patients combined.

Original Secondary Outcome Measures (submitted: October 4, 2010)

Cardiac Hospitalization or Death [ Time Frame: 2 years of follow-up on average ]

Cardiac hospitalization or death, whichever occurs first.

Current Other Pre-specified Outcome Measures (submitted: May 24, 2018)

• Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP) [ Time Frame: 2 years of follow-up on average ]
  Number of patients whose first VT or VF required antitachycardia pacing (ATP)
• Number of Patients Whose First VT/VF Required ICD Shock [ Time Frame: 2 years of follow-up on average ]
  number of patients whose first VT or VF required ICD shock

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ranolazine Implantable Cardioverter-Defibrillator Trial
• Official Title: Late Sodium Current Blockade in High-Risk ICD Patients
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Ischemic Cardiomyopathy
• Nonischemic Cardiomyopathy
• Heart Failure

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.

Other Name: Ranexa

Study Arms

• Active Comparator: 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.
  Intervention: Drug: Ranolazine
• Placebo Comparator: 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.
  Intervention: Drug: Ranolazine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 30, 2015): 1012
• Original Estimated Enrollment (submitted: October 4, 2010): 1440
• Actual Study Completion Date: February 28, 2017
• Actual Primary Completion Date: February 28, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01215253
• Other Study ID Numbers: U01HL096607( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: The RAID PI and Steering Committee with investigators from enrolling sites have designed a series of secondary substudies that will be disseminated as abstracts and manuscripts. External proposal of analyses of the RAID trial data will be reviewed bye the Steering Committee and analyses will be conducted by the Data Coordinating Center (DCC) of the trial.

• Current Responsible Party: Wojciech Zareba, University of Rochester
• Original Responsible Party: Wojciech Zareba, MD, PhD, University of Rochester
• Current Study Sponsor: University of Rochester
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Wojciech Zareba, MD PhD; University of Rochester

• PRS Account: University of Rochester
• Verification Date: July 2018